The effects of ageing on the pigmented nerve cells of the human locus caeruleus and substantia nigra

Summary The nucleolar volume and melanin content of the human locus caeruleus and substantia nigra has been measured in 70 persons of age range new born to 91 years, all of whom were at death free from overt neurological illness. Both cell types show a reduction in nucleolar size with advancing age, which becomes disproportionately larger towards old age. At 90 years of age, the change in nucleolar volume in cells of the locus caeruleus amounts to about 5% whereas cells of the substantia nigra show a loss of 20%. The greater decrease in nucleolar volume in cells of the substantia nigra is attributed to the higher concentration of melanin pigment occurring in these cells at old age, rather than the absolute amount present. This marked decline in nucleolar volume in cells of substantia nigra indicates a reduced activity in the cell which, in turn, may be reflected in the difficulty in control and coordination in muscular activity commonly seen in normal elderly persons.     

黑色素在医学诊疗上的应用进展

黑色素是分布最为广泛的自然色素之一。由于其特殊的化学结构,黑色素可作为一种新型诊疗介质,具有巨大的开发应用潜力。本文围绕黑色素在疾病诊疗中的应用进展进行综述。     

8－甲氧补骨脂素对小鼠黑素瘤细胞黑素生成的调节及相关信号转导研究

目的研究光化疗法中光敏剂8 -甲氧补骨脂素(8 -MOP)在诱导白癜风色素减退皮损复色过程中所起的作用及其分子机制。方法用体外培养的B16F10鼠黑素瘤细胞作模型 ,观察了不同浓度(10～500μmol/L)8 -MOP对B16F10细胞的形态、酪氨酸酶活性和黑素含量的影响。结果50或100μmol/L浓度的8 -MOP处理细胞48h后 ,B16F10细胞的树状突明显增多延长 ,胞浆内出现较多的棕褐色颗粒。8 -MOP并能以浓度依赖方式提高酪氨酸酶活性和黑素含量 ,较对照组高2～3倍(P<0.01),且在50、100μmol/L浓度时这种作用呈现最强。此外还发现8 -MOP尚能浓度依赖地抑制细胞生长 ,100μmol/L时与对照组相比细胞抑制高达60 % ,500μmol/L时细胞几乎不能生长。用蛋白激酶A或C的激活剂 ,异丁基甲基黄嘌呤 (IBMX)和佛波酯 (TPA)与8 -MOP联合处理细胞发现8 -MOP诱导黑素生成作用能被IBMX加强 ,被长时程作用的TPA抑制。结论8 -MOP能以浓度依赖方式提高酪氨酸酶活性和黑素含量,在体外直接诱导鼠黑素瘤细胞黑素生成 ,蛋白激酶A和蛋白激酶C信号途径参与8 -MOP诱导黑素生成作用的调节。     

Glucokinase inhibitor glucosamine stimulates feeding and activates hypothalamic neuropeptide Y and orexin neurons

Maintaining glucose levels within the appropriate physiological range is necessary for survival. The identification of specific neuronal populations, within discreet brain regions, sensitive to changes in glucose concentration has led to the hypothesis of a central glucose-sensing system capable of directly modulating feeding behaviour. Glucokinase (GK) has been identified as a glucose-sensor responsible for detecting such changes both within the brain and the periphery. We previously reported that antagonism of centrally expressed GK by administration of glucosamine (GSN) was sufficient to induce protective glucoprivic feeding in rats. Here we examine a neurochemical mechanism underlying this effect and report that GSN stimulated food intake is highly correlated with the induction of the neuronal activation marker cFOS within two nuclei with a demonstrated role in central glucose sensing and appetite, the arcuate nucleus of the hypothalamus (ARC) and lateral hypothalamic area (LHA). Furthermore, GSN stimulated cFOS within the ARC was observed in orexigenic neurons expressing the endogenous melanocortin receptor antagonist agouti-related peptide (AgRP) and neuropeptide Y (NPY), but not those expressing the anorectic endogenous melanocortin receptor agonist alpha-melanocyte stimulating hormone (α-MSH). In the LHA, GSN stimulated cFOS was found within arousal and feeding associated orexin/hypocretin (ORX), but not orexigenic melanin-concentrating hormone (MCH) expressing neurons. Our data suggest that GK within these specific feeding and arousal related populations of AgRP/NPY and ORX neurons may play a modulatory role in the sensing of and appetitive response to hypoglycaemia.     

