The master molecular regulators and mechanisms determining longevity and health span include nitr... more The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.
Alzheimer’s disease (AD) is one of the serious and progressive neurodegenerative disorders in the... more Alzheimer’s disease (AD) is one of the serious and progressive neurodegenerative disorders in the elderly worldwide. Various genetic, environmental, and lifestyle factors are associated with its pathogenesis that affect neuronal cells to degenerate over the period of time. AD is characterized by cognitive dysfunctions, behavioural disability, and psychological impairments due to the accumulation of amyloid beta (Aβ) peptides and neurofibrillary tangles (NFT). Several research reports have shown that flavonoids are the polyphenolic compounds that significantly improve cognitive functions and inhibit or delay the amyloid beta aggregation or NFT formation in AD. Current research has uncovered that dietary use of flavonoid-rich food sources essentially increases intellectual abilities and postpones or hinders the senescence cycle and related neurodegenerative problems including AD. During AD pathogenesis, multiple signalling pathways are involved and to target a single pathway may relie...
Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and pr... more Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and proteins [...]
Background: It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays ... more Background: It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little information is available about the role of the lymphatic system. We previously reported that Aβ is cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone. Objective: To confirm and expand our initial finding that Aβ is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular “waste” products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aβ being cleared into peripheral lymph nodes. Method...
American Journal of Physiology-Endocrinology and Metabolism, 1994
The effects of melatonin treatment on cardiac sarcolemmal membrane function were investigated in ... more The effects of melatonin treatment on cardiac sarcolemmal membrane function were investigated in alloxan-injected rats. Ca(2+)-stimulated adenosine-triphosphatase (ATPase, Ca2+ pump) and Mg(2+)-ATPase activities were depressed significantly in sarcolemmal preparations from alloxan-injected rats compared with levels in control rats. These deficits were observed 2 days after alloxan injection, and they were accompanied by an increase in the density of voltage-sensitive calcium channels, as measured by the [3H]nitrendipine-binding assay. In a dose-dependent manner, treatment of rats with melatonin before alloxan injection significantly overcame the suppression of Ca(2+)-stimulated ATPase in cardiac sarcolemma. Melatonin (1, 5, and 10 mg/kg) overcame Ca(2+)-stimulated ATPase suppression by 13, 35, and 70%, respectively. In addition, melatonin at a dose of 10 mg/kg also prevented the suppression of the Mg(2+)-ATPase by 31%. The number of [3H]nitrendipine-binding sites was not influenced ...
This editorial summarizes the eight articles that have been collected for the Special Issue entit... more This editorial summarizes the eight articles that have been collected for the Special Issue entitled “Tryptophan in Nutrition and Health 2 [...]
Eine gezielte diatetische Zufuhr von L-Arginin ist bei Arteriosklerose und anderen Herz-Kreislauf... more Eine gezielte diatetische Zufuhr von L-Arginin ist bei Arteriosklerose und anderen Herz-Kreislauf-Erkrankungen angezeigt. Die Aminosaure zeichnet sich durch hohe Wirksamkeit und gute Vertraglichkeit aus und kann eine medikamentose Therapie ideal erganzen.
Numerous studies have demonstrated that melatonin is a potent scavenger of some of the most react... more Numerous studies have demonstrated that melatonin is a potent scavenger of some of the most reactive and dangerous free radicals [1-4]. Its capacity of protecting cells from oxidative damage has been widely documented and repeatedly reviewed [4-6]. The mechanisms by which melatonin interacts with free radicals are partially understood, and two major products have been identified. Under general considerations, hydroxyl radicals (AE OH) can react with melatonin in three different ways: (1) by abstraction of an electron, (2) by abstraction of a hydrogen atom, or (3) by addition. Although hydrogen abstraction, leading to the formation of a neutral melatonyl radical, has been observed [7], electron abstractions is, as far as we can see, the quantitatively most important pathway of oxidation. The resulting melatonyl cation radical subsequently combines with an O 2 AE) [2, 4], a reaction by which the electrons are Abstract: Melatonin's O-methyl and N-acetyl residues are not only the basis of its amphilicity enabling the molecule to enter all organs and all subcellular compartments, but are also decisive for its antioxidant properties. We have compared melatonin's redox chemistry with that of several structural analogs: tryptamine, N-acetyltryptamine, serotonin, N-acetylserotonin, 5-methoxytryptamine, 6-chloromelatonin and 2-iodomelatonin. Scavenging of hydroxyl radicals (AE OH) was measured in a scavenger