Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biosynthesis of glycoconjugates such as N-glycoproteins and GPI-anchored proteins in eukaryotes and cell wall peptidoglycan and lipopolysaccharide in bacteria requires lipid intermediates to be flipped rapidly across the endoplasmic reticulum or bacterial cytoplasmic membrane (so-called biogenic membranes). Rapid flipping is also required to normalize the number of glycerophospholipids in the two leaflets of the bilayer as the membrane expands in a growing cell. Although lipids diffuse rapidly in the plane of the membrane, the intrinsic rate at which they flip across membranes is very low. Biogenic membranes possess dedicated lipid transporters or flippases to increase flipping to a physiologically sufficient rate. The flippases are "ATP-independent" and facilitate "downhill" transport. Most predicted biogenic membrane flippases have not been identified at the molecular level, and the few flippases that have been identified by genetic approaches have not been biochemically validated. Here we summarize recent progress on this fundamental topic and speculate on the mechanism(s) by which biogenic membrane flippases facilitate transbilayer lipid movement.
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PMID:Flipping lipids: why an' what's the reason for? 1968 62

The endoplasmic reticulum (ER) unfolded protein response (UPR) restores equilibrium to the ER, but prolonged expression of the UPR effector CHOP (GADD153) is cytotoxic. We found that CHOP expression induced by ER stress was suppressed by prior engagement of toll-like receptor (TLR) 3 or 4 through a TRIF-dependent pathway. TLR engagement did not suppress phosphorylation of PERK or eIF-2alpha, which are upstream of CHOP, but phospho-eIF-2alpha failed to promote translation of the CHOP activator ATF4. In mice subjected to systemic ER stress, pretreatment with low dose lipopolysaccharide (LPS), a TLR4 ligand, suppressed CHOP expression and apoptosis in splenic macrophages, renal tubule cells and hepatocytes, and prevented renal dysfunction and hepatosteatosis. This protective effect of LPS did not occur in Trif(-/-) mice or in wild-type mice in which CHOP expression was genetically restored. Thus, TRIF-mediated signals from TLRs selectively attenuate translational activation of ATF4 and its downstream target gene CHOP. We speculate that this mechanism evolved to promote survival of TLR-expressing cells that experience prolonged levels of physiological ER stress in the course of the host response to invading pathogens.
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PMID:Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling. 1985 86

Sepsis is characterized by systematic inflammation where oxidative damage plays a key role in organ failure. This study was designed to examine the impact of the antioxidant metallothionein (MT) on lipopolysaccharide (LPS)-induced cardiac contractile and intracellular Ca(2+) dysfunction, oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Mechanical and intracellular Ca(2+) properties were examined in hearts from FVB and cardiac-specific MT overexpression mice treated with LPS. Oxidative stress, activation of mitogen-activated protein kinase pathways (ERK, JNK and p38), ER stress, autophagy and inflammatory markers iNOS and TNFalpha were evaluated. Our data revealed enlarged end systolic diameter, decreased fractional shortening, myocyte peak shortening and maximal velocity of shortening/relengthening as well as prolonged duration of relengthening in LPS-treated FVB mice associated with reduced intracellular Ca(2+) release and decay. LPS treatment promoted oxidative stress (reduced glutathione/glutathione disulfide ratio and ROS generation). Western blot analysis revealed greater iNOS and TNFalpha, activation of ERK, JNK and p38, upregulation of ER stress markers GRP78, Gadd153, PERK and IRE1alpha, as well as the autophagy markers Beclin-1, LCB3 and Atg7 in LPS-treated mouse hearts without any change in total ERK, JNK and p38. Interestingly, these LPS-induced changes in echocardiographic, cardiomyocyte mechanical and intracellular Ca(2+) properties, ROS, stress signaling and ER stress (but not autophagy, iNOS and TNFalpha) were ablated by MT. Antioxidant N-acetylcysteine and the ER stress inhibitor tauroursodeoxycholic acid reversed LPS-elicited depression in cardiomyocyte contractile function. LPS activated AMPK and its downstream signaling ACC in conjunction with an elevated AMP/ATP ratio, which was unaffected by MT. Taken together, our data favor a beneficial effect of MT in the management of cardiac dysfunction in sepsis.
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PMID:Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsis. 1991 57

