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.
Virus-like particles are commonly found in highly infectious scrapie brain fractions and cell lines, suggesting a viral source of prion diseases. However, new evidence indicates that these particles are likely the result of mucopolysaccharidosis; a lysosomal storage disease where similar particles are observed, along with neuronal degeneration. Heparan sulfate proteoglycans (HSPGs) have long been implicated in prion diseases including demonstrated impairment of glycosaminoglycan metabolism. In this work, unusual levels of glypican-1 and heparan sulfate in cell cultures treated with prion protein antibodies are disclosed, further evidence for a lysosomal storage disorder and suggestive of a HSPG origin for prion diseases.
Chronic liver disease (CLD) constitutes a major cause of morbidity and mortality worldwide. Follow-up studies have documented that the majority of patients with CLD never reach the cirrhotic stage, while others display a higher progression rate leading to liver failure at relatively short intervals. This phenomenon has never been adequately explained. Recent evidence suggests that the renin–angiotensin system (RAS) is a major coordinator of chronic liver inflammation and subsequent fibrosis development, a process often termed hepatic remodeling. Combining these data with the “natural neutralizing antibodies theory” led us to the assumption that there could be an intrinsic anti-remodeling mechanism consisted of natural antibodies against components of the RAS. Varying degrees of activation of this defense mechanism could account for the variability in disease progression rate among patients with CLD. Identifying the main components of this mechanism allowed us to develop a ratio, designated remodeling index, as a measure of an individual's predilection towards cirrhosis. We believe that this index could be used as a safe, non-invasive and cost effective tool for assessing progression rate in normotensive patients with early CLD, thus alleviating the need for repeated liver biopsies.
The kidney is a major source of systemic erythropoietin, despite itself showing little angiogenesis. Based on paper by Schumacher VA et-al. [J Am Soc Nephrol 2007;18:719–29] that renal synthesis of an inhibitory VEGF variant (VEGF165b) blocks local angiogenesis, we hypothesise that the chronic hypoxia in the renal medulla, due to limited perfusion through vasa recta stimulates continuous renal erythropoietin secretion.
Human endogenous retroviruses (HERVs) represent the footprints of previous retroviral infections. They are integrated within the human germ line and constitute approximately 7% of our genome. They have the potential to harm, given their capacity to alter the cellular metabolism, and could be involved in various pathological processes such as systemic lupus erythematosus or multiple sclerosis. In this respect it has been found that the stimulation of HERVs genome expression was observed after a steroid hormone treatment, stating the first evidence that an enhanced expression of the HERVs genome by hormones may be involved in the etiology of breast cancer. There is now increasing evidence that HERVs may in fact be involved in the etiology of schizophrenia, a disorder characterized by heterogeneous presence of positive, negative and cognitive symptoms that affect all aspects of mental activity, with a first peak incidence for males and females in the decade 15–24 and a second peak at age 55–64 for females, both periods characterized by two moments of significant hormonal changes. In connection with genetic aspects, several studies suggest a linkage between chromosome 22 (22q) and schizophrenia, being different genes of this chromosomal region reported as candidate genes for association with the disorder. Likewise, in a closely region of these genes, on 22q13, is located a gene named APOBEC3G, a potent intrinsic inhibitor of retroviral replication that also includes some HERVs. We propose that hormonal changes that coincide with two peak incidences in schizophrenia produce an enhancement in the expression of some HERV families implicated in the etiopathology of the disorder. The expression of HERVs is followed by a defective action of APOBEC3G that avoids carry out its function, that is, the inhibition of retroviral replication. This altered process might play a critical role in the etiopathogenesis of schizophrenia.
Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory manifestation that occurs subsequent to initiation of highly active antiretroviral therapy in terminal (HAART) HIV infection, mainly due to the restoration of robust immune responses directed against latent microbial antigens. IRIS is believed to be multifactorial and less studied. Herein, we postulate that hypothalamo–pituitary–adrenal (HPA) dysregulation, a well-documented manifestation in HIV/AIDS, could possibly disturb the balance between pro-inflammatory and anti-inflammatory cytokines leading to clinical IRIS. Drugs, opportunistic infections, stress and numerous intrinsic and extrinsic factors have been described to be the possible causes of IRIS in HIV illness.
Drugs that block P-glycoprotein-modulated efflux of antiepileptic drugs in the brain, lead to increase their intracellular concentration. Addition of R-verapamil as one enantiomer of verapamil to antiepileptic drugs may facilitate the penetration of drugs to the brain and prevents their efflux from CNS without serious cardiovascular side effects.
