Hyperglycemia and Some Aspects of Leukocyte Activation In Vitro

Mikhalchik, Elena V.; Lipatova, V. A.; Basyreva, L. Yu.; Панасенко, О. М.; Гусев, С. А.; Сергиенко, В. И.

doi:10.1007/s10517-021-05147-x

Cited by 7 publications

(5 citation statements)

References 14 publications

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“…According to our results, fasting glucose and the HbA1c of DR subjects correlated with the in vitro NET release. It has been reported that hyperglycemia is one external stimulus that is able to induce NET release in diabetic DR subjects [22,38]. In this sense, higher levels of fast glucose and HbA1c were found in all diabetic subjects, suggesting that NET release in diabetic subjects could be used as an indicator of disease deterioration.…”

Section: Discussionmentioning

confidence: 82%

Spontaneous Neutrophil Extracellular Traps Release Are Inflammatory Markers Associated with Hyperglycemia and Renal Failure on Diabetic Retinopathy

Magaña-Guerrero,

Aguayo-Flores,

Buentello-Volante

et al. 2023

Biomedicines

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Diabetic retinopathy (DR) is the major microvascular complication of diabetes and causes vitreous traction and intraretinal hemorrhages leading to retinal detachment and total blindness. The evolution of diabetes is related to exacerbating inflammation caused by hyperglycemia and activation of inflammatory cells. Neutrophils are cells able to release structures of extracellular DNA and proteolytic enzymes called extracellular traps (NETs), which are associated with the persistence of inflammation in chronic pathologies. The purpose of the study was to determine the usefulness of neutrophil traps as indicators of DR progression in patients with type 2 diabetes (T2DM). We performed a case–control study of seventy-four cases classified into five groups (non-proliferative DR, mild, moderate, severe, and proliferative) and fifteen healthy controls. We found correlations between NETs and a diagnostic time of T2DM (r = 0.42; p < 0.0001), fasting glucose (r = 0.29; p < 0.01), glycated hemoglobin (HbA1c) (r = 0.31; p < 0.01), estimated glomerular filtration rate (eGFR) (r = −0.29; p < 0.01), and plasma osmolarity (r = 0.25; p < 0.01). These results suggest that due to NETs being associated with clinical indicators, such as HbA1c and eGFR, and that NETs are also associated with DR, clinical indicators might be explained in part through an NET-mediated inflammation process.

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Section: Discussionmentioning

confidence: 82%

Spontaneous Neutrophil Extracellular Traps Release Are Inflammatory Markers Associated with Hyperglycemia and Renal Failure on Diabetic Retinopathy

Magaña-Guerrero,

Aguayo-Flores,

Buentello-Volante

et al. 2023

Biomedicines

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“…There are contradictory literature data on NETosis in hyperglycemia. A number of publications report activation of NETosis in hyperglycemia and diabetes mellitus [ 47 , 48 ]; others assert that hyperglycemia is a factor preventing NET formation in diabetes mellitus patients [ 49 ]. One way or another, our results demonstrated that HSA modified under conditions modeling hyperglycemia (treatment with MG) did not enhance NET-like structure formation in whole blood of healthy subjects and had no effect on PMA-induced NETosis ( Table 2 ; Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…Coincidences of HSA-MG effects on neutrophil activity appeared in the present study, with features of neutrophils in diabetes mellitus type 2 patients assumed in Table S3 (see Supplementary Materials) . In particular, NET formation, exocytosis of AGs and Lum-CL are not increased in type 2 diabetes [ 58 , 59 ] and are not affected by HSA-MG. On the contrary, expression of CD11b, NADPH oxidase activity and Luc-CL are increased in the case of type 2 diabetes [ 33 , 47 , 60 , 61 , 62 , 63 , 64 ] and after the addition of HSA-MG to neutrophils. Finally, the inhibition of MPO activity was described in the case of type 2 diabetes mellitus [ 59 , 65 ] as well as in the case of interaction HSA-MG with MPO in vitro.…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal-Modified Human Serum Albumin Binds to Leukocyte Myeloperoxidase and Inhibits its Enzymatic Activity

