Christina Piperi

Inflammatory Process in Type 2 Diabetes

Abstract:  Population‐based studies have shown strong relationship between inflammatory markers and metabolic disturbances, obesity, and atherosclerosis, whereas inflammation has been considered as a “common soil” between these clinical entities and type 2 diabetes (T2D). The accumulation of macrophages in adipose tissue (AT), the common origin of macrophages and adipocytes, the prevalent presence of peripheral mononuclear cells, and apoptotic β cells by themselves seem to be the sources of inflammation present in T2D, since they generate the mediators of the inflammatory processes, namely cytokines. The main cytokines involved in the pathogenesis of T2D are interleukin‐1β (IL‐1β), with an action similar to the one present in type 1 diabetes, tumor necrosis factor‐α (TNF‐α), and IL‐6, considered as the main regulators of inflammation, leptin, more recently introduced, and several others, such as monocyte chemoattractant protein‐1, resistin, adiponectin, with either deleterious or beneficial effects in diabetic pathogenesis. The characterization of these molecules targeted diabetes treatment beyond the classical interventions with lifestyle changes and pharmaceutical agents, and toward the determination of specific molecular pathways that lead to low grade chronic inflammatory state mainly due to an immune systems unbalance.

Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome

objective  Women with polycystic ovary syndrome (PCOS) carry a number of cardiovascular risk factors and are considered to be at increased risk for atherosclerosis. Elevated concentrations of advanced glycation end‐products (AGE), which exert their effects through interaction with specific receptors (RAGE), have been implicated in the cellular and tissue damage during atherosclerotic processes.

Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS).

Background  Nonenzymatic advanced glycation and oxidation end‐products, advanced glycation end‐products (AGEs), impart a potent impact on vessels and other tissues in diabetic state and in euglycaemic conditions with increased oxidative stress.

Inflammatory and endothelial markers in women with polycystic ovary syndrome

Background  Women with polycystic ovary syndrome (PCOS) carry a pattern of cardiovascular risk factors. Endothelial dysfunction and chronic inflammation are early findings in the atherosclerotic process. The purpose of the study was to investigate the coexistence of active inflammation markers and endothelial dysfunction in young women with PCOS, and their relationship with metabolic and hormonal abnormalities of the syndrome.

Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries

The aim of the present study was to investigate the localization/immunohistochemical distribution of AGEs and RAGE, as well as their putative signalling mediator NF-κB in ovaries of women with polycystic ovary syndrome (PCOS) compared to normal. Archival ovarian-tissue samples from biopsies of six women with PCOS and from six healthy of similar age women, were examined immunohistochemically with monoclonal anti-AGEs, anti-RAGE and anti-NF-κB(p50/p65) specific antibodies. In healthy women, AGE immunoreactivity was observed in follicular cell layers (granulosa and theca) and luteinized cells, but not in endothelial cells. PCOS specimens displayed AGE immunoexpression in theca interna and granulosa cells as well as in endothelial cells, but staining of granulosa cells was stronger than in that of normal ovaries. RAGE was highly expressed in normal and PCOS tissues. Normal tissue exhibited no staining differences between granulosa cell layer and theca interna. However, in PCOS ovaries, granulosa cells displayed stronger RAGE expression compared to theca interna cells in comparison to controls. NF-κB(p50/p65) was expressed in the cytoplasm of theca interna and granulosa cells of both normal and PCOS ovaries; whereas the NF-κB p65 subunit was only observed in granulosa cells nuclei in PCOS tissue. In conclusion, these findings demonstrate for the first time that RAGE and AGE-modified proteins with activated NF-κB are expressed in human ovarian tissue. Furthermore, a differential qualitative distribution of AGE, RAGE and NF-κB p65 subunit was observed in women with PCOS compared to healthy controls, where a stronger localization of both AGE and RAGE was observed in the granulosa cell layer of PCOS ovaries.

Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases.

CONTEXT Advanced glycation, the major posttranslational modification of proteins, DNA, and lipids, is accelerated under conditions of increased oxidative stress, hyperglycemia, and hypoxia contributing to a variety of metabolic diseases such as diabetes mellitus, obesity, inflammation, polycystic ovarian syndrome, ischemic cardiovascular disease, and neurodegenerative disorders. The potential role of advanced glycation in endoplasmic reticulum (ER) homeostasis is largely unknown. EVIDENCE ACQUISITION Basic and clinical peer-reviewed articles on advanced glycation and ER stress related to metabolic regulation were searched in PubMed from 2000-2011. The resulting articles as well as relevant cited references were reviewed. EVIDENCE SYNTHESIS Recent evidence indicates that hyperglycemia, hypoxia, and oxidative stress, apart of triggering advanced glycation, can also adversely affect ER function, leading to pathogenic ER stress, followed by the unfolded protein response. The concomitant presence of advanced glycation in the same conditions with ER stress suggests their crosstalk in the progression of diseases associated with hypoxic and oxidative stress. CONCLUSION Current data support the direct or indirect induction of ER stress response by advanced glycation end products or advanced glycation end product precursors in the pathogenesis of metabolic diseases. Inhibitors of advanced glycation acting as potent ER stress modulators with beneficial effects in restoring ER homeostasis and adjusting physiological unfolded protein response level present an emerging therapeutic approach with significant applications, especially in the context of metabolic dysfunction.

