Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085437 (bacterial meningitis)
 4,038 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major aetiological agent of human bacterial meningitis is Neisseria meningitidis. During the course of disease and host colonization, the bacterium has to withstand limited oxygen availability. Nitrogen oxide and nitrogen oxyanions are thought to be present, which may constitute an alternative sink for electrons from the N. meningitidis respiratory chain. A partial denitrification pathway is encoded by the aniA nitrite reductase gene and the norB nitric oxide reductase gene. Analysis of the completed genome sequences of two N. meningitidis strains is used to generate a model for the membrane-associated respiratory chain of this organism. Analysis of aniA expression indicates it to be controlled primarily by oxygen and secondarily by nitrite. The ability of N. meningitidis to denitrify relies on microaerobic growth conditions. Here we show that under microaerobic conditions nitrite supplements oxygen as an alternative respiratory substrate.
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PMID:Microaerobic denitrification in Neisseria meningitidis. 1566 85

The human pathogen Neisseria meningitidis is the major causative agent of bacterial meningitis. The organism is usually treated as a strict aerobe and is cultured under fully aerobic conditions in the laboratory. We demonstrate here that although N. meningitidis fails to grow under strictly anaerobic conditions, under oxygen limitation the bacterium expresses a denitrification pathway (reduction of nitrite to nitrous oxide via nitric oxide) and that this pathway supplements growth. The expression of the gene aniA, which encodes nitrite reductase, is regulated by oxygen depletion and nitrite availability via transcriptional regulator FNR and two-component sensor-regulator NarQ/NarP respectively. Completion of the two-step denitrification pathway requires nitric oxide (NO) reduction, which proceeds after NO has accumulated during batch growth under oxygen-limited conditions. During periods of NO accumulation both nitrite and NO reduction are observed aerobically, indicating N. meningitidis can act as an aerobic denitrifier. However, under steady-state conditions in which NO is maintained at a low concentration, oxygen respiration is favoured over denitrification. NO inhibits oxidase activity in N. meningitidis with an apparent Ki NO = 380 nM measured in intact cells. The high respiratory flux to nitrite after microaerobic growth and the finding that accumulation of the denitrification intermediate NO inhibits oxygen respiration support the view that denitrification is a pathway of major importance in N. meningitidis.
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PMID:The pathogen Neisseria meningitidis requires oxygen, but supplements growth by denitrification. Nitrite, nitric oxide and oxygen control respiratory flux at genetic and metabolic levels. 1623 28

It has been reported that active oxygen and/or free radicals are produced in the central nervous system (CNS) compartment in patients with bacterial meningitis, so it is supposed that the levels of endogenous antioxidative scavengers in the cerebrospinal fluid (CSF) are elevated as an adaptive reaction to bacterial meningitis, which exerts severe stress on the human body. We assumed that they are also elevated in patients with convulsive diseases. Nitric oxide (NO) and endogenous antioxidative scavengers (glutathione (GSH), glutathione peroxidase (GPX), (total) superoxide dismutase (T-SOD), manganese superoxide dismutase (Mn-SOD), and catalase) were measured in CSF from a group of child patients with various neurological diseases and a control group. NO, GSH, and GPX activities in CSF from the patients with convulsive diseases were significantly higher than in those with aseptic meningitis or in the controls. Furthermore, all parameters in CSF from patients with bacterial meningitis were significantly higher than in any other group. The present study suggests that oxidative stress may be associated with the pathophysiology of convulsion and that its clinical attenuation will lead to improvement in the prognosis for convulsive diseases.
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PMID:A comparative study of nitric oxide, glutathione, and glutathione peroxidase activities in cerebrospinal fluid from children with convulsive diseases/children with aseptic meningitis. 1637 49

Reactive oxygen and nitrogen species are produced by the human immune system in response to infection. Methods to detoxify these reactive species are vital to the survival of human pathogens, such as Neisseria meningitidis, which is the major aetiological agent of bacterial meningitis. Following activation, macrophages produce superoxide (O(2)(-)), hydrogen peroxide (H(2)O(2)) and nitric oxide (NO). The toxicity of O(2)(-), generated using X/Xo (xanthine/xanthine oxidase), and H(2)O(2) was investigated in the presence and absence of the NO donor DEA-NONOate [2-(N,N-diethylamino)-diazenolate-2-oxide diethylammonium salt]. Most of the toxicity from X/Xo was due to H(2)O(2). In N. meningitidis, NO decreased the toxicity of the H(2)O(2). In contrast, in the enteric bacterium Escherichia coli, NO increased the toxicity of the H(2)O(2).
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PMID:Effect of combined oxidative and nitrosative stress on Neisseria meningitidis. 1641 21