competition assay based on ABTS cation radical (ABTS AE+) formation. The capability of undergoing single-electron transfer reactions was studied using an ABTS AE+ reduction assay, reflecting the more general property of scavenging organic cation radicals. Direct scavenging of superoxide anions (O 2 AE)), under noncatalyzed conditions, was investigated in a hematoxylin autoxidation assay. Measurements of chemiluminescence were used for studying scavenging of O 2 AE) under catalyzed conditions, either by hemin-mediated interaction or by combination with the respective indolyl cation radicals. Light emission was determined in the absence or presence of the AE OH scavenger dimethylsulfoxide and the O 2 AE) scavenger Tiron. Products formed by oxidation of the respective indoles in a moderately alkaline, hemin-catalyzed H 2 O 2 system were analyzed by thin-layer chromatography and fluorometry. Absence of either the O-methyl or the N-acetyl residue causes marked diminutions in the capacities of scavenging AE OH and ABTS AE+ as well as in chemiluminescence emitted during oxidation. The importance of the N-acetyl group is insofar remarkable as it seems, at first glance, to be isolated from the indolic moiety; interactions between side chain and indolic moiety are therefore decisive for melatonin's redox properties. The 5-hydroxylated compounds are not generally more efficient scavengers, but particularly better reducers of ABTS AE+ ; in the alkaline H 2 O 2 system generating AE OH and O 2 AE) , melatonin was much more rapidly oxidized than the 5-hydroxylated and non-substituted analogs. Oxidative products formed from any of the compounds studied contained much less of substituted kynuramines as in the case of melatonin, indicating that radical chain termination by O 2 AE) is considerably more efficient with melatonin. These findings are supported by measurements of chemiluminescence, which largely reflects pyrrole ring cleavage as a result of combination with superoxide anions. In this regard, only 6-chloromelatonin equalled melatonin, whereas the efficiency of 2-iodomelatonin was much lower, another indication for the importance of 2,3-dioxygenation.
Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and ... more Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and of low molecular weight antioxidants (LMWAs) are described in various phylogenetically distant organisms. Substantial amplitudes are detected in several cases, suggesting the significance of rhythmicity in avoiding excessive oxidative stress. Mammalian and/or avian glutathione peroxidase and, as a consequence, glutathione reductase activities follow the rhythm of melatonin. Another hint for an involvement of melatonin in the control of redox processes is seen in its high-affinity binding to cytosolic quinone reductase 2, previously believed to be a melatonin receptor. Although antioxidative protection by pharmacological doses of melatonin is repeatedly reported, explanations of these findings are still insufficient and their physiological and chronobiological relevance is not yet settled. Recent data indicate a role of melatonin in the avoidance of mitochondrial radical formation, a function which may prevail over direct scavenging. Rhythmic changes in oxidative damage of protein and lipid molecules are also reported. Enhanced oxidative protein modification accompanied by a marked increase in the circadian amplitude of this parameter is detected in the Drosophila mutant rosy, which is deficient in the LMWA urate. Preliminary evidence for the significance of circadian rhythmicity in diminishing oxidative stress comes from clock mutants. In Drosophila, moderately enhanced protein damage is described for the arrhythmic and melatonin null mutant per0, but even more elevated, periodic damage is found in the short-period mutant per(s), synchronized to LD 12:12. Remarkably large increases in oxidative protein damage, along with impairment of tissue integrity and--obviously insufficient--compensatory elevations in protective enzymes are observed in a particularly vulnerable organ, the Harderian gland, of another short-period mutant tau, in the Syrian hamster. Mice deficient in the per2 gene homolog are reported to be cancer-prone, a finding which might also relate to oxidative stress. In the dinoflagellate Lingulodinium polyedrum [Gonyaulax polyedra], various treatments that cause oxidative stress result in strong suppressions of melatonin and its metabolite 5-methoxytryptamine (5-MT) and to secondary effects on overt rhythmicity. The glow maximum, depending on the presence of elevated 5-MT at the end of subjective night, decreases in a dose-dependent manner already under moderate, non-lethal oxidative stress, but is restored by replenishing melatonin. Therefore, a general effect of oxidative stress may consist in declines of easily oxidizable signaling molecules such as melatonin, and this can have consequences on the circadian intraorganismal organization and expression of overt rhythms. Recent findings on a redox-sensitive input into the core oscillator via modulation of NPAS2/BMAL1 or CLK/BMAL1 heterodimer binding to DNA indicate a direct influence of cellular redox balance, including oxidative stress, on the circadian clock.