The expression of C/EBP homologous protein (CHOP), which is an endoplasmic reticulum (ER) stress-induced transcription factor, induces apoptosis. Our previous study demonstrated that lipopolysaccharide (LPS)-induced CHOP expression does not induce apoptosis, but activates a pro-IL-1beta activation process. However, the mechanism by which CHOP activates different pathways, depending on the difference in the inducing stimuli, remains to be clarified. The present study shows that LPS rapidly activates the ER function-protective pathway, but not the PERK pathway in macrophages. PERK plays a major role in CHOP induction, and other ER stress sensors-mediated pathways play minor roles. The induction of CHOP by LPS was delayed and weak, in comparison with CHOP induction by ER stress-inducer thapsigargin. In addition, LPS-pre-treatment or overexpression of ER chaperone, IgH chain binding protein (BiP), prevented ER stress-mediated apoptosis. LPS plus IFN-gamma-treated macrophages produce a larger amount of nitric oxide (NO) in comparison with LPS-treated cells. Treatment with the NO donor, SNAP (S-nitro-N-acetyl-dl-penicillamine), induces CHOP at an earlier period than LPS treatment. The depletion of NO retards CHOP induction and prevents apoptosis in LPS plus IFN-gamma-treated cells. We concluded that apoptosis is prevented in LPS-treated macrophages, because the ER function-protective mechanisms are induced before CHOP expression, and induction level of CHOP is low.
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PMID:Molecular mechanisms of the LPS-induced non-apoptotic ER stress-CHOP pathway. 1991 55

Organismal phylogeny depends on cell division, stasis, mutational divergence, cell mergers (by sex or symbiogenesis), lateral gene transfer and death. The tree of life is a useful metaphor for organismal genealogical history provided we recognize that branches sometimes fuse. Hennigian cladistics emphasizes only lineage splitting, ignoring most other major phylogenetic processes. Though methodologically useful it has been conceptually confusing and harmed taxonomy, especially in mistakenly opposing ancestral (paraphyletic) taxa. The history of life involved about 10 really major innovations in cell structure. In membrane topology, there were five successive kinds of cell: (i) negibacteria, with two bounding membranes, (ii) unibacteria, with one bounding and no internal membranes, (iii) eukaryotes with endomembranes and mitochondria, (iv) plants with chloroplasts and (v) finally, chromists with plastids inside the rough endoplasmic reticulum. Membrane chemistry divides negibacteria into the more advanced Glycobacteria (e.g. Cyanobacteria and Proteobacteria) with outer membrane lipolysaccharide and primitive Eobacteria without lipopolysaccharide (deserving intenser study). It also divides unibacteria into posibacteria, ancestors of eukaryotes, and archaebacteria-the sisters (not ancestors) of eukaryotes and the youngest bacterial phylum. Anaerobic eobacteria, oxygenic cyanobacteria, desiccation-resistant posibacteria and finally neomura (eukaryotes plus archaebacteria) successively transformed Earth. Accidents and organizational constraints are as important as adaptiveness in body plan evolution.
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PMID:Deep phylogeny, ancestral groups and the four ages of life. 2000 90

