Are there sex differences in pain? For experimentally delivered somatic stimuli, females have lower thresholds, greater ability to discriminate, higher pain ratings, and less tolerance of noxious stimuli than males. These differences, however, are small, exist only for certain forms of stimulation and are affected by many situational variables such as presence of disease, experimental setting, and even nutritive status. For endogenous pains, women report more multiple pains in more body regions than men. With no obvious underlying rationale, some painful (...) diseases are more prevalent among females, others among males and, for many diseases, symptoms differ between females and males. Sex differences in attitudes exist that affect not only reporting, coping, and responses to treatment, but also measurement and treatment. So many variables are operative, however, that the most striking feature of sex differences in reported pain experience is the apparent overall lack of them. On the other hand, deduction from known biological sex differences suggests that these are powerful sex differences in the operation of pain mechanisms. First, the vaginal canal provides an additional route in women for internal trauma and invasion by pathological agents that puts them at greater risk for developing hyperalgesia in multiple body regions. Second, sex differences in temporal patterns are likely to give rise to sex differences in how pain is and stimuli are interpreted, a situation that could lead to a greater variability and wider range of pains without obvious peripheral pathology among females. Third, sex differences in the actions of sex hormones suggest pain-relevant differences in the operation of many neuroactive agents, opiate and nonopiate systems, nerve growth factor, and the sympathetic system. Thus, while inductive analysis of existing data demonstrate more similarities than differences in pain experience between females and males, deductive analysis suggests important operational sex differences in its production. (shrink)

It is commonly presumed that abiotic membranes were colonized by proteins later on. Yet, hydrophobic peptides could have formed primordial protein‐dominated membranes on their own. In a metabolism‐first context, “autocatalytically closed” sets of statistical peptides could organize a self‐maintaining protometabolism, assisted by an unfolding set of ribotide‐related cofactors. Pairwise complementary ribotide cofactors may have formed docking guides for stochastic peptide formation, before replicating RNA emerged from this subset. Tidally recurring wet‐drying cycles and an early onset of photosynthetic activities (...) are considered most likely to meet the thermodynamic requirements. Conceivably, the earliest peptide‐dominated vesicles were engaged in light harvesting, together with isoprenoid‐tethered pigments, rather than providing an external boundary. Early on, the bulk of prebiotic organic matter can have formed a contiguous layer covering the mineral sediment, held in place by colloidal coherence of a hydrogel matrix. This unconventional scenario assumes a late onset of cellular individualization – perhaps from within, resembling endosporogenesis. (shrink)

Drosophila responds to a septic injury by the rapid synthesis of antimicrobial peptides. These molecules are predominantly produced by the fat body, a functional equivalent of mammalian liver, and are secreted into the hemolymph where their concentrations can reach up to 100 μM. Six distinct antibacterial peptides (plus isoforms) and one antifungal peptide have been characterized in Drosophila and their genes cloned. The induction of the gene encoding the antifungal peptide relies on the spätzle/Toll/cactus gene cassette, which is (...) involved in the control of dorsoventral patterning in the embryo, and shows interesting structural and functional similarities with cytokine‐induced activation of NF‐ϰB in mammalian cells. An additional pathway, dependent on the as yet unidentified imd (for immune‐deficiency) gene, is required for the full induction of the antibacterial peptide genes. Mutants deficient for the Toll and imd pathways exhibit a severely reduced survival to fungal and bacterial infections, respectively. Recent data on the molecular mechanisms underlying recognition of non‐self are also discussed in this review. (shrink)

The vertebrate immune system uses an impressive arsenal of mechanisms to combat harmful cellular states such as infection. One way is via cells delivering real‐time snapshots of their protein content to the cell surface in the form of short peptides. Specialized immune cells (T cells) sample these peptides and assess whether they are foreign, warranting an action such as destruction of the infected cell. The delivery of peptides to the cell surface is termed antigen processing and presentation, (...) and decades of research have provided unprecedented understanding of this process. However, predicting the capacity for a given peptide to be immunogenic—to elicit a T cell response—has remained both enigmatic and a long sought‐after goal. In the era of big data, a point is being approached where the steps of antigen processing and presentation can be quantified and assessed against peptide immunogenicity in order to build predictive models. This review presents new findings in this area and contemplates challenges ahead. (shrink)

