Colorectal cancer is the leading cause of cancer-related mortality in the western world. It is also the third most common cancer diagnosed in both men and women in the United States with a recent estimate for new cases of colorectal cancer in the year 2012 being around 103,170. Various risk factors for colorectal cancer include life-style, diet, age, personal and family history, and racial and ethnic background. While a few cancers are certainly preventable but this does not hold true for colon cancer as it is often detected in its advanced stage and generally not diagnosed until symptoms become apparent. Despite the fact that several options are available for treating this cancer through surgery, chemotherapy, radiation therapy, immunotherapy, and nutritional-supplement therapy, but the success rates are not very encouraging when used alone where secondary complications appear in almost all these therapies. To maximize the therapeutic-effects in patients, combinatorial approaches are essential. In this review we have discussed the therapies previously and currently available to patients diagnosed with colorectal-cancer, focus on some recent developments in basic research that has shaded lights on new therapeutic-concepts utilizing macrophages/dendritic cells, natural killer cells, gene delivery, siRNA-, and microRNA-technology, and specific-targeting of tyrosine kinases that are either mutated or over-expressed in the cancerous cell to treat these cancer. Potential strategies are discussed where these concepts could be applied to the existing therapies under a comprehensive approach to enhance the therapeutic effects.
AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis and a central player in glucose and lipid metabolism, is potentially implicated in the pathogenesis of Alzheimer's disease (AD). AMPK activity decreases in AD brain, indicating decreased mitochondrial biogenesis and function. Emerging evidence demonstrates that AMPK activation is a potential target for improving perturbed brain energy metabolism that is involved in the pathogenesis of AD. The roles of AMPK in the pathogenesis of AD include β-amyloid protein (Aβ) generation and tau phosphorylation. In particular, AMPK may regulate Aβ generation through modulating neuronal cholesterol and sphingomyelin levels and through regulating APP distribution in the lipid rafts. AMPK is activated by phosphorylation of Thr-172 by LKB1 complex in response to increase in the AMP/ATP ratio and by calmodulin-dependent protein kinase kinase-beta in response to elevated Ca(2+) levels, which contributes to regulating Aβ generation. AMPK is a physiological tau kinase and can increase the phosphorylation of tau at Ser-262. AMPK can also directly phosphorylate tau at Thr-231 and Ser-396/404. Furthermore, AMPK activation decreases mTOR signaling activity to facilitate autophagy and promotes lysosomal degradation of Aβ. However, AMPK activation has non-neuroprotective property and may lead to detrimental outcomes, including Aβ generation and tau phosphorylation. Therefore, it is still unclear whether AMPK could serve a potential therapeutic target for AD, and hence, further studies will be needed to clarify the role of AMPK in AD.
Autophagy plays a critical role in multiple pathological lesions of Alzheimer's disease (AD), such as the formation of amyloid plaques from amyloid-β (Aβ) production and accumulation via dysregulating amyloid precursor protein turnover and enhancing the activity of β- and/or γ-secretases, intraneuronal neurofibrillary tangles (NFT) because of tau hyperphosphorylation, and neuronal apoptosis. Dysfunction of the autophagy-lysosome system also contributes to Aβ accumulation and the formation of tau oligomers and insoluble aggregates, because induction of autophagy enhances the clearance of both soluble and aggregated forms of Aβ and tau proteins. The mammalian target of rapamycin (mTOR) pathway plays a central role in controlling protein homeostasis and negatively regulates autophagy. Inhibition of mTOR by rapamycin improves cognitive deficits and rescues Aβ pathology and NFTs by increasing autophagy. Several mTOR signaling components may be potential biomarkers of cognitive impairment in the clinical diagnosis of AD. Thus, mTOR-related agents through the control of autophagy-lysosome protein degradation are emerging as an important therapeutic target for AD.
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