Bioscience hypotheses最新文献

Neurodegenerative trinucleotide (CAG) repeat disorders are caused by the expansion of polyglutamine tracts within the disease proteins. Some of these proteins have an unknown function. How expanded polyglutamine causes target neurons to degenerate is not clear. Recent evidence suggests that intercellular miscommunication may contribute to polyglutamine pathogenesis in CAG repeat disorders. Polyglutamine induced degeneration of the target neuron can be mediated via glia–neuron interactions. Here we hypothesize that during the neurodegenerative process the failure of cell–cell interactions have more severe consequences than alterations in intracellular neuron biology. We further believe that bidirectional communication between neurons and glia is a prerequisite for the normal development and function of either cell type. Understanding intercellular signaling mechanisms such as glial trophic factors and their receptors, cell adhesion or other well-defined signaling molecules provides opportunities for developing potential therapies.

The hippocampus is especially vulnerable to damage caused by metabolic dysregulation. However distinct sub-regions within the hippocampus differ by their relative susceptibility to such damage. Region CA1 pyramidal neurons are most sensitive to metabolic perturbations while region CA3 pyramidal neurons show more resistance, and these unique profiles of susceptibility are but one example that differentiates CA1/CA3 neurons. We present here a hypothesis that inextricably links the unique biochemistries of learning and memory in region CA1, to that of cell survival signaling, and in so doing, suggest an explanation for region CA1 susceptibility to metabolic dysfunction. Further, we propose a signaling mechanism to explain how both pathways can be simultaneously regulated. Critical to this process is the protein phosphatase PHLPP1. Finally we discuss the implications of this hypothesis and the inherent challenges it poses for treatment of neurological disorders resulting in reduced hippocampal function by increased neuron death.

Astrocyte-elevated gene-1 was cloned as a human immunodeficiency virus-1-inducible and tumor necrosis factor-α-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Astrocyte-elevated gene-1 down-regulates the expression of the glutamate transporter excitatory amino acid transporter 2, thus, it is implicated in glutamate-induced excitotoxic damage to neurons as evident in human immunodeficiency virus-associated neurodegeneration. However, accumulating evidences imply that astrocyte-elevated gene-1 might play a pivotal role in the pathogenesis, progression and metastasis of diverse cancers. Astrocyte-elevated gene-1 expression is elevated in diverse cancers, overexpression of astrocyte-elevated gene-1 increases while siRNA inhibition of astrocyte-elevated gene-1 decreases migration and invasion of cancer cells, respectively. Astrocyte-elevated gene-1 exerts its effects by activating the nuclear factor kappa B pathway, the oncogenic Ha-ras could up-regulate astrocyte-elevated gene-1 expression by inducing the binding of c-Myc to the astrocyte-elevated gene-1 promoter and astrocyte-elevated gene-1 inhibited prostate cancer progression through up-regulation of FOXO3a activity. These provocative findings are intensifying interest in astrocyte-elevated gene-1 as a crucial regulator of tumor progression and metastasis and as a potential mediator of neurodegeneration. The evidences to show the expression of astrocyte-elevated gene-1 in breast cancer and its correlation with clinicopathologic features, including the survival of patients with breast cancer confirm the hypotheses that astrocyte-elevated gene-1 is a novel predictor of poor prognosis for cancer patients.