et al. 2022

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Hyperglycemia in diabetes mellitus induces modification of proteins by glucose and its derivative methylglyoxal (MG). Neutrophils perform their bactericidal activity mainly via reactive halogen (RHS) and oxygen (ROS) species generation catalyzed by myeloperoxidase (MPO) stored in neutrophil azurophilic granules (AGs) and membrane NADPH oxidase, respectively. Herein, we study the binding of human serum albumin (HSA) modified with MG (HSA-MG) to MPO and its effects on MPO activity and release by neutrophils. Peroxidase activity of MPO was registered by oxidation of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, and chlorinating activity by decolorization of Celestine blue B dye. Binding of HSA-MG to MPO was studied by affinity chromatography, disc-electrophoresis, ligand Western blotting and enzyme-linked solid phase immunoassay using monoclonal antibodies (mAbs) to MPO. ROS and RHS generation were detected by lucigenin (Luc) and luminol (Lum) chemiluminescence (CL), respectively. Neutrophil degranulation was assessed by flow cytometry using fluorescent labeled antibodies to the marker proteins CD63 from AGs and CD11b from peroxidase-negative granules (PNGs). NETosis was assayed by quantifying DNA network-like structures (NET-like structures) in blood smears stained by Romanowsky. HSA-MG bound to MPO, giving a stable complex (Kd = 1.5 nM) and competing with mAbs, and non-competitively inhibited peroxidase and chlorinating MPO activity and induced degranulation of PNGs but not of AGs. HSA-MG enhanced Luc-CL per se or following PMA, unlike Lum-CL, and did not affect spontaneous or PMA-stimulated NETosis. Thus, HSA modified under hyperglycemia-like conditions stimulated NADPH oxidase of neutrophils but dampened their functions dependent on activity of MPO, with no effect on its release via degranulation or NETosis. This phenomenon could underlie the downregulation of bactericidal activity of MPO and neutrophils, and hence of innate immunity, giving rise to wound healing impairment and susceptibility to infection in patients with hyperglycemia.

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“…Circulating NETs are known to contribute to clot formation and vascular endothelial cell damage [9,14,26]. Experimental data indicate that hyperglycemia promotes neutrophil priming/activation and NETosis [28,29]. There are also published data showing that NETs in T2DM interfere with wound healing [15].…”

Section: Discussionmentioning

confidence: 99%

Effect of Vitamin D3 in combination with Omega‐3 Polyunsaturated Fatty Acids on NETosis in Type 2 Diabetes Mellitus Patients

Basyreva

Вахрушева

Леткеман

et al. 2021

Oxidative Medicine and Cellular Longevity

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An understanding of the consequences of oxidative/halogenative stress triggered by neutrophil activation is impossible without considering NETosis. NETosis, formation of neutrophil extracellular traps (NETs), is known to promote microthrombus formation and impair wound healing in type 2 diabetes mellitus (T2DM) patients. Therefore, there is a need to search for drugs and treatment approaches that could prevent excessive NET formation. We aimed to evaluate the effect of vitamin D3 in combination with omega-3 polyunsaturated fatty acids (vitamin D3/omega-3 PUFAs) on NETosis in T2DM patients with purulent necrotizing lesions of the lower extremities. Patients and healthy subjects had vitamin D3 deficiency. Patients received, beyond standard treatment, 6000 IU of vitamin D3 and 480 mg of omega-3 PUFAs, and healthy subjects 1000 IU of vitamin D3 and 240 mg of omega-3 PUFAs daily for seven days. Neutrophil activation in ex vivo blood by phorbol-12-myristate-13-acetate (PMA) was used as a NETosis model. The percentage of blood NETs relative to leukocytes (NETbackground) before vitamin D3/omega-3 PUFA supplementation was 3.2%-4.9% in healthy subjects and 1.7%-10.8% in patients. These values rose, respectively, to 7.7%-9.1% and 4.0%-17.9% upon PMA-induced NETosis. In addition, the leukocyte count decreased by 700-1300 per 1 μL in healthy subjects and 700-4000 per 1 μL in patients. For both patients and healthy subjects, taking vitamin D3/omega-3 PUFAs had no effect on NETbackground but completely inhibited PMA-induced NET formation, though neutrophils exhibited morphological features of activation. Also, leukocyte loss was reduced (to 500 per 1 μL). For patients on standard treatment alone, changes occurred neither in background NETs and leukocytes nor in their amount after PMA stimulation. The decreased ability of neutrophils to generate NETs, which can be achieved by vitamin D3/omega-3 PUFA supplementation, could have a positive effect on wound healing in T2DM patients and reduce the incidence and severity of complications.

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Hyperglycemia and Some Aspects of Leukocyte Activation In Vitro

Cited by 7 publications

References 14 publications

Spontaneous Neutrophil Extracellular Traps Release Are Inflammatory Markers Associated with Hyperglycemia and Renal Failure on Diabetic Retinopathy

Spontaneous Neutrophil Extracellular Traps Release Are Inflammatory Markers Associated with Hyperglycemia and Renal Failure on Diabetic Retinopathy

Methylglyoxal-Modified Human Serum Albumin Binds to Leukocyte Myeloperoxidase and Inhibits its Enzymatic Activity

Effect of Vitamin D3 in combination with Omega‐3 Polyunsaturated Fatty Acids on NETosis in Type 2 Diabetes Mellitus Patients

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