Anne Huotari

In vivo delivery of a peptide, ghrelin antagonist, with mesoporous silicon microparticles.

Peptides may represent potential treatment options for many severe illnesses. However, they need an effective delivery system to overcome rapid degradation after their administration. One possible way to prolong peptide action is to use particulate drug delivery systems. In the present study, thermally hydrocarbonized mesoporous silicon (THCPSi) microparticles (38-53 microm) were studied as a peptide delivery system in vivo. D-lys-GHRP6 (ghrelin antagonist, GhA) was used as a model peptide. The effects of GhA-loaded THCPSi microparticles on food intake (s.c., GhA dose 14 mg/kg) and on blood pressure (s.c., GhA dose 4 mg/kg) were examined in mice and rats, respectively. In addition, the effects of THCPSi microparticles (2 mg) on cytokine secretion in mice after single s.c. administration were examined by determining several cytokine plasma concentrations. The present results demonstrate that GhA can be loaded into THCPSi microparticles with a high loading degree (20% w/w). GhA loaded THCPSi microparticles inhibited food intake for a prolonged time, and increased blood pressure more slowly than encountered with a GhA solution. Furthermore, THCPSi microparticles did not increase cytokine activity. The present results suggest that THCPSi might be used as a drug delivery system for peptides.

VITAMIN D AND LIVING IN NORTHERN LATITUDES - AN ENDEMIC RISk AREA FOR VITAMIN D DEFICIENCy

OBJECTIVES: To review the current literature on the health effects of vitamin D, especially the effects on inhabitants living in the northern latitudes. STUDY DESIGN: Literature review. METHODS: The scientific literature concerning health effects of vitamin D was reviewed and the current dietary recommendations for inhabitants living in northern latitudes were discussed. RESULTS: Vitamin D is a steroid-structured hormone produced in the skin upon exposure to UVB-radiation or obtained from certain food products (for example, liver). Its production is mediated by the vitamin D receptor, which belongs to the nuclear receptor family, and exerts its function as a transcription factor regulating several target genes. Active metabolites of vitamin D play an important role in calcium and phosphate homeostasis. Deficiency of vitamin D results in diminished bone mineralization and an increased risk of fractures. In addition, vitamin D is connected to a variety of other diseases that include different cancer types, muscular weakness, hypertension, autoimmune diseases, multiple sclerosis, type 1 diabetes, schizophrenia and depression. CONCLUSIONS: Vitamin D plays a fundamental role in calcium and phosphate homeostasis. A deficiency of vitamin D has been attributed to several diseases. Since its production in the skin depends on exposure to UVB-radiation via the sunlight, the level of vitamin D is of crucial importance for the health of inhabitants who live in the Nordic latitudes where there is diminished exposure to sunlight during the winter season. Therefore, fortification or supplementation of vitamin D is necessary for most of the people living in the northern latitudes during the winter season to maintain adequate levels of circulating 25(OH)D3 to maintain optimal body function and prevent diseases.

Serum adiponectin and resistin levels in major depressive disorder

Lehto SM, Huotari A, Niskanen L, Tolmunen T, Koivumaa‐Honkanen H, Honkalampi K, Ruotsalainen H, Herzig K‐H, Viinamäki H, Hintikka J. Serum adiponectin and resistin levels in major depressive disorder.

Serum chemokine levels in major depressive disorder

OBJECTIVE To examine the role of chemokines of two major chemokine families, CC and CXC, in major depressive disorder (MDD) in a population-based sample. METHOD The serum levels of CC chemokines MCP-1 and MIP-1beta, and CXC chemokine IL-8 were measured from 122 participants (MDD group, n=61; controls, n=61). Depression severity was assessed with the 29-item Hamilton Depression Rating Scale. RESULTS The MDD group had lower levels of MCP-1, MIP-1beta and IL-8 than the healthy controls. The likelihood of major depressive disorder for participants with chemokine levels below the median (MCP-1: < 26.26 pg/mL; MIP-1beta: < 42.57 pg/mL; IL-8: < 2.86 pg/mL) was 3.6 (p=0.002) for MIP-1beta and 2.4 (p=0.037) for IL-8 in regression models adjusted for age, gender, body mass index, smoking, and alcohol consumption. MCP-1 did not associate with the presence of MDD after adjustments for potential confounders. Further adjustments for somatic illnesses or medications did not affect these findings. CONCLUSION Our findings suggest that depression-related alterations of inflammatory markers may be more complex than previously assumed, and that at least some of the chemokines may be down-regulated.