N,N-Dimethylformamide (DMF) is an organic solvent extensively used in industries such as synthetic leather, fibers and films, and induces liver toxicity and carcinogenesis. Despite a series of experimental and clinical reports on DMF-induced liver failure, the mechanism of toxicity is yet unclear. This study investigated whether DMF in combination with a low dose of hepatotoxicant enhances hepatotoxicity, and if so, on what mechanistic basis. Treatment of rats with either DMF (50-500mg/kg/day, for 3 days) or a single low dose of CCl(4) (0.2ml/kg) alone caused small increases in plasma transaminases and lactate dehydrogenase activities. However, combinatorial treatment of DMF with CCl(4) markedly increased blood biochemical changes. Histopathology confirmed the synergism in hepatotoxicity. Moreover, DMF+CCl(4) caused PARP cleavage and caspase-3 activation, but decreased the level of Bcl-xL, all of which confirmed apoptosis of hepatocytes. Consistently, DMF+CCl(4) treatment markedly increased lipid peroxidation. By contrast, treatment of DMF in combination with lipopolysaccharide, acetaminophen or d-galactosamine caused no enhanced hepatotoxicity. Given the link between endoplasmic reticulum (ER) dysfunction and cell death, ER stress response was monitored after DMF and/or CCl(4) treatment. Whereas either DMF or CCl(4) treatment alone marginally changed the expression levels of glucose-regulated protein 78 and 94 and phosphorylated PKR-like ER-localized eIF2alpha kinase, concomitant treatment with DMF and CCl(4) synergistically induced them with increases in glucose-regulated protein 78 and C/EBP homologous protein mRNAs. Our results demonstrate that DMF treatment in combination with CCl(4) synergistically increases hepatocyte death, which may be associated with the induction of severe ER stress.
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PMID:Synergistic hepatotoxicity of N,N-dimethylformamide with carbon tetrachloride in association with endoplasmic reticulum stress. 2009 84

Interleukin 13 (IL-13) has been shown to induce the death of activated microglia. We observed that IL-13, but not IL-4 or IL-10, significantly enhanced endoplasmic reticulum (ER) stress induction, apoptosis and death in microglia activated by lipopolysaccharide (LPS). IL-13 enhanced ER stress-regulated calpain activation and calpain-II expression in LPS-activated microglia. Calpain-II siRNA effectively reversed the IL-13 + LPS-activated caspase-12 activation. Expression of heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) was also increased in activated microglia, and this was effectively blocked by IL-13 and recombinant calpain. Both HO-1 inhibitor and PPAR-gamma antagonist augmented, but calpain inhibitor and PPAR-gamma agonists reversed, apoptosis induction in activated microglia. Transfection of PPAR-gamma siRNA effectively inhibited HO-1 protein expression in activated microglia. LPS stimulated transcriptional activation of HO-1 via an increase in PPAR-gamma DNA binding activity, which was reversed by IL-13. These results indicate that an ER stress-related calpain-down-regulated PPAR-gamma/HO-1 pathway is involved in the IL-13-enhanced activated death of microglia.
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PMID:IL-13 downregulates PPAR-gamma/heme oxygenase-1 via ER stress-stimulated calpain activation: aggravation of activated microglia death. 2022 86

It is known that Rab1 regulates the expression and function of beta-adrenoceptors (beta-ARs) in many cells. However, the effect of these changes in rat pulmonary microvascular endothelial cells (RPMVECs) is not known. In the present study, we investigated the role of Rab1, a Ras-like GTPase that coordinates protein transport from the endoplasmic reticulum (ER) to the Golgi body and regulates the cell-surface targeting and function of endogenous beta-ARs in RPMVECs in the presence of lipopolysaccharide (LPS). We found that lentivirus-driven expression of wild-type Rab1 (Rab1WT) in RPMVECs strongly enhanced the amount of beta-ARs on the cell surface, whereas the dominant-negative mutant Rab1N124I significantly attenuated beta-ARs expression on the cell surface. In addition, LPS stimulation significantly reduced beta-ARs expression on the cell surface in RPMVECs; however, this effect was reversed by over-expression of wild-type Rab1WT. Fluorescent microscopy analysis demonstrated that expression of Rab1N124I and Rab1 small interfering RNA (siRNA) significantly induced the accumulation of green fluorescent protein (GFP)-tagged beta(2)-AR in the ER. Consistent with their effects on beta-ARs export, Rab1WT and Rab1N124I differentially modified the beta-AR-mediated activation of extracellular signal-regulated kinase1/2 (ERK1/2). Importantly, over-expression of Rab1WT markedly reduced LPS-induced hyper-permeability of RPMVECs by increasing the expression of beta(2)-AR on the cell surface. These data reveal that beta-ARs function in RPMVECs could be modulated by manipulating beta-ARs traffic from the ER to the Golgi body. We propose the ER-to-Golgi transport as a regulatory site for control of permeability of RPMVECs.
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PMID:Rab1 GTPase promotes expression of beta-adrenergic receptors in rat pulmonary microvascular endothelial cells. 2041 17

