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1.
Yeung TM Chia LA Kosinski CM Kuo CJ 《Cellular and molecular life sciences : CMLS》2011,68(15):2513-2523
The gastrointestinal epithelium is a highly organised tissue that is constantly being renewed. In order to maintain homeostasis,
the balance between intestinal stem cell (ISC) self-renewal and differentiation must be carefully regulated. In this review,
we describe how the intestinal stem cell niche provides a unique environment to regulate self-renewal and differentiation
of ISCs. It has traditionally been believed that the mesenchymal myofibroblasts play an important role in the crosstalk between
ISCs and the niche. However, recent evidence in Drosophila and in vertebrates suggests that epithelial cells also contribute to the niche. We discuss the multiple signalling pathways
that are utilised to regulate stemness within the niche, including members of the Wnt, BMP and Hedgehog pathways, and how
aberrations in these signals lead to disruption of the normal crypt–villus axis. Finally, we also discuss how CDX1 and inhibition
of the Notch pathway are important in specifying enterocyte and goblet cell differentiation respectively. 相似文献
2.
The intestinal mucosa faces the challenge of regulating the balance between immune tolerance towards commensal bacteria, environmental
stimuli and food antigens on the one hand, and induction of efficient immune responses against invading pathogens on the other
hand. This regulatory task is of critical importance to prevent inappropriate immune activation that may otherwise lead to
chronic inflammation, tissue disruption and organ dysfunction. The most striking example for the efficacy of the adaptive
nature of the intestinal mucosa is birth. Whereas the body surfaces are protected from environmental and microbial exposure
during fetal life, bacterial colonization and contact with potent immunostimulatory substances start immediately after birth.
In the present review, we summarize the current knowledge on the mechanisms underlying the transition of the intestinal mucosa
during the neonatal period leading to the establishment of a stable, life-long host–microbial homeostasis. The environmental
exposure and microbial colonization during the neonatal period, and also the influence of maternal milk on the immune protection
of the mucosa and the role of antimicrobial peptides, are described. We further highlight the molecular mechanisms of innate
immune tolerance in neonatal intestinal epithelium. Finally, we link the described immunoregulatory mechanisms to the increased
susceptibility to inflammatory and infectious diseases during the neonatal period. 相似文献
3.
From axon–glial signalling to myelination: the integrating role of oligodendroglial Fyn kinase 总被引:1,自引:1,他引:0
Central nervous system myelination requires recognition and signalling processes between neuronal axons and oligodendrocytes.
Complex cellular rearrangements occur in myelination-competent oligodendrocytes requiring spatio-temporal control mechanisms.
Although the molecular repertoire is becoming increasingly transparent, the signalling mechanisms governing myelination initiation
are only poorly understood. The non-receptor tyrosine kinase Fyn has been implicated in axon–glial signal transduction and
in several cellular processes required for oligodendrocyte maturation and myelination. Here, we review oligodendroglial Fyn
signalling and discuss the role of Fyn in axon–glia interaction mediating myelination. 相似文献
4.
Endoplasmic reticulum stress responses 总被引:7,自引:0,他引:7
Schröder M 《Cellular and molecular life sciences : CMLS》2008,65(6):862-894
In homeostasis, cellular processes are in a dynamic equilibrium. Perturbation of homeostasis causes stress. In this review
I summarize how perturbation of three major functions of the endoplasmic reticulum (ER) in eukaryotic cells–protein folding,
lipid and sterol biosynthesis, and storing intracellular Ca2+ – causes ER stress and activates signaling pathways collectively termed the unfolded protein response (UPR). I discuss how
the UPR reestablishes homeostasis, and summarize our current understanding of how the transition from protective to apoptotic
UPR signaling is controlled, and how the UPR induces inflammatory signaling.
Received 21 August 2007; received after revision 26 October 2007; accepted 29 October 2007 相似文献
5.
Peutz-Jeghers syndrome (PJS, OMIM 175200) is an unusual inherited intestinal polyposis syndrome associated with distinct peri-oral
blue/black freckling [1–9]. Variable penetrance and clinical heterogeneity make it difficult to determine the exact frequency
of PJS [4]. PJS is a cancer predisposition syndrome. Affected individuals are at high risk for intestinal and extra-intestinal
cancers. In 1997, linkage studies mapped PJS to chromosome 19p [10, 11], and subsequently a serine/threonine kinase gene defect
(LKB1) was noted in a majority of PJS cases [12, 13]. A phenotypically similar syndrome has been produced in an LKB1 mouse
knockout model [14–18]. Several PJS kindred without LKB1 mutations have been described, suggesting other PJS loci [19–22].