Increased plasma levels of 8-iso-PGF2α and IL-6 in an elderly population with depression

Oxidative damage and immune-inflammatory activation have been suggested to play a role in depression. The purpose of the study was to investigate possible associations and interactions of these pathophysiological mechanisms in geriatric depression by determining the levels of plasma 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) and interleukin-6 (IL-6) in elderly depressed individuals. Subjects over 60 years of age with depression and controls were randomly selected from a population in the community after screening with the Geriatric Depression Scale. Plasma concentrations of 8-iso-PGF2alpha and IL-6 were measured in both groups. Depressed patients had significantly higher mean (+/-S.D.) 8-iso-PGF2alpha levels compared to healthy controls (245.01+/-179.92 pg/ml vs 97.64+/-42.72 pg/ml, respectively). Similarly, the same groups demonstrated significantly elevated IL-6 levels compared with controls (58.73+/-39.90 pg/ml vs 15.41+/-9.27 pg/ml). This study indicates an association between increased levels of plasma 8-iso-PGF2alpha and IL-6 with depressive symptomatology in elderly individuals and indicates the necessity for further investigation, possibly within the framework of an integrated involvement of oxidative damage and inflammation in the pathophysiology of depression in the elderly.

Cytokine Secretion in Long-standing Diabetes Mellitus Type 1 and 2: Associations with Low-grade Systemic Inflammation

Low-grade systemic chronic inflammation is a very well-known feature of diabetes mellitus (DM). The purpose of this study was the assessment of the proinflammatory cytokine secretion profile in long-standing diabetes along with the presence of features of systemic inflammation. Metabolic parameters and serum high-sensitivity C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor-α levels were determined in 20 patients with type 1 DM and 21 patients with type 2 DM and compared to 34 healthy subjects. The number of cytokine-secreting peripheral blood mononuclear cells (PBMCs), before and after mitogenic stimulation, was also determined in the same groups. Adverse lipid profile, higher levels of inflammatory markers, and higher count of cytokine-secreting cells were observed more prevalently in type 2 diabetics than in controls. After stimulation, the increase in number of cytokine-secreting cells was higher in controls. In conclusion, patients with DM have evidence of low-grade inflammation and abnormal PBMC function that could be related to long-term sequelae, the accelerated atherosclerotic process, and the susceptibility to infections.

Role of microRNAs in gliomagenesis: targeting miRNAs in glioblastoma multiforme therapy

Introduction: Gliomas consist of a very heterogeneous group of malignant tumors, accounting for 50 – 60% of primary brain tumors. Despite all the efforts of cytoreductive surgery in combination with intense chemoradiotherapy, glioblastoma multiforme (GBM, glioma grade IV) still has a dismal prognosis. Current research is focused on molecular targeting to overcome resistance to conventional therapy. MicroRNAs (miRNAs), small non-coding RNAs, represent endogenous agents of RNA interference, dramatically changing expression of target proteins. Their role in brain physiology as well as GBM development has attracted intense research efforts pointing toward therapeutic potential and immediate targeting for sensitization of glioma cells to chemo and/or radiotherapy. Areas covered: This review is focused on the variable role of miRNAs in gliomagenesis and their possible clinical relevance in patients survival and prognosis. It further addresses the potential application of selected miRNAs as therapeutic targets or agents in GMB, including data from clinical studies in other central nervous system tumors. Expert opinion: Although miRNA-targeted therapy is still in its initial stage and clinical trials with glioma/brain tumor patients are under recruitment or currently running, several miRNAs have been selected as promising tumor biomarkers, with increased potential to reduce disease progression in combination to conventional first-line therapy for gliomas.

Evaluation of serum lipids and high-density lipoprotein subfractions (HDL2, HDL3) in postmenopausal patients with breast cancer.

Breast cancer patients are known to be at increased risk for developing other chronic diseases including cardiovascular disease. Studies by different investigators have shown a correlation between increased dietary fat or hypercholesterolemia and the occurrence of breast cancer. Since previous studies on lipoprotein subfractions in this type of cancer have been inconsistent, we evaluated the lipids and lipoprotein subfraction levels in postmenopausal patients with breast cancer in an attempt to identify the risk for the development of cardiovascular disease.The study included 132 patients, 56 of which were suffering from breast cancer, 32 from pancreatic and 44 age-matched controls. Total cholesterol (TC), triglycerides and lipoprotein fractions as well as TC/High density lipoprotein (HDL) and HDL2/HDL3 ratios were estimated by standard laboratory techniques.An increase in triglycerides and a decrease in HDL-cholesterol, especially in the HDL2 subfraction, were observed in patients with breast cancer as compared to the controls (P < 0.05). The maximum changes in TC, and HDL concentrations were observed in patients with advanced disease. Analysis of indexes of atherosclerosis (TC/HDL, and HDL2/HDL3 ratios) demonstrated that breast cancer patients had significantly higher TC/HDL ratio (6.44 ± 1.24) compared with controls (3.43 ± 0.57, p = 0.001), and patients with pancreatic cancer (3.79 ± 0.15, p = 0.027).The results have demonstrated an unfavourable lipid profile in untreated breast cancer patients with high atherosclerosis indexes. This observation is of great importance, considering the potential use of endocrine therapy that could result in further deterioration of lipid indexes. We propose the evaluation and monitoring of lipid profile prior and after the induction of hormonal therapy in breast cancer patients, as a routine in clinical setting. (Mol Cell Biochem 268: 19–24, 2005)