Proteins are targeted to plastids by N‐terminal transit peptides, which are recognized by protein import complexes in the organelle membranes. Historically, transit peptide properties have been defined from vascular plant sequences, but recent large‐scale genome sequencing from the many plastid‐containing lineages across the tree of life has provided a much broader representation of targeted proteins. This includes the three lineages containing primary plastids (plants and green algae, rhodophytes and glaucophytes) and also the seven major lineages that contain secondary plastids, (...) “secondhand” plastids derived through eukaryotic endosymbiosis. Despite this extensive spread of plastids throughout Eukaryota, an N‐terminal transit peptide has been maintained as an essential plastid‐targeting motif. This article provides the first global comparison of transit peptide composition and summarizes conservation of some features, the loss of an ancestral motif from the green lineages including plants, and modifications to transit peptides that have occurred in secondary and even tertiary plastids. BioEssays 29:1048–1058, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Peptides serve as important signalling molecules in development and differentiation in the simple metazoan Hydra. A systematic approach (The Hydra Peptide Project) has revealed that Hydra contains several hundreds of peptide signalling molecules, some of which are neuropeptides and others emanate from epithelial cells. These peptides control biological processes as diverse as muscle contraction, neuron differentiation, and the positional value gradient. Signal peptides cause changes in cell behaviour by controlling target genes such as matrix metalloproteases. The abundance (...) of peptides in Hydra raises the question of whether, in early metazoan evolution, cell–cell communication was based mainly on these small molecules rather than on the growth‐factor‐like cytokines that control differentiation and development in higher animals. BioEssays 23:420–427, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Bioactive peptides are a group of diverse intercellular signalling molecules. Almost half a century of research on this topic has resulted in an enormous amount of data. In this essay, a general perspective to interpret all these data will be given. In classical endocrinology, neuropeptides were thought of as simple signalling molecules that each elicit one response. However, the fact that the total bioactive peptide signal is far from simple puts this view under pressure. Cells and tissues express many (...) different bioactive peptides and they are also able to respond to many different bioactive peptides, indicating that multiple receptors and signal transduction pathways are present in a single cell. Therefore, the authors suggest that the bioactive peptide signalling system should be regarded in the context of network and systems biology. Bioactive peptides can best be viewed as an extension of the protein interaction network that allows regulating and fine‐tuning the metabolism of the different cells and tissues in the body. The cell thus responds to the ‘peptidome’ instead of to a single peptide. The intracellular part of this signalling network consists of the various signalling transduction cascades. Recently, new systems biology approaches have emerged for the modelling of cell signalling. The network and systems biology approach is also able to shed new light on the evolution of intercellular signalling. (shrink)

Neuropeptides vasopressin and oxytocin regulate a variety of behaviors ranging from maternal and pair bonding to aggression and fear. Their role in modulating fear responses has been widely recognized, but not yet well understood. Animal and human studies indicate the major role of the amygdala in controlling fear and anxiety. The amygdala is involved in detecting threat stimuli and linking them to defensive behaviors. This is accomplished by projections connecting the central nucleus of the amygdala (CeA) to the brain stem (...) and to hypothalamic structures, which organize fear responses. A recent study by Huber et al1 demonstrates that vasopressin and oxytocin modulate the excitatory inputs into the CeA in opposite manners. Therefore this finding elucidates the mechanisms through which these neuropeptides may control the expression of fear. BioEssays 27:869–873, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Both W9 and OP3‐4 were known to bind the receptor activator of NF‐κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide‐induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, (...) an upstream molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3‐4 accelerated BMP‐2‐induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL‐binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP‐2‐induced bone regeneration by the RANKL‐binding peptides. (shrink)

It has long been thought that the central nervous system is able to influence the progression of disease. Furthermore, there is now overwhelming evidence that the communication pathways are bidirectional. A variety of immune system peptides are now known to be capable of transmitting information from the immune system to the central nervous system. These immunotransmitters include interleukins, interferons and thymosine peptides which have the capability of modulating slow‐wave sleep as well as the release of neuro‐ and pituitary (...) peptides. In some instances, release of these peptides during early development may have long lasting, if not permanent effects upon the normal development of neuro‐endocrine circuits. Collectively these various brain mediated events appear to contribute in various and diverse ways to defense against pathogens. It is becoming more and more apparent that certain abnormalities within the immune system may be the consequence of a neurological abnormality. The converse is also true. (shrink)