In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1beta (IL-1beta). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis. Transforming growth factor beta (TGFbeta) is a potent deactivator of PMN and macrophages since TGFbeta suppresses the production of ROI, RNI and IL-1. Here, we report that the deletion of the TGFbeta receptor II gene in PMN enhances PMN recruitment into the CNS of mice with Streptococcus pneumoniae meningitis. This was associated with more efficient clearance of bacteria, and almost complete prevention of intracerebral necrotizing vasculitis. Differences in PMN in the CNS of infected control mice and mice lacking TGFbeta receptor II were not explained by altered expression of chemokines acting on PMN. Instead, TGFbeta was found to impair the expression of L (leucocyte)-selectin on PMN from control mice but not from mice lacking TGFbeta receptor II. L-selectin is known to be essential for PMN recruitment in bacterial meningitis. We conclude that defective TGFbeta signalling in PMN is beneficial in bacterial meningitis by ameliorating migration of PMN and bacterial clearance.
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PMID:TGFbeta receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis. 1689 35

N-acetylcysteine (NAC) is neuroprotective in animal models of acute brain injury such as caused by bacterial meningitis. However, the mechanism(s) by which NAC exerts neuroprotection is unclear. Gene expression of endothelin-1 (ET-1), which contributes to cerebral blood flow decline in acute brain injury, is partially regulated by reactive oxygen species, and thus a potential target of NAC. We therefore examined the effect of NAC on tumor necrosis factor (TNF)-alpha-induced ET-1 production in cerebrovascular endothelial cells. NAC dose dependently inhibited TNF-alpha-induced preproET-1 mRNA upregulation and ET-1 protein secretion, while upregulation of inducible nitric oxide synthase (iNOS) was unaffected. Intriguingly, NAC had no effect on the initial activation (i.e., IkappaB degradation, nuclear p65 translocation, and Ser536 phosphorylation) of NF-kappaB by TNF-alpha. However, transient inhibition of NF-kappaB DNA binding suggested that NAC may inhibit ET-1 upregulation by inhibiting (a) parallel pathway(s) necessary for full transcriptional activation of NF-kappaB-mediated ET-1 gene expression. Similar to NAC, the MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and the protein kinase inhibitor H-89 selectively inhibited ET-1 upregulation without affecting nuclear p65 translocation, suggesting that NAC inhibits ET-1 upregulation via inhibition of mitogen- and stress-activated protein kinase (MSK). Supporting this notion, cotreatment with NAC inhibited the TNF-alpha-induced rise in MSK1 and MSK2 kinase activity, while siRNA knock-down experiments showed that MSK2 is the predominant isoform involved in TNF-alpha-induced ET-1 upregulation.
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PMID:Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase. 1702 64

Despite antibiotic therapy, supportive intensive care, and adjunctive treatment with dexamethasone, the mortality and morbidity remain high in patients with bacterial meningitis. The intracranial complications that mainly contribute to the poor outcome are in part a result of the production of reactive oxygen and nitrogen species. Experimental studies have shown that the prognosis for bacterial meningitis can be improved by the administration of antioxidants. Especially adjunctive therapy with N-acetyl-L-cystein (NAC) was shown to have mainly positive effects. Since NAC is already in clinical use in high doses for treating other diseases (e.g., acetaminophen intoxication) and only minor side effects have been observed, there is justified hope that adjunctive therapy with NAC could improve the prognosis of patients with bacterial meningitis.
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PMID:[N-acetyl-L-cysteine as a therapeutic option in bacterial meningitis]. 1723 23

