Recent advances in the chemistry of melanins have begun to disclose a number of important structure-property-function relationships of crucial relevance to the biological role of human pigments, ...including skin (photo) protection and UV-susceptibility. Even slight variations in the monomer composition of black eumelanins and red pheomelanins have been shown to determine significant differences in light absorption, antioxidant, paramagnetic and redox behavior, particle morphology, surface properties, metal chelation and resistance to photo-oxidative wear-and-tear. These variations are primarily governed by the extent of decarboxylation at critical branching points of the eumelanin and pheomelanin pathways, namely the rearrangement of dopachrome to 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA), and the rearrangement of 5-S-cysteinyldopa o-quinoneimine to 1,4-benzothiazine (BTZ) and its 3-carboxylic acid (BTZCA). In eumelanins, the DHICA-to-DHI ratio markedly affects the overall antioxidant and paramagnetic properties of the resulting pigments. In particular, a higher content in DHICA decreases visible light absorption and paramagnetic response relative to DHI-based melanins, but markedly enhances antioxidant properties. In pheomelanins, likewise, BTZCA-related units, prevalently formed in the presence of zinc ions, appear to confer pronounced visible and ultraviolet A (UVA) absorption features, accounting for light-dependent reactive oxygen species (ROS) production, whereas non-carboxylated benzothiazine intermediates seem to be more effective in inducing ROS production by redox cycling mechanisms in the dark. The possible biological and functional significance of carboxyl retention in the eumelanin and pheomelanin pathways is discussed.
Early diagnosis of malignant melanoma is critical for effective treatment and reduced patient mortality. However, current clinical and histological variables show limited accuracy in diagnosis. Serum ...or urine level of 5-S-cysteinyldopa (5-S-CD) is a commonly used melanoma biomarker in Japan owing to its increased sensitivity compared with other melanoma markers. However, its use as a diagnostic marker has shown some limitations. Therefore, here we examined the combination of 5-S-CD with melanoma inhibitory activity, which showed sensitivity in detecting melanoma comparable with that of 5-S-CD, and interleukin-8, a cytokine linked with melanoma progression, in a cohort of Japanese patients with melanoma. Our results revealed that the triple combination of 5-S-CD, melanoma inhibitory activity, and interleukin-8 showed high diagnostic accuracy in detecting melanoma compared with each of the individual factors. Importantly, the triple marker showed specificity and utility in detecting early-stage melanoma. Our results suggest the utility of the triple marker as a diagnostic biomarker for melanoma patients.
Neurocutaneous melanosis is caused by postzygotic NRAS mutations in neural crest cells, resulting in large or multiple nevi in the skin and proliferation of leptomeningeal melanocytes in the central ...nervous system. The onset of neurological symptoms is usually before the age of 2 years, but it can also occur in adults. A 35-year-old male had been asymptomatic for a long time after excision of a large congenital melanocytic nevus, but he developed headache, disturbance of consciousness, and seizure. Methotrexate was ineffective, cerebral pressure was decreased by spinal drainage, and steroid pulse therapy was temporarily effective. Seizures and disturbance of consciousness worsened and the patient died on the 92nd day. Cerebrospinal fluid human melanin black-45 immunostaining and serum 5-S-cysteinyldopa (5-S-CD) were useful in diagnosing melanocytic proliferation, and serum 5-S-CD may be useful in predicting prognosis.
The pheomelanin precursor 5-S-cysteinyldopa (5SCD) exhibits promising potential as a urinary and serum biomarker for melanoma. Nonetheless, it is important to note that 68.8% of early-stage melanoma ...cases remained undetected when employing 5SCD as a biomarker, underscoring the inadequacy of its efficacy, especially in identifying stage I/II melanoma. In lieu of detecting free 5SCD, the hydrolysis products of pheomelanin, namely, 4-amino-3-hydroxyphenylalanine (4-AHP) and 3-amino-4-hydroxyphenylalanine (3-AHP) offer the prospect of achieving heightened sensitivity and broader scope in early-stage melanoma diagnosis through direct chemical processes. This study introduces an innovative gas chromatography-mass spectrometry (GC-MS) methodology to identify early-stage melanoma by comparing the concentrations of AHPs across 80 stage I/II melanoma patients against 32 healthy controls. The approach demonstrated linear response within the 0.5-20 μg/mL range for reference AHPs detection. The urine levels of AHPs were 1.3 ± 0.5 μg/mL in the control/volunteer group (n = 32), 8.1 ± 1.6 μg/mL in stage I and II melanoma patients (n = 28), and 6.3 ± 1.9 μg/mL in stage II melanoma patients (n = 52). The findings unequivocally underscore the diagnostic promise of AHPs as a robust tool for early-stage melanoma assessment in laboratory medicine.