I hypothesize here that the ability of probiotics to synthesize neuroactive compounds provides a unifying microbial endocrinology‐based mechanism to explain the hitherto incompletely understood action of commensal microbiota that affect the host's gastrointestinal and psychological health. Once ingested, probiotics enter an interactive environment encompassing microbiological, immunological, and neurophysiological components. By utilizing a trans‐disciplinary framework known as microbial endocrinology, mechanisms that would otherwise not be considered become apparent since any candidate would need to be shared among all three components. The (...) range of neurochemicals produced by probiotics includes neurochemicals for which receptor‐based targets on immune and neuronal elements (intestinal and extra‐intestinal) have been well characterized. Production of neurochemicals by probiotics therefore allows for their consideration as delivery vehicles for neuroactive compounds. This unifying microbial endocrinology‐based hypothesis, which may facilitate the selection and design of probiotics for clinical use, also highlights the largely unrecognized role of neuroscience in understanding how microbes may influence health.Editor's suggested further reading in BioEssays Harvesting the biological potential of the human gut microbiome Abstract. (shrink)

In this paper I attempt to study the notion of “folding of a semiotic continuum” in a direction of a possible application to the biological processes. More specifically, the process of obtaining protein structures is compared in this paper to the folding of a semiotic continuum. Consequently, peptide chain is presented as a continuous line potential to be formed in order to create functional units. The functional units are protein structures having certain function in the cell or organism. Moreover, protein (...) folding is analyzed in terms of tension between syntax and semantics. (shrink)

Atrial natriuretic peptides appear to elicit their actions in some target tissues by binding to a novel cell‐surface transmembrane protein which possesses both peptide binding and guanylate cyclase activities. Ligand binding stimulates enzyme activity to produce increased intracellular concentrations of cyclic GMP which, in turn, mediates the cell's physiological response.

Affective disorders arise in stressful situations from aberrant sensory information integration that affects energetic nutrient (i.e., glucose) utilization to the cognitive centers of the brain. Because energy flow is mediated by molecular signals and receptors that evolved before the first complex brains, the phylogenetically oldest signaling systems are essential in the etiology of affective disorders. The corticotropin‐releasing factor (CRF) peptide subfamily is a phylogenetically old metazoan peptide family and is pivotal for regulating organismal energy response associated with stress. Highly conserved, (...) both the CRF peptide family and its receptors possess a structural relationship to the teneurins, and their receptors, latrophilins, respectively. The CRF homologous region of teneurin is defined as the “teneurin C‐terminal associated peptide” (TCAP) and antagonizes CRF action, regulates mitochondrial energy production, and is anxiolytic in vivo. Here, it is postulated that TCAP represents an ancient peptide that mediates intercellular information transfer of stressful and noxious events by regulating energy utilization among neurons. (shrink)

Over the past decade, high‐throughput studies have identified many novel transcripts. While their existence is undisputed, their coding potential and functionality have remained controversial. Recent computational approaches guided by ribosome profiling have indicated that translation is far more pervasive than anticipated and takes place on many transcripts previously assumed to be non‐coding. Some of these newly discovered translated transcripts encode short, functional proteins that had been missed in prior screens. Other transcripts are translated, but it might be the process of (...) translation rather than the resulting peptides that serves a function. Here, we review annotation studies in zebrafish to discuss the challenges of placing RNAs onto the continuum that ranges from functional protein‐encoding mRNAs to potentially non‐functional peptide‐producing RNAs to non‐coding RNAs. As highlighted by the discovery of the novel signaling peptide Apela/ELABELA/Toddler, accurate annotations can give rise to exciting opportunities to identify the functions of previously uncharacterized transcripts. (shrink)

The central dogma of molecular biology dictates that, with only a few exceptions, information proceeds from DNA to protein through an RNA intermediate. Examining the enigmatic steps from prebiotic to biological chemistry, we take another road suggesting that primordial peptides acted as template for the self-assembly of the first nucleic acids polymers. Arguing in favour of a sort of archaic “reverse translation” from proteins to RNA, our basic premise is a Hadean Earth where key biomolecules such as amino acids, (...) polypeptides, purines, pyrimidines, nucleosides and nucleotides were available under different prebiotically plausible conditions, including meteorites delivery, shallow ponds and hydrothermal vents scenarios. Supporting a protein-first scenario alternative to the RNA world hypothesis, we propose the primeval occurrence of short two-dimensional peptides termed “selective amino acid- and nucleotide-matching oligopeptides” (henceforward SANMAOs) that noncovalently bind at the same time the polymerized amino acids and the single nucleotides dispersed in the prebiotic milieu. In this theoretical paper, we describe the chemical features of this hypothetical oligopeptide, its biological plausibility and its virtues from an evolutionary perspective. We provide a theoretical example of SANMAO’s selective pairing between amino acids and nucleosides, simulating a poly-Glycine peptide that acts as a template to build a purinic chain corresponding to the glycine’s extant triplet codon GGG. Further, we discuss how SANMAO might have endorsed the formation of low-fidelity RNA’s polymerized strains, well before the appearance of the accurate genetic material’s transmission ensured by the current translation apparatus. (shrink)

