Endocrine Caredoi: 10.4183/aeb.2013.249

249Acta Endocrinologica (Buc), vol. IX, no. 2, p. 249-262, 2013

*Correspondence to: Bogdan Gurzu MD, “Gr T Popa” University of Medicine and Pharmacy, School of Medicine, Department of Functional Sciences, 16th Universitatii street, Iasi, 700115, Romania, E-mail: bgurzu@yahoo.com

Abstract Background. Weight loss associ-ated with long-term lifestyle changes has significant beneficial effects on metabolic syndrome (MetS) features on obese patients; unfortunately, the weight recidivism rate is high and the weight fluctuations could in-crease the cardiovascular and metabolic risk. On the other hand, there are many data about the endocrine role of adipose tissue. Objective. Taking into account the imbalance between pro-inflammatory and anti-inflammatory cytokines secreted by adipose tissue on obese patients, this study assessed the effects of one month-long su-pervised lifestyle change (SLC) program without weight loss on the MetS-associated inflammatory status. Methods. The study included 29 obese adults with MetS. The SLC program included supervised moderate physical ac-tivities and diet for one month. The levels of adipocytokines, lipids and inflammatory markers were analyzed before and after one month SLC program, and 2 months later at follow-up. Results. At follow-up, the leptin, vascular endothelial growth factor (VEGF), and hsCRP levels decreased, whereas the interleukin-4 (IL-4) and high-density

lipoprotein (HDL) cholesterol levels increased from their baseline levels. So, an SLC program, even in the absence of weight loss, could have an extended anti-inflammatory effect by decreasing the pro-inflammatory adipocytokines. Conclusion. Our data furthermore emphasize the importance of the adipocytokines gender-related variation for a more personalized evaluation protocol on obese patients.

Key words: adipocytokines, inflammation, obesity, metabolic syndrome, gender differences.

IntROduCtIOn

Long-term lifestyle change (LC) programs focusing on weight loss could significantly decrease the risk of cardio-vascular disease and diabetes mellitus in patients with metabolic syndrome (MetS) (1-3). However, the weight fluc-tuations frequently observed in people trying to lose weight could increase the cardiovascular and metabolic risk (4, 5). MetS is associated with a systemic pro-

effeCt Of supeRvIsed lIfestyle ChAnges On MetABOlIC syndROMe-AssOCIAted InflAMMAtIOn

F. Mitu1,3, I.L. Dumitriu2, C.E. Schiriac4, L.G. Vata2, B. Gurzu2,*

“Gr. T. Popa” University of Medicine and Pharmacy - Faculty of Medicine, 1Department of Internal Medicine, 2Department of Functional Sciences,

3Rehabilitation Hospital - Cardiology Clinic, 4Praxis Medical Investigations, Iasi, Romania

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inflammatory status because of an im-balance in the proinflammatory and anti-inflammatory adipose tissue - secreted adipocytokines (6, 7). This imbalance is characterized by decreased levels of interleukin (IL)-4, IL-10, and adiponectin, and by increased circulating levels of IL-1, IL-6, tumor necrosis factor alpha (TNFα), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP), and leptin (6-15), some of them being well known risk markers for cardiovascular disease and/or diabetes mellitus (16-19). All these changes could be reversed by weight loss interventions involving long-term diet management and/or physical exercise (10, 14, 15, 20, 21).

There are studies that further-more confirm the beneficial effects of LC programs on the systemic inflam-matory state (6, 11) commonly seen in obese patients, even in the absence of weight loss (22-24). Taking into account published data (2, 3, 6, 7) concerning the significance of inflammation on MetS-associated cardiovascular and metabolic risks, we studied the effects of a month-long supervised initiation of a lifestyle change (SLC) program (i.e., physical exercise and diet without weight loss) on circulatory levels of adipocytokines, proinflammatory markers and lipids in obese patients with MetS. The biological parameters were measured at the beginning of study,

Meanstd.