The present study was performed to examine if catechol oxidation is higher in brains from patients with Parkinson’s disease compared to age-matched controls, and if catechol oxidation increases with ...age. Brain tissue from Parkinson patients and age-matched controls was examined for oxidation of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylalanine (DOPA) to corresponding quinones, by measurement of 5-
S
-cysteinyl-dopamine, 5-
S
-cysteinyl-DOPAC and 5-
S
-cysteinyl-DOPA. The cysteinyl catechols are assumed to be biomarkers for DA, DOPAC and DOPA autoxidation and part of the biosynthetic pathway of neuromelanin. The concentrations of the 5-
S
-cysteinyl catechols were lower, whereas the 5-
S
-cysteinyl-DA/DA and 5-
S
-cysteinyl-DOPAC/DOPAC ratios tended to be higher in the Parkinson group compared to controls, which was interpreted as a higher degree of oxidation. High 5-
S
-cysteinyl-DA/DA ratios were found in the substantia nigra of a sub-population of the Parkinson group. Based on 5-
S
-cysteinyl-DA/DA ratios, dopamine oxidation was found to increase statistically significantly with age in the caudate nucleus, and non-significantly in the substantia nigra. In conclusion, the occurrence of 5-
S
-cysteinyl-DA, 5-
S
-cysteinyl-DOPAC and 5-
S
-cysteinyl-DOPA was demonstrated in dopaminergic brain areas of humans, a tendency for higher oxidation of DA in the Parkinson group compared to controls was observed as well as a statistically significant increase in DA oxidation with age. Possibly, autoxidation of DA and other catechols are involved in both normal and pathological ageing of the brain. This study confirms one earlier but small study, as well as complements one study on non-PD cases and one study on both PD cases and controls on NM bound or integrated markers or catechols.
Quality and Maintenance of manufacturing systems are closely related functions of any organization. Over a period of time two concepts have emerged which are Total Productive Maintenance (TPM) and ...Total Quality Management (TQM) along with other concepts to achieve World Class Manufacturing system. In this paper experience of implementing Total Productive Maintenance is shared and investigated for a company manufacturing automotive component. Concept is implemented in the machine shop having CNC turning centers of different capacity. Overall Equipment Effectiveness is used as the measure of success of TPM implementation. The losses associated with equipment effectiveness are identified. All the pillars of TPM are implemented in a phased manner eliminating the losses and thus improving the utilization of CNC machines.
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is characterized for being an idiopathic and multifactorial disease. Extensive research has been conducted ...to explain the origin of the disease, but it still remains elusive. It is well known that dopamine oxidation, through the endogenous formation of toxic metabolites, is a key process in the activation of a cascade of molecular events that leads to cellular death in the hallmark of PD. Thio-catecholamines, such as 5-S-cysteinyl-dopamine, 5-S-glutathionyl-dopamine and derived benzothiazines, are endogenous metabolites formed in the dopamine oxidative degradation pathway. Those metabolites have been shown to be highly toxic to neurons in the substantia nigra pars compacta, activating molecular mechanisms that ultimately lead to neuronal death. In this review we describe the origin, formation and the toxic effects of 5-S-cysteinyl-dopamine and its oxidative derivatives that cause death to dopaminergic neurons. Furthermore, we correlate the formation of those metabolites with the neurodegeneration progress in PD. In addition, we present the reported neuroprotective strategies of products that protect against the cellular damage of those thio-catecholamines. Finally, we discuss the advantages in the use of 5-S-cysteinyl-dopamine as a potential biomarker for PD.
•Dopamine oxidation leads to the endogenous formation of toxic metabolites.•5-S-cysteinyl-dopamine is a neuroxic metabolite to dopaminergic neurons.•Natural products are neuroprotectors against cell toxicity of 5-S-Cys-DA.•5-S-Cys-DA can be used as a potential biomarker for PD diagnosis.
We treated two cases of oral polypoidal malignant melanoma （PMM） with marked exophytic growth. We noted changes in levels of serum 5-S-cysteinyldopa （5-S-CD）, a tumor marker. Case 1 was a 51-year-old ...man. A brownish polypoidal mass of 55×40×40mm was found in the right mandibular gingiva, and was identified by biopsy to be malignant melanoma. 5-S-CD decreased from 12.5nmol/l before surgery to 3.9nmol/l after surgery. The 5-S-CD 3 years after operation is within the reference value range, and currently the course is good with no recurrence. Case 2 was an 81-year-old woman. A black polypoidal mass of 50×40×25mm was found in the right maxillary gingiva, and was identified by biopsy to be malignant melanoma. 5-S-CD decreased from 26.9nmol/l before surgery to 4.3nmol/l after surgery. The oral primary PMM was considered to be rare in these two cases. In addition, serum 5-S-CD could be useful in the oral cavity region.
Parkinson’s disease is characterized by a progressive and selective loss of dopaminergic neurons in the substantia nigra. Recent investigations have shown that conjugates such as the 5-
...S-cysteinyl-dopamine, possess strong neurotoxicity and may contribute to the underlying progression of the disease pathology. Although the neuroprotective actions of flavonoids are well reported, that of hydroxycinnamates and other phenolic acids is less established. We show that the hydroxycinnamates caffeic acid and
p-coumaric acid, the hydroxyphenethyl alcohol, tyrosol, and a Champagne wine extract rich in these components protect neurons against injury induced by 5-
S-cysteinyl-dopamine
in vitro. The protection induced by these polyphenols was equal to or greater than that observed for the flavonoids, (+)-catechin, (−)-epicatechin and quercetin. For example,
p-coumaric acid evoked significantly more protection at 1
μM (64.0
±
3.1%) than both (−)-epicatechin (46.0
±
4.1%,
p
<
0.05) and (+)-catechin (13.1
±
3.0%,
p
<
0.001) at the same concentration. These data indicate that hydroxycinnamates, phenolic acids and phenolic alcohol are also capable of inducing neuroprotective effects to a similar extent to that seen with flavonoids.
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