Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes.

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Dendritic cells (DCs) have been proposed to play a critical role as adjuvants in vaccination and immunotherapy. In this study we evaluated the combined effect of soluble Leishmania donovani Ag (SLDA)-pulsed syngeneic bone marrow-derived DC-based immunotherapy and antimony-based chemotherapy for the treatment of established murine visceral leishmaniasis. Three weekly injections of SLDA-pulsed DCs into L. donovani-infected mice reduced liver and splenic parasite burden significantly, but could not clear parasite load from these organs completely. Strikingly, the conventional antileishmanial chemotherapy (sodium antimony gluconate) along with injections of SLDA-pulsed DCs resulted in complete clearance of parasites from both these organs. Repetitive in vitro stimulation of splenocytes from uninfected or L. donovani-infected mice with SLDA-pulsed DCs led to the emergence of CD4+ T cells with characteristics of Th1 cells. Our data indicate that DC-based immunotherapy enhances the in vivo antileishmanial potential of antimony or vice versa.

The major objective of the present study was to demonstrate the actions of exogenous melatonin on ovaprim (synthetic GnRH and domperidone)-induced final oocyte maturation focusing on the oxidative status of pre-ovulatory follicles in the carp Catla catla. Accordingly, gravid carp during the early spawning phase of the reproductive cycle were injected with melatonin and/or ovaprim at different time intervals or luzindole (a pharmacological blocker of melatonin receptors) before their administration. We studied their effects on the latency period, the rate of germinal vesicle breakdown (GVBD; a visual marker of final oocyte maturation) in oocytes, and the levels of maturation-promoting factor (MPF), as well as oxidative stress, different antioxidants, melatonin and MT1 melatonin receptor protein in the extracts of pre-ovulatory follicles. Notably, melatonin treatment 2 h before the injection of ovaprim resulted in the shortest latency period as well as the highest rate of GVBD and MPF formation. Exogenous melatonin, irrespective of the injection schedule, caused a significant reduction in intra-follicular oxidative stress and an increase in the levels of both enzymatic and nonenzymatic antioxidants, melatonin and its receptor protein. Concentrations of ovarian melatonin in each fish exhibited a significant negative correlation with the level of oxidative stress, but a positive correlation with the rate of GVBD and the activity/level of different antioxidants. However, no significant effects of melatonin and/or ovaprim were detected in luzindole-pretreated carp. Collectively, the present study provides the first evidence that melatonin pretreatment in carp ameliorates ovaprim actions on the process of final oocyte maturation by the formation of MPF and alleviates oxidative stress in pre-ovulatory follicles by stimulating different antioxidants.