Medical hypotheses
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Given the progressive and constant increase of average life expectancy, an increasing number of elderly patients undergo surgery. After surgery, elderly patients often exhibit a transient reversible state of cerebral cognitive alterations. Among these cognitive dysfunctions, a state of delirium may develop. ⋯ These dysfunctions are much more evident in the occurrence of stress-regulating transmission and in the alteration of intra-cellular signal transduction systems. In addition, more essential cellular processes, that play an important role in neurotransmitter synthesis and release, such as intra-neuronal signal transduction and second messenger system, may be altered. Keeping in mind the functions of the central muscarinic cholinergic system and its multiple interactions with drugs of anesthesia, it seems possible to hypothesize that the inhibition of muscarinic cholinergic receptors could have a pivotal role in the pathogenesis not only of post-operative delirium but also the more complex phenomena of post-operative cognitive dysfunction.
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Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic breast cancer respond to trastuzumab as a single agent, whereas the remaining cases do not demonstrate tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. ⋯ In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody trastuzumab. Moreover, the inhibition of FAS-driven lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing trastuzumab resistance in breast carcinomas.
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Reducing sugars can react non-enzymatically with amino groups of protein to form Amadori products. These early glycation products undergo further complex reaction such as rearrangement, dehydration, and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs in various tissues has been known to progress at an accelerated rate under hyperglycemic conditions in diabetes. ⋯ Since several lines of evidence have shown anti-atherogenic effects of Chlorella on animal models, we hypothesize here that the beneficial aspects of Chlorella on atherosclerosis could be ascribed, at least in part, to its AGE inhibitory property and that Chlorella may have therapeutic potentials in treatment of patients with other AGE-related disorders such as diabetic microangiopathy and Alzheimer's disease. In this paper, we would like to propose the possible ways of testing our hypotheses. Does daily intake of Chlorella reduce the risk of the incidence and progression of diabetic vascular complications including atherosclerosis? Does Chlorella treatment prevent the development of Alzheimer's disease and/or improve the cognitive impairment of patients with this disorder? If the answers are yes, are plasma or tissue levels of AGE in these patients actually suppressed by Chlorella treatment? And, does the extent of the AGE reduction by Chlorella predict the beneficial effects of Chlorella on these disorders? These prospective studies will provide further valuable information whether blockade by Chlorella of the AGE formation could be clinically relevant.
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A non-enzymatic reaction between ketones or aldehydes and the amino groups of proteins contributes to the aging of proteins and to pathological complications of diabetes. Under hyperglycemic conditions in diabetes, this process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions and rearrangements to become irreversible crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). ⋯ Since RAGE is a signal-transducing receptor for AGEs and subsequently evokes inflammatory responses in various types of cells, thus eliciting angiogenesis and thrombogenesis, we hypothesize here that blockade of RAGE expression by nifedipine may have therapeutic potentials in treatment of patients with various AGE-related disorders. In this paper, we would like to propose the possible ways of testing our hypothesis. Does nifedipine treatment reduce the development and progression of diabetic vascular complications? If the answer is yes, is this beneficial effect of nifedipine superior than that of other DHPs with equihypotensive properties? Does nifedipine treatment decrease the incidence of melanoma and/or prolong the survival of patients with this devastating disorder? These prospective studies will provide further valuable information whether blockade by nifedipine of the AGE-RAGE signaling could be clinically relevant.