Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melatonin administration has been reported to have beneficial effects on immune function in some clinical studies and in several animal models of immune dysfunction. Furthermore, recent studies suggest beneficial effects of melatonin on depressed immune function following trauma-hemorrhage. Nonetheless, it remains unknown whether this hormone has any salutary effects on survival following hemorrhagic shock and subsequent septic challenge. Male C3H/HeN mice were bled to and maintained at a mean arterial blood pressure of 35 +/- 5 mm Hg for 90 min, adequately resuscitated, and 48 hr thereafter subjected to sepsis (cecal ligation and puncture; CLP). Melatonin-treated mice received either short-term treatment on Days 1 and 2 after hemorrhage or continuous treatment throughout the study. Treatment with vehicle (10% ethanol in normal saline) or melatonin (10 mg/kg body weight) was administered daily starting in the evening of the day of hemorrhage/sham-operation. Short-term melatonin administration after hemorrhage significantly improved survival in animals subjected to septic challenge. Continuous melatonin treatment did not improve survival, as compared to vehicle-treated mice subjected to shock and CLP. Moreover, continuous melatonin treatment in sham-operated animals significantly increased mortality compared to short-term-treated and vehicle-treated animals. While the mechanisms of the differential effects of melatonin administration are yet to be clearly defined, this study, nonetheless, demonstrates the salutary effects of short-term melatonin administration in the treatment of immune dysfunction following hemorrhagic shock.
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PMID:Melatonin administration following hemorrhagic shock decreases mortality from subsequent septic challenge. 890 55

Melatonin has recently been investigated as a biological response modifier in sepsis and hypovolemic shock. Although melatonin is reported to influence a variety of inflammatory and immune responses, evidence supporting its effects on important macrophage-derived mediators is incomplete. This study was designed to determine whether melatonin alters the release TNF, IL-6, and reactive oxygen intermediates by activated macrophages. TNF and IL-6 bioactivity in LPS-stimulated Wistar rat alveolar macrophage and RAW 264.7 cell culture supernatants were unchanged by pretreatment with melatonin. Similarly, macrophage production of reactive oxygen intermediates, including H2O2 and superoxide anion, were unaffected by melatonin pretreatment. PMA-stimulated H2O2 production was determined in rat alveolar macrophages and RAW 264.7 cells. Superoxide anion generation was determined in the rat alveolar macrophage NR8383 cell line. Melatonin, at concentrations ranging from 10(-7) to 10(-4) M, does not alter LPS-stimulated TNF and IL-6, or PMA-stimulated H2O2 and superoxide anion production by the macrophage populations studied. These observations are in contrast to previous reports. Further studies are necessary to determine whether melatonin indirectly influences macrophage function by actions on nonmacrophage cell populations.
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PMID:Effect of melatonin on activated macrophage TNF, IL-6, and reactive oxygen intermediates. 964 91

Free radicals have been implicated in the pathogenesis of neonatal sepsis and its complications. This study was conducted to determine the changes in the clinical status and the serum levels of lipid peroxidation products [malondialdehyde (MDA) and 4-hydroxylalkenals (4-HDA)] in 10 septic newborns treated with the antioxidant melatonin given within the first 12 h after diagnosis. Ten other septic newborns in a comparable state were used as "septic" controls, while 10 healthy newborns served as normal controls. A total of 20 mg melatonin was administered orally in two doses of 10 mg each, with a 1-h interval. One blood sample was collected before melatonin administration and two additional blood samples (at 1 and 4 h) were collected after melatonin administration to assess serum levels of lipid peroxidation products. Serum MDA + 4-HDA concentrations in newborns with sepsis were significantly higher than those in healthy infants without sepsis; in contrast, in septic newborns treated with melatonin there was a significant reduction (p < 0.05) of MDA + 4-HDA to the levels in the normal controls at both 1 and 4 h (p < 0.05). Melatonin also improved the clinical outcome of the septic newborns as judged by measurement of sepsis-related serum parameters after 24 and 48 h. Three of 10 septic children who were not treated with melatonin died within 72 h after diagnosis of sepsis; none of the 10 septic newborns treated with melatonin died. To our knowledge, this is the first study where melatonin was given to human newborns.
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PMID:Effects of melatonin treatment in septic newborns. 1172 23

