Bioscience hypotheses最新文献

We have previously shown that AIDS-associated lymphomas and lymphoma cell lines contain mitochondrial genome concatemers not present in normal T-lymphocytes. Since cellular homeostasis and energy production rely heavily on mitochondrial DNA (mtDNA) stability, mutations in the mtDNA have long been linked to the development of various types of cancers. In most of the cases, however, neoplastically transformed cells harbor non-mutated mtDNA. Herein, we propose an alternative mechanism that shows how the formation of mitochondrial genome concatemers may promote oncogenic transformation of normal lymphoid progenitor cells when no mtDNA mutations or chromosomal aberrations are present. We detected high reactive oxygen species (ROS) levels in the lymphoma samples tested despite no identification of putative mutations in the coding mtDNA. We propose that the formation of atypical mtDNA configurations (i.e. dimers and concatemers) interferes with normal mitochondrial function. Unstable mitochondria lead to abnormal assembly and dysfunction of the oxidative phosphorylation (OXPHOS) complexes, eventually leading to oxidative stress from elevated production of intracellular ROS. ROS have been reported to activate transcription factors associated with cellular proliferation and apoptosis inhibition. Therefore, we hypothesize that formation of mitochondrial genome concatemers can augment endogenous ROS levels capable of promoting oncogenic transformation of normal lymphoid progenitor cells.

Infantile hemangiomas are common vascular tumours which exhibit a rapid proliferating phase followed by spontaneously involuting for a long time. The formation and development mechanisms are not clear yet. Recent studies show that hemangioma-derived stem cells have multipotential differentiation abilities, including endothelial and mesenchymal differentiation. In addition, mesenchymal stem cell has the capability of inducing endothelial cell apoptosis, differentiating into adipocytes and triggering the involution of hemangiomas. Thus we hypothesize that mesenchymal stem cell may be the source of spontaneously regression of hemangiomas. Further investigations may be needed to develop potential therapeutic implications of mesenchymal stem cell in treating hemangiomas.

This article compares two hypotheses regarding the mechanisms responsible for aging in humans and other mammals. In the passive mechanism, aging is the result of inadequacies in maintenance and repair functions that act to prevent or repair damage from fundamental deteriorative processes. In the active mechanism, a life span management system purposely limits life span by deactivating maintenance and repair processes beyond a species-specific age.

As described here, the active mechanism provides a much better fit to observational evidence while the passive mechanism provides a much better fit to traditional evolutionary mechanics theory. However, there are many other observations that conflict with traditional theory and consequently a number of alternative evolutionary mechanics theories have been developed since 1962. Several of these alternatives support active life span management and aging theories providing a rationale for active life span management have been developed based on each of those alternatives.

This issue is very important to our ability to treat age-related diseases and conditions. If indeed the passive mechanism is correct, then efforts should continue to be exerted to find treatments for each different manifestation of aging, independently of the others. If the active concept is valid it is clear that there are, in addition, substantial opportunities for finding agents that generally delay aging and simultaneously ameliorate multiple manifestations of aging.

In the past, the evolutionary issues have been used as essentially the entire justification for summarily rejecting active theories. Given the public health considerations and the increasing number of issues surrounding evolutionary mechanics theory, this is no longer a reasonable or responsible path.

Several processes including oxidative stress and neuroinflammation are implicated in the pathogenesis of schizophrenia. The dysregulated activation of a transcription factor, nuclear factor-E2-related factor-2 (Nrf2) which regulates the expression and coordinated induction of a battery of cytoprotective, antioxidant, and anti-inflammatory genes in response to oxidative stress and inflammation, might play a critical role in the pathogenesis of schizophrenia.

Preeclampsia is a severe pregnancy complication that originates in the placenta and is characterized by shallow trophoblast invasion into the spiral arteries. Immunological imbalances associated with abnormal uterine spiral arteries remodeling during pregnancy have been identified to contribute to the onset and progression of preeclampsia. Interferon (IFN)-γ has a bilateral role in mediating uterine spiral artery remodeling and may lead to preeclampsia under abnormal circumstances. Until recently, the mechanism that regulates the balance between IFN-γ-mediated artery remodeling and IFN-γ-induced Th1 cell activation is ambiguous; but recent studies suggest an important part for galectin-9 in the immune regulation. Therefore, we hypothesize that the galectin-9 expression by uterine endometrial epithelial cells plays a key role in the regulation of the dual function of IFN-γ. Engaging galectin-9 with its receptor on activated Th1 cells causes an inhibitory signal, resulting in apoptosis of Th1 cells and negatively regulates Th1 type immunity. We further hypothesize that failure of galectin-9 expression by endometrial epithelial cells may dampen the endovascular remodeling process and thus result in preeclampsia. This hypothesis proposes a new mechanism in the immunological balance at the uteroplacental interface. Also this hypothesis will help to find out new cause for preeclamspsia and provide new strategy for disease treatment.

