Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of Parkinson's disease is not known. Nevertheless, a significant body of biochemical data from human brain autopsy studies and from animal models points to an ongoing process of oxidative stress in the substantia nigra, which could initiate dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary event. Oxidative stress, as induced by the neurotoxins 6-hydroxydopamine and MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), has been used in animal models to investigate the process of neurodegeneration to facilitate the development of antioxidant, neuroprotective drugs. It is apparent in these animal models that radical scavengers, iron chelators, dopamine agonists, nitric oxide synthase inhibitors and certain calcium channel antagonists provide neuroprotection against such toxins if given prior to the insult. Furthermore, recent work from human and animal studies has provided evidence of an inflammatory process. This expresses itself as proliferation of activated microglia in the substantia nigra, activation and translocation of transcription factors and neurotrophic factor (NF), kappa-beta and elevation of cytotoxic cytokines, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. Both radical scavengers and iron chelators prevent lipopolysaccharide (LPS) and iron-induced activation of NF kappa-beta. If an inflammatory response is involved in Parkinson's disease, it would be logical to consider antioxidants and the newly developed, non-steroidal, anti-inflammatory drugs such as cyclo-oxygenase (COX2) inhibitors as a form of treatment. However, to date there has been little or no success in the clinical treatment of neurodegenerative diseases (for example, Parkinson's disease, ischaemia etc.) where neurons die, while in animal models the same drugs provide neuroprotection. This may indicate that either the animal models employed do not reflect the events in neurodegenerative diseases, or that because neuronal death involves a cascade of events, a single neuroprotective drug is not effective. Thus, consideration should be given to multi-neuroprotective drug therapy in Parkinson's disease, similar to the approach taken in AIDS and cancer therapy.
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PMID:MPTP and 6-hydroxydopamine-induced neurodegeneration as models for Parkinson's disease: neuroprotective strategies. 1099 72

This study was performed to examine the effects of the calcium channel blockers, nifedipine, amlodipine, diltiazem, and verapamil on the activation of the transcription factor NF-kappaB. A549 cells, a human epithelium-like lung carcinoma cell line, were transfected with the NF-kappaB reporter plasmid, which contains the luciferase gene driven by promoters containing a TATA element and 5 copies of the kappaB cis-acting element, and co-transfected with 0.2 microg of pSV2neo vector using LipofectAMINE. Nifedipine significantly decreased the expression of luciferase protein stimulated with IL-1beta (1 ng/mL) compared with controls: 80+/-4% at 3 micromol/L, 47+/-2% at 10 micromol/L and 30+/-2% at 30 micromol/L (each, n=3, p<0.0001). The inhibitory effect of nifedipine on promoter activity was concentration-dependent, with a maximal effect obtained at 30 micromol/L. In contrast, high concentrations (30 micromol/L) of amlodipine, diltiazem or verapamil decreased promoter activity to only 89+/-3%, 90+/-3% or 87+/-2% of control, respectively. A comparable inhibitory effect of nifedipine was observed when cells were stimulated with tumor necrosis factor (TNF)-alpha (50 ng/mL), or phorbol 12-myristate 13-acetate (PMA, 100 ng/mL). Electrophoretic mobility shift assay by lipopolysaccharide stimulation, using the RAW 264.7 macrophage cell line, also showed inhibition of NF-kappaB activation by nifedipine in concentrations of 30 and 50 micromol/L. Nifedipine possesses the unique property of inhibiting NF-kappaB, which may be independent of its calcium channel blocking activity, and may, in part, explain its immunosuppressive effect.
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PMID:Nifedipine inhibits activation of transcription factor NF-kappaB. 1110 67