deviationMinimum Maximum

Age (years) 62.11 7.87 51 76

BMI (kg/m2) 35.07 4.35 30 49

Waist circumference (cm) 112.24 11.18 95 147

sBp (mmhg) 138.74 9.79 120 160

dBp (mmhg) 82.00 6.90 70 100

fpg (mmol/l) 5.39 0.42 4.70 6.10

Alt (u/l) 26.61 14.42 13.19 83.00

Ast (u/l) 22.59 7.35 16 50

ggt (u/l) 32.69 31.33 11.00 152.80

Bun (g/l) 0.31 0.13 0.14 0.54

Creatinine (mg/dl) 0.94 0.16 0.70 1.28

uric Acid (mg/dl) 4.32 1.35 3.00 7.23

esR (mm) 19.21 9.24 5. 34

Chol (mg/dl) 208.35 41.40 150 312

hdl -Chol (mg/dl) 43.25 5.76 32 50

ldl - Chol (mg/dl) 132.71 36.38 83 234

tg (mg/dl) 171.41 30.02 110 216

hsCRp (mg/dl) 8.86 6.76 0.53 20.66

Table 1. Main characteristics of 29 obese patients with metabolic syndrome at baseline

BMI: body mass index; BP: blood pressure; FPG: fasting plasma glucose; ALT : alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyltransferase; BUN: blood urea nitrogen; ESR: erythrocyte sedimentation rate; Chol: cholesterol; TG: triglycerides; hsCRP: high-sensitivity C – reactive protein.

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at the end of the SLC program, and at 2 months after the completion of the program to determine if, and to what degree, previously found changes could be preserved. Comparative analysis of dynamics of studied parameters gives us the possibility to evaluate the potential possible usage of studied parameters for appreciating the response of obese patients to LC program.

MethOds

Subjects This study included obese adults newly diagnosed with MetS, as defined by the National Cholesterol Educa-tion Program Expert Panel on Detec-tion, Evaluation, and Treatment of High Blood Cholesterol in Adults/Adult Treatment Panel III (NCEP/ATP III). The patients were enrolled in a super-vised lifestyle change (SLC) program at the Cardiology Clinic of the Rehabilita-tion Hospital (Iasi, Romania). The SLC program included medical advice and educational sessions, and individualized strategy of moderate physical activities and diet. Exclusion criteria were acute or chronic respiratory diseases; systemic diseases; smoking; use of oral anti-dia-betic agent and/or insulin; use of weight loss drugs and/or current participation in weight loss-targeted programs (e.g., fitness, diet); or conditions that may im-pede participation in the program. All subjects received statin therapy. Table 1 shows the participants’ main characteris-tics at baseline. Study design Cardiologists selected partici-pants in accordance with the exclusion criteria from newly diagnosed obese

patients with MetS who had been admit-ted to the SLC program at the Cardiolo-gy Clinic of the Rehabilitation Hospital. The participants gave written, informed consent. The study took place over a period of 3 months (day 1– day 84) and was carried out in two stages. The first stage (day 1 – day 28) aimed to familiarize the patient with a new lifestyle and initiate the physical activity and diet. To accomplish the proposed aims subjects were hospitalized in the first week. During this week they performed physical exercises under the supervision of a physical therapist, attended the informative meetings with a dietitian (twice per week) and initiated the diet by reducing the caloric intake with at least 500 kcal (but no more than 1000 kcal) per day from each patient current level (25). The daily-supervised exercise regimen consisted of pedaling a bicycle ergometer for 45–60 min at the training heart rate, which was defined as 60%–75% of the maximal heart rate attained during maximal ergometry (26). In the next three weeks the subjects were discharged, but returned to the hospital (as out-patients) for supervised physical activities (five times per week). The dietetic counseling sessions also continued in order to help patients to implement the diet at their home. After completing 1 month of the supervised program, patients were instructed to maintain the healthy lifestyle at home for another 2 months (days 28–84) without any medical supervision (the second stage of the study). The follow-up visit was on day 84 (i.e., end of the study). The second stage of the study lasted two months (day 28 – day 84) dur-