Thirty years ago, Unger and Orci proposed the bihormonal-abnormality hypothesis, which highlighted that both deficient insulin secretion and excessive glucagon levels contributed to the hyperglycemic state in type 2 diabetes. The plasma free fatty acid (FFAs) concentrations are higher in patients with diabetes and prediabetes, suggesting that FFAs may be involved in the pathophysiology of diabetes. In type 2 diabetes, at least in the obese form, insulin does not seem to correct the exaggerated alpha cell responses. This phenomenon suggests that the inability of insulin to suppress the glucagon level could be caused by alpha cell insulin resistance. However, it has remained unclear whether alpha cell insulin resistance is caused by FFAs. Recent studies have demonstrated that long-term exposure to elevated FFA levels leads to hypersecretion of glucagon and accumulation of triglycerides (TG) in clonal alpha-TC1-6 cells, but the mechanism of FFA-induced alpha cell insulin resistance is unclear. We hypothesize that long-term exposure to FFAs reduces AMP-activated protein kinase (AMPK) activity and increases TG accumulation in alpha cells, leading to impaired insulin signaling of alpha cells and hypersecretion of glucagon. This hypothesis provides the first detailed examination of the effects of FFAs on alpha cells with glucagon hypersecretion. It potentially suggests that improving alpha cell insulin resistance as well as reversing lipotoxicity will normalize alpha cell function and may benefit glucose control. Consequently, AMPK and insulin-related pathways in alpha cells could be potential targets for controlling glucagon secretion and glucose counter-regulation.

Scarring of cornea, glaucoma, after-cataract and also proliferative vitreoretinopathy(PVR) related tractional retina detachment, age related macular degeneration and diabetic retinopathy etc., which are the major and seriously impair vision diseases in eyes, with various appearance and different therapy method, but maybe they have the similar pathogenesis—fibrosis, and all the above ocular diseases can be regarded as fibrotic disorders. Thus inhibition of the fibrotic process may provide a potentially novel therapeutic approach to the treatment of these ocular diseases mentioned above. Now numerous studies have proved that BMP-7 significantly reversed renal, hepatic, pulmonary fibrosis, including inhibition of Transforming growth factor-β (TGF-β) production, suppression of epithelial-to-mesenchymal transition (EMT), and repair of severely damaged epithelial cells. So it is reasonable to refer that BMP-7 may have the same preventive effect in these ocular fibrotic disorders. A potential clinical therapy can be developed by using the anti-fibrosis effect of BMP-7.

Color vision is known to play an important role in the discrimination and perception of object characteristics. More recently, there are a few trials found that red light stimulation was related with the development of myopia, though the mechanism is unclear. We assume that red light has two effects on the development of myopia. Individuals who are more sensitive to red light tend to develop myopia under white illumination and are unlikely to be myopic under red light: red light can help to inhibit the progress of myopia. By contrast, individuals who are equal sensitive to red light and green light are susceptible to be myopia under red light and keep stable refraction under white light. Thus whether red light illumination leads to myopia depends on the relative sensitivity of L and M cones. If confirmed, this hypothesis may lead to the formulation of new pathogenesis and new therapeutic approaches to myopia.

Type 2 diabetes is characterized by insulin resistance and β-cell dysfunction. The pathway of acylation-stimulating protein (ASP) and its specific receptor, C5a-like receptor 2 (C5L2), involves in the effective clearance of plasma glucose and free fat acid. Abnormal ASP-C5L2 pathway may induce insulin resistance, as well as cause hyperglycemia and elevated plasma free fat acid. High levels of plasma glucose and free fat acid induce β-cell apoptosis and dysfunction. We proposed that the abnormality of ASP-C5L2 pathway contributes to progression of type 2 diabetes.

Homocysteine is a sulfur-containing amino acid produced during the metabolism of methionine and elevated plasma levels of homocysteine have been linked to an increased risk of atherosclerosis and cardiovascular ischemic events by numerous authors. Several mechanisms by which elevated homocysteine impairs vascular function have been proposed including impairment of endothelial function and at least some of those mechanisms are induced via homocysteine-associated DNA hypomethylation. Oral administration of folic acid and B vitamins, required for remethylation of homocysteine to methionine, decreased plasma total homocysteine levels but clinical trials using folic acid and B vitamins did not confirm that the decreased plasma levels of homocysteine through diet or drugs may be paralleled by a reduction in cardiovascular risk. In our view a plausible explanation for the discordance between the epidemiologic studies and the results of the clinical trials may be related to the homocysteine-associated global DNA hypomethylation which cannot easily be reversed by homocysteine-lowering therapy.