The basal hypothesis discussed here is the idea that brain architecture could be plastic on a very basal, genetic level due to sexual recombination and reassortment of alleles of genes related to brain development, e.g., neuronal cell adhesion molecules (NCAMs) and others.
Traditional methods such as chemotherapy and radiation therapy offer only limited success in treating cancer. Part of the reason is related to our misunderstanding of what cancer is: it is not the cause but the consequence of a weakened living system. Localized cellular stress, caused by toxins, mutagens or radiation, coupled with a weakened systemic response or inability to support or defend the cells that are under attack, cause these cells to revert to an ancient, unicellular mode of survival, therefore cutting links with the overarching organism and defend themselves from the threat as if they were individual entities. We hypothesize that strengthening the organism, specifically the immune system, is a more promising approach toward a cure for cancer than attempting to exterminate cancer cells. The hypothesis can be tested by experiments that are designed to strengthen the immune system by both traditional means (e.g., ingestion of natural substances known to increase the activity of the immune system, such as fruits, vegetables, and nuts), diminish immune system inhibitors released by cancer cells (e.g., TGF-β), and by the injection of heat-killed or genetically altered pathogenic bacteria to trigger a massive response (fever response) of the immune system into the affected area and compare those results to traditionally used methods.
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.
A characteristic feature of the life history of humans and some other species of social mammals is a long post-reproductive period. This condition is of a physiological nature in females (menopause), whereas in males it is largely of a behavioral nature. We discuss the hypothesis that old, post-reproductive individuals in these species may act as repositories of acquired knowledge, thereby providing an evolutionary benefit for their group. According to this view, the group's investment into the care for their older members is overcompensated by the benefits gained from the experience of these individuals (“senators”). This phenomenon is suggested to be largely independent from the degree of genetic relatedness within the group. We put forward a list of several necessary preconditions for the senator phenomenon to evolve. The presence or absence of these preconditions can be studied empirically.
Calcification of the pulmonary artery has been found in a large number of racing horses. The majority of calcified lesions are found immediately distal to the primary arterial bifurcation. Increased arterial wall stress levels have been previously demonstrated at these locations, with the wall stress levels increasing under intra-luminal pressures associated with exercise. We hypothesize therefore that the formation of calcified lesions is mediated by transient and repeated increases in pulmonary artery intra-luminal pressure. The presence of calcified lesions would likely further exacerbate the levels of wall stress, leading to growth of the lesions. A level of wall stress may exist above which calcified lesions form, and a second level may exist above which the calcified lesions grow at an increased rate. A computer model of pulmonary artery wall stress with calcified lesions was created, and wall stress levels were found to be greatest at the periphery of the calcified lesions. Osteo/chondrocyte-like cells have also been found at the periphery of the calcified lesions and could be responsible for collagen deposition and lesion growth, mediated by local wall stress levels. These increased levels of wall stress could place racehorses at a greater risk of acute pulmonary arterial rupture at the site of the calcified lesions, due to the high levels of intra-luminal pressure within the pulmonary artery during exercise. The hypothesis may also have implications in the etiology of human vascular diseases.
A significant subset of head and neck carcinomas are infected with human papilloma virus; prophylactic vaccines can prevent such HPV+ cancers but are ineffective for invasive HPV+ cancers. We intend to make them therapeutic by means of systemic T regulatory cell depletion.
The autosomal dominant spinocerebellar ataxias (SCA) are a heterogeneous group of disorders that differ in the extent of neuropathological involvement of cerebellum, brainstem, and basal ganglia. Neuropsychiatric symptoms, such as depressive and memory symptoms, are common presenting symptoms in SCA patients. A mechanistic connection between different regions of the brain involved in major depression comes from the down regulation of glial function. We hypothesize that the impaired S100B signaling pathway is a common link between SCA and major depression, and that the onset of neuropsychiatric symptoms in patients with SCA are due to glial dysfunction in specific areas of the brain. Understanding of S100B dependent pathway will help develop new therapeutic strategies for treating cerebellar disorders and depression.
The medial longitudinal fascicle and the optic nerve are often affected in multiple sclerosis which causes internuclear ophthalmoplegia and optic neuritis. During prenatal development axons of both neuronal pathways are subjected to midline crossing in the central nervous system. Transmembrane receptor proteins like robos and dcc that interact with the chemorepellents and attractants slit and netrin are expressed in developing axons that cross the midline and are likely to play a role postnatally. It is hypothesized and discussed that these receptor proteins represent a specific antigen targeted by autoimmune processes in multiple sclerosis.