Mitochondrial nitric oxide synthase (mtNOS) is expressed constitutively, although it might be induced. Nitric oxide (NO) is a physiological regulator of mitochondrial respiration. Melatonin prevents mitochondrial oxidative damage and inhibits iNOS expression induced by bacterial lipopolysaccharide (LPS). The loss of melatonin with age may be related to the age-dependent mitochondrial damage. Thus, we examined the protective role of melatonin against the effects of LPS on mtNOS and on respiratory complexes activity in liver and lung mitochondria from young and old rats. The activity of mtNOS in control lung was low and did not change with age. LPS administration (10 mg/kg, i.v.) significantly increased mtNOS expression and activity and NO production in lung mitochondria, and the effect was greater in old rats. LPS administration also reduced the age-dependent decrease of the respiratory complexes I and IV. Melatonin administration (60 mg/kg, i.p.) prevented the LPS toxicity, decreasing mitochondrial NOS activity and NO production. Melatonin also counteracted LPS-induced inhibition of complexes I and IV. In general, the actions of melatonin were stronger in older animals than in younger ones. The results suggest that an inducible component of mtNOS, together with mitochondrial damage, occurs during sepsis, and melatonin prevents the mitochondrial failure that occurs during endotoxemia.
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PMID:Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. 1267 Aug 78

Sepsis is commonly associated with enhanced generation of reactive oxygen metabolites, which lead to multiple organ dysfunction. The aim of this study was to examine the role of melatonin, a potent antioxidant, in protecting the intestinal and bladder tissues against damage in a rat model of sepsis. Sepsis was induced by cecal ligation and perforation (CLP) in Wistar Albino rats. Sham operated (control) and CLP group received saline or melatonin (10 mg/kg, ip) 30 minutes prior to and 6 hours after the operation. Sixteen hours after the surgery, rats were decapitated and the intestinal and urinary bladder tissues were used for contractility studies, or stored for the measurement of malondialdehyde (MDA) content -an index of lipid peroxidation-, glutathione (GSH) levels -a key antioxidant- and myeloperoxidase (MPO) activity- an index of neutrophil infiltration-. Ileal and bladder MDA levels in the CLP group were significantly increased (p < 0.001) with concomitant decreases in GSH levels (p < 0.01 - p < 0.001) when compared to the control group. Similarly, MPO activity was significantly increased (p < 0.001) in both ileum and bladder tissues. On the other hand, melatonin treatment significantly reversed (p < 0.001) the elevations in MDA and MPO levels, while reduced GSH levels were increased back to the control levels (p < 0.01 - p < 0.001). In the CLP group, the contractility of the ileal and bladder tissues decreased significantly compared with controls. Melatonin treatment of the CLP group restored these responses. In this study, CLP induced dysfunction of the ileal and bladder tissue of rats was reversed by melatonin treatment. Moreover, melatonin, as an antioxidant, abolished the elevation in lipid peroxidation products and myeloperoxidase activity, and reduction in the endogenous antioxidant glutathione and thus protected the tissues against sepsis-induced oxidative damage.
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PMID:Melatonin treatment protects against sepsis-induced functional and biochemical changes in rat ileum and urinary bladder. 1468 50

Sepsis has been associated with a lipopolysaccharide (LPS) induced bacterial infection and causes biochemical, hemodynamic and physiological alterations in a system. Erythrocyte deformability is very critical for a microcirculatory system to function effectively. Hence, we were interested in examining the effects of a potent antioxidant, melatonin (Mel), on lipid peroxidation and deformability of eythrocytes in LPS-induced experimental sepsis. Male Swiss Albino rats were used in 6 groups, each group comprising of 10 animals. The first group was the control, and the other groups were administered LPS (10 mg/kg, i.p.), Mel (10 mg/kg, i.p.), LPS + L-NAME (5 mM, i.p.), Mel + LPS and Mel + LPS + L-NAME, respectively. Deformability of the RBCs decreased significantly (p < 0.05) in the LPS group in comparison to all other groups. This reduction was prevented with both L-NAME and Mel, but was not as significant as when administering L-NAME or Mel alone. This result was adversely seen in nitric oxide levels, i.e. RBCD was reduced when the NO levels were higher. Therefore in the Mel group the NO levels were reduced while the RBCD enhanced. In addition to these, as an index of lipid peroxidation, the Malondialdehyde levels were elevated in LPS groups whereas the deformability was reduced. This lipid peroxidation was suppressed by Mel and/or L-NAME significantly, where the RBCD was enhanced. These results show that, Melatonin can elevate the RBCD in experimental sepsis due to its nitric oxide scavenging activity and antioxidant effect as revealed by lipid peroxidation.
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PMID:Lipid peroxidation and deformability of red blood cells in experimental sepsis in rats: The protective effects of melatonin. 1500 32

Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress, which may lead to a decrease in the activities of mitochondrial complexes and ATP production, and, as a consequence, a further increase in free radical generation. A vicious cycle thus results under these conditions of oxidative stress with the final consequence being cell death by necrosis or apoptosis. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.
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PMID:Melatonin and mitochondrial function. 1518 71