Alzheimer's disease (AD) is a neurodegenerative disease exhibiting amyloid beta (Aβ) peptide accumulation as a key characteristic. Autophagy, which is dysregulated in AD, participates in the metabolism of Aβ. Unexpectedly, we recently found that autophagy, in addition to its degradative function, also mediates the secretion of Aβ. This finding adds Aβ to an increasing number of biomolecules, the secretion of which is mediated by autophagy. We also showed that inhibition of Aβ secretion through genetic deletion of autophagy leads to intracellular (...) Aβ accumulation, which enhanced neurodegeneration induced by autophagy deficiency. Hence, autophagy may play a central role in two pathological hallmarks of AD: Aβ amyloidosis and neurodegeneration. Herein, we summarize the role of autophagy in AD with focus on Aβ metabolism in light of the recently established role of autophagy in protein secretion. We discuss potential routes for autophagy‐mediated Aβ secretion and suggest experimental approaches to further elucidate its mechanisms. (shrink)

The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment containing the (...) 5'-flanking region of the human APOE gene . Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

Despite their seemingly endless diversity, proteins adopt a limited number of structural forms. It has been estimated that 80% of proteins will be found to adopt one of only about 400 folds, most of which are already known. These folds are largely formed by a limited ‘vocabulary’ of recurring supersecondary structure elements, often by repetition of the same element and, increasingly, elements similar in both structure and sequence are discovered. This suggests that modern proteins evolved by fusion and recombination from (...) a more ancient peptide world and that many of the core folds observed today may contain homologous building blocks. The peptides forming these building blocks would not in themselves have had the ability to fold, but would have emerged as cofactors supporting RNA‐based replication and catalysis (the ‘RNA world’). Their association into larger structures and eventual fusion into polypeptide chains would have allowed them to become independent of their RNA scaffold, leading to the evolution of a novel type of macromolecule: the folded protein. BioEssays 25:837–846, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Much progress has been made in recent years regarding the mechanisms of targeting of secretory proteins to, and across, the endoplasmic reticulum (ER) membrane. Many of the cellular components involved in mediating translocation across this bilayer have been identified and characterized. Polypeptide domains of secretory proteins, termed signal peptides, have been shown to be necessary, and in most cases sufficient, for entry of preproteins into the lumen of the ER. These NH2‐ terminal segments appear to serve multiple roles in (...) targeting and translocation. The structural features which mediate their multiple functions are currently the subject of intense study. (shrink)

Three‐dimensional (3D) structures have been used to explore the evolution of proteins for decades, yet they have rarely been utilized to study the molecular evolution of peptides. Here, we highlight areas in which 3D structures can be particularly useful for studying the molecular evolution of peptide toxins. Although we focus our discussion on animal toxins, including one of the most widespread disulfide‐rich peptide folds known, the inhibitor cystine knot, our conclusions should be widely applicable to studies of the evolution (...) of disulfide‐constrained peptides. We show that conserved 3D folds can be used to identify evolutionary links and test hypotheses regarding the evolutionary origin of peptides with extremely low sequence identity; construct accurate multiple sequence alignments; and better understand the evolutionary forces that drive the molecular evolution of peptides.Also watch the video abstract. (shrink)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated Abeta1-40 (...) localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

Peptides possessing both natriuretic and smooth muscle relaxant activities have been isolated from heart atria and their structures have been determined. The peptides designated ANP (atrial natriuretic peptide) regulate salt and water balance and blood pressure. The scope of this article is to provide a summary of recent research developments directed towards understanding the molecular nature of atrial natriuretic peptides.