Distinct Effects of Calorie Restriction and Resveratrol on Diet-Induced Obesity and Fatty Liver Formation

The potential of resveratrol to mimic beneficial effects of calorie restriction (CR) was investigated. We compared the effects of both CR (70% of ad libitum energy intake) or resveratrol (2 g/kg or 4 g/kg food) on high-fat diet-induced obesity and fatty liver formation in C57Bl/6J mice, and we examined their effects on calorimetry, metabolic performance, and the expressions of inflammatory genes and SIRT proteins. We found that resveratrol with 4 g/kg dose partially prevented hepatic steatosis and hepatocyte ballooning and induced skeletal muscle SIRT1 and SIRT4 expression while other examined parameter were unaffected by resveratrol. In contrast, CR provided superior protection against diet-induced obesity and fatty liver formation as compared to resveratrol, and the effects were associated with increased physical activity and ameliorated adipose tissue inflammation. CR increased expressions of SIRT3 in metabolically important tissues, suggesting that the beneficial effects of CR are mediated, at least in part, via SIRT3-dependent pathways.

Betaine supplementation causes increase in carnitine metabolites in the muscle and liver of mice fed a high‐fat diet as studied by nontargeted LC‐MS metabolomics approach

SCOPE Betaine (BET) reduces diet-induced liver lipid accumulation, and may relieve obesity-related metabolic disturbances. The aim of our study was to analyze metabolite alterations after supplementation of BET, polydextrose (PDX, a soluble dietary fiber), or their combination (BET PDX) via drinking water to C57BL/6J mice fed a high-fat (HF) diet. METHODS AND RESULTS BET supplementation increased BET levels in plasma, muscle, and liver (p < 0.05), and the nontargeted LC-MS metabolite profiling revealed an increase in several metabolites in the carnitine biosynthesis pathway after BET supplementation both in liver and muscle. These included carnitine and acetylcarnitine (1.4-fold, p < 0.05), propionylcarnitine and γ-butyrobetaine (1.5-fold, p < 0.05), and several other short-chain acylcarnitines (p < 0.05) in muscle. These changes were slightly higher in the BET PDX group. Furthermore, BET reduced the HF diet induced accumulation of triglycerides in liver (p < 0.05). The supplementations did not attenuate the HF diet induced increase in body weight gain or the increase in adipose tissue mass. Instead, the combination of BET and PDX tended to increase adiposity. CONCLUSION Our results suggest that increased availability of BET in different tissues, especially in muscle, after BET supplementation has an impact on carnitine metabolism, and this could further explain the link between BET and lipid metabolism.

Wild blueberries (Vaccinium myrtillus) alleviate inflammation and hypertension associated with developing obesity in mice fed with a high-fat diet.

Background Low-grade metabolic inflammation and hypertension are primary mechanisms involved in obesity-associated adverse health effects. Berries, especially Nordic wild blueberries (hereafter referred to as bilberries), represent an important source of dietary anthocyanins, a group of polyphenols with potential beneficial effects to combat obesity-associated metabolic disturbances. Methods The effects of 5% or 10% (w/w) of whole bilberries (BB) were studied on the development of obesity and its metabolic disturbances in C57BL mice fed with a high-fat diet (HFD) for three months. Cytokines, inflammatory cells, systolic blood pressure, glucose tolerance, insulin sensitivity, weight gain, body fat, food consumption and energy metabolism were assessed. Results Bilberries ameliorated type 1 pro-inflammatory responsiveness induced by HFD. This was indicated by the altered cytokine profile and the reduced prevalence of interferon gamma -producing T-cells, in particular T helper type 1 cells. Bilberries also prevented the progression of obesity associated long term increase in systolic blood pressure in mice. Conclusions Bilberries reduce the development of systemic inflammation and prevent the progression of chronic hypertension, thus supporting their potential role in alleviating the adverse health effects associated with developing obesity.

Unemployment and ill health: a connection through inflammation?