Our results show that melatonin and N-acetyl-5-methoxykynurenamine (aMK) physiologically regulate both the electron transport chain (ETC) and OXPHOS, increasing the electron transport and ATP synthesis by normal mitochondria. Melatonin also counteracts mitochondrial oxidative damage induced by t-butyl hydroperoxide, recovering glutathione levels and ATP production. However, the effects of melatonin not only depend of its antioxidant properties, since the indoleamine specifically interacts with complex I and IV of the ETC increasing their activity. Experiments in vivo showed that melatonin administration prevents sepsis-induced ETC damage decreasing the activity and expression of INOS and mtNOS, thus reducing intramitochondrial nitric oxide (NO) and peroxynitrite (ONOO-) levels. Consequently, mitochondrial ETC ad ATP production recovered to normal conditions. The presence of specific binding of melatonin in mitochondrial matrix led us to explore the genomic role of the indoleamine in these organelles. In vivo and in vitro experiments showed that administration of melatonin increased mtONA transcriptional activity of the subunits 1-3 of the complex IV. These effects correlated well with the effects of melatonin on complex IV activity. The data suggest a new rate for melatonin to regulate mitochondrial homeostasis. Due to the relationships between mitochondrial damage, aging and neurodegenerative diseases, the effects of melatonin here described further support its antiaging and neuroprotective properties.
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PMID:Mitochondrial regulation by melatonin and its metabolites. 1520 73

Melatonin, or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from unicells to vertebrates. This indoleamine may act as a protective agent in disease conditions such as Parkinson's, Alzheimer's, aging, sepsis and other disorders including ischemia/reperfusion. In addition, melatonin has been proposed as a drug for the treatment of cancer. These disorders have in common a dysfunction of the apoptotic program. Thus, while defects which reduce apoptotic processes can exaggerate cancer, neurodegenerative disorders and ischemic conditions are made worse by enhanced apoptosis. The mechanism by which melatonin controls cell death is not entirely known. Recently, mitochondria, which are implicated in the intrinsic pathway of apoptosis, have been identified as a target for melatonin actions. It is known that melatonin scavenges oxygen and nitrogen-based reactants generated in mitochondria. This limits the loss of the intramitochondrial glutathione and lowers mitochondrial protein damage, improving electron transport chain (ETC) activity and reducing mtDNA damage. Melatonin also increases the activity of the complex I and complex IV of the ETC, thereby improving mitochondrial respiration and increasing ATP synthesis under normal and stressful conditions. These effects reflect the ability of melatonin to reduce the harmful reduction in the mitochondrial membrane potential that may trigger mitochondrial transition pore (MTP) opening and the apoptotic cascade. In addition, a reported direct action of melatonin in the control of currents through the MTP opens a new perspective in the understanding of the regulation of apoptotic cell death by the indoleamine.
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PMID:Melatonin mitigates mitochondrial malfunction. 1561 31

Septic shock, the most severe problem of sepsis, is a lethal condition caused by the interaction of a pathogen-induced long chain of sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. The lethal effects of septic shock are associated with the production and release of numerous pro-inflammatory biochemical mediators including cytokines, nitric oxide and toxic oxygen and nitrogen radicals, together with development of massive apoptosis. As melatonin has remarkable properties as a cytokine modulator, antioxidant and anti-apoptotic agent, the present study was designed to evaluate the possible protective effect of melatonin against LPS-induced septic shock in Swiss mice. We observed that intraperitoneally (i.p.) administered-melatonin (10 mg/kg) 30 min prior, and 1 hr after i.p. LPS injection (0.75 mg/animal) markedly protected mice from the LPS lethal effects with 90% survival rates for melatonin and 20% for LPS-injected mice after 72 hr. The melatonin effect was mediated by modulating the release of pro-/anti-inflammatory cytokine levels, protection from oxidative damage and counteracting apoptotic cell death. Melatonin was able to partially counteract the increase in LPS-induced pro-inflammatory cytokine levels such as tumor necrosis factor-alpha, IL-12 and interferon-gamma at the local site of injection, while it increased the production of the anti-inflammatory cytokine IL-10 both locally and systemically. Furthermore, melatonin inhibited the LPS-induced nitrite/nitrate and lipid peroxidation levels in brain and liver and counteracted the sepsis-associated apoptotic process in spleen. In conclusion, we have demonstrated that melatonin improves the survival of mice with septic shock via its pleiotropic functions as an immunomodulator, antioxidant and anti-apoptotic mediator.
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PMID:Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro-/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects. 1620 96


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