Apoptosis in Alzheimer's disease—an update

Alzheimer's disease (AD) is the most common human neurodegenerative disorder characterized by the progressive deterioration of cognition and memory in association with the presence of senile plaques, neurofibrillary tangles, and massive loss of neurons. Most cases of AD are late-onset and sporadic, but in some cases the disease is inherited as an autosomal dominant trait. Four different genes, the amyloid precursor protein, apolipoprotein E, and presenilins 1 and 2 have been implicated in the etiology of familial AD. It is now generally accepted that massive neuronal death due to apoptosis is a commmon characteristic in the brains of patients suffering from neurodegenerative diseases, and apoptotic cell death has been found in neurons and glial cells in AD. This review summarizes the current findings regarding the evidence for apoptosis in AD and discusses the possible involvement of apoptosis-regulating factors in the pathology of AD. Modification of the apoptotic cascade could be considered as a primary therapeutic strategy for the disease.     

Regulation of Nrf2—an update

Nrf2:INrf2 (Keap1) are cellular sensors of oxidative and electrophilic stress. Nrf2 is a nuclear factor that controls the expression and coordinated induction of a battery of genes that encode detoxifying enzymes, drug transporters, antiapoptotic proteins, and proteasomes. In the basal state, Nrf2 is constantly degraded in the cytoplasm by its inhibitor, INrf2. INrf2 functions as an adapter for Cul3/Rbx1 E3 ubiquitin ligase-mediated degradation of Nrf2. Chemicals, including antioxidants, tocopherols including α-tocopherol (vitamin E), and phytochemicals, and radiation antagonize the Nrf2:INrf2 interaction and lead to the stabilization and activation of Nrf2. The signaling events involve preinduction, induction, and postinduction responses that tightly control Nrf2 activation and repression back to the basal state. Oxidative/electrophilic signals activate unknown tyrosine kinases in a preinduction response that phosphorylates specific residues on Nrf2 negative regulators, INrf2, Fyn, and Bach1, leading to their nuclear export, ubiquitination, and degradation. This prepares nuclei for unhindered import of Nrf2. Oxidative/electrophilic modification of INrf2 cysteine 151 followed by PKC phosphorylation of Nrf2 serine 40 in the induction response results in the escape or release of Nrf2 from INrf2. Nrf2 is thus stabilized and translocates to the nucleus, resulting in a coordinated activation of gene expression. This is followed by a postinduction response that controls the “switching off” of Nrf2-activated gene expression. GSK3β, under the control of AKT and PI3K, phosphorylates Fyn, leading to Fyn nuclear localization. Fyn phosphorylates Nrf2 Y568, resulting in nuclear export and degradation of Nrf2. The activation and repression of Nrf2 provide protection against oxidative/electrophilic stress and associated diseases, including cancer. However, deregulation of INrf2 and Nrf2 due to mutations may lead to nuclear accumulation of Nrf2 that reduces apoptosis and promotes oncogenesis and drug resistance.     

Polyamine analogues – an update

Summary. The polyamines are growth factors in both normal and cancer cells. As the intracellular polyamine content correlates positively with the growth potential of that cell, the idea that depletion of polyamine content will result in inhibition of cell growth and, particularly tumour cell growth, has been developed over the last 15 years. The polyamine pathway is therefore a target for development of rationally designed, antiproliferative agents. Following the lessons from the single enzyme inhibitors (α-difluoromethylornithine DFMO), three generations of polyamine analogues have been synthesised and tested in vitro and in vivo. The analogues are multi-site inhibitors affecting multiple reactions in the pathway and thus prevent the up-regulation of compensatory reactions that have been the downfall of DFMO in anticancer chemotherapy. Although the initial concept was that the analogues may provide novel anticancer drugs, it now seems likely that the analogues will have wider applications in diseases involving hyperplasia.     

P2 receptor-mediated modulation of neurotransmitter release—an update

Presynaptic nerve terminals are equipped with a number of presynaptic auto- and heteroreceptors, including ionotropic P2X and metabotropic P2Y receptors. P2 receptors serve as modulation sites of transmitter release by ATP and other nucleotides released by neuronal activity and pathological signals. A wide variety of P2X and P2Y receptors expressed at pre- and postsynaptic sites as well as in glial cells are involved directly or indirectly in the modulation of neurotransmitter release. Nucleotides are released from synaptic and nonsynaptic sites throughout the nervous system and might reach concentrations high enough to activate these receptors. By providing a fine-tuning mechanism these receptors also offer attractive sites for pharmacotherapy in nervous system diseases. Here we review the rapidly emerging data on the modulation of transmitter release by facilitatory and inhibitory P2 receptors and the receptor subtypes involved in these interactions.     