BackgroundUnemployment is a source of acute and long-term psychosocial stress. Acute and chronic psychosocial stress can induce pronounced changes in human immune responses. In this study we tested our hypothesis that stress-induced low-grade tissue inflammation is more prevalent among the unemployed.MethodsWe determined the inflammatory status of 225 general population subjects below the general retirement age (65 years in Finland). Those who had levels of both interleukin-6 (≥ 0.97 pg/mL) and high-sensitivity C-reactive protein (≥ 1.49 mg/L) above the median were assessed to have an elevated inflammatory status (n = 72).ResultsAn elevated inflammatory status was more common among the unemployed than among other study participants (59% versus 30%, p = 0.011). In the final multivariate model, those who were unemployed had over five-fold greater odds for having an elevated inflammatory status (OR 5.20, 95% CI 1.55-17.43, p = 0.008).ConclusionThis preliminary finding suggests that stress-induced low-grade inflammation might be a link between unemployment and ill health.

Effect of surface chemistry of porous silicon microparticles on glucagon-like peptide-1 (GLP-1) loading, release and biological activity

Recently, mesoporous silicon (PSi) microparticles have been shown to extend the duration of action of peptides, reducing the need for frequent injections. Glucagon-like peptide 1 (GLP-1) is a potential novel treatment for type 2 diabetes. The aim of this study was to evaluate whether GLP-1 loading into PSi microparticles reduce blood glucose levels over an extended period. GLP-1 (pI 5.4) was loaded and released from the negatively charged thermally oxidized (TOPSi, pI 1.8) and thermally carbonized (TCPSi, pI 2.6) PSi microparticles and from the novel positively charged amine modified microparticles, designated as TOPSi-NH2-D (pI 8.8) and TCPSi-NH2-D (pI 8.8), respectively. The adsorption of GLP-1 onto the PSi microparticles could be increased 3-4-fold by changing the PSi surface charge from negative to positive, indicating that the positive surface charge of PSi promoted an electrostatic interaction between the negatively charged peptide. All the GLP-1 loaded PSi microparticles lowered the blood glucose levels after a single s.c. injection but surprisingly, TOPSi-NH2-D and TCPSi-NH2-D were not able to prolong the effect when compared to TOPSi, TCPSi or GLP-1 solution. However, TOPSi-NH2-D and TCPSi-NH2-D microparticles were able to carry improved payloads of active GLP-1 encouraging continuing further attempts to achieve sustained release.

Genetic and environmental determinants of total and high-molecular weight adiponectin in families with low HDL-cholesterol and early onset coronary heart disease

OBJECTIVE Plasma adiponectin and high-density lipoprotein cholesterol (HDL-C) exhibit a well-known positive metabolic correlation. Neither heritability nor genome-wide linkage analysis for the high-molecular weight (HMW) adiponectin is available. This work estimates the genetic and environmental determinants and the heritabilities of the adiponectins and lipid traits in Finnish families with early onset coronary heart disease (CHD) and low HDL-C. METHODS Heritability and genome-wide univariate linkage analysis was performed for total and HMW adiponectin in extended families from Northern Finland with early onset CHD and low HDL-C using a variance components approach. The genetic and environmental correlations between the plasma adiponectins and various lipid traits were also studied and a bivariate analysis for HDL-C and the adiponectins carried out. RESULTS In the partial correlation analysis (adjusted for sex, age, BMI and statin use) the adiponectins showed a stronger correlation with HDL-C (total 0.57, p=0.001, HMW 0.51, p<0.005) than with any other lipid trait in unrelated subjects. Our estimates detected strong heritability for total (0.53+/-0.10), HMW (0.51+/-0.10) and the HMW/total adiponectin ratio (0.68+/-0.11). Univariate linkage analysis showed suggestive evidence of linkage on chromosome 11p15 for total adiponectin and on 3q13.2-q24 and 6p21 for the HMW adiponectin. The strongest environmental cross-correlation between the adiponectins and lipids was seen between HDL-C and total adiponectin (rhoe=0.64, p<0.05), whereas the strongest genetic correlation was detected between low-density lipoprotein cholesterol and the HMW adiponectin (rhog=-0.48, p<0.05). CONCLUSION No significant genetic correlations between HDL-C and the adiponectins were observed. Therefore, the metabolic association between HDL-C and adiponectin is most likely regulated by complex genetic pathways and environmental factors.