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Upregulation of chemokine CX3CL1 and its receptor CX3CR1 occurs in the diabetic human placenta. Metformin, an insulin-sensitizing biguanide, is used in the therapy of diabetic pregnancy. By preventing the activation of NF-κB, metformin exhibits anti-inflammatory properties. We examined the influence of hyperglycemia (25 mmol/L glucose; HG group; N = 36) on metformin-mediated effects on CX3CL1 and TNF-α production by placental lobules perfused extracorporeally. Additionally, CX3CR1 expression and contents of CX3CR1, TNF-α receptor 1 (TNFR1), and NF-κB proteins in the placental tissue were evaluated. Placentae perfused under normoglycemia (5 mmol/L glucose; NG group; N = 36) served as the control. Metformin (2.5 and 5.0 mg/L; subgroups B and C) lowered the production of CX3CL1 and TNF-α in a dose-dependent and time-dependent manner. Hyperglycemia did not weaken the strength of these metformin effects. Moreover, CX3CL1 levels after perfusion with 5.0 mg/L metformin were reduced by 33.28 and 33.83% (at 120 and 150 min, respectively) in the HG-C subgroup versus 24.98 and 23.66% in the NG-C subgroup, which indicated an augmentation of the metformin action over time in hyperglycemia. CX3CR1 expression was significantly higher in the HG-B and HG-C subgroups compared to that in the NG-B and NG-C subgroups. Increased CX3CR1 protein content in the placental lysates was observed in subgroups B and C. The two higher metformin concentrations significantly decreased the levels of NF-κBp65 protein content in both groups. However, the decrease was significantly stronger in hyperglycemia. TNFR1 upregulation in the HG group was not affected by metformin. Further studies on metformin therapy during pregnancy are needed, including safety issues. [ABSTRACT FROM AUTHOR]

Hyperglycemia-induced hyperactivity of chemokine CX3CL1 (fractalkine) occurs in the human placenta. Anti-inflammatory/antioxidant activities of resveratrol (3,5,4′-trihydroxy-trans-stilbene) are related to the modulation of chemokine CX3CL1 and its receptor, CX3CR1, signaling pathways. We examined the influence of high glucose (25 mmol/L glucose; HG group; N=36) on resveratrol-mediated effects on CX3CL1 and TNF-α production by the placental lobule, CX3CR1 expression and contents of CX3CR1, TNF-α receptor 1 (TNFR1), and NF-κB proteins in placental tissue. The placental lobules perfused under normoglycemic conditions formed the control NG group (N=36). Resveratrol (50 and 100 μM; subgroups B and C) administered into the perfusion fluid lowered the production of both CX3CL1 and TNF-α. The reductions in CX3CL1 levels were more evident in the NG group. CX3CR1 expression was significantly higher in the NG subgroups B and C compared to the HG subgroups B and C (385.2 and 426.5% versus 199.3 and 282.4%, resp.). An increase in CX3CR1 protein content in placental lysates was observed in the NG subgroups B and C. Also, resveratrol significantly decreased NF-κBp65 protein content only in the NG group, not affecting hyperglycemia-elicited TNFR1 upregulation. In conclusion, euglycemia assures optimal effects of resveratrol pertaining to CX3CL1/CX3CR1 signaling in the placenta. Future studies on resveratrol are needed, especially those including maternal-fetal risk assessments. [ABSTRACT FROM AUTHOR]

Chemokine CX3CL1 is unique, possessing the ability to act as a dual agent: chemoattractant and adhesive compound. Acting via its sole receptor CX3CR1, CX3CL1 participates in many processes in human placental tissue, including inflammation and angiogenesis. Strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokines secretion, CX3CL1 may act locally as a key angiogenic factor. Both clinical observations and histopathological studies of the diabetic placenta have confirmed an increased incidence of hypoxia and inflammatory reactions with defective angiogenesis. In this study we examined comparatively (diabetes class C complicated versus normal pregnancy) the correlation between CX3CL1 content in placental tissue, the mean CX3CR1 expression, and density of the network of placental microvessels. A sandwich enzyme immunoassay was applied for CX3CL1 measurement in placental tissue homogenates, whereas quantitative immunohistochemical techniques were used for the assessment of CX3CR1 expression and the microvascular density. Significant differences have been observed for all analyzed parameters between the groups. The mean concentration of CX3CL1 in diabetes was increased and accompanied by augmented placental microvessel density as well as a higher expression of CX3CR1. In conclusion, we suggest involvement of CX3CL1/CX3CR1 signaling pathway in the pathomechanism of placental microvasculature remodeling in diabetes class C. [ABSTRACT FROM AUTHOR]