The management of PJS is complex and evolving. New endoscopic technologies may improve management of intestinal polyposis.
Identification of specific genetic mutations and their targets will more accurately assess the clinical course, and help gage
the magnitude of cancer risk for affected individuals.
Received 20 February 2006; received after revision 5 May 2006; accepted 15 June 2006 相似文献
6.
Epidemiological studies establish a link between Type 2 diabetes (T2DM) and Alzheimer’s disease (AD), both leading causes
of morbidity and mortality in the elderly. These diseases also share clinical and biochemical features suggesting common pathogenic
mechanisms. Specifically, both are amyloidoses as they are characterized by fibrillar protein aggregates – amylin in T2DM
pancreatic islets, and β-amyloid (Aβ) and neurofibrillary tangles (NFTs) in AD brain. Amylin aggregation is associated with
pancreatic β-cell loss, and Aβ and NFT formation with neuronal cell loss. We discuss the possibility that amylin and Aβ exert
their toxicity by similar mechanisms, with components of the pathocascades shared, and that therapies based on amyloidogenic
properties are beneficial for both T2DM and AD.
Received 27 January 2009; received after revision 17 February 2009; accepted 23 February 2009 相似文献
7.
Sabine D. Jordan A. Christine Könner Jens C. Brüning 《Cellular and molecular life sciences : CMLS》2010,67(19):3255-3273
The central nervous system (CNS) is capable of gathering information on the body’s nutritional state and it implements appropriate
behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures
the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related
feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates
that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal
circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus,
to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the
development of obesity and type 2 diabetes mellitus. 相似文献
8.
Apolipoprotein E (apoE) ɛ4 allele is a genetic risk factor for late-onset familial and sporadic Alzheimer’s disease (AD).
In the central nervous system, apoE is secreted mainly by astrocytes as a constituent of high-density lipoproteins. A recent
study using apoE knockout mice provided strong evidence that apoE promotes cerebral deposition of amyloid β protein (Aβ).
However, no clear explanation of the pathogenesis of apoE-induced AD has been provided. Here we discuss two possible mechanisms
by which apoE might enhance Aβ deposition. One is the intracellular pathway in which apoE is internalized by neurons and induces
lysosomal accumulation of Aβ and amyloidogenic APP (amyloid precursor protein) fragments, leading to neuronal death. The other
is the extracellular pathway in which apoE-containing lipoproteins are trapped by Aβ1–42 deposits mobilizing soluble Aβ peptides
and consequently enlarge amyloid plaques. These two mechanisms may operate at different stages of AD pathogenesis and suggest
a chaperone-like function for the apoE molecule.
Received 4 February 1999; received after revision 9 April 1999; accepted 23 April 1999 相似文献
9.
Summary During the regression of exocrine pancreas caused by a diet poor in protides, an organic iron compound accumulates at the end of intestinal villi: small granules in the upper part of enterocytes, larger particles in macrophages of the connective axis. Alkaline phosphatase activity disappears from the striated border of the enterocytes concerned. 相似文献
10.
Ouellette AJ 《Cellular and molecular life sciences : CMLS》2011,68(13):2215-2229
Paneth cells at the base of small intestinal crypts of Lieberkühn secrete high levels of α-defensins in response to cholinergic
and microbial stimuli. Paneth cell α-defensins are broad spectrum microbicides that function in the extracellular environment
of the intestinal lumen, and they are responsible for the majority of secreted bactericidal peptide activity. Paneth cell
α-defensins confer immunity to oral infection by Salmonella enterica serovar Typhimurium, and they are major determinants of the composition of the small intestinal microbiome. In addition to
host defense molecules such as α-defensins, lysozyme, and Pla2g2a, Paneth cells also produce and release proinflammatory mediators
as components of secretory granules. Disruption of Paneth cell homeostasis, with subsequent induction of endoplasmic reticulum
stress, autophagy, or apoptosis, contributes to inflammation in diverse genetic and experimental mouse models. 相似文献
11.
Endocannabinoids and β-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels 总被引:3,自引:0,他引:3
van der Stelt M Mazzola C Esposito G Matias I Petrosino S De Filippis D Micale V Steardo L Drago F Iuvone T Di Marzo V 《Cellular and molecular life sciences : CMLS》2006,63(12):1410-1424
We investigated the involvement of endocannabinoids in the control of neuronal damage and memory retention loss in rodents
treated with the β-amyloid peptide (1–42) (BAP). Twelve days after stereotaxic injection of BAP into the rat cortex, and concomitant
with the appearance in the hippocampus of markers of neuronal damage, 2-arachidonoyl glycerol, but not anandamide, levels
were enhanced in the hippocampus. VDM-11 (5 mg/kg, i.p.), an inhibitor of endocannabinoid cellular reuptake, significantly
enhanced rat hippocampal and mouse brain endocannabinoid levels when administered sub-chronically starting either 3 or 7 days
after BAP injection and until the 12–14th day. VDM-11 concomitantly reversed hippocampal damage in rats, and loss of memory
retention in the passive avoidance test in mice, but only when administered from the 3rd day after BAP injection. We suggest
that early, as opposed to late, pharmacological enhancement of brain endocannabinoid levels might protect against β-amyloid
neurotoxicity and its consequences.