Pneumococcal meningitis remains a serious disease with a case fatality rate of 15%-25%. Furthermore, long-term residues affect up to 50% of survivors. One of the most frequent sequelae is sensorineural hearing loss, which occurs in 26% of survivors of pneumococcal meningitis. Unfortunately, sufficient treatment regimens are still missing. New insights into the pathology and pathophysiology of meningitis-associated hearing loss have come from animal models of bacterial meningitis. Most likely, bacteria reach the cochlea through the cochlear aquaeduct. Once arrived in the perilymphatic spaces, they induce a severe suppurative labyrinthitis. The blood-labyrinth barrier breaks, hair cells are damaged, and neurons in the spiral ganglion undergo cell death, leading to meningitis-associated hearing loss. Reactive oxygen and nitrogen species, in particular peroxynitrite, seem to be among the crucial mediators of cochlear damage and hearing loss during meningitis. In our rat model of pneumococcal meningitis, adjunctive therapy with the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-bencoic acid)-porphyrin (MnTBAP) and N-Acetyl-L-Cystein (NAC) significantly attenuated acute and long-term hearing loss. In several other animal studies of pneumococcal meningitis, adjunctive antioxidant therapy also protected infected animals from intracranial complications. Therefore, the use of antioxidants seems to be a promising future treatment option in pneumococcal meningitis.
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PMID:Nitrogen and oxygen molecules in meningitis-associated labyrinthitis and hearing impairment. 1808 15

This study assessed the validity of cerebrospinal fluid oxidative status of pediatric patients with central nervous system diseases, using the Diacron-Reactive Oxygen Metabolites test (d-Roms; Diacron International s.r.l.; Grosseto, Italy). Eighty-seven pediatric patients (8 with bacterial meningitis, 18 with aseptic meningitis, 23 with febrile seizures, 6 with rotavirus gastroenteritis-induced convulsions, 16 with epilepsy, 2 with adrenoleukodystrophy, 2 with multiple sclerosis, and 12 control subjects) were enrolled. An analysis of the infection-associated group (bacterial meningitis, aseptic meningitis, febrile seizures, and rotavirus gastroenteritis-induced convulsions) indicated that cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels in the bacterial meningitis group were significantly higher than in other infection-associated groups. In the bacterial meningitis group, the cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels obtained after improvement were significantly decreased compared with pre-improvement values. In the noninfection-associated group (epilepsy, adrenoleukodystrophy, and multiple sclerosis), the cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels in symptomatic epilepsy patients were higher than in cryptogenic epilepsy patients and control subjects, but not significantly. Progressive patients with adrenoleukodystrophy or multiple sclerosis demonstrated high Diacron-Reactive Oxygen Metabolite levels compared with another early-stage adrenoleukodystrophy patient. Oxidative stress may be associated with the pathogenesis of various pediatric central nervous system diseases. Cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels may correlate with clinical status in these diseases.
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PMID:Cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels in pediatric patients with central nervous system diseases. 1863 49

One of the causes of sensorineural hearing loss is the loss of auditory hair cells following exposure to environmental stresses. Auditory hair cell death in response to cochlear trauma occurs via both necrosis and apoptosis. Apoptosis of hair cells involves the caspase and MAPK/JNK pathways which are activated by oxidative stress and secretion of inflammatory cytokines in response to trauma. Identification of the pathways that lead to apoptosis provides therapeutic targets for the conservation of hearing. Antioxidants reduce the level of reactive oxygen species and reactive nitrogen species generated by oxidative stress in response to acoustic trauma, aminoglycoside and platinum-based drugs. Caspase inhibitors affect both the extrinsic and intrinsic apoptotic pathways thereby reducing cisplatin, aminoglycoside, hydraulic trauma and ischemia-induced hearing losses. Corticosteroid therapy reduces inflammation and inhibits apoptosis while activating pro-survival pathways in the organ of Corti following exposure to noise, vibration, cisplatin, aminoglycoside, ischemia/reperfusion injury, bacterial meningitis and electrode insertion trauma. Inhibitors of JNK signaling pathway prevent apoptosis of auditory hair cells following electrode insertion trauma, acute labyrinthitis, acoustic trauma and aminoglycoside ototoxicity. This review provides an overview of the different pathways involved in auditory hair cell death following an environmental stress and both traditional and newly developed drugs that are currently being studied or used for the treatment of acute hearing loss. Recent patents related to otoprotective strategies to conserve hearing and auditory hair cells are also discussed in this review.
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PMID:The injured cochlea as a target for inflammatory processes, initiation of cell death pathways and application of related otoprotectives strategies. 2016 5


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