Lithium ion (Li+) is used as mood stabilizer in mood disorder for more than 60 years, but its mode of action remains largely obscure. Due to similarities with Mg2+, Li+ affects many biological processes dependent on Mg2+. During the past 10 years, a body of evidence has highlighted the inhibition of glycogen synthase kinase-3 (GSK-3) as a possible mechanism of therapeutic action of Li+. GSK-3 corresponds to two kinase-type enzymes (GSK-3α and GSK-3β), able to phosphorylate many proteins in neuronal and non-neuronal cells and, thereby, to exert a regulatory role in many cellular functions. GSK-3 itself is negatively regulated by phosphorylation produced by several enzymes, including Akt. It is currently believed that direct inhibition of GSK-3 by Li+ has no therapeutic relevance since only observed with Li+ concentrations toxic in humans. In contrast, Li+ concentrations consistent with therapeutic action in human activate Akt and, thereby, strongly inhibit the activity of GSK-3 [1]. Experimental animal studies have shown that the inhibitory effects of Li+ on responses to psychostimulants are related to an action on GSK-3 [2]. These behavioral responses can be compared to manic episodes and these results suggest that the antimanic effect of Li+ is mediated through GSK-3 inhibition. Several other studies suggest that antidepressant-like responses of Li+, assessed by behavioral tests in animal, depend on the GSK-3 inhibition [3]. Altogether, these preclinical data tend to attribute to the GSK-3 inhibition both antimanic and antidepressant effects, and perhaps a mood stabilizing effect. However, in the absence of clear understanding of mood disorder etiology, evaluating the exact contribution of GSK-3 inhibition to clinical effects of Li+ remains a complex issue.

High-fat, high-carbohydrate (HFHC) meals induce an inflammatory response in mononuclear cells (MNC). Here, we studied the interaction between metabolic and inflammatory signalling pathways by the measurement of postprandial effects of three different test meals on intracellular Akt, S6 kinase (S6K)/mammalian target of rapamycin and NF-κB signalling in human MNC. We recruited six healthy, lean individuals. Each individual ingested three different meals in the morning separated by at least 3 d: a HFHC meal; an oral lipid-tolerance test meal; a healthy breakfast. Blood samples were obtained before and 1, 2, 4, 6 and 8 h after ingestion. Plasma insulin and IL-6 levels were measured. Intracellular metabolic and inflammatory signalling pathways were assessed by measuring the phosphorylation of Akt kinase and S6K, the degradation of inhibitory κB-α (IκB-α) protein and the DNA binding activity of NF-κB in MNC. mRNA expression levels of the Akt and NF-κB target genes Mn superoxide dismutase (MnSOD), CC-chemokine-receptor 5 (CCR5), intercellular adhesion molecule 1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) were measured by quantitative RT-PCR. We found a positive correlation of Akt phosphorylation with NF-κB activation (NF-κB binding activity: r 0·4500, P= 0·0003; IκB-α protein levels: r − 0·5435, P< 0·0001), a negative correlation of plasma insulin levels with NF-κB binding activity (r − 0·3993, P= 0·0016) and a positive correlation of plasma insulin levels with S6K activation (r 0·4786, P< 0·0001). The activation of Akt and pro-inflammatory NF-κB signalling was supported by the up-regulation of the respective target genes MnSOD and CCR5. In conclusion, the present data suggest a postprandial interaction between the metabolic and inflammatory signalling pathways Akt and NF-κB in MNC.

Several metabolic disturbances during obesity are associated with adipose tissue-altered functions. Adipocytes contain the renin–angiotensin system (RAS), which regulates signalling pathways that control angiogenesis via Akt in an autocrine fashion. Soya protein (Soy) consumption modifies the gene expression pattern in adipose tissue, resulting in an improved adipocyte function. Therefore, the aim of the present work is to study whether dietary Soy regulates the expression of RAS and angiogenesis-related genes and its association with the phosphorylated state of Akt in the adipose tissue of obese rats. Animals were fed a 30 % Soy or casein (Cas) diet containing 5 or 25 % fat for 160 d. mRNA abundance was studied in the adipose tissue, and Akt phosphorylation and hormone release were measured in the primary adipocyte culture. The present results show that Soy treatment in comparison with Cas consumption induces lower angiotensin release and increased insulin-stimulated Akt activation in adipocytes. Furthermore, Soy consumption varies the expression of RAS and angiogenesis-related genes, which maintain cell size and vascularity in the adipose tissue of rats fed a high-fat diet. Thus, adipocyte hypertrophy and impaired angiogenesis, which are frequently observed in dysfunctional adipose tissue, were avoided by consuming dietary Soy. Taken together, these findings suggest that Soy can be used as a dietary strategy to preserve adipocyte functionality and to prevent obesity abnormalities.

Although resveratrol has widely been studied for its potential health benefits, little is known about its metabolic effects in humans. Our aims were to determine whether the polyphenol resveratrol improves insulin sensitivity in type 2 diabetic patients and to gain some insight into the mechanism of its action. After an initial general examination (including blood chemistry), nineteen patients enrolled in the 4-week-long double-blind study were randomly assigned into two groups: a resveratrol group receiving oral 2 × 5 mg resveratrol and a control group receiving placebo. Before and after the second and fourth weeks of the trial, insulin resistance/sensitivity, creatinine-normalised ortho-tyrosine level in urine samples (as a measure of oxidative stress), incretin levels and phosphorylated protein kinase B (pAkt):protein kinase B (Akt) ratio in platelets were assessed and statistically analysed. After the fourth week, resveratrol significantly decreased insulin resistance (homeostasis model of assessment for insulin resistance) and urinary ortho-tyrosine excretion, while it increased the pAkt:Akt ratio in platelets. On the other hand, it had no effect on parameters that relate to β-cell function (i.e. homeostasis model of assessment of β-cell function). The present study shows for the first time that resveratrol improves insulin sensitivity in humans, which might be due to a resveratrol-induced decrease in oxidative stress that leads to a more efficient insulin signalling via the Akt pathway.

Oxysterols arise from the enzymic or non-enzymic oxidation of cholesterol and have been shown to be cytotoxic to certain cell lines. In particular, apoptosis induced by the oxysterol 7β-hydroxycholesterol (7β-OH) has been associated with the generation of oxidative stress, cytochrome c release and caspase activation. Due to the fundamental importance of apoptosis in pathological processes, the identification of substances capable of modulating this form of cell death is now actively researched. The objective of the present study was to investigate if apigenin, lycopene and astaxanthin could inhibit 7β-OH-induced apoptosis in U937 cells. Pretreatment with 0·1 μm-astaxanthin protected against apoptosis, while lycopene did not oppose the adverse effects of 7β-OH. At low concentrations, apigenin did not protect against oxysterol-induced apoptosis; however, at higher concentrations it intensified cell death. Additionally, we investigated the effect of 7β-OH, apigenin and astaxanthin on the activation of the serine threonine kinase Akt (phosphorylated Akt:Akt ratio) to determine whether the effect on cell viability and growth was linked to the Akt signalling pathway. Akt activation was decreased in the oxysterol-treated cells compared with control cells; however, this did not attain significance. Interestingly, activation of Akt was significantly reduced compared with control cells following incubation with apigenin and astaxanthin both in the absence and in the presence of 7β-OH. Our data suggest that apigenin, lycopene and astaxanthin failed to protect against 7β-OH-induced apoptosis, and the decrease in cell viability and the increase in apoptotic nuclei induced by the antioxidants appear to be associated with down regulation of Akt activity.