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ing which subjects were not supervised at all. Patients willingly agreed to par-ticipate. Subjects who failed to complete the SLC program (dietetic counseling sessions and supervised physical ac-tivities) in the first month of study were excluded from this study. Plasma sam-ples were collected at the beginning of the SLC program (day 1 (i.e., baseline)), at the end of the SLC program (day 28) and at follow-up (day 84 (i.e., end of the study)). This study was carried out in accordance with the World Medical Association Declaration of Helsinki and was approved from an ethical standpoint by the Ethics Committee of the “Gr. T. Popa” University of Medicine and Phar-macy Iasi, Romania. Cytokine and growth factors high-sensitivity array Plasma samples collected from these patients (at day 1, 28 and 84) were used. An evidence investigator cytokine and growth factors high-sensitivity array (RANDOX Laboratories UK), was used, as been previously described (27), to analyze the following twelve cytokines: IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, epidermal growth factor (EGF), VEGF, interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP-1). Additional biochemical variables High-sensitivity C - reactive protein (hsCRP), cholesterol, low-den-sity lipoprotein – cholesterol (LDL-C), high-density lipoprotein – cholesterol (HDL-C), and triglyceride (TG) levels were measured by the usual biochemical techniques at the beginning of the study and at days 28 and day 84. Plasma lep-tin and adiponectin were measured by

the ELISA technique in accordance with the manufacturer’s according to protocol provided by the manufacturer (Phoenix Pharmaceuticals, USA). Statistical analysis Statistical analysis was per-formed with SPSS 17.0.1 software. The Wilcoxon Signed Rank test was used to assess changes in biochemical parameters during the study. The Spearman’s rank correlation coefficient was calculated to determine correlations among the studied parameters. The Mann - Whitney test was used to determine differences in dependent variable distributions linking gender (i.e., men vs. women).

Results

Cardiologists have selected 92 participants in accordance with the exclusion criteria. During the three month study, 33 of the patients required anti-inflammatory therapy, the oral anti-diabetics and / or insulin. 11 patients dropped out the physical activity program. In the last three weeks of the first stage 19 patients had avoided the meetings with dietitian or announced they waive the diet, but have continued the physical exercise program. Data obtained from the remaining 29 patients (52% women and 48% men) who completed the lifestyle changes program will be presented below (Table 1). There were no significant variations of the weight after the SLC program (101.24±10.43 kg; p=0.056) and at the end of study (101.45±10.01 kg; p=0.061), compared to its baseline values (102.12±10.63 kg). Blood samples were collected on day 1, at the end of SLC program

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(day 28), and at the end of the study (day 84). Statistical analysis was performed to identify any significant changes in the studied parameters of the obtained samples (i.e., day 28 vs. day 1; day 84 vs. day 1; and day 84 vs. day 28). There

were no significant variations among the samples in the levels of IL-1α, IL-10, IFNγ, TNFα, and EGF. The IL-1β was significantly lower on day 28 (2.29±1.01 ng/mL) than day 1 (4.73±4.96 pg/mL, p=0.0083) or day 84 (2.90±0.93

Figure 1. Circulating levels of adipocytokines in 29 obese adults with metabolic syndrome. Blood samples were collected on the first day of study (day 1), at the end of supervised lifestyle change program (day 28) and at the end of the study (day 84). The boxes represent the quartiles, the median, and the extreme values minimum; 25th, 50th, and 75th quartiles; and maximum are plotted. Levels of each biological parameter on day 1, day 28 and day 84 were compared. Square brackets above the box plots indicate the existence of a statistically significant difference between any two of three values for each cytokine. Keys to the p values: *p < 0.05, **p < 0.01, ***p <0.001.

