Stres oksydacyjny indukowany hiperglikemią w cukrzycy ciążowej (GDM)

An imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defence mechanisms results in the development of oxidative stress. Biological consequences of this state involve oxidative damage of key cellular components such as nucleic acids, lipids, or proteins and, in turn, impairment of cell and tissue function. Evidence from clinical and experimental studies supports the notion that oxidative stress is one of pathologic factors associated with gestational diabetes mellitus (GDM), metabolic disorder defined as any degree of glucose intolerance with onset or first recognition during pregnancy. It has been established that high blood glucose concentrations in diabetic pregnancy induce oxidative stress by several mechanisms, including an enhanced ROS production in mitochondria, the polyol pathway and the hexosamine pathway, as well as protein kinase C (PKC) activation and an advanced glycation end-products (AGEs) formation, and changes in biomarkers of free radical-induced damage and antioxidant defences have been detected in maternal diabetes. Moreover, hyperglycaemia-induced oxidative stress is related with some congenital anomalies in diabetic pregnancy. The current article provides an overview how oxidative stress is related to GDM, with special emphasis on the involvement of the hyperglycaemia-induced mechanisms in ROS overproduction, followed by discussion of indicators of oxidative stress. In addition, the relationship between oxidative stress and congenital malformations in diabetic pregnancy is described.Brak równowagi między produkcją reaktywnych form tlenu (ROS) a ich usunięciem przez antyoksydacyjne mechanizmy obronne prowadzi do rozwoju stresu ok­sydacyjnego. Biologicznymi konsekwencjami tego stanu są oksydacyjne uszkodzenia kluczowych składników komórkowych, takich jak kwasy nukleinowe, białka lub lipidy, które prowadzą do upośledzenia funkcji komórek i tkanek. Dowody pochodzące z badań klinicznych i eksperymentalnych popierają koncepcję, że stres oksydacyjny jest jednym z patologicznych czynników związanych z cukrzycą ciążową (GDM), definiowaną jako różny stopień zaburzeń tolerancji węglowodanów po raz pierwszy rozpoznany lub rozwijający się podczas ciąży. Ustalono, że wysokie stężenia glukozy we krwi kobiet z GDM indukują stres oksydacyjny poprzez kilka mechanizmów, w tym zwiększoną produkcję ROS w mitochondriach, szlak poliolowy, szlak heksozoaminy, aktywację kinazy białkowej C (PKC) oraz tworzenie końcowych produktów zaawansowanej glikacji (AGEs). Zmiany zarówno w biomarkerach uszkodzeń oksydacyjnych, jak i antyoksydacyjnym systemie obronnym były wykryte u pacjentek z GDM. Ponadto stres oksydacyjny indukowany hiperglikemią w GDM jest związany z roz­wojem wad wrodzonych płodu. Niniejszy artykuł stanowi podsumowanie wiedzy o związku stresu oksydacyjnego z cukrzycą ciążową, ze szczególnym podkreśleniem udziału mechanizmów indukowanych hiperglikemią, które prowadzą do nadprodukcji ROS, oraz omówieniem wskaźników stresu oksydacyjnego. Opisano także związek między stresem oksydacyjnym a występowaniem wad wrodzonych płodu podczas cukrzycy w ciąży

Ocena leukocytarnej ekspresji SIRT1 u kobiet ze zdiagnozowaną cukrzycą ciążową (GDM) w trzecim trymestrze ciąży

