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  • 2-NBDG br Conclusion With the large and increasing number of

    2019-07-08


    Conclusion With the large and increasing number of cancer survivors in the world, such people are seeking a longer and good quality of life. CICI is subtle with loss of learning ability, memory, attention, executive function and processing speed, and these conditions can be long-lasting or short-term, affecting the quality of life of cancer survivors. Patients are eager to recover a normal life not only physically, but also mentally. That this condition is so debilitating necessitates, in our opinion, that urgent investigations into the biochemical mechanisms of CICI,ranging from the effects of anti-cancer drugs, prevention and protection of patients from cognitive deficits, and other side effects. Based on the discussion in this review, it is impossible to attribute CICI to a single mechanism or simple candidate protein, molecule or gene. Multiple pathogenic mechanisms most likely are involved. The cross-talk and interaction among all possible candidates erect a complicated network of processes that lead to eventual neuronal apoptosis and cognitive deficits in many cancer survivors. Altered 2-NBDG structures, decreased neural plasticity and telomere shortening could be contributing 2-NBDG to the observed long term cognitive dysfunction. Brain resident DNA damage, hormone changes and gene polymorphism also likely contribute to CICI. Neural inflammation and oxidative damage to key proteins, lipids, DNA and membranes are considered to be fundamental phenomena underlying CICI mechanisms, potentially leading to other contributors to CICI. Anti-cancer drugs could produce oxidative stress in the periphery, cause protein oxidation, lipid peroxidation, DNA damage and telomere shortening, and increase the permeability of BBB to pro-inflammatory cytokines. We propose that key pro-inflammatory cytokines, including TNF-α, that are elevated in the periphery by ROS associated chemotherapeutic drugs, cross the BBB, to lead to subsequent neuronal death, particularly in the hippocampus and pre-frontal cortex. These changes result in the clinical presentation of CICI. After increased oxidative stress in the periphery leading to events described above, elevation of TNF-α-mediated oxidative stress, inflammatory cytokines and mitochondrial damage are found in brain. Subsequent opening of the mitochondrial permeability transition pore leads to release cyt c to activate apoptotic pathways. Therefore, we hypothesize that CICI results secondary to apoptosis of neurons in brain (Fig. 2.). Continued studies of CICI in preclinical and clinical settings are necessary to narrow the list of potential mechanistic players noted in this review and determine their likely interactions that cause this serious loss of quality of life of cancer survivors. Such studies are ongoing in our laboratories.
    Transparency document
    Introduction Obesity results from a chronic anabolic state characterized either by increased caloric intake or reduced energy expenditure, or yet, the association of both conditions [1,2]. Experimental studies have shown that dietary factors, particularly saturated fats, trigger an inflammatory response in the hypothalamus, which impair the activity of key neurons involved in the regulation of whole body energy status [[3], [4], [5], [6], [7]]. TLR4 signaling and the induction of endoplasmic reticulum stress are the triggers of the molecular machinery that connect the increased consumption of dietary fats with the installation of hypothalamic inflammation [4,6,7]. In addition, studies have provided evidence for the involvement of resident microglia and astrocytes as the cellular components of this inflammatory process [[8], [9], [10], [11], [12]]. The hypothesis that, upon induction of hypothalamic inflammation, peripheral immune cells could be recruited to the hypothalamus in order to expand the inflammatory response is currently under intense investigation. In this context, it was demonstrated that the chemokine CX3CL1 (fractalkine) is rapidly induced in the hypothalamus following the introduction of a high-fat diet (HFD) and acts as a mediator for the recruitment of bone marrow derived cells to expand the hypothalamic microglia involved in the generation of inflammation [8]. Moreover, a recent study has provided a detailed characterization of the nature of peripheral monocyte migration to the hypothalamus [9].