The master molecular regulators and mechanisms determining longevity and health span include nitr... more The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.
Alzheimer’s disease (AD) is one of the serious and progressive neurodegenerative disorders in the... more Alzheimer’s disease (AD) is one of the serious and progressive neurodegenerative disorders in the elderly worldwide. Various genetic, environmental, and lifestyle factors are associated with its pathogenesis that affect neuronal cells to degenerate over the period of time. AD is characterized by cognitive dysfunctions, behavioural disability, and psychological impairments due to the accumulation of amyloid beta (Aβ) peptides and neurofibrillary tangles (NFT). Several research reports have shown that flavonoids are the polyphenolic compounds that significantly improve cognitive functions and inhibit or delay the amyloid beta aggregation or NFT formation in AD. Current research has uncovered that dietary use of flavonoid-rich food sources essentially increases intellectual abilities and postpones or hinders the senescence cycle and related neurodegenerative problems including AD. During AD pathogenesis, multiple signalling pathways are involved and to target a single pathway may relie...
Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and pr... more Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and proteins [...]
Background: It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays ... more Background: It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little information is available about the role of the lymphatic system. We previously reported that Aβ is cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone. Objective: To confirm and expand our initial finding that Aβ is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular “waste” products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aβ being cleared into peripheral lymph nodes. Method...
American Journal of Physiology-Endocrinology and Metabolism, 1994
The effects of melatonin treatment on cardiac sarcolemmal membrane function were investigated in ... more The effects of melatonin treatment on cardiac sarcolemmal membrane function were investigated in alloxan-injected rats. Ca(2+)-stimulated adenosine-triphosphatase (ATPase, Ca2+ pump) and Mg(2+)-ATPase activities were depressed significantly in sarcolemmal preparations from alloxan-injected rats compared with levels in control rats. These deficits were observed 2 days after alloxan injection, and they were accompanied by an increase in the density of voltage-sensitive calcium channels, as measured by the [3H]nitrendipine-binding assay. In a dose-dependent manner, treatment of rats with melatonin before alloxan injection significantly overcame the suppression of Ca(2+)-stimulated ATPase in cardiac sarcolemma. Melatonin (1, 5, and 10 mg/kg) overcame Ca(2+)-stimulated ATPase suppression by 13, 35, and 70%, respectively. In addition, melatonin at a dose of 10 mg/kg also prevented the suppression of the Mg(2+)-ATPase by 31%. The number of [3H]nitrendipine-binding sites was not influenced ...
This editorial summarizes the eight articles that have been collected for the Special Issue entit... more This editorial summarizes the eight articles that have been collected for the Special Issue entitled “Tryptophan in Nutrition and Health 2 [...]
Eine gezielte diatetische Zufuhr von L-Arginin ist bei Arteriosklerose und anderen Herz-Kreislauf... more Eine gezielte diatetische Zufuhr von L-Arginin ist bei Arteriosklerose und anderen Herz-Kreislauf-Erkrankungen angezeigt. Die Aminosaure zeichnet sich durch hohe Wirksamkeit und gute Vertraglichkeit aus und kann eine medikamentose Therapie ideal erganzen.
Numerous studies have demonstrated that melatonin is a potent scavenger of some of the most react... more Numerous studies have demonstrated that melatonin is a potent scavenger of some of the most reactive and dangerous free radicals [1-4]. Its capacity of protecting cells from oxidative damage has been widely documented and repeatedly reviewed [4-6]. The mechanisms by which melatonin interacts with free radicals are partially understood, and two major products have been identified. Under general considerations, hydroxyl radicals (AE OH) can react with melatonin in three different ways: (1) by abstraction of an electron, (2) by abstraction of a hydrogen atom, or (3) by addition. Although hydrogen abstraction, leading to the formation of a neutral melatonyl radical, has been observed [7], electron abstractions is, as far as we can see, the quantitatively most important pathway of oxidation. The resulting melatonyl cation radical subsequently combines with an O 2 AE) [2, 4], a reaction by which the electrons are Abstract: Melatonin's O-methyl and N-acetyl residues are not only the basis of its amphilicity enabling the molecule to enter all organs and all subcellular compartments, but are also decisive for its antioxidant properties. We have compared melatonin's redox chemistry with that of several structural analogs: tryptamine, N-acetyltryptamine, serotonin, N-acetylserotonin, 5-methoxytryptamine, 6-chloromelatonin and 2-iodomelatonin. Scavenging of hydroxyl radicals (AE OH) was measured in a scavenger competition assay based on ABTS cation