The effects of nifedipine on the death and proliferation of gingival fibroblasts were investigated to elucidate the mechanism of gingival overgrowth that is associated with chronic administration of Ca2+ channel blockers. The number of adhered viable and dead fibroblasts obtained from healthy human gingiva increased after confluence, whereas cell death was inhibited by nifedipine in a concentration-dependent manner. A similar inhibition was also observed in the presence of other calcium channel blockers, such as nicardipine, diltiazem, and verapamil. When gingival fibroblasts were co-cultured with RAW264 (macrophage-like) cells, lipopolysaccharide (LPS) caused the concentration-dependent death of fibroblasts. Nifedipine significantly inhibited the LPS-induced cell death. Although neither LPS nor N-ethyl-2-(1-ethyl-2-hydroxy-2-nitroso-hydrazino)-ethanamine, a nitric oxide donor, directly caused fibroblast death, 3-morpholino-sydnonimine (SIN-1), a peroxynitrite donor, induced fibroblast death, regardless of the presence of RAW cells. The cell death induced by SIN-1 was not affected by nifedipine treatment. LPS stimulation caused an increase in the immunoreactivity of inducible nitric oxide synthase (iNOS) and in the nitrite concentration in the incubation medium of RAW cells. The induction of iNOS was completely prevented by the incubation with nifedipine. The inhibition by nifedipine of nitrite production in RAW cells was also observed after treatment with nicardipine, but not with either diltiazem or verapamil. Therefore, the inhibition by nifedipine of both adherence- and LPS-stimulated macrophage-induced death of fibroblasts may be the mechanism of gingival overgrowth seen during chronic treatment with Ca(2+) channel blockers.
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PMID:Inhibition by nifedipine of adherence- and activated macrophage-induced death of human gingival fibroblasts. 1124 57

Treatment with lipopolysaccharide (LPS) for 72 h was shown to dose-dependently increase nitric oxide production from 6-day-old retinal cultures. Cell death, as determined by lactate dehydrogenase (LDH) release and an increase in neuronal labelling for TUNEL, was elevated concurrently. During treatment there was an increase of both inducible nitric oxide synthase and glial fibrillary acidic protein labelling in glial cells and a reduction in the number of gamma-aminobutyric acid-positive neurones. The NOS inhibitors, N-nitro-L-arginine methyl ester, dexamethasone and indomethacin potently inhibited both nitric oxide stimulation and cell death caused by LPS. In this study, the beta(2)- (ICI-18551), beta(1)- (betaxolol) and mixed beta(1)/beta(2)- (timolol, metipranolol) adrenergic receptor antagonists were all shown to attenuate LPS-induced LDH release from these cultures, but to have no effect on LPS-stimulated nitric oxide production. This effect was mimicked by the calcium channel blocker, nifedipine. Interestingly, the beta-adrenergic receptor agonists, salbutamol, arterenol and isoproterenol were also able to attenuate cell death caused by LPS. Moreover, these compounds also inhibited LPS-stimulated nitric oxide release. These studies suggest that LPS stimulates nitric oxide release from cultured retinal glial cells and that this process leads to neurone death. beta-adrenergic receptor agonists prevent the effects of LPS by inhibiting the stimulation of nitric oxide production. The data also suggest that beta-adrenergic receptor antagonists can attenuate LPS-induced death of neurones, but that these compounds act in a manner that is neurone-dependent, is mimicked by blockade of calcium channels and is independent of the stimulation of nitric oxide release.
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PMID:Beta-adrenergic receptor agonists and antagonists counteract LPS-induced neuronal death in retinal cultures by different mechanisms. 1296 22

Toll-like receptors (TLRs) have been previously shown to mediate oxidative burst in chicken heterophils. This study was conducted to begin to map the molecular pathways that regulate TLR-mediated oxidative burst. Peripheral blood heterophils from neonatal chicks were isolated and exposed to known inhibitors of signal transduction pathways for either 20 min (genistein, verapamil, or chelerythrine) or 120 min (pertussis toxin) at 39 degrees C. The cells were then stimulated for 30 min at 39 degrees C with Salmonella enteritidis lipopolysaccharide (LPS) or Staphylococcus aureus lipoteichoic acid (LTA). The heterophil oxidative burst was then quantitated by luminol-dependent chemiluminescence (LDCL). Genistein (a tyrosine kinase inhibitor), verapamil (a calcium channel blocker), chelerythrine (a protein kinase C inhibitor), and pertussis toxin (a G-protein inhibitor) significantly reduced LPS-stimulated oxidative burst in chicken heterophils by 34, 50, 63, and 51%, respectively. Although genistein had a statistically significant effect on reducing LPS-stimulated LDCL biologically it seems to play only a minor role within the oxidative burst pathway. Heterophils stimulated with the gram-positive TLR agonist, LTA, activated a different signal transduction pathway since chelerythrine was the only inhibitor that significantly reduced (72%) LTA-stimulated oxidative burst. These findings demonstrate that distinct signal transduction pathways differentially regulate the stimulation of oxidative burst in avian heterophils. Pertussis toxin-sensitive, protein kinase C-dependent, Ca(++)-dependent G proteins appear to regulate oxidative burst of avian heterophils stimulated with gram-negative agonist LPS; whereas, a protein kinase C-dependent signal transduction pathway plays the major role activating the oxidative burst of avian heterophils stimulated with gram-positive agonists. The distinct differences in the response of heterophils to these two agonists illustrate the specificity of TLRs to pathogen-associated molecular patterns (PAMP)s.
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PMID:Differential activation of signal transduction pathways mediating oxidative burst by chicken heterophils in response to stimulation with lipopolysaccharide and lipoteichoic acid. 1452 75