Autoimmune disorders are connected with the actions of sex hormones. Clinical observations have shown that especially estrogens are involved in these phenomena. In some cases the administration of estrogens can increase the pathological symptoms of a disorder, while in others they can cause disease remission. In multiple autoimmune diseases, type I interferons, a family of cytokines acting through the common receptor IFNAR1/IFNAR2, seem to have action convergent with that of estrogens. We hypothesize that this coincidence is not accidental and type I interferons can regulate the level of estrogen receptor alpha (ERα) and consequently change the sensitivity of immune cells to estrogen's action. There is evidence that ERα is responsible for the effects exerted by estrogens and that this phenomenon mainly involves antigen-presenting cells. On the other hand, research on IFN-tau, a type I interferon family members, showed that this cytokine can modulate ERα levels in ovine endometrium. Because of the common receptor for these interferons, we suspect that other type I interferons can act in this way not only in endometrial cells, but also in immune cells. If there is such a mechanism, it can be exploited in the therapy of immune disorders, especially autoimmune disease, for example through simultaneous administration of less toxic interferons and estrogens.
Traditional non-steroidal anti-inflammatory drugs, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors control inflammation. While these drugs are formulated to reduce one of the cardinal signs of inflammation by reducing prostaglandin levels at the site of inflammation, COX-1 inhibitors induce inflammation in the stomach as well as the small bowel. The COX-2 inhibitors, a large portion of the non-steroidal anti-inflammatory drug market, provide a gastro-intestinally safer class of drugs. However, COX-2 inhibitors induce vasoconstriction via actions in renal and cardiovascular tissues. Since COX-2 inhibitors also have anticancer potential, it is worthwhile to design drug formulations that will not cause hypertension or cardiovascular damage. An attempt has thus been made in this article to formulate a hypothesis to circumvent the COX inhibitors induced inflammation and vasoconstriction through COX independent activation of calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide found throughout the vascular and sensory nervous system.
Emerging data suggest a significant involvement of estrogens in the development and clinical course of asthma. Yet, little is known regarding the effects of 17β-estradiol (estradiol; E2) metabolism in asthma. E2 is metabolized by 2-hydroxylation and subsequent O-methylation to 2-methoxyestradiol (2ME) and by 16-hydroxylation to estriol (16α-hydroxyestradiol; 16HE2) and to 16α-estrone (16HE1). 2ME is a non-estrogenic metabolite which exhibits anti-mitogenic, anti-inflammatory and anti-angiogenic effects, whereas 16HE2 and 16HE1 are estrogenic metabolites with mitogenic, pro-inflammatory, and angiogenic properties.
The brain's wrong-sidedness, or contralaterality, is one of life's great mysteries. Unlike invertebrates, all vertebrates from fish to mammals possess a forebrain with hemispheres innervated from sense organs on the body's opposite side. The vertebrate chambered eye has long been implicated as the cause for this paradox but no credible or testable theory had previously been postulated to support such an idea. Ramon y Cajal, the founder of neurobiology, made such a claim in the early 1900s but failed to provide adequate evidence. Here we show that the eye indeed appears to be the inverting culprit based on this author's entirely original, but untested, concept of a cyclopean origin to vertebrates at a time when single-eyed chordates were evolving to double-eyed agnathan fish.
Industrialized farming relies on bee keepers transporting hives to the vicinity of large areas of mono-crops for crop pollination. Hives are typically moved multiple times per growing season to satisfy the pollination need. A phenomenon wherein colonies of honey bees collapse in large numbers has been threatening crops in North America. Honey bees are hosts to at least two pathogenic mites; Varroa destructor and Acarapis woodi (a tracheal mite). Pyrethrums are a group of flowering plants which include Chrysanthemum coccineum, Chrysanthemum cinerariifolium, Chrysanthemum marschallii, and related species. These plants produce potent insecticides, also named pyrethrums, which are powerful mite toxins. We believe that a honey bee dietary deficiency of pyrethrums and other micro-nutrients from pyrethrum producing plants allows parasitic mites to either kill the honey bees directly or reduce honey bee resistance to other pathogens. Intermittent feeding of honey bees on pyrethrum producing plants might reverse or prevent colony collapse disorder.
