Figure 1: The result of One and Two-way analysis of variance (ANOVA) to investigate the interactive effects of resistance training and genistein on serum levels of VCAM
*** (p≤0.001) Increases serum levels of VCAM Sham and Diabetic control compared to Health control group
### (p≤0.001), ## (p≤0.01) Reduction serum levels of VCAM in genistein and Resistance training + genistein groups compared to Diabetic control group
It can be concluded that resistance training modulated the effect of genistein in reducing serum levels of VCAM
Figure 2: The result of One and Two-way analysis of variance (ANOVA) to investigate the interactive effects of resistance training and genistein on serum levels of ICAM
*** (p≤0.001) Increases serum levels of ICAM Sham and Diabetic control compared to Health control group
##(p≤0.01) Increases serum levels of ICAM in c Diabetic control group compared to Sham group.
& (p≤0.05), &&& (p≤0.001) Reduction serum levels of ICAM in genistein groups and Resistance training groups compared to Control group.
It can be concluded that resistance training and genistein consumption do not have an interactive effect on reducing serum levels of ICAM.
Figure 3: The result of One and Two-way analysis of variance (ANOVA) to investigate the interactive effects of resistance training and genistein on serum levels of CRP
*** (p≤0.001) Increases serum levels of ICAM Sham and Diabetic control compared to Health control group
# (P≤0.05), ### (p≤0.001) Reduction serum levels of CRP in Resistance training groups and Resistance training + genistein group compared to Diabetic control group.
Based on the results of two-way analysis of variance, it can be concluded that genistein consumption has modified the effect of resistance training, however, resistance training and genistein consumption interactively reduce serum levels of CRP.
Discussion
The results of this study showed that genistein consumption has a significant effect on the reduction of serum levels of VCAM and ICAM in diabetic rats, but does not have a significant effect on serum levels of CRP in diabetic rats with streptozotocin. Researchers believe that diabetic patients face problems such as cardiovascular risk factors, including hypertension and impaired fat profile, which a total of these risk factors is known as metabolic syndrome
(18). Inflammation is known to be a potential risk in the onset of atherosclerosis, and sudden death due to heart attacks and diabetes
(19). Evidence suggests the effect of cellular and vascular adhesion molecules on the evolution of atherosclerosis. The connection of blood cells to the arterial surface is one of the first events in the diagnosis of atherosclerosis
(20). Increased blood glucose levels in diabetic patients have been reported to increase serum levels of ICAM-1, VCAM-1 and CRP
(6). Cell damage in diabetes and the development of insulin resistance are closely related to the presence of oxidative stress in the cell. Oxidative stress is likely to increase the risk of diabetes directly by reducing insulin sensitivity and destruction of insulin producing cells and degradation of pancreatic cells. Also, oxidative stress can be incrementally and actively involved in the production of systemic inflammation and increased levels of pro-inflammatory cytokines
(21). Most researchers believe that elevated cholesterol, neutrophil accumulation and hypoxia in the cell will result in the production of inactive IL-1β formulation, and inactive IL-1β with caspase-1 interfering into an active form of IL-1β results in IL- 6 as well as CRP
(22). Nevertheless, genistein isoflavone via cAMP /PKA increases the production of NOS and NO from non-genomic pathways. The c-AMP central molecule has many messaging pathways and plays an important role in maintaining the vascular function. The pathway activity of cAMP/PKA causes endothelial nitric oxide phosphorylation, which results in its activity and thus the production of NO. In addition, the activation of the pathway of cAMP/PKA inhibits vascular inflammation by suppressing the adhesion of leukocytes to endothelial cells and thus decreasing ICAM-1 and VCAM-1
(23, 24). Genestein also reduces weight, through a protein-based diet, increases the mass of pancreatic beta cells and increases serum insulin levels in diabetic disease, and subsequently facilitates the transfer of glucose to the cell wall; following the reduction in weight and reduced fat mass, the reduction of pro-inflammatory factors from the Nf-kB signaling pathway can be pointed. Genistein results in reducing the production of CRP via inhibiting the inhibitory protein of IκBα (Inhibitor of NF-κB alpha), increasing the phosphorylation of IKK (an enzyme which inhibits the protein IκB), and the phosphorylation of IL-1β receptors
(25, 26). In confirmation of the findings of the present study, eight weeks of taking one mg / kg of body weight of genistein had a significant effect on the reduction of Nf-kB and IL-1β in ovariectomized rats and overariectomized and diabetic rats with full food fatty regime and STZ
(25). Daily consumption of 30 mg per kg of body weight of genistein for eight weeks had a significant effect on the improvement of fat profile in STZ-diabetic rats, thus reducing low density lipoproteins and low density lipoprotein and cholesterol can reduce inflammation
(14). Also, in line with the current study, the researchers showed that the use of genistein reduced the expression of ICAM-1 and VCAM-1 levels in endothelial cells of humans
(27, 28); six months of genistein consumption at an amount of 30-54 mg / dl per day showed no significant effect on the reduction of CRP levels in women with menopause
(29). On the other hand, studies have shown that consumption of soy and its products to improve inflammatory factors is dosage-dependent. Regarding the relationship of inflammation and its role in the adhesion of leukocyte cells in endothelial cells, controversial results were reported on the dosage
(23, 24).