Although considered an immunologically privileged site, the central nervous system (CNS) can display significant inflammatory responses, which may play a pathogenic role in a number of neurological diseases. Microglia appear to be particularly important for initiating and sustaining CNS inflammation. These cells exist in a quiescent form in the normal CNS, but acquire macrophage-like properties (including active phagocytosis, upregulation of proteins necessary for antigen presentation, and production of proinflammatory cytokines) after stimulation with inflammatory substances such as lipopolysaccharide (LPS). Recent studies have focused on elucidating the role of neurons in the regulation of microglial inflammatory responses. In the present study, we demonstrate, using neuron-microglial cocultures, that neurons are capable of inhibiting LPS-induced tumor necrosis factor-alpha (TNF-alpha) production by microglia. This inhibition appears to be dependent on secretion of substances at axon terminals, as treatment with the presynaptic calcium channel blocker omega-conotoxin abolishes this inhibitory effect. Moreover, we show that conditioned medium from neuronal cultures similarly inhibits microglial TNF-alpha production, which provides additional evidence that neurons secrete inhibitory substances. We previously demonstrated that the transmembrane protein-tyrosine phosphatase CD45 plays an important role in negatively regulating microglial activation. The recent characterization of CD22 as an endogenous ligand of this receptor led us to investigate whether neurons express this protein. Indeed, we were able to demonstrate CD22 mRNA and protein expression in cultured neurons and mouse brain, using reverse transcriptase-polymerase chain reaction and antibody-based techniques. Furthermore, we show that neurons secrete CD22, which functions as an inhibitor of microglial proinflammatory cytokine production.
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PMID:Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. 1509 67

Diltiazem is a calcium channel blocker that suppresses the activation of a variety of immune cells, such as T and B cells, NK cells, monocytes and dendritic cells (DCs). It has been used in the treatment of cardiovascular disorders and has been widely included in clinical protocols to prevent rejection after kidney transplantation. In line with these data, we previously showed that diltiazem directly affects maturation of human DCs and the production of IL-12. Here, we extended our analysis studying the effect of diltiazem on the transcription of IL-12 p35 and p40 subunits focusing on the activity of nuclear factor-kappa B (NF-kappa B). A marked reduction of NF-kappa B binding to the kappa B sequences present within the p35 and p40 subunit promoters was observed in diltiazem-treated DCs following the stimulation with lipopolysaccharide (LPS) or CD40L. In order to examine the mechanisms by which NF-kappa B binding activity is reduced by diltiazem, we analyzed the NF-kappa B inhibitor, I kappa B alpha. No significant differences were observed in the phosphorylation and/or the degradation of I kappa B alpha. On the other hand, the subcellular distribution of NF-kappa B subunits was clearly affected in diltiazem-treated DCs following LPS stimulation, with a reduced nuclear translocation of p65, and RelB, and a nuclear accumulation of p50 subunit. Thus, all together, our data provided evidence that in addition to the inhibition of p65/p50 nuclear translocation, the selective induction and translocation of p50/p50 homodimers is an important mechanism by which diltiazem inhibits NF-kappa B activity, and in turn, IL-12 expression.
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PMID:Inhibition of interleukin-12 expression in diltiazem-treated dendritic cells through the reduction of nuclear factor-kappa B transcriptional activity. 1565 34

