NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes

Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.     

IL-1RN gene polymorphism is associated with peri-implantitis

Objectives: Interleukin (IL)‐1α, IL‐1β and their natural specific inhibitor IL‐1 receptor antagonist (IL‐1ra) play a key role in the regulation of the inflammatory response in periodontal tissues. Polymorphisms in the IL‐1 gene cluster have been associated with severe adult periodontitis. We aimed to investigate the IL‐1 gene cluster polymorphisms in patients with peri‐implantitis. Material and methods: The study included 120 North Caucasian individuals. A total of 71 patients (mean age 68 years, 76% smokers) demonstrating peri‐implantitis at one or more implants as evidenced by bleeding and/or pus on probing and bone loss amounting to >3 threads on Brånemark implants and 49 controls (mean age 66 years, 45% smokers) with clinical healthy mucosa and no bone loss around the implants were recruited for the study. The titanium implants, ad modum Brånemark, had been in function for at least 2 years. Mouthwash samples were collected and used for genotyping of the bi‐allelic polymorphisms IL‐1A^?889, IL‐1B⁺³⁹⁵³, IL‐1B^?511 and a variable number of tandem repeat IL‐1RN gene polymorphisms using PCR technique. Results: Significant differences were found in the carriage rate of allele 2 in the IL‐1RN gene between peri‐implantitis patients and controls (56.5% vs. 33.3%, respectively; odds ratios (OR) 2.6; 95% confidence interval (CI) 1.2–5.6; P=0.015). Logistic regression analysis taking smoking, gender and age into account confirmed the association between the IL‐1RN allele 2 carriers and peri‐implantitis (OR 3; 95% CI 1.2–7.6; P=0.02). Conclusions: Our results provide evidence that IL‐1RN gene polymorphism is associated with peri‐implantitis and may represent a risk factor for this disease.     

Transverse craniofacial features and their genetic predisposition in families with nonsyndromic unilateral cleft lip and palate.

OBJECTIVE: The purpose of this study was to evaluate the transverse craniofacial form in families with nonsyndromic cleft lip and palate (NSCLP). It was hypothesized that affected as well as noncleft NSCLP family members are characterized by a common array of craniofacial features that differ from the general population. DESIGN: This was a prospective cross-sectional investigation that included affected children with NSCLP and their noncleft parents and siblings. PATIENTS, PARTICIPANTS: A total of 114 subjects (14 affected girls, 17 affected girls, 15 unaffected male siblings, 10 unaffected female siblings, 29 unaffected biological mothers, and 29 unaffected biological fathers) were included. Subject records comprised of posteroanterior cephalometric radiographs obtained from all 114 subjects. MAIN OUTCOME MEASURES: The width of midfacial structures, including the orbit and nose, was increased in NSCLP families, compared with published norms. Interestingly, the face was disproportionally wider in relation to total facial height. The transverse craniofacial form of children with or without clefts significantly correlated with that of their parents. Mothers displayed strong correlation with their affected and unaffected sons, whereas fathers correlated to their daughters, suggesting a possible sex-linked developmental influence. CONCLUSION: Better understanding of the genetic inheritance of craniofacial features associated with cleft lip and palate may ultimately contribute to the development of cleft risk assessment methods.