There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory 'braking signals', including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)--6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.

http://dro.deakin.edu.au/eserv/DU:30052827/berk-aspirinareview-2013.pdf

Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness

Aims. Activins A and B, and their binding protein, follistatin, regulate glucose metabolism and inflammation. Consequently, their role in type 2 diabetes (T2D) was examined. Methods. Blood was taken from fasted participants (34 males; 58 females; 50–75 years) with diabetes or during an oral glucose tolerance test (OGTT). Clinical parameters were assessed, and blood assayed for activins, follistatin, and C-reactive protein. Results. Serum levels of activin A (93.3 ± 27.0 pg/mL, mean ± SD), B (81.8 ± 30.8 pg/mL), or follistatin (6.52 ± 3.15 ng/mL) were not different () between subjects with normal OGTT (), impaired glucose tolerance and/or fasting glucose (), or T2D (). However, activin A and/or activin B were positively correlated with parameters of insulin resistance and T2D, including fasting glucose (), fasting insulin (), glycated hemoglobin (), and homeostasis model assessment of insulin resistance (HOMA-IR; ). Follistatin was positively correlated with HOMA-IR alone (). Conclusions. These data indicate that serum measurements of activin A, B, or follistatin cannot discriminate risk for T2D in individual patients, but the activins display a positive relationship with clinical parameters of the disease.

/pdf/correlation-between-blood-activin-levels-and-clinical-4aa2etyekn.pdf

Correlation between blood activin levels and clinical parameters of type 2 diabetes.

https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(13)00004-X.pdf

Shared dysregulated pathways lead to Parkinson's disease and diabetes

Kaempferol alleviates insulin resistance via hepatic IKK/NF-κB signal in type 2 diabetic rats.

VOLUME 33 NUMBER 4 APRIL 2015 NATURE BIOTECHNOLOGY main source of improvement, showing an average increase of 122% across all methods and algorithms (Fig. 1e,f). These results substantially reinforce the conclusions from our original paper2 and show that we can achieve a large improvement on a wide range of methods using our approach. A last claim of Bastiaens et al.1 is that our approximation based on correlation decay disagrees with biological reality. We concur that in certain cases a local perturbation may increase as it propagates along a network path, rather than decay. However, our application of the silencing method focused on statistical similarity measures, such as correlations, which always decrease along paths, and by definition cannot exceed unity. Moreover, even regarding perturbations, we argue that such amplification is not typical in biological networks. Indeed, if small perturbations were repeatedly amplified during their propagation, the implications on the stability and robustness of living cells would be dramatic; every local disturbance would lead to a macroscopic response and the modular nature of the cell’s functionality would be constantly distracted by the cross-talk between distant genes. Thus, it is not surprising that both theoretical and empirical analyses of cellular dynamics indicate, time and again, that the impact of perturbations is, in most cases, strictly local13. Studies have shown that perturbations typically feature an exponential decay as they penetrate the network14–18. Others have quantified the impact of perturbations by measuring cascade sizes, that is, the number of genes that exhibit a significant response following a perturbation. These reports find that most cascades are tiny and only rarely does a perturbation affect a substantial number of genes19–21. This paucity of large cascades further supports the notion that most perturbations do not penetrate deeply into the network. Finally, the premise of network inference relies on the notion that the magnitude of the terms in the prediction matrix Gij correlates with the likelihood of direct linkage6–9. If, as Bastiaens et al.1 suggest, there are cases where the Gij terms systematically increase with the distance between i and j, then in these cases Gij is a poor candidate for network inference in general, with or without silencing, and thus we would not consider it a suitable input for our method. To summarize, although we disagree with much of the criticism made by Bastiaens et al., we wish to thank them for raising several important issues and igniting a discussion that has ultimately led to the development of the improved silencing algorithm presented here.

Opportunities for drug repositioning from phenome-wide association studies

Aspirin is a kind of anti-inflammatory drug and may be used to reverse hyperglycemia, hyperinsulinemia, and dyslipidemia by improving insulin resistance. We hypothesized that aspirin improves insulin resistance in type 2 diabetes by inhibiting hepatic nuclear factor kappa-β (NF-κB) activation and serum tumor necrosis factor-α (TNF-α). Adult male Wistar rats were randomly divided into four groups: control, untreated diabetic, diabetic treated with metformin (100 mg/kg/day), and diabetic treated with aspirin (120 mg/kg/day). Diabetes was induced by high-fat feeding and a low dose of streptozotocin (30 mg/kg). After treatment, plasma glucose, insulin, lipids, free fatty acids (FFAs) concentrations and serum TNF-α were determined. The expression of NF-κB in hepatocytes was analyzed by immunohistochemistry and western blot. The results showed administration of aspirin caused no significant lowering in fasting glucose level but significant reduction of hepatic NF-κB expression and serum TNF-α level with improved insulin resistance compared to the diabetic group. The relevant analysis showed positive correlation between the expression of homeostasis model assessment-insulin resistance (HOMA-IR) and NF-κB (r = 0.799, P < 0.01); HOMA-IR and serum TNF-α (r = 0.790, P < 0.01). It is concluded that aspirin improves insulin resistance by inhibiting hepatic NF-κB activation and TNF-α level in streptozotocin-induced type 2 diabetic rats.

/pdf/effect-of-aspirin-on-the-expression-of-hepatocyte-nf-kb-and-1f2ynujy4o.pdf

Effect of Aspirin on the Expression of Hepatocyte NF-κB and Serum TNF-α in Streptozotocin-Induced Type 2 Diabetic Rats

Serious complications as a result of type 2 diabetes mellitus (T2DM) are becoming a major health concern. In the present study, it was hypothesized that telomerase activity is upregulated in vascular smooth muscle cells (VSMCs) during proliferation in T2DM and that the application of telomerase inhibitors impedes the proliferation of VSMCs in vitro. Male Wistar rats were randomly allocated into the normal control (NC) or diabetic (DM) group. Diabetes was induced by high‑fat feeding and a low dose of streptozotocin (STZ; 30 mg/kg). Primary VSMC cultures were exposed to normal (5.5 mM) or high (25 mM) glucose and insulin (100 nM) in the presence and absence of various concentrations of antisense oligoribonucleotides (ASODNs) for varying lengths of time. Telomerase activity and the proliferation of VSMCs were measured. Results showed that there was a significant increase in the levels of fasting glucose, insulin, triglycerides (TG) and free fatty acids (FFAs) in the diabetic group. Telomerase activity and the proliferation of VSMCs were significantly higher in the diabetic group in vivo and in the high glucose and insulin (HGI)-treated group in vitro (P<0.01). ASODNs significantly inhibited the proliferation of VSMCs in a concentration- and time‑dependent manner (P<0.01). In conclusion, hyperglycemia and hyperinsulinemia stimulate telomerase activity and the proliferation of VSMCs, while the inhibition of telomerase activity reduces the proliferation of VSMCs, indicating that telomerase may be involved in the pathological process of diabetic vascular disease.

/pdf/the-effect-of-telomerase-activity-on-vascular-smooth-muscle-2cwzwl7g0f.pdf

Junling Yi

Papers

Effect of Aspirin on the Expression of Hepatocyte NF-κB and Serum TNF-α in Streptozotocin-Induced Type 2 Diabetic Rats

The effect of telomerase activity on vascular smooth muscle cell proliferation in type 2 diabetes in vivo and in vitro