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ng/mL, p=0.027). MCP1 similarly decreased after the SLC program (from 151.40±15.16 ng/mL to 136.04±17.12 ng/mL, p=0.0057), but then increased until the end of study. Compared to the baseline level, the levels of IL-2 (10.32±5.78 vs. 14.16±8.09 pg/mL; p=0.0016), IL-6 (15.07±13.07 vs. 22.00±19.07 pg/mL; p=0.036) and IL-8 (28.31±14.07 vs. 41.58±24.32 pg/mL; p=0.009) were significantly lower after the SLC program. IL-4 was significantly higher on day 84 than on day 1 (17.17±4.82 pg/mL vs. 12.08±7.45 pg/mL, p=0.0075). VEGF was significantly decreased on day 84 (14.99±5.02 pg/mL) than on either day 1 (28.93±19.82 pg/mL, p=0.0008) or day 28 (21.99±5.88 pg/mL, p=0.0061). The hsCRP levels showed a stable decrease after the SLC program (3.88±3.31 pg/mL; p=0.0022) and at the end of study (4.95±3.99 pg/mL; p=0.0064), compared to its baseline values (8.86±6.76 pg/mL). The triglyceride levels during the study were not significantly different (Fig. 1). The cholesterol and LDL cholesterol levels decreased after the SLC program, but there were significant differences only on day 84. The HDL cholesterol level was significantly higher on day 84 (47.92±6.80 mg/dL, p=0.039) than on day 1 (42.89±5.33 mg/dL). The circulating levels of leptin decreased, being lower on day 84 (29.68 ± 19.94 ng/mL) than at baseline (44.52±24.68 ng/mL, p=0.011) and at the end of the SLC program (39.31±23.23 ng/mL, p=0.0067). The adiponectin level had a completely different variation pattern; it increased significantly on day 28 (5.32±2.43 μg vs. 3.58±1.56 μg/ml; p= 0.0058) and returned close to its baseline

level at the end of study. Taking into account published data indicating gender differences in MetS (28,29), we investigated gender differences in circulating levels of all studied biological parameters (Fig. 2). On day 84, the IL-4 levels were significantly higher in men than in women 20.64±3.52 pg/mL vs. 14.05±3.55 pg/ml, p=0.015). Basal levels of VEGF were higher in men than in women (37.97±26.43 pg/mL vs. 20.79±3.07 pg/mL; p=0.041). Adiponectin (6.41±2.71 μg/mL vs. 4.11±1.38 μg/mL; p=0.023) and IFNγ (8.77±3.64 pg/mL vs. 6.84±2.94 pg/mL; p=0.015) levels were elevated in women only on day 28. Leptin and EGF were higher in female patients; however, only for EGF were the differences (women vs. men) significant on day 1 (13.69±7.29 vs. 5.16±0.63, p=0.0038), day 28 (10.99±4.11 vs. 5.59±1.01, p=0.0007), and day 84 (11.79±4.95 vs. 7.12±2.78, p= 0.014). Leptin levels were significantly higher in women on day 1 (56.00±18.31 ng/mL vs. 31.77±25.41 ng/mL, p=0.0076) and day 28 (53.25±21.95 ng/mL vs. 23.81±12.60 ng/mL, p=0.0093), but not on day 84. We also tested whether the studied parameters had any correlations with clinical baseline measures. VEGF was negatively correlated with diastolic blood pressure (correlation coefficient = -0.538; p = 0.017) and positively correlated with age (correlation coefficient = 0.579; p = 0.0094). The erythrocyte sedimentation rate was positively correlated with IL-2 (correlation coefficient = 0.465; p = 0.04) and with IFNγ (correlation coefficient = 0.596; p = 0.007). Table 2 presents the significant correlations

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among cytokines, adipocytokines, and blood lipids. Only values from the same blood sample were compared (day 1, day 28, or day 84).

dIsCussIOn

The results suggested that even a one month supervised lifestyle change, without any weight loss, may lead to long-term improvement of the inflammatory status and has vasoprotective effects in obese patients with MetS (Figs 1 and 2). Our data did not reveal any significant changes in the levels of TNFα, IL-1α, IFNγ, or EGF. On the other hand, IL-1β, IL-2, IL-6, and IL-8 decreased by the end

of the SLC program; 2 months later this status had not been maintained (Fig. 1). These results agree with published data that emphasize the autocrine/paracrine roles of adipocytokines and support that only long-term LC could modify the level of these circulating biomarkers (28-30). The inflammatory CRP levels decreased after the completion of the SLC program (day 24), compared to the baseline level. The levels remained significantly lower on day 84 (Fig. 1). In agreement with previously published data (10,13), hsCRP levels were positively correlated with the levels of IL-6 and other inflammatory mediators (Table 2). There were no gender-