The crude extract of Achillea millefolium (Am.Cr) was studied for its possible hepatoprotective effect against d-galactosamine (d-GalN) and lipopolysaccharide (LPS) induced hepatitis in mice and antispasmodic effect in isolated gut preparations to rationalize some of the folklore uses. Co-administration of d-GalN (700 mg/kg) and LPS (25 microg/kg) produced 100% mortality in mice. Pre-treatment of animals with Am.Cr (300 mg/kg) reduced the mortality to 40%. Co-administration of d-GalN (700 mg/kg) and LPS (1 microg/kg) significantly raised the plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with values in the control group (p < 0.05). Pre-treatment of mice with Am.Cr (150-600 mg/kg) significantly prevented the toxins induced rise in plasma ALT and AST (p < 0.05). The hepatoprotective effect of Am.Cr was further verified by histopathology of the liver, which showed improved architecture, absence of parenchymal congestion, decreased cellular swelling and apoptotic cells, compared with the toxin group of animals. In isolated rabbit jejunum preparations, Am.Cr caused a concentration-dependent (0.3-10 mg/mL) relaxation of both spontaneous and K(+)-induced contractions as well as shifting the Ca(++) concentration-response curves (CRCs) to the right, similar to that caused by verapamil. These results indicate that the crude extract of Achillea millefolium exhibits a hepatoprotective effect, which may be partly attributed to its observed calcium channel blocking activity.
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PMID:Studies on hepatoprotective, antispasmodic and calcium antagonist activities of the aqueous-methanol extract of Achillea millefolium. 1661 41

Diphenylhydantoin (DPH) is widely used as an anticonvulsant drug. We examined the effects of DPH on osteoclast differentiation and function using in vivo and in vitro assay systems. Transgenic mice overexpressing a soluble form of RANKL (RANKL Tg) exhibited increased osteoclastic bone resorption. Injection of DPH into the subcutaneous tissue overlying calvaria of RANKL Tg mice suppressed the enhanced resorption in the calvaria. In co-cultures of mouse osteoblasts and bone marrow cells, DPH inhibited lipopolysaccharide (LPS)-induced osteoclast formation. DPH affected neither the mRNA expression of RANKL and osteoprotegerin nor the growth of mouse osteoblasts in culture. On the other hand, DPH inhibited the RANKL-induced formation of osteoclasts in cultures of mouse bone marrow-derived macrophages (BMMphis) and of human peripheral blood-derived CD14(+) cells. DPH concealed LPS-induced bone resorption in mouse calvarial organ cultures and inhibited the pit-forming activity of mouse osteoclasts cultured on dentine slices. DPH suppressed the RANKL-induced calcium oscillation and expression of nuclear factor of activated T cells c1 (NFATc1) and c-fos in BMMphis. Moreover, DPH inhibited the RANKL-induced nuclear localization and auto-amplification of NFATc1 in mature osteoclasts. Both BMMphis and osteoclasts expressed mRNA of a T-type calcium channel, Cav3.2, a target of DPH. Blocking the expression of Cav3.2 by short hairpin RNAs significantly suppressed RANKL-induced osteoclast differentiation. These results suggest that DPH inhibits osteoclast differentiation and function through suppression of NFATc1 signaling. The topical application of DPH may be a therapeutic treatment to prevent bone loss induced by local inflammation such as periodontitis.
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PMID:Diphenylhydantoin inhibits osteoclast differentiation and function through suppression of NFATc1 signaling. 1929 14

Neuroinflammation plays an important role in the progression of Alzheimer's disease (AD) and is characterized by the presence of activated microglia. We investigated whether chronic neuroinflammation affects the induction of N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and NMDAR-independent LTP which is expressed by voltage-dependent calcium channel (VDCC). Chronic neuroinflammation was induced by administration of lipopolysaccharide (LPS) (28 days, 0.35 microg/h) to the fourth ventricle. The Morris water maze test was conducted to measure the memory impairment and then excitatory postsynaptic potentials were recorded extracelluarly from stratum radiatum in the rat hippocampal CA1 area to examine the changes in synaptic plasticity induced by LPS infusion. Chronic administration of LPS induced remarkable memory impairment. The field recording experiments revealed that the induction of both NMDAR-dependent LTP and NMDAR-independent LTP were impaired in the hippocampal Schaffer collateral-CA1 synapse in animals chronically infused with LPS. The present results show that chronic neuroinflammation can lead to the impaired spatial memory and attenuation of VDCC-dependent LTP as well as NMDAR-dependent LTP. The attenuation of synaptic plasticity may be caused by the impairment of both NMDAR and L-type Ca2+ via elevated levels of inflammatory proteins, which may underlie aspects of dementia.
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PMID:Chronic brain inflammation impairs two forms of long-term potentiation in the rat hippocampal CA1 area. 1942 26


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