Clinical and experimental biomedical studies have shown Type 2 diabetes mellitus (T2DM) to be a risk factor for the development of Alzheimer's disease (AD). This study demonstrates the effect of metformin, a therapeutic biguanide administered for T2DM therapy, on β-amyloid precursor protein (APP) metabolism in in vitro, ex vivo and in vivo models. Furthermore, the protective role of insulin against metformin is also demonstrated. In LAN5 neuroblastoma cells, metformin increases APP and presenilin levels, proteins involved in AD. Overexpression of APP and presenilin 1 (Pres 1) increases APP cleavage and intracellular accumulation of β-amyloid peptide (Aβ), which, in turn, promotes aggregation of Aβ. In the experimental conditions utilized the drug causes oxidative stress, mitochondrial damage, decrease of Hexokinase-II levels and cytochrome C release, all of which lead to cell death. Several changes in oxidative stress-related genes following metformin treatment were detected by PCR arrays specific for the oxidative stress pathway. These effects of metformin were found to be antagonized by the addition of insulin, which reduced Aβ levels, oxidative stress, mitochondrial dysfunction and cell death. Similarly, antioxidant molecules, such as ferulic acid and curcumin, are able to revert metformin's effect. Comparable results were obtained using peripheral blood mononuclear cells. Finally, the involvement of NF-κB transcription factor in regulating APP and Pres 1 expression was investigated. Upon metformin treatment, NF-κB is activated and translocates from the cytoplasm to the nucleus, where it induces increased APP and Pres 1 transcription. The use of Bay11-7085 inhibitor suppressed the effect of metformin on APP and Pres 1 expression.
Traditional Mediterranean diet (MedDiet) is a common dietary pattern characterizing a lifestyle and culture proven to contribute to better health and quality of life in Mediterranean countries. By analyzing the diet of centenarians from the Sicani Mountains and eating habits of inhabitants of Palermo, it is reported that a close adherence to MedDiet is observed in the countryside, whereas in big towns this adherence is not so close. This has an effect on the rates of mortality at old age (and reciprocally longevity) that are lower in the countryside than in big towns. Concerning the health effects of the diet, the low content of animal protein and the low glycaemic index of the Sicilian MedDiet might directly modulate the insulin/IGF-1 and the mTOR pathways, known to be involved in ageing and longevity. In particular, the reduction of animal protein intake may significantly reduce serum IGF-1 concentrations and inhibit mTOR activity with a down-regulation of the signal that leads to the activation of FOXO3A and, consequently, to the transcription of homeostatic genes that favour longevity. The down-regulation of both IGF-1 and mTORC1 also induces an anti-inflammatory effect. In addition to the effects on sensing pathways, many single components of MedDiet are known to have positive effects on health, reducing inflammation, optimizing cholesterol and other important risk factors of age-related diseases. However, a key role is played by polyphenols represented in high amount in the Sicilian MedDiet (in particular in extra virgin olive oil) that can work as hormetins that provide an environmental chemical signature regulating stress resistance pathways such as nuclear factor erythroid 2-related factor 2.
The Mediterranean diet (Mediet) is an eating pattern characterizing a lifestyle and culture that has been reported to contribute to better health and quality of life. The Mediet reflects food patterns typical of Mediterranean regions, where olive oil plays an essential role in the food pyramid. Olive oil is located in the middle and it is considered the principal source of dietary fat because of its high nutritional quality (particularly extra virgin olive oil). Several studies have shown the effect of the Mediet on healthy status by lowering the rates of coronary heart disease, certain cancers, and some other age-related chronic diseases. Although the scientific literature regarding diet and life span is complex and with different opinions, there are studies that demonstrate the beneficial effects of the Mediet on longevity. Therefore, the Mediet may be considered as including several nutraceuticals that favourably influence health. In the present review we discuss two Mediterranean populations from the island of Ikaria (Greece) and the Sicani Mounts (Sicily, Italy) whose longevity is attributed to a close adherence to the Mediet.
Abstract-Neurodegenerative diseases such as Alzheimer, Parkinson, amyotrophic lateral sclerosis, and Huntington are incurable and debilitating conditions that result in progressive death of the neurons. The definite diagnosis of a neurodegenerative disorder is disadvantaged by the difficulty in obtaining biopsies and thereby to validate the clinical diagnosis with pathological results. Biomarkers are valuable indicators for detecting different phases of a disease such as prevention, early onset, treatment, progression, and monitoring the effect of pharmacological responses to a therapeutic intervention. Inflammation occurs in neurodegenerative diseases, and identification and validation of molecules involved in this process could be a strategy for finding new biomarkers. The ideal inflammatory biomarker needs to be easily measurable, must be reproducible, not subject to wide variation in the population, and unaffected by external factors. Our review summarizes the most important inflammation biomarkers currently available, whose specificity could be utilized for identifying and monitoring distinctive phases of different neurodegenerative diseases.
Vgamma9/Vdelta2 T cells can contribute to protective immune response against Mycobacterium tuberculosis, although the extent to which and mechanisms by which they could actually protect against human tuberculosis remain unclear. We have previously reported that Vgamma9/Vdelta2 T cells from tuberculin purified protein derivative (PPD)-positive children, either healthy or affected by different clinical forms of tuberculosis, strongly proliferate to different phosphoantigens in vitro, whereas Vgamma9/Vdelta2 T cells from PPD-negative healthy subjects proliferate very poorly. We report here that Vgamma9/Vdelta2 T cells from tuberculous children have an increased proliferative activity, but decreased interferon (IFN)-gamma production and granulysin expression. After successful chemotherapy, the Vgamma9/Vdelta2 T cell proliferative response strongly decreased, whereas IFN-gamma and granulysin production consistently increased. Disease-associated changes in Vgamma9/Vdelta2 T cell effector functions in patients with tuberculosis are consistent with the possibility that these T cells may play a protective role in immune response against M. tuberculosis infection.
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