Background. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, has been implicated as a key regulator of glucose/lipid metabolism, insulin secretion as well as adiponectin production and inflammation in metabolic disorders, including type 2 diabetes mellitus (T2DM). However, its role in gestational diabetes mellitus (GDM) remains widely unknown. Since GDM is associated with inflammation, the aim of this study was to determine whether leukocyte SIRT1 mRNA expression is alteredin GDM women in the third trimester of pregnancy, and whether this change is correlated with clinical characteristics of patients. Methods. Leukocytes were isolated from the blood of GDM (n = 135) and normal glucose tolerant (NGT;n = 52) pregnant women. After extracting RNA from leukocytes, a quantitative real-time polymerase chain reaction (qRT-PCR) approach was performed to assess SIRT1 gene expression in these cells. Univariate regression analyses were applied to investigate correlations between SIRT1 expression and clinic parameters of patients. Results. Leukocyte SIRT1 mRNA was increased 1.7-foldin the GDM vs. NGT subjects (p = 0.001) and it positively correlated with 2 h glucose concentration during oral glucose tolerance test (OGTT) in the whole studygroup and negatively correlated with pregnancy agein the GDM and NGT groups. The positive association was also observed between SIRT1 mRNA and plasma high density lipoprotein (HDL) cholesterol level in the NGT subjects. Conclusions. GDM is accompanied by leukocyte SIRT1 mRNA over expression associated with hyperglycemia. Additionally, there is a close and beneficial relationship between enhanced leukocyte SIRT1 expression and increased plasma HDL-cholesterol level during normal pregnancy.Wstęp. Sirtuina 1 (SIRT1) jest NAD+-zależną deacetylazą, która odgrywa istotną rolę w regulacji metabolizmu węglowodanów i lipidów, sekrecji insuliny, produkcji adiponektyny oraz stanu zapalnego w chorobach metabolicznych, w tym cukrzycy typu 2 (T2DM). Do tej pory brak jest informacji o związku leukocytarnej SIRT1 z cukrzycą ciążową (GDM). Zważywszy związek SIRT1 ze stanem zapalnym, celem badania było określenie zmian w poziomie ekspresji SIRT1 mRNA w leukocytach kobiet z GDM w trzecim trymestrze ciąży i skorelowanie ich z klinicznymi parametrami pacjentek. Materiały i metody. Leukocyty wyizolowano z krwi pobranej od kobiet ciężarnych z GDM (n = 135) oraz kobiet ciężarnych z prawidłową gospodarką węglowodanową (NGT; n = 52). Po ekstrakcji RNA z leukocytów poziom ekspresji SIRT1 mRNA w tych komórkach określono metodą ilościowego qRT-PCR. Korelacje między ekspresją SIRT1 a klinicznymi parametrami pacjentek analizowano z wykorzystaniem regresji jednokrotnych. Wyniki. Ekspresja SIRT1 była 1,7-krotnie wyższa w leukocytach kobiet z GDM niż w grupie kobiet z NGT (p = 0,001) i dodatnio korelowała ze stężeniem glukozy w 2. godzinie testu doustnego obciążenia glukozą (OGTT) w całej badanej populacji pacjentek oraz ujemnie korelowała z wiekiem ciąży kobiet zarówno w grupie GDM, jak i NGT (p < 0,05). Stwierdzono również istotną statystycznie dodatnią korelację międzyekspresją SIRT1 a stężeniem cholesterolu frakcji HDL w grupie NGT (p < 0,05). Wnioski. GDM towarzyszy podwyższona ekspresja SIRT1 w leukocytach, która jest związana z hiperglikemią. Ponadto zaobserwowano istnienie bliskiego i korzystnego związku między podwyższonymi poziomami ekspresji SIRT1 a cholesterolem frakcji HDLu kobiet z prawidłowym przebiegiem ciąży

Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer

The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM) and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane), a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa, has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects

SIRT1 and metabolic syndrome

Both obesity and type 2 diabetes mellitus, two major components of metabolic syndrome, become healthepidemics in the world. Over the past decade, advances in understanding the role of some regulators participatingin lipid and carbohydrate homeostasis have been made.Of them, SIRT1, the mammalian orthologue of the yeast Sir2 protein has been identified. SIRT1 is a nuclearNAD+-dependent deacetylase that targets many transcriptional modulators, including PPAR-α and -γ (peroxisomeproliferator-activated receptors α and γ), PGC-1α (PPAR-γ coactivator-1α), FOXO (forkhead box O proteins),and nuclear factor κB (NF-κB), thereby this enzyme mediates a wide range of physiological processes like apoptosis,fat metabolism, glucose homeostasis, and neurodegeneration.In this article, we discuss how SIRT1 regulates lipid and carbohydrate metabolism, and insulin secretion indifferent metabolic organs/tissue, including liver, muscle, pancreas, and fat. Additionally, the role of this enzymein reduction of inflammatory signalling is highlighted

Transcriptomic Dysregulation of Inflammation-Related Genes in Leukocytes of Patients with Gestational Diabetes Mellitus (GDM) during and after Pregnancy: Identifying Potential Biomarkers Relevant to Glycemic Abnormality

Although the immune system has been implicated in the pathophysiology of gestational diabetes mellitus (GDM) and postpartum abnormal glucose tolerance (AGT), little is known about the transcriptional response of inflammation-related genes linked to metabolic phenotypes of GDM women during and after pregnancy, which may be potential diagnostic classifiers for GDM and biomarkers for predicting AGT. To address these questions, gene expression of IL6, IL8, IL10, IL13, IL18, TNFA, and the nuclear factor κB (NFκB)/RELA transcription factor were quantified in leukocytes of 28 diabetic women at GDM diagnosis (GDM group) and 1-year postpartum (pGDM group: 10 women with AGT and 18 normoglycemic women), using a nested RT-PCR method. Control pregnancies with normal glucose tolerance (NGT group; n = 31) were closely matched for maternal age, gestational age, pre-pregnancy BMI, pregnancy weight, and gestational weight gain. Compared with the NGT group, IL8 was downregulated in the GDM group, and IL13 and RELA were upregulated in the pGDM group, whereas IL6, IL10, and IL18 were upregulated in the GDM and pGDM groups. The TNFA level did not change from pregnancy to postpartum. Associations of some cytokines with glycemic measures were detected in pregnancy (IL6 and RELA) and postpartum (IL10) (p < 0.05). Receiver operating characteristic (ROC) curves showed that IL6, IL8, and IL18, if employed alone, can discriminate GDM patients from NGT individuals at GDM diagnosis, with the area under the ROC curves (AUCs) of 0.844, (95% CI 0.736–0.953), 0.771 (95% CI 0.651–0.890), and 0.714 (95% CI 0.582–0.846), respectively. By the logistic regression method, we also identified a three-gene panel (IL8, IL13, and TNFA) for postpartum AGT prediction. This study demonstrates a different transcriptional response of the studied genes in clinically well-characterized women with GDM at GDM diagnosis and 1-year postpartum, and provides novel transcriptomic biomarkers for future efforts aimed at diagnosing GDM and identifying the high risk of postpartum AGT groups

