Toll like receptors play a role in general immunity, eye infection and inflammation : TLRs for nanodelivery

Dendritic cells [DCs] are potent antigen presenting cells [APC], which plays a vital role in immune system by detecting and capturing pathogens in the body. DCs perform a pivotal role in induction of T cell response. Regulation of immune response can be achieved by specific antigen [Ag] delivery to DCs. A delivery system that can efficiently target and present Ags to DCs for the purpose of anti-tumour activity is currently a topic of significant research interest. DCs are receiving attention due to their key role in anti cancer host response and due to their adjuvanic property in tumour vaccines. Role of toll like receptors [TLR] in innate immune system and their part in eventual stimulation of adaptive immunity is exploited to develop vaccines. TLR agonists in conjugation with vaccines are shown to increase therapeutic efficacy in some cases. TLRs also play a vital role in protecting the cornea from invading pathogens. Due to adverse effects in the treatment of ocular inflammations, cancer and in viral infections, an alternate approach such as the use of TLRs will solve the inquisitive question regarding side effects. The intended delivery is attained by the use of nanoparticles which in turn leads to prolonged half-life in the body. Co-delivery of Ags, TLRs and immunomodulators using nanoparticles has been demonstrated to elicit potent cellular immune responses and are currently under development of clinically applicable immunisations and vaccines.

Blockade of 5-HT2A receptors suppresses hyperthermic but not cardiovascular responses to psychosocial stress in rats

The aim of this study was to determine whether 5-HT2A receptors mediate cardiovascular and thermogenic responses to acute psychological stresses. For this purpose, adult male Wistar hooded rats instrumented for telemetric recordings of either electrocardiogram (ECG) (n=12) or arterial pressure (n=12) were subjected, on different days, to four 15-min episodes of social defeat. Prior to stress, animals received s.c. injection of the selective 5-HT2A receptor antagonist SR-46349B (trans-4-((3Z)3-[(2-dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate) (at doses of 0.3, 1.0 and 3.0 mg/kg) or vehicle. The drug had no effect on basal heart rate or heart rate variability indexes, arterial pressure, and core body temperature. Social defeat elicited significant and substantial tachycardic (347±7 to 500±7 bpm), pressor (77±4 to 97±4 mm Hg) and hyperthermic (37.0±0.3 to 38.5±0.1 °C) responses. Blockade of 5-HT2A receptors, at all doses of the antagonist, completely prevented stress-induced hyperthermia. In contrast, stress-induced cardiovascular responses were not affected by the blockade (except small reduction of tachycardia by the highest dose of the drug). We conclude that in rats, 5-HT2A receptors mediate stress-induced hyperthermic responses, but are not involved in the genesis of stress-induced rises in heart rate or arterial pressure, and do not participate in cardiovascular control at rest.

Differential involvement of rat medial prefrontal cortex dopamine receptors in modulation of hypothalamic- pituitary-adrenal axis responses to different stressors

Recent investigations have implicated the medial prefrontal cortex (mPFC) in modulation of subcortical pathways that contribute to the generation of behavioural, autonomic and endocrine responses to stress. However, little is known of the mechanisms involved. One of the key neurotransmitters involved in mPFC function is dopamine, and we therefore aimed, in this investigation, to examine the role of mPFC dopamine in response to stress in Wistar rats. In this regard, we infused dopamine antagonists SCH23390 or sulpiride into the mPFC via retrodialysis. We then examined changes in numbers of cells expressing the c-fos immediate-early gene protein product, Fos, in subcortical neuronal populations associated with regulation of hypothalamic-pituitary-adrenal (HPA) axis stress responses in response to either of two stressors; systemic injection of interleukin-1β, or air puff. The D1 antagonist, SCH23390, and the D2 antagonist, sulpiride, both attenuated expression of Fos in the medial parvocellular hypothalamic paraventricular nucleus (mpPVN) corticotropin-releasing factor cells at the apex of the HPA axis, as well as in most extra-hypothalamic brain regions examined in response to interleukin-1β. By contrast, SCH23390 failed to affect Fos expression in response to air puff in any brain region examined, while sulpiride resulted in an attenuation of the air puff-induced response in only the mpPVN and the bed nucleus of the stria terminalis. These results indicate that the mPFC differentially processes the response to different stressors and that the two types of dopamine receptor may have different roles.

Leptin resistance in a polygenic, hyperleptinemic animal model of obesity and NIDDM : Psammomys obesus

OBJECTIVE: To investigate the effects of leptin administration to Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes mellitus.

DESIGN: Longitudinal intervention study utilising three separate leptin treatment protocols lasting 7-14 d.

MEASUREMENTS: Body weight and food intake were measured daily, body fat and muscle content were estimated by carcass analysis on completion of the study. Blood glucose, plasma insulin, leptin, triglycerides and cholesterol were measured at baseline and twice each week during the study.

RESULTS: Relatively high doses of leptin were required to significantly reduce food intake and body fat content in lean Psammomys obesus, but had no discernible effect on their obese littermates.

CONCLUSION: As a species, Psammomys obesus appear to be relatively insensitive to the effects of leptin administration, compared with other rodents. Obese Psammomys obesus are leptin resistant relative to their lean littermates.

Leptin and the development of obesity and diabetes in Psammomys obesus

The recently discovered ob gene and its circulating product, leptin, may be critical factors in the control of energy balance. Recent studies in ob/ob mice, which lack circulating leptin, have shown dramatic reductions in food intake and bodyweight after leptin treatment. In addition, studies in both humans with obesity and animal models of obesity have demonstrated hyperleptinemia. Here, we report a longitudinal study examining changes in circulating leptin during the development of obesity and diabetes in Psammomys obesus. Over the 8 weeks of the study, lean animals increased their bodyweight by 154% and leptin levels remained essentially unchanged. In contrast, animals that developed obesity (223 % increase in bodyweight), hyperglycemia, and hyperinsulinemia also developed hyperleptinemia between 4 weeks and 8 weeks of age. These results demonstrate that the development of hyperleptinemia is associated with the development of obesity and subsequent metabolic abnormalities.

Exposure to a high-fat diet alters leptin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits

The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 μg) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: −54%, paraventricular: −69%, and dorsomedial hypothalamus: −65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked “selective leptin resistance” in these animals.

Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level.

The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. We here provide genetic and biochemical evidence that the metabolic and immune functions of leptin can be uncoupled at the receptor level. First, homozygous mutant fatt/fatt mice carry a spontaneous splice mutation causing deletion of the leptin receptor (LR) immunoglobulin-like domain (IGD) in all LR isoforms. These mice are hyperphagic and morbidly obese, but display only minimal changes in size and cellularity of the thymus, and cellular immune responses are unaffected. These animals also displayed liver damage in response to concavalin A comparable to wild-type and heterozygous littermates. Second, treatment of healthy mice with a neutralizing nanobody targeting IGD induced weight gain and hyperinsulinaemia, but completely failed to block development of experimentally induced autoimmune diseases. These data indicate that leptin receptor deficiency or antagonism profoundly affects metabolism, with little concomitant effects on immune functions.

Association of serum leptin and ghrelin with depressive symptoms in a Japanese working population: a cross-sectional study

Leptin and ghrelin have been implicated in the pathogenesis of major depression. However, evidence is lacking among apparently healthy people. This study examined the relationship of these appetite hormones to depressive symptoms in a Japanese working population.