Retinopathy and nephropathy – current view

The Kumamoto and UKPDS studies of type-2 diabetes demonstrated that high glucose mean faster worsening for both diabetic retinopathy and nephropathy. However, why so many type-2 diabetics develop nephropathy but no retinopathy? Why so many type-2 diabetics have severe retinopathy and little or no nephropathy? The answer may be genetic susceptibility.

Hypothesis: the “flip-flop” effect of aldose reductase gene

When the CC genotype (high aldose reductase expression) of the (−106) polymorphism of the aldose reductase gene was linked to enhanced retinal susceptibility to hyperglycemia, it was expected that it would also accelerate nephropathy. As the case was the opposite, we now hypothesize that in the kidney, higher aldose reductase activity reduces susceptibility to hyperglycaemia by means of shifting glucose away from the synthesis of Transforming Growth Factor-Beta (TGF-β), a stimulator of mesangial expansion – the landmark of diabetic nephropathy. As the CT & TT genotypes (lower expression of aldose reductase) have effects that are the opposite of those of CC genotype, i.e. retinopathy-protection & nephropathy proneness, we have coined the term “flip-flop”, an acronym taken from electronics, meaning a system that is bi-stable.

If the “flip-flop” was confirmed – what then?

Those diabetics who are retinopathy-protected & nephropathy-prone (CT & TT), should not be given aldose reductase inhibitors (which could worsen nephropathy) but the new breed of TGF-β inhibitors. This might be a first step towards “genetic individualization of diabetes therapy”.

Valproic acid (VPA) is well established as a first-line and widely used antiepileptic agent. It is well tolerated in most patients and the main issues of concern of VPA are hematological toxicity, tertogenicity and idiosyncratic hepatotoxicity. Recently, researches have showed that VPA monotherapy could cause immunological function disorder, characterized that VPA monotherapy induced imbalance of oxidative/antioxidative status. Measures of oxidative stress were elevated while the antioxidative agent like Reduced glutathione (GSH) was degraded. Besides, antioxidants vitamin C and vitamin E can protect hepatocyte from VPA toxicity. In addition, in a eukaryon, social amoeba dictyostelium discoideum, VPA inhibit the chemotactic cell movement and endocytosis/exocytosis by attenuating its phospholipid signaling. Neutrophil is an important composition of innate immunity, it works mainly through phagocytosis and oxidization. The phagocytosis and oxidization activity are the basic and primitive function of neutrophils which are mimic to that of a eukaryon. Herein, we hypothesize that VPA, may have unexpected effects on the endocytic and oxidative function of neutrophil. The potential unfavorable subsequent events in the individuals with VPA treatment would be in the increased episodes of infection. Any agent to boost neutrophlic endocytic and antioxidative function may be helpful to the epileptic patients.

Paclitaxel, a representative of taxanes, exhibits cytotoxic effects against a broad range of tumors. Strikingly, an emerging body of data suggests that paclitaxel also exerts effects on immune system by stimulating anti-tumor and anti-autoimmunity effects, supporting the idea that paclitaxel suppresses tumor through several mechanisms and not solely through inhibiting cell division. Based on the accumulating data, we hypothesized that paclitaxel may inhibit autoimmune diseases by sparing or actively increasing the number of CD4(+) CD25(+) Treg cells. The hypothesis, if proved to be correct, will significantly improve our understanding of the tumor immunity, autoimmunity and its related pathological effects. It will influence our choice on immunosuppressive drugs for cancer patients with autoimmune diseases. It will also impact the immunotherapy for tumors.

We hypothesize that aging of mesenchymal stem cells breaking the balance between arterial mineral deposition and resorption results in vascular calcification. It is believed that it is a new idea about revealing pathogenesis of artery calcification and defining a range of novel and exciting therapeutic approaches.