Cutaneous gene therapy – an update

In this paper we review various strategies for gene transfer into the skin, their applications and show some of our own examples. The skin is the most accessible somatic tissue. Inherited skin diseases, such as epidermolysis bullosa and ichthyosis, and various systemic metabolic disorders are under investigation as potential candidate diseases for cutaneous gene transfer. Research is directed against genetic therapy of wounds and malignancies as well. So far, cutaneous gene transfer only has been used experimentally, but several clinical trials are under preparation.     

Could an increase in airway smooth muscle shortening velocity cause airway hyperresponsiveness?

Airway hyperresponsiveness (AHR) is a characteristic feature of asthma. It has been proposed that an increase in the shortening velocity of airway smooth muscle (ASM) could contribute to AHR. To address this possibility, we tested whether an increase in the isotonic shortening velocity of ASM is associated with an increase in the rate and total amount of shortening when ASM is subjected to an oscillating load, as occurs during breathing. Experiments were performed in vitro using 27 rat tracheal ASM strips supramaximally stimulated with methacholine. Isotonic velocity at 20% isometric force (Fiso) was measured, and then the load on the muscle was varied sinusoidally (0.33 ± 0.25 Fiso, 1.2 Hz) for 20 min, while muscle length was measured. A large amplitude oscillation was applied every 4 min to simulate a deep breath. We found that: 1) ASM strips with a higher isotonic velocity shortened more quickly during the force oscillations, both initially (P < 0.001) and after the simulated deep breaths (P = 0.002); 2) ASM strips with a higher isotonic velocity exhibited a greater total shortening during the force oscillation protocol (P < 0.005); and 3) the effect of an increase in isotonic velocity was at least comparable in magnitude to the effect of a proportional increase in ASM force-generating capacity. A cross-bridge model showed that an increase in the total amount of shortening with increased isotonic velocity could be explained by a change in either the cycling rate of phosphorylated cross bridges or the rate of myosin light chain phosphorylation. We conclude that, if asthma involves an increase in ASM velocity, this could be an important factor in the associated AHR.     

NCL diseases — clinical perspectives

The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage disorders and together are the most common degenerative brain diseases in childhood. They are a group of disorders linked by the characteristic accumulation of abnormal storage material in neurons and other cell types, and a degenerative disease course. All NCLs are characterized by a combination of dementia, epilepsy, and motor decline. For most childhood NCLs, a progressive visual failure is also a core feature. The characteristics of these symptoms can vary and the age at disease onset ranges from birth to young adulthood. Genetic heterogeneity, with fourteen identified NCL genes and wide phenotypic variability render diagnosis difficult. A new NCL classification system based on the affected gene and the age at disease onset allows a precise and practical delineation of an individual patient's NCL type. A diagnostic algorithm to identify each NCL form is presented here. Precise NCL diagnosis is essential not only for genetic counseling, but also for the optimal delivery of care and information sharing with the family and other caregivers. These aspects are challenging because there are also potential long term complications which are specific to NCL type. Therefore care supported by a specifically experienced team of clinicians is recommended. As the underlying pathophysiological mechanism is still unclear for all NCL forms, the development of curative therapies remains difficult. This article is part of a Special Issue entitled: The neuronal ceroid lipofuscinoses or Batten Disease.     

Peanuts—Especially their diseases

Economic Botany - Peanuts have been grown in at least 38 States, have been of commercial importance in 12 of them, and in 1945 were cultivated on more than four million acres in the United States...     

Is metabolic syndrome X an inflammatory condition?

It is suggested that metabolic syndrome X is a low-grade systemic inflammatory condition.     

Thymic epithelial progenitor cells and thymus regeneration： an update

The thymus provides the essential microenvironment for T-cell development and maturation. Thymic epithelial cells （TECs）, which are composed of thymic cortical epithelial cells （cTECs） and thymic medullary epithelial cells （mTECs）, have been well documented to be critical for these tightly regulated processes. It has long been controversial whether the common progenitor cells of TECs could give rise to both cTECs and mTECs. Great progress has been made to characterize the common TEC progenitor cells in recent years. We herein discuss the sole origin paradigm with regard to TEC differentiation as well as these progenitor cells in thymus regeneration.