Injection of a peptide of 36 amino acids into virgin Drosophila females changes their reproductive properties drastically: males are rejected and egg laying is increased. The neuronal and physiological properties of the virgin state are replaced by a new pattern of behavior and stimulation of egg production and deposition. Under natural conditions, the peptide is synthesized by the male and transferred into the female during copulation. The sex‐peptide, therefore, can be considered as a pheromone. In this review, I shall limit (...) my discussion to Drosophila melanogaster. (shrink)

It has been convincingly shown that peptides play important roles in the regulation and maintenance of a variety of tissues and organs in living animals. However, little is known concerning the potential role of peptides as signaling molecules in developmental processes. In Hydra, there is circumstantial evidence that small diffusible molecules act as morphogens in the regulation of patterning processes. In order to view the entire spectrum of peptide signaling molecules, we initiated a project aiming at the systematic (...) identification of peptide signaling molecules in Hydra. In this review, we describe three peptide signaling molecules and one family of peptides that function as signaling molecules in the processes of axial pattern formation and neuron differentiation in Hydra. These peptides are produced by epithelial cells and are therefore termed “epitheliopeptides”. We discuss the importance of epitheliopeptides in developmental processes within a subset of hydrozoans. (shrink)

Amyloid β peptide (βA4) accumulates as plaques in the brains of individuals with Alzheimer's disease and Down's syndrome, and may contribute to the cognitive decline that is a feature of these diseases. βA4 is a normal product of cell metabolism, derived from the amyloid precursor protein (APP), but the biological functions of these molecules are not fully known. A hypothetical, descriptive model of the biological interrelationships between βA4 and APP is presented. APPS, the soluble form of APP, which is released (...) at the neuronal surface, and βA4 are envisaged as physiological ligands which have reciprocal paracrine effects on neuronal growth and neurite extension. Differential expression of these factors, manifest as changes in the APPS:βA4 ratio, may therefore have growth‐promoting or growth‐inhibiting effects on neurons. These effects may be mediated through separate cell‐surface interactions but common intracellular effector systems, such as calcium and protein kinase C. In turn, the intracellular events may control the relative production of each ligand from APP through negative feedback loops. Disturbances of these control mechanisms may permit pathological overproduction, and hence accumulation, of βA4. Such a model may also have therapeutic implications. (shrink)

The demonstration of opioid receptors by radioligand binding and the discovery of their endogenous peptide ligands has provided a new class of compounds that can be used for the development of novel opioids. The number of potential receptor targets for such opioids has been expanded by the identification of multiple opioid receptor types The development of highly selective opioid peptides using the principles of conformational restriction permits the analysis of the structure‐activity requirements of each receptor type, and is facilitating (...) the elucidation of the functional properties of the different opioid receptors. (shrink)

There is evidence that many peptide growth factors and hormones act in the intracellular space after either internalization or retention in their cells of synthesis. These factors, commonly called intracrines, are structurally diverse while sharing some common functional features. Reports of intracellular peptide hormone binding and action are reviewed here. Also, this laboratory has made proposals regarding the origin and actions of intracrines and these areas are further explored. Intracrine interactions and the relationship of intracrines to transcription factors are discussed. (...) The intracellular/intracrine renin–angiotensin system (iRAS) is reviewed to illustrate the intracrine analogue of a well‐established physiological system. The role of intracrine action in metazoan development is also considered. BioEssays 25:401–409, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The beta thymosins are a highly conserved family of strongly polar 5 kDa polypeptides that are widely distributed among vertebrate classes; most are now known to bind to monomeric actin and inhibit its polymerization. One beta thymosin, beta four, (Tβ4) is the predominant form in mammalian cells, present at up to 0.5 mM. Many species are known to produce at least two beta thymosin isoforms, in some cases in the same cell. Their expression can be separately regulated. When present outside (...) the cell, the N‐terminal tetrapeptide of beta four appears to affect cell cycle regulation; beta thymosins or smaller fragments derived from them may have additional regulatory functions. We suggest that many developmental changes in beta thymosin levels within cells and tissues may be related to changes in G‐actin pool size. (shrink)

Growth and morphogenesis in the mammary gland depend on locally derived growth factors such as those in the epidermal growth factor (EGF) superfamily. Cripto-1 (CR-1, human; Cr-1, mouse)—also known as teratocarcinoma-derived growth factor-1—is a novel EGF-related protein that induces branching morphogenesis in mammary epithelial cells both in vitro and in vivo and inhibits the expression of various milk proteins. In the mouse, Cr-1 is expressed in the growing terminal end buds in the virgin mouse mammary gland and expression increases during (...) pregnancy and lactation. Cr-1/CR-1 is overexpressed in mouse and human mammary tumors and inappropriate overexpression of Cr-1 in mouse mammary epithelial cells can lead to the clonal expansion of ductal hyperplasias. Taken together, this evidence suggests that Cr-1/CR-1 performs a role in normal mammary gland development and that it might contribute to the early stages of mouse mammary tumorigenesis and the pathobiology of human breast cancer. BioEssays 1999;21:61–70. Published 1999 John Wiley & Sons, Inc. (shrink)

