Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have an increased prevalence of insulin resistance (IR) and related disorders. Elevated serum levels of cellular adhesion molecules (CAMs) reflect low-grade chronic inflammation and have been associated with several insulin-resistant states. The objective of this study is to investigate whether soluble inflammatory markers [soluble intercellular adhesion molecule-1 (sICAM-1), soluble endothelial leukocyte adhesion molecule-1 (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1) and C-reactive protein (CRP)] are altered in PCOS and to further elucidate the effect of metformin treatment on their levels. METHODS: Two young populations were studied [62 women with PCOS and 45 normal women of similar age, BMI and waist-to-hip ratio (WHR)]. Plasma levels of sICAM-1, sVCAM-1, sE-selectin and high-sensitivity CRP (hsCRP) were measured in both groups. Additionally, the effect of metformin on these molecules was investigated in 22 women with PCOS who accepted to metformin protocol (1700 mg daily for a 6-month period). RESULTS: In the total population studied, plasma levels of hsCRP (mg/l), sICAM-1 (ng/ml) and sE-selectin (ng/ml) were higher in the PCOS group compared with those in controls (hsCRP 1.31 ± 0.22 versus 0.92 ± 0.27, P = 0.014, sICAM-1 301.21 ± 24.80 versus 209.86 ± 17.05, P = 0.025, sE-selectin 57.37 ± 4.08 versus 45.67 ± 4.62, P = 0.045, respectively). sVCAM-1 (ng/ml) did not differ statistically among the two groups (P = 0.896). A significant reduction in hsCRP and sVCAM-1 was achieved after 6 months of metformin administration: PCOS pretreatment hsCRP 1.92 ± 0.60 versus PCOS post-treatment hsCRP 0.52 ± 0.26, P = 0.005; PCOS pretreatment sVCAM-1 668.09 ± 98.38 versus PCOS post-treatment sVCAM-1 365.82 ± 99.77, P = 0.039. CONCLUSION: These findings imply the presence of chronic inflammation in women with PCOS. Metformin decreases the levels of plasma inflammatory indices. Further investigation is required to determine whether these findings may prove to be of clinical significance for PCOS patients.

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.