The results showed that eight weeks of resistance training had a significant effect on the reduction of serum ICAM and CRP levels and a non-significant decrease in VCAM in diabetic rats; inflammation is known as an indirect risk factor in increasing arteriosclerosis and sudden death due to heart attacks and diabetes
(18). However, sports activities seem to be inhibiting inflammatory mediators from adipose tissue by increasing anti-inflammatory cytokines; in fact, sports activities enhance antioxidant defense and reduce free radicals, and hence can lead to a reduction in the inflammatory indices
(6, 8). Also, sports activities can reduce the levels of VCAM, ICAM and CRP in the bloodstream by reducing the production of cytokines in adipose tissue, muscle and mononuclear cells, and indirectly by increasing insulin sensitivity and improving endothelial function. Studies have shown that increased caloric intake can lead to a reduction in CRP in several ways, including weight loss
(30). Physical activity may be effective in modulating vascular inflammation by modulating effective mechanisms for regulation of adhesion molecules such as renin angiotensin system and reducing the release of chemical intermediates and pro-inflammatory copies such as Nf-kB. Inhibitory NF-KB is present in the cytoplasm in inactive mode, and mediates the onset of endothelial activity by intermediaries and the translation of ICAM-1
(31). In addition, angiotensin-2 by stimulating NADPH oxidase, increases the incidence of ICAM-1
(32). Each of the above-mentioned mechanisms can partly justify the changes in the concentration of adhesion molecules. Also, sports activity, on the one hand, improves antioxidant defense of the endothelial and blood, and inhibits nitric oxide destruction by active oxygen particles; and on the other hand, by increasing the production of nitric oxide by endothelial cells, and as a result of vessel tuning, platelet aggregation is controlled, and the level of adhesion of the mediators to the vascular wall is controlled, thereby modifying endothelial activity and general inflammation
(33). However, the mechanism of resistance training to reduce inflammation is not well defined. In line with the current study, the researchers stated that resistance training with different intensities reduced the levels of CRP and HS-CRP in young men
(34), and diabetic and non-diabetic rats
(35); eight weeks of moderate and high intensity endurance training reduced serum levels of ICAM-1 and insignificantly decreased the serum levels of VCAM and CRP in diabetic rats
(6). Eight weeks of endurance training and high intensity interval training also reduced the serum levels of ICAM-1 and VCAM-1 in obese men, while in normal weight group only VCAM-1 was significantly reduced after endurance training (36); eight weeks of resistance training significantly decreased the serum levels of ICAM-1 and CRP. However, eight weeks of resistance training did not significantly reduce serum levels of VCAM-1 in diabetic rats
(37). In addition, resistance and endurance training significantly decreased ICAM-1, VCAM-1 and CRP levels in old obese women
(38, 39). On the other hand, inconsistent with the current study, aerobic exercise and weight loss had no significant effect on ICAM-1 and VCAM-1 changes in obese women
(40). The reasons for the inconsistency of this study with the current study can be seen in the differences in the population and the statistical sample, as well as the differences in the initial levels of research variables. Eight weeks, three sessions and 40 minutes of endurance training for each session with an intensity of 75% of maximum heart rate did not have a significant effect on the levels of VCAM-1 in middle-aged women
(41). Among the reasons of inconsistency of this study with the present study can be the difference in the type, intensity and training in two studies. Also, 12 weeks of resistance training did not have any significant effect on ICAM-1 and VCAM-1 changes in type 2 diabetic rats
(5). The reasons for the inconsistency of this study with the present study are the differences in the intensity of training and the differences in animal modeling.
Also, the results of the present study showed that resistance training and genistein consumption had interactive effects on the reduction of serum levels of VCAM and CRP in diabetic rats. However, the interaction of resistance training and the consumption of genistein in reducing serum levels of ICAM was not significant. Regarding the interactive effects of genistein consumption and exercise training on adhesion molecules, no study was found, however, many researchers have investigated the interactive effect of training and the consumption of genistein. For example, eight weeks of resistance training and concurrent consumption of 10 and 30 mg / kg of genistein had interactive effects on reducing leptin and improving the lipid profile of diabetic rats with streptozotocin
(1); also, endurance training and consumption of 30 mg/kg of body weight of genistein had a significant effect on the improvement of lipid profile
(14) and decreased serum levels of VCAM, CRP, brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-α (TNF-α) in diabetic rats with streptozotocin
(6, 24, 42). Studies show that resistance training and genistein consumption in the present study have been able to inhibit vascular inflammation by suppressing the adhesion of leukocytes to endothelial cells and thus reduce ICAM-1 and VCAM-1 via cAMP/PKA
(23, 24) signaling pathway activation, decreasing Nf-kB
(32, 35), Due to the influence of inflammatory factors such as Nf-Kb on the increase of adhesion cells, it seems that failure to measure this factor is considered as one of the limitations of the present study. Therefore, it is suggested that in future studies, for further information on the interactive effects of exercise and genistein, this factor should also be measured alongside the adhesion cells. Regarding the use of different drugs such as insulin and metformin in diabetic patients, it seems that the lack of control of drug interventions is another limitation of this study. Therefore, in future studies, it is suggested that groups should be considered to control other factors affecting physiological factors in diabetic patients in order to make such research more practical. Also, due to the effect of genistein solvent on VCAM levels, it seems that one of the limitations of the research is the effect of dimethyl sulfoxide on the variables of the research. Therefore, it is recommended in future studies to investigate the effect of this solvent on the standard amount of adhesion molecules in rats.
Conclusion
Resistance training and genistein consumption simultaneously appear to reduce the risk of cardiovascular disease and atherosclerosis in diabetic rats. However, further studies in this area are necessary. It is also recommended to conduct such studies in human samples with seamless cautiousness.
Acknowledgments
The author would like to express her heartiest thanks and gratitude to all individuals who cooperated with conducting the current research study.
Conflict of interest
There are no conflicts of interest for the authors.