In 1941, Gellhorn and colleagues reported experiments in which modest reductions of blood sugar were induced in hypophysectomized/adrenodemedullated (HA) rats by intraperitoneal injection of human blood. Based on the effects of intraperitoneal injections of known amounts of Lilly insulin on blood sugar in HA rats, Gellhorn estimated that the "insulin" content of normal human blood (collected two and a half hours "after luncheon") was 200uU/ml (Gellhorn, Feldman, and Allen 1941). However, discrepancies between measurements of plasma insulin concentration by in vitro (...) bioassays, which began in earnest in the late 1940s and early 1950s, and, beginning in 1960, by radioimmunoassay (RIA), intimated that insulin was not .. (shrink)

Zonulin is a physiological modulator of intercellular tight junctions, which upregulation is involved in several diseases like celiac disease (CeD). The polyQ gliadin fragment binds to the CXCR3 chemokine receptor that activates zonulin upregulation, leading to increased intestinal permeability in humans. Here, we report a general hypothesis based on the structural connection between the polyQ sequence of the immunogenic CeD protein, gliadin, and enteric coccidian parasites proteins. Firstly, a novel interaction pathway between the parasites and the host is described based (...) on the structural similarities between polyQ gliadin fragments and the parasite proteins. Secondly, a potential connection between coccidial infections as a novel environmental trigger of CeD is hypothesized. Therefore, this report represents a promising breakthrough for coccidian research and points out the potential role of coccidian parasites as a novel trigger of CeD that might define a preventive strategy for gluten‐related disorders in general. Also see the video abstract here: https://youtu.be/oMaQasStcFI. (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated (...) region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Mitochondria are increasingly being recognized as information hubs that sense cellular changes and transmit messages to other cellular components, such as the nucleus, the endoplasmic reticulum (ER), the Golgi apparatus, and lysosomes. Nonetheless, the interaction between mitochondria and the nucleus is of special interest because they both host part of the cellular genome. Thus, the communication between genome‐bearing organelles would likely include gene expression regulation. Multiple nuclear‐encoded proteins have been known to regulate mitochondrial gene expression. On the contrary, no mitochondrial‐encoded (...) factors are known to actively regulate nuclear gene expression. MOTS‐c (mitochondrial open reading frame of the 12S ribosomal RNA type‐c) is a recently identified peptide encoded within the mitochondrial 12S ribosomal RNA gene that has metabolic functions. Notably, MOTS‐c can translocate to the nucleus upon metabolic stress (e.g., glucose restriction and oxidative stress) and directly regulate adaptive nuclear gene expression to promote cellular homeostasis. It is hypothesized that cellular fitness requires the coevolved mitonuclear genomes to coordinate adaptive responses using gene‐encoded factors that cross‐regulate the opposite genome. This suggests that cellular gene expression requires the bipartite split genomes to operate as a unified system, rather than the nucleus being the sole master regulator. (shrink)

In this article, it is hypothesized that a fundamental chemical reactivity exists between some non‐lipid constituents of cellular membranes and ester‐based lipids, the significance of which is not generally recognized. Many peptides and smaller organic molecules have now been shown to undergo lipidation reactions in model membranes in circumstances where direct reaction with the lipid is the only viable route for acyl transfer. Crucially, drugs like propranolol are lipidated in vivo with product profiles that are comparable to those produced (...) in vitro. Some compounds have also been found to promote lipid hydrolysis. Drugs with high lytic activity in vivo tend to have higher toxicity in vitro. Deacylases and lipases are proposed as key enzymes that protect cells against the effects of intrinsic lipidation. The toxic effects of intrinsic lipidation are hypothesized to include a route by which nucleation can occur during the formation of amyloid fibrils. (shrink)

Current models of insulin binding to the insulin receptor (IR) propose (i) that there are two binding sites on the surface of insulin which engage with two binding sites on the receptor and (ii) that ligand binding involves structural changes in both the ligand and the receptor. Many of the features of insulin binding to its receptor, namely B‐chain helix interactions with the leucine‐rich repeat domain and A‐chain residue interactions with peptide loops from another part of the receptor, are also (...) seen in models of relaxin and insulin‐like peptide 3 binding to their receptors. We show that these principles can likely be extended to the group of mimetic peptides described by Schäffer and coworkers, which are reported to have no sequence identity with insulin. This review summarizes our current understanding of ligand‐induced activation of the IR and highlights the key issues that remain to be addressed. (shrink)