The apoptosome: physiological, developmental, and pathological modes of regulation

Apoptosis, a form of programmed cell death, is executed by a family of zymogenic proteases known as caspases, which cleave an array of intracellular substrates in the dying cell. Many proapoptotic stimuli trigger cytochrome c release from mitochondria, promoting the formation of a complex between Apaf-1 and caspase-9 in a caspase-activating structure known as the apoptosome. In this review, we describe knockout and knockin studies of apoptosome components, elegant structural and biochemical experiments, and analyses of the apoptosome in various cancers and other disease states, all of which have provided new insight into this critical locus of apoptotic control.     

From the cradle to the clinic: VEGF in developmental, physiological, and pathological angiogenesis

Formation of new blood vessels, which is fundamental in embryonic development, occurs through a combination of angiogenesis and vasculogenesis. Angiogenesis also plays a vital role postnatally, especially in reparative processes such as wound and fracture healing. Some of these events, especially in fracture healing, recapitulate processes observed in developmental angiogenesis. However, dysregulated angiogenesis is well documented to underlie a number of pathological disorders, including rheumatoid arthritis (RA). The vascular endothelial growth factor (VEGF)/VEGF receptor system is the best characterized regulator of angiogenesis. VEGF is expressed in a range of cells in response to soluble mediators (such as cytokines and growth factors), cell-bound stimuli (such as CD40 ligand), and environmental factors (such as hypoxia). As a consequence, this molecule is vital in the modulation of physiological and pathological angiogenesis. This review will focus in particular on the role played by VEGF in embryogenesis and skeletal growth, in fracture healing (in which increased angiogenesis is likely to be beneficial in promoting union), and in RA (in which excessive angiogenesis is thought to play a significant role in disease pathogenesis). In the not-too-distant future, targeting VEGF may prove to be of benefit in the treatment of diseases associated with excessive or aberrant angiogenesis, such as malignancies and RA.     

Antibody microarrays: promises and problems

Antibody microarrays have enormous potential for becoming a tool that will allow, at the protein level, the type of global characterization of molecular mixtures that DNA microarrays already make possible at the RNA and DNA level. However, the much higher complexity of proteins both in terms of their sheer number and their structural and biochemical diversity necessitates an even more sophisticated analysis process. Its eventual realization will be demanding to achieve and requires further developments on many technical aspects, not in the least because the understanding of proteins is still comparatively less comprehensive than that of nucleic acids prior to the emergence of array technologies.     

Glycobiology: Progress, problems, and perspectives

This review highlights different aspects of glycobiology with analysis of recent progress in the study of biosynthesis, degradation, and biological role of glycoconjugates and of hereditary diseases related to the metabolism of these compounds. In addition, the review presents some analysis of the papers of other authors who have contributed to this special issue.     

GABA-benzodiazepine interactions: physiological, pharmacological and developmental aspects

Many of the pharmacological actions of the benzodiazepines can be attributed to their actions on gamma-aminobutyric acid (GABA) systms in the brain. Electrophysiological studies on dorsal raphe neurons indicate that the benzodiazepines act postsynaptically to potentiate GABAergic inhibition in this midbrain nucleus. Direct binding studies have shown that both in vitro and in vivo binding of [3H]diazepam to a specific high affinity benzodiazepine binding site in cerebral cortical tissue are enhanced by the direct in vitro addition of GABA and GABA agonists or by pretreatment of animals with GABA analogs and agents that elevate GABA levels in brain. Ontogenic development of [3H]diazepam binding in brain parallels the development of the sodium-independent [3H]GABA binding. The ability of GABA to enhance benzodiazepine binding is present throughout development and inversely related to age. These data suggest that there is a functionally significant interaction between the benzodiazepines and GABA throughout development and at maturity. A model is proposed to relate these interactions to conformational changes in a benzodiazepine/GABA/Cl- ionophore complex.     

Fibulins: physiological and disease perspectives

The fibulins are a family of proteins that are associated with basement membranes and elastic extracellular matrix fibres. This review summarizes findings from studies of animal models of fibulin deficiency, human fibulin gene mutations, human tumours and injury models that have advanced our understanding of the normal and pathological roles of members of this formerly obscure family.     

Mitochondrial glutathione transport: physiological, pathological and toxicological implications

Although most cellular glutathione (GSH) is in the cytoplasm, a distinctly regulated pool is present in mitochondria. Inasmuch as GSH synthesis is primarily restricted to the cytoplasm, the mitochondrial pool must derive from transport of cytoplasmic GSH across the mitochondrial inner membrane. Early studies in liver mitochondria primarily focused on the relationship between GSH status and membrane permeability and energetics. Because GSH is an anion at physiological pH, this suggested that some of the organic anion carriers present in the inner membrane could function in GSH transport. Indeed, studies by Lash and colleagues in isolated mitochondria from rat kidney showed that most of the transport (>80%) in that tissue could be accounted for by function of the dicarboxylate carrier (DIC, Slc25a10) and the oxoglutarate carrier (OGC, Slc25a11), which mediate electroneutral exchange of dicarboxylates for inorganic phosphate and 2-oxoglutarate for other dicarboxylates, respectively. The identity and function of specific carrier proteins in other tissues is less certain, although the OGC is expressed in heart, liver, and brain and the DIC is expressed in liver and kidney. An additional carrier that transports 2-oxoglutarate, the oxodicarboxylate or oxoadipate carrier (ODC; Slc25a21), has been described in rat and human liver and its expression has a wide tissue distribution, although its potential function in GSH transport has not been investigated. Overexpression of the cDNA for the DIC and OGC in a renal proximal tubule-derived cell line, NRK-52E cells, showed that enhanced carrier expression and activity protects against oxidative stress and chemically induced apoptosis. This has implications for development of novel therapeutic approaches for treatment of human diseases and pathological states. Several conditions, such as alcoholic liver disease, cirrhosis or other chronic biliary obstructive diseases, and diabetic nephropathy, are associated with depletion or oxidation of the mitochondrial GSH pool in liver or kidney.     