Recent findings indicate that endoplasmic reticulum (ER) stress is significantly increased in adipose tissue of obese human subjects and is critical to the initiation and integration of pathways of inflammation and insulin action. But the factors inducing ER stress in human adipose tissue are unknown. The common factors increased in obesity and linked to insulin resistance are hyperglycaemia, hyperlipidemia and also endotoxemia. Therefore, our aims were to investigate: (1) the role of lipopolysaccharide (LPS), high glucose (HG) and saturated fatty acids (SFA) as inducers of ER stress in primary human adipocytes and (2) whether salicylate, a known anti-inflammatory compound, can alleviate this effect. Components of the ER stress pathways were studied in human abdominal subcutaneous (AbSc) adipose tissue (AT) from obese and lean. Following the culture and differentiation of primary human preadipocytes, these adipocytes were treated with LPS, HG, tunicamycin (Tun) and SFA either alone or in combination with sodium salicylate (Sal). Markers of ER stress were significantly increased in AbSc AT of obese. Differentiated human adipocytes treated with LPS, Tun, HG and SFA showed significant activation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and activating transcription factor 6 (ATF6) and their down-stream targets. Sal alleviated this effect and activated AktSer473 phosphorylation. This study presents important evidence that: (1) there is increased ER stress in adipose tissue of obese individuals, (2) LPS, hyperglycaemia and saturated fatty acids induce significant ER stress in primary human adipocytes and (3) this induction is alleviated by salicylate.
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PMID:Lipopolysaccharide, high glucose and saturated fatty acids induce endoplasmic reticulum stress in cultured primary human adipocytes: Salicylate alleviates this stress. 2051 57

Lipids orchestrate biological processes by acting remotely as signaling molecules or locally as membrane components that modulate protein function. Detailed insight into lipid function requires knowledge of the subcellular localization of individual lipids. We report an analysis of the subcellular lipidome of the mammalian macrophage, a cell type that plays key roles in inflammation, immune responses, and phagocytosis. Nuclei, mitochondria, endoplasmic reticulum (ER), plasmalemma, and cytoplasm were isolated from RAW 264.7 macrophages in basal and activated states. Subsequent lipidomic analyses of major membrane lipid categories identified 229 individual/isobaric species, including 163 glycerophospholipids, 48 sphingolipids, 13 sterols, and 5 prenols. Major subcellular compartments exhibited substantially divergent glycerophospholipid profiles. Activation of macrophages by the Toll-like receptor 4-specific lipopolysaccharide Kdo(2)-lipid A caused significant remodeling of the subcellular lipidome. Some changes in lipid composition occurred in all compartments (e.g., increases in the levels of ceramides and the cholesterol precursors desmosterol and lanosterol). Other changes were manifest in specific organelles. For example, oxidized sterols increased and unsaturated cardiolipins decreased in mitochondria, whereas unsaturated ether-linked phosphatidylethanolamines decreased in the ER. We speculate that these changes may reflect mitochondrial oxidative stress and the release of arachidonic acid from the ER in response to cell activation.
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PMID:Subcellular organelle lipidomics in TLR-4-activated macrophages. 2057 76


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