Figure 2. Gender differences. Plasma levels of adipocytokines on male patients (n=9); and female patients (n=10). Blood samples were collected on the first day of study (day 1), at the end of supervised lifestyle change program (day 28) and at the end of the study (day 84). The T-bars indicate the 5th and 95th percentile levels. The bottom and top of the boxes are the lower and upper quartiles. The median level is identified by a horizontal line inside the box. Levels of each biological parameter on day 1, day 28 and day 84 were analysed separately for men and women. The bars above the graphs indicate the existence of a statistically significant difference between the levels of studied parameter in men as compared with women. Keys to the p values: *p < 0.05, **p < 0.01, ***p < 0.001.

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related differences in the hsCRP levels during the study. IFN-γ plays a major role in inflammation of adipose tissue and vascular dysfunction (31-33). Our results confirmed previously published data about the proinflammatory roles of this cytokine. IFN-γ was negatively correlated with adiponectin (day 1), and positively correlated with TNFα and other proinflammatory cytokines. On the other hand, at the end of the SLC program (on day 28), there was a significant gender-related difference in the IFN-γ levels, with lower values in men than in women. The interleukins IL-4 and IL-10 have numerous anti-inflammatory effects (14,15,20). The one-month SLC program did not modify the IL-10 levels. These results are in agreement with previously published studies reporting IL-10 variation that is induced only by weight loss-focused LC programs (14, 20). At the end of the study (day 84), the IL-4 levels were significantly higher than the baseline level, which sustained the positive, anti-inflammatory effects of the SLC program. The IL-4 level was significantly higher in men than in women, suggesting a possible gender-related difference of LC-induced anti-inflammatory effects. Epidermal growth factor is a proinflammatory mediator involved in vascular remodeling, atherosclerosis, and inflammation (27). The basal levels of EGF were positively correlated IL-8 and MCP-1. EGF levels were not significantly modified during the study (Fig. 1), but were higher in women than in men (Fig. 2). This supports the gender-related particularity of MetS-associated inflammatory status. Monocyte chemoattractant protein 1 is involved in the development of the

proinflammatory state associated with MetS (7,30). In agreement with published data (30) our results showed that MCP-1 levels decreased significantly after the SLC program, but this positive effect was not maintained until the end of study. Published data indicate that IL-8 is a key player in obesity-related cardiovascular complications (7). We did not find any association of IL-8 with basal BMI, waist circumference, or the level of hsCRP or HDL-C. IL-8 was instead positively correlated with other proinflammatory and atherogenic cytokines (e.g., IL-2 and IL-6). These results are in accordance with published data that indicate a clustering of various risk factors for cardiovascular disease in the pathogenesis of MetS (10). VEGF modulates vascular development, and elevated levels of VEGF are associated with the proinflammatory state in MetS (31). Our results showed a significant decrease in the VEGF level on day 84 (i.e., 2 months after the completion of the SLC program). On the other hand, after the SLC program VEGF lost its negative correlation with HDL-C (from day 1). On day 28 and day 84, VEGF levels were significantly lower than the baseline level (Fig. 1) and did not present any gender-related differences (Fig. 2). In MetS patients, a long-term weight loss-focused LC program is necessary to produce a significant and stable reduction of leptin and increase in adiponectin (15,20). Our results indicate a different variation in leptin levels than in adiponectin levels (Fig. 1). Adiponectin levels increased only at the end the SLC program (and were significantly higher in women than in men; Fig. 2), but decreased at day 84 (Fig. 1).

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Table 2. Spearman correlation coefficient (rho) for correlations among plasma levels of studied parameters

Blood samples were collected on the first day of study (day 1), at the end of supervised lifestyle change program (day 28) and at the end of the study (day 84). Correlations were studied separately for day 1, day 24 and day 84. Only significant coefficients are reported. **. Correlation is significant at the 0.01 level (2-tailed). *. Correlation is significant at the 0.05 level (2-tailed). IL: Interleukin; EGF: epidermal growth factor; VEGF: vascular endothelial growth factor; IFNγ interferon gamma; TNFα: tumor necrosis factor alpha; MCP-1: monocyte chemoattractant protein-1. hsCRP: High-sensitivity C – reactive protein. HDL-Chol: HDL – cholesterol; LEP: leptin; ADPN: adiponectin.