The Influence of Dietary Fatty Acids on Immune Responses

Diet-derived fatty acids (FAs) are essential sources of energy and fundamental structural components of cells. They also play important roles in the modulation of immune responses in health and disease. Saturated and unsaturated FAs influence the effector and regulatory functions of innate and adaptive immune cells by changing membrane composition and fluidity and by acting through specific receptors. Impaired balance of saturated/unsaturated FAs, as well as n-6/n-3 polyunsaturated FAs has significant consequences on immune system homeostasis, contributing to the development of many allergic, autoimmune, and metabolic diseases. In this paper, we discuss up-to-date knowledge and the clinical relevance of the influence of dietary FAs on the biology, homeostasis, and functions of epithelial cells, macrophages, dendritic cells, neutrophils, innate lymphoid cells, T cells and B cells. Additionally, we review the effects of dietary FAs on the pathogenesis of many diseases, including asthma, allergic rhinitis, food allergy, atopic dermatitis, rheumatoid arthritis, multiple sclerosis as well as type 1 and 2 diabetes

Expression Profile of Diabetes-Related Genes Associated with Leukocyte Sirtuin 1 Overexpression in Gestational Diabetes

Although compelling evidence indicates that Sirtuin 1 (SIRT1) plays a prominent role in type 2 diabetes, its relationship with gestational diabetes (GDM) remains elusive. This study was aimed at identifying diabetes-related genes and cellular pathways linked to changes of leukocyte SIRT1 expression at the time of GDM diagnosis. For this purpose, 122 GDM patients were screened for leukocyte SIRT1 expression, and two subgroups were distinguished, namely GDM/SIRT1(↑) (n = 30, p < 0.05) and GDM/SIRT1(↔) (n = 92, p > 0.05), with significant and insignificant changes in leukocyte SIRT1 expression compared to a normal glucose tolerant (NGT) group (n = 41), respectively. PCR array analysis identified 11 diabetes-related genes with at least a ± 2-fold difference in expression in GDM/SIRT1(↑) patients (n = 9) vs. NGT controls (n = 7); in addition, significant differences in the expression of four of the six investigated genes were confirmed between the entire GDM/SIRT1(↑) group and the whole NGT group (p < 0.05). Interestingly, of these four genes, only ACLY expression was found to significantly differ between GDM/SIRT1(↑) and GDM/SIRT1(↔). This study demonstrates that under hyperglycemic conditions, leukocyte SIRT1 overexpression is accompanied by an over-abundance of three transcripts and an under-abundance of another; these four govern related metabolism, inflammation, and transport functions, suggesting that such alterations might represent systemic biological adaptations with a unique ACLY under-expression in GDM/SIRT1(↑) women

Dual Stimulus-Dependent Effect of Oenothera paradoxa

Although a growing body of evidence suggests that plant polyphenols can modulate human immune responses, their simultaneous action on monocyte and neutrophil oxidative burst is currently poorly understood. Based on the hypothesis that various polyphenols contained in plant extracts might affect the oxidative burst of phagocytes, we evaluated the effects of ethanolic O. paradoxa extract polyphenols on monocyte and neutrophil oxidative burst in vitro activated by different stimuli, including opsonized bacteria E. coli, phorbol 12-myristate 13-acetate (PMA), and formyl-methionyl-leucyl-phenylalanine (fMLP). Samples were analyzed by the dihydrorhodamine flow cytometry assay. Our results showed that the extract repressed significantly and dose-dependently reactive oxygen species production in both cell types stimulated with E. coli and PMA (P < 0.05) and its inhibitory efficiency was stimulus- and cell-type-dependent. Interestingly, there was significant stimulatory effect of the extract on bursting phagocytes induced by fMLP (P < 0.05). Additionally, several flavonoids and phenolic compounds as well as penta-galloyl-β-(D)-glucose (PGG), the representative of hydrolyzable tannins, were identified in the 60% extract by high-performance liquid chromatography (HPLC) coupled to electrospray ionization in negative ion mode. In summary, the ethanolic O. paradoxa extract, rich in flavonoids and phenolic compounds, exhibits dual stimulus-dependent effect on the respiratory burst in human leukocytes; hence, it might affect immune responses in humans