Received 26 January 2006; received after revision 24 March 2006; accepted 12 April 2006 相似文献
12.
The murine epidermis contains resident T cells that express a canonical γδ TCR and arise from fetal thymic precursors. These
cells are termed dendritic epidermal T cells (DETC) and use a TCR that is restricted to the skin in adult animals. DETC produce
low levels of cytokines and growth factors that contribute to epidermal homeostasis. Upon activation, DETC can secrete large
amounts of inflammatory molecules which participate in the communication between DETC, neighboring keratinocytes and langerhans
cells. Chemokines produced by DETC may recruit inflammatory cells to the epidermis. In addition, cell–cell mediated immune
responses also appear important for epidermal–T cell communication. Information is provided which supports a crucial role
for DETC in inflammation, wound healing, and tumor surveillance. 相似文献
13.
Schmidt T Ben-Batalla I Schultze A Loges S 《Cellular and molecular life sciences : CMLS》2012,69(9):1391-1414
Ample clinical and preclinical evidence indicates that macrophages interact with tumor cells as well as with virtually all
populations of host cells present in the tumor microenvironment. This crosstalk can strongly promote malignancy, but also
has in principle the potential to inhibit tumor growth. Thus, it is of the utmost importance to improve our understanding
of the mechanisms driving the pro- and antimalignant behavior of tumor-associated macrophages (TAMs) in order to develop better
anticancer therapies. In this review, we discuss the biological consequences of reciprocal interactions between TAMs, cancer
cells, endothelial cells, fibroblasts and other leukocyte subfractions within tumors. It was recently elucidated that tumors
specifically educate macrophages to secrete growth arrest-specific gene 6 (Gas6), the common ligand of the Tyro3, Axl, Mer
receptor (TAMR) family. In turn, Gas6 fosters tumor growth by promoting cancer cell proliferation. Therefore, the Gas6–TAMR
axis might represent a novel target for disrupting tumor–macrophage crosstalk. We summarize here what is known about TAMR
and their ligands in (human) cancer biology. In order to shed more light on the role of macrophages in human cancer, we additionally
provide an overview of what is currently known about the prognostic impact of TAMs in human cancer. 相似文献
14.
Eleonora Dondossola Anna Gasparri Angela Bachi Renato Longhi Marie-Hélène Metz-Boutigue Bruno Tota Karen B. Helle Flavio Curnis Angelo Corti 《Cellular and molecular life sciences : CMLS》2010,67(12):2107-2118
Fibroblast adhesion can be modulated by proteins released by neuroendocrine cells and neurons, such as chromogranin A (CgA)
and its N-terminal fragment vasostatin-1 (VS-1, CgA1–78). We have investigated the mechanisms of the interaction of VS-1 with fibroblasts and of its pro-adhesive activity and have
found that the proadhesive activity of VS-1 relies on its interaction with the fibroblast membrane via a phospholipid-binding
amphipathic α-helix located within residues 47–66, as well as on the interaction of the adjacent C-terminal region 67–78,
which is structurally similar to ezrin–radixin–moesin-binding phosphoprotein 50 (a membrane-cytoskeleton adapter protein),
with other cellular components critical for the regulation of cell cytoskeleton. 相似文献
15.
Xuezhi Kang Dongman Chao Quanbao Gu Guanghong Ding Yingwei Wang Gianfranco Balboni Lawrence H. Lazarus Ying Xia 《Cellular and molecular life sciences : CMLS》2009,66(21):3505-3516
Hypoxic/ischemic disruption of ionic homeostasis is a critical trigger of neuronal injury/death in the brain. There is, however,
no promising strategy against such pathophysiologic change to protect the brain from hypoxic/ischemic injury. Here, we present
a novel finding that activation of δ-opioid receptors (DOR) reduced anoxic Na+ influx in the mouse cortex, which was completely blocked by DOR antagonism with naltrindole. Furthermore, we co-expressed
DOR and Na+ channels in Xenopus oocytes and showed that DOR expression and activation indeed play an inhibitory role in Na+ channel regulation by decreasing the amplitude of sodium currents and increasing activation threshold of Na+ channels. Our results suggest that DOR protects from anoxic disruption of Na+ homeostasis via Na+ channel regulation. These data may potentially have significant impacts on understanding the intrinsic mechanism of neuronal
responses to stress and provide clues for better solutions of hypoxic/ischemic encephalopathy, and for the exploration of
acupuncture mechanism since acupuncture activates opioid system. 相似文献
16.
Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons 总被引:6,自引:1,他引:5
Chronic gestational exposure to ethanol has profound adverse effects on brain development. In this regard, studies using
in vitro models of ethanol exposure demonstrated impaired insulin signaling mechanisms associated with increased apoptosis
and reduced mitochondrial function in neuronal cells. To determine the relevance of these findings to fetal alcohol syndrome,
we examined mechanisms of insulin-stimulated neuronal survival and mitochondrial function using a rat model of chronic gestational
exposure to ethanol. In ethanol-exposed pups, the cerebellar hemispheres were hypoplastic and exhibited increased apoptosis.
Isolated cerebellar neurons were cultured to selectively evaluate insulin responsiveness. Gestational exposure to ethanol
inhibited insulin-stimulated neuronal viability, mitochondrial function, Calcein AM retention (membrane integrity), and GAPDH
expression, and increased dihydrorosamine fluorescence (oxidative stress) and pro-apoptosis gene expression (p53, Fas-receptor,
and Fas-ligand). In addition, neuronal cultures generated from ethanol-exposed pups had reduced levels of insulin-stimulated
Akt, GSK-3β, and BAD phosphorylation, and increased levels of non-phosphorylated (activated) GSK-3β and BAD protein expression.
The aggregate results suggest that insulin-stimulated central nervous system neuronal survival mechanisms are significantly
impaired by chronic gestational exposure to ethanol, and that the abnormalities in insulin signaling mechanisms persist in
the early postnatal period, which is critical for brain development.
Received 21 January 2002; received after revision 28 February 2002; accepted 25 March 2002 相似文献
17.
Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated pore loop channels. HCN channels are unique among
vertebrate voltage-gated ion channels, in that they have a reverse voltage-dependence that leads to activation upon hyperpolarization.
In addition, voltage-dependent opening of these channels is directly regulated by the binding of cAMP. HCN channels are encoded
by four genes (HCN1–4) and are widely expressed throughout the heart and the central nervous system. The current flowing through
HCN channels, designated Ih or If, plays a key role in the control of cardiac and neuronal rhythmicity (“pacemaker current”). In addition, Ih contributes to several other neuronal processes, including determination of resting membrane potential, dendritic integration
and synaptic transmission. In this review we give an overview on structure, function and regulation of HCN channels. Particular
emphasis will be laid on the complex roles of these channels for neuronal function and cardiac rhythmicity.
Received 22 August 2008; received after revision 22 September 2008; accepted 24 September 2008 相似文献
18.
19.
Gabriela Brumatti Marika Salmanidis Paul G. Ekert 《Cellular and molecular life sciences : CMLS》2010,67(10):1619-1630
Cytokines and growth factors play a crucial role in the maintenance of haematopoietic homeostasis. They transduce signals
that regulate the competing commitments of haematopoietic stem cells, quiescence or proliferation, retention of stem cell
pluripotency or differentiation, and survival or demise. When the balance between these commitments and the requirements of
the organisms is disturbed, particularly when it favours survival and proliferation, cancer may result. Cell death provoked
by loss of growth factor signalling is regulated by the Bcl-2 family of apoptosis regulators, and thus survival messages transduced
by growth factors must regulate the activity of these proteins. Many aspects of direct interactions between cytokine signalling
and regulation of apoptosis remain elusive. In this review, we explore the mechanisms by which cytokines, in particular Interleukin-3
and granulocyte–macrophage colony-stimulating factor, promote cell survival and suppress apoptosis as models of how cytokine
signalling and apoptotic pathways intersect. 相似文献
20.
Animals, ranging from basal metazoans to primates, are host to complex microbial ecosystems; engaged in a symbiotic relationship
that is essential for host physiology and homeostasis. Epithelial surfaces vary in the composition of colonizing microbiota
as one compares anatomic sites, developmental stages and species origin. Alterations of microbial composition likely contribute
to susceptibility to several distinct diseases. The forces that shape the colonizing microbial composition are the focus of
much current investigation, and it is evident that there are pressures exerted both by the host and the external environment
to mold these ecosystems. The focus of this review is to discuss recent studies that demonstrate the critical importance of
host factors in selecting for its microbiome. Greater insight into host–microbiome interactions will be essential for understanding
homeostasis at mucosal surfaces, and developing useful interventions when homeostasis is disrupted. 相似文献