Tau phosphorylation: physiological and pathological consequences

The microtubule-associated protein tau, abundant in neurons, has gained notoriety due to the fact that it is deposited in cells as fibrillar lesions in numerous neurodegenerative diseases, and most notably Alzheimer's disease. Regulation of microtubule dynamics is the most well-recognized function of tau, but it is becoming increasingly evident that tau plays additional roles in the cell. The functions of tau are regulated by site-specific phosphorylation events, which if dysregulated, as they are in the disease state, result in tau dysfunction and mislocalization, which is potentially followed by tau polymerization, neuronal dysfunction and death. Given the increasing evidence that a disruption in the normal phosphorylation state of tau plays a key role in the pathogenic events that occur in Alzheimer's disease and other neurodegenerative conditions, it is of crucial importance that the protein kinases and phosphatases that regulate tau phosphorylation in vivo as well as the signaling cascades that regulate them be identified. This review focuses on recent literature pertaining to the regulation of tau phosphorylation and function in cell culture and animal model systems, and the role that a dysregulation of tau phosphorylation may play in the neuronal dysfunction and death that occur in neurodegenerative diseases that have tau pathology.     

Glucose transporters: physiological and pathological roles

Glucose is a primary energy source for most cells and an important substrate for many biochemical reactions. As glucose is a need of each and every cell of the body, so are the glucose transporters. Consequently, all cells express these important proteins on their surface. In recent years developments in genetics have shed new light on the types and physiology of various glucose transporters, of which there are two main types—sodium–glucose linked transporters (SGLTs) and facilitated diffusion glucose transporters (GLUT)—which can be divided into many more subclasses. Transporters differ in terms of their substrate specificity, distribution and regulatory mechanisms. Glucose transporters have also received much attention as therapeutic targets for various diseases. In this review, we attempt to present a simplified view of this complex topic which may be of interest to researchers involved in biochemical and pharmacological research.     

Lactoferrin,myeloperoxidase, and ceruloplasmin: complementary gearwheels cranking physiological and pathological processes

Copper-containing plasma protein ceruloplasmin (Cp) forms a complex with lactoferrin (Lf), an iron-binding protein, and with the heme-containing myeloperoxidase (Mpo). In case of inflammation, Lf and Mpo are secreted from neutrophil granules. Among the plasma proteins, Cp seems to be the preferential partner of Lf and Mpo. After an intraperitoneal injection of Lf to rodents, the “Cp–Lf” complex has been shown to appear in their bloodstream. Cp prevents the interaction of Lf with protoplasts of Micrococcus luteus. Upon immunoprecipitation of Cp, the blood plasma becomes depleted of Lf and in a dose-dependent manner loses the capacity to inhibit the peroxidase activity of Mpo, but not the Mpo-catalyzed oxidation of thiocyanate in the (pseudo)halogenating cycle. Antimicrobial effect against E. coli displayed by a synergistic system that includes Lf and Mpo–H₂O₂–chloride, but not thiocyanate, as the substrate for Mpo is abrogated when Cp is added. Hence, Cp can be regarded as an anti-inflammatory factor that restrains the halogenating cycle and redirects the synergistic system Mpo–H₂O₂–chloride/thiocyanate to production of hypothiocyanate, which is relatively harmless for the human organism. Structure and functions of the “2Cp–2Lf–Mpo” complex and binary complexes Cp–Lf and 2Cp–Mpo in inflammation are discussed.     

Epigenetics of major psychosis: progress, problems and perspectives

Understanding the origins of normal and pathological behavior is one of the most exciting opportunities in contemporary biomedical research. There is increasing evidence that, in addition to DNA sequence and the environment, epigenetic modifications of DNA and histone proteins may contribute to complex phenotypes. Inherited and/or acquired epigenetic factors are partially stable and have regulatory roles in numerous genomic activities, thus making epigenetics a promising research path in etiological studies of psychiatric disease. In this article, we review recent epigenetic studies examining the brain and other tissues, including those from individuals with schizophrenia (SCZ) and bipolar disorder (BPD). We also highlight heuristic aspects of the epigenetic theory of psychiatric disease and discuss the future directions of psychiatric epigenetics.     

Superparasitism in gregarious hymenopteran parasitoids: ecological, behavioural and physiological perspectives

Abstract.  Superparasitism in gregarious wasps occurs with the deposition of a clutch of eggs by a female into a host already parasitized by itself or a conspecific female. This review synthesizes and interprets the available results in the literature reported from field studies, and from behavioural and physiological investigations. To study superparasitism at the ecosystem level, methodological issues have to be solved to determine threshold values beyond which multiple offspring can be indisputably classified as originating from superparasitism. This life strategy is then discussed from the parasitoid's perspective, considering time and egg limitation, host discrimination, clutch size, offspring body size and sex ratio, as well as development time and survival rate of offspring, with special emphasis on physiological facilitation and constraints. Then, superparasitism in gregarious species is evaluated from the host's angle, addressing host survivorship and development, host food consumption and growth. Although superparasitism may be beneficial for either the first or the superparasitizing female, depending on the system, it is detrimental for both of them under conditions of extreme superparasitism. Recent methodological and experimental advances encourage further studies on the adaptive host choice under field and laboratory conditions, as well as on mechanisms underlying success of the first or the superparasitizing female and their progeny.