Para

met

ers

IL2 IL6 IL8 IL10 VEGF IFNγ TNFα MCP1 EGF hsCRP HDL -Chol LEP ADPN

day 1

IL1α .852** .501* .643** .770** .600**

IL2 .535* .567* .677** .735** .580** .688**

IL6 .758** .554* .612**

IL8 .458* .244 .803** .623** .568*

IL10 .753** .549* .477*

VEGF -.693**

IFNγ .484* .481* .321 -.460*

TNFα .482* .352

MCP1 .727** .333

EGF .674**

day 28

IL1α -.527* .618** .532*

IL1β .611** .556* .493* 0.521* .541*

IL2 .721** .721** .671** .535* .689**

IL4 .516* .525* .470*

IL6 .851** .505* .630** .618** .570*

IL8 .477* .461* .721** .477*

IFNγ .491* .573* .555*

TNFα .460*

MCP1 .539*

EGF .484* .470*

LEP .567* .530*

day 84

IL1α .518* .634** .467* .499* .714** -.564*

IL1β .477*

IL2 .670** .698** 0.463*

IL4 -.544*

IL6 .856** .479*

IL8 -.532*

IFNγ .502* .482*

MCP1 .492* -.520*

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By contrast, leptin was significantly different on day 84 than on days 1 and 28. However, on days 1 and 28, the leptin levels were significantly higher in women than in men and decreased without any significant difference on day 84 (Fig. 2). The positive correlation on day 28 (Table 2) and the dynamics of leptin and adiponectin variations (Fig. 1) could suggest that even a month-long SLC program could have positive effects on the regulation of adipokine secretion. It could also be more helpful than either physical training or diet without weight loss, which lack an anti-inflammatory effect (42-49). Furthermore, these effects are more important in women than in men. In our study, HDL-C levels were significantly higher at the end of the study than at baseline, confirming the long-term effect of the SLC program. These data are in accordance with published data showing an improvement in the HDL-C level after supervised programs that combined diet management and exercise in patients with MetS (10,20,21). On the other hand, taking into account previously published studies (33-38), the variations and correlations of HDL-C, VEGF, leptin, adiponectin, and hsCRP suggest that a SLC program could have a positive effect on vascular function because of the decreased inflammatory state. The cholesterol, LDL-cholesterol and triglyceride levels decreased but only for cholesterol and LDL-cholesterol the decreasing was significant (day 84). The differences between our results and published data (39, 40) could be explained by statin therapy, the lack of significant weight changes, diet type or the short term of SLC intervention.

There are several limitations to the present study. First, the data from only a relatively small number of patients were considered because of the exclusion criteria. We attempted to compensate for this limitation through the collection method and statistical analysis of the obtained data. Second, all the women included in this study are in the post-menopausal stage. Therefore, all data about gender-related differences in the variations of adipocytokine levels have to take this into consideration (41). The obtained data nevertheless confirm the existence of differences between the inflammatory status and response to a SLC program in male patients (e.g., IL-4) and female patients (e.g., leptin and adiponectin). In conclusion, the results indicated that undergoing 1 month of a supervised program without weight loss could have anti-inflammatory and vasoprotective effects, as reflected by the variation in the levels of circulatory cytokines and adipocytokines (e.g., IL-1β, IL-2, IL-6, IL-8, MCP-1, hsCRP, and adiponectin) at the end of an SLC program. Furthermore, the presence of adipocytokine variations (increased IL-4; decreased VEGF, hsCRP, and leptin levels), that were present after 2 months without any medical supervision, could serve as useful parameters for appreciating a favorable long-term response to a lifestyle change program.

Conflict of interest The authors confirm that there are no conflicts of interest. Acknowledgements This study was supported by

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the Romanian National Ministry of Education and Research grant PN-II-ID-PCE_2_2670/2008 and by the “Gr. T. Popa” University of Medicine and Pharmacy internal research grant 17247/2011.

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