radical (ABTS AE+) formation. The capability of undergoing single-electron transfer reactions was studied using an ABTS AE+ reduction assay, reflecting the more general property of scavenging organic cation radicals. Direct scavenging of superoxide anions (O 2 AE)), under noncatalyzed conditions, was investigated in a hematoxylin autoxidation assay. Measurements of chemiluminescence were used for studying scavenging of O 2 AE) under catalyzed conditions, either by hemin-mediated interaction or by combination with the respective indolyl cation radicals. Light emission was determined in the absence or presence of the AE OH scavenger dimethylsulfoxide and the O 2 AE) scavenger Tiron. Products formed by oxidation of the respective indoles in a moderately alkaline, hemin-catalyzed H 2 O 2 system were analyzed by thin-layer chromatography and fluorometry. Absence of either the O-methyl or the N-acetyl residue causes marked diminutions in the capacities of scavenging AE OH and ABTS AE+ as well as in chemiluminescence emitted during oxidation. The importance of the N-acetyl group is insofar remarkable as it seems, at first glance, to be isolated from the indolic moiety; interactions between side chain and indolic moiety are therefore decisive for melatonin's redox properties. The 5-hydroxylated compounds are not generally more efficient scavengers, but particularly better reducers of ABTS AE+ ; in the alkaline H 2 O 2 system generating AE OH and O 2 AE) , melatonin was much more rapidly oxidized than the 5-hydroxylated and non-substituted analogs. Oxidative products formed from any of the compounds studied contained much less of substituted kynuramines as in the case of melatonin, indicating that radical chain termination by O 2 AE) is considerably more efficient with melatonin. These findings are supported by measurements of chemiluminescence, which largely reflects pyrrole ring cleavage as a result of combination with superoxide anions. In this regard, only 6-chloromelatonin equalled melatonin, whereas the efficiency of 2-iodomelatonin was much lower, another indication for the importance of 2,3-dioxygenation.
Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and ... more Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and of low molecular weight antioxidants (LMWAs) are described in various phylogenetically distant organisms. Substantial amplitudes are detected in several cases, suggesting the significance of rhythmicity in avoiding excessive oxidative stress. Mammalian and/or avian glutathione peroxidase and, as a consequence, glutathione reductase activities follow the rhythm of melatonin. Another hint for an involvement of melatonin in the control of redox processes is seen in its high-affinity binding to cytosolic quinone reductase 2, previously believed to be a melatonin receptor. Although antioxidative protection by pharmacological doses of melatonin is repeatedly reported, explanations of these findings are still insufficient and their physiological and chronobiological relevance is not yet settled. Recent data indicate a role of melatonin in the avoidance of mitochondrial radical formation, a function which may prevail over direct scavenging. Rhythmic changes in oxidative damage of protein and lipid molecules are also reported. Enhanced oxidative protein modification accompanied by a marked increase in the circadian amplitude of this parameter is detected in the Drosophila mutant rosy, which is deficient in the LMWA urate. Preliminary evidence for the significance of circadian rhythmicity in diminishing oxidative stress comes from clock mutants. In Drosophila, moderately enhanced protein damage is described for the arrhythmic and melatonin null mutant per0, but even more elevated, periodic damage is found in the short-period mutant per(s), synchronized to LD 12:12. Remarkably large increases in oxidative protein damage, along with impairment of tissue integrity and--obviously insufficient--compensatory elevations in protective enzymes are observed in a particularly vulnerable organ, the Harderian gland, of another short-period mutant tau, in the Syrian hamster. Mice deficient in the per2 gene homolog are reported to be cancer-prone, a finding which might also relate to oxidative stress. In the dinoflagellate Lingulodinium polyedrum [Gonyaulax polyedra], various treatments that cause oxidative stress result in strong suppressions of melatonin and its metabolite 5-methoxytryptamine (5-MT) and to secondary effects on overt rhythmicity. The glow maximum, depending on the presence of elevated 5-MT at the end of subjective night, decreases in a dose-dependent manner already under moderate, non-lethal oxidative stress, but is restored by replenishing melatonin. Therefore, a general effect of oxidative stress may consist in declines of easily oxidizable signaling molecules such as melatonin, and this can have consequences on the circadian intraorganismal organization and expression of overt rhythms. Recent findings on a redox-sensitive input into the core oscillator via modulation of NPAS2/BMAL1 or CLK/BMAL1 heterodimer binding to DNA indicate a direct influence of cellular redox balance, including oxidative stress, on the circadian clock.
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Papers by Burkhard Poeggeler