Neuromelanin magnetic resonance imaging of nigral volume loss in patients with Parkinson’s disease

Parkinson’s disease (PD) is characterized by progressive degeneration of melanin-containing neurons in the substantia nigra pars compacta (SNc). Pathological change has not been detected by neuroimaging techniques in patients with PD in vivo. We examined 80 patients with PD to determine whether degeneration of the SNc is detectable in vivo by MRI. The age-matched controls consisted of 54 patients who had suffered mild acute ischemic stroke. Axial T1-weighted MRI were obtained with a 3-Tesla MRI scanner. The border of the neuromelanin-sensitive region in the SNc was traced manually on these images, and the volume of this area was calculated. The mean volumes for the left and right SNc were significantly reduced in patients with PD compared to the controls. Volume loss became marked in parallel with disease severity and duration. Neuromelanin MRI may be considered as a biomarker of nigral degeneration in patients with PD.     

Melanin, a promising radioprotector: Mechanisms of actions in a mice model

The radioprotective effect of extracellular melanin, a naturally occurring pigment, isolated from the fungus Gliocephalotrichum simplex was examined in BALB/C mice, and the probable mechanism of action was established. At an effective dose of 50 mg/kg body weight, melanin exhibited both prophylactic and mitigative activities, increasing the 30-day survival of mice by 100% and 60%, respectively, after exposure to radiation (7 Gy, whole body irradiation (WBI)). The protective activity of melanin was primarily due to inhibition of radiation-induced hematopoietic damages as evidenced by improvement in spleen parameters such as index, total cellularity, endogenous colony forming units, and maintenance of circulatory white blood cells and platelet counts. Melanin also reversed the radiation-induced decrease in ERK phosphorylation in splenic tissue, which may be the key feature in its radioprotective action. Additionally, our results indicated that the sustained activation of AKT, JNK and P38 proteins in splenic tissue of melanin pre-treated group may also play a secondary role. This was also supported by the fact that melanin could prevent apoptosis in splenic tissue by decreasing BAX/Bcl-XL ratio, and increasing the expressions of the proliferation markers (PCNA and Cyclin D1), compared to the radiation control group. Melanin also reduced the oxidative stress in hepatic tissue and abrogated immune imbalance by reducing the production of pro-inflammatory cytokines (IL6 and TNFα). In conclusion, our results confirmed that fungal melanin is a very effective radioprotector against WBI and the probable mechanisms of radioprotection are due to modulation in pro-survival (ERK) signaling, prevention of oxidative stress and immunomodulation.     

Refinement of arylthiosemicarbazone pharmacophore in inhibition of mushroom tyrosinase

Melanin play a major role in human skin protection and their biosynthesis is vital. Due to their color, they contribute to the skin pigmentation. Tyrosinase is a key enzyme involved in the first stage of melanin biosynthesis, it catalyzes the transformation of tyrosine into l-dopaquinone. The aim of the present study was to study molecules able to inhibit tyrosinase to be used in treating depigmentation-related disorders. In this study, we targeted arylthiosemicarbazone analogs with the aim to contribute to the identification of the optimal aryl ring to be linked to the thiosemicarbazone moiety. The biological activity was evaluated on commercial mushroom tyrosinase which was purified prior use. The results demonstrated that several of our compounds (1a-h, 1j, 1r and 5) had more potent inhibitory activities than kojic acid which was used as the reference inhibitor.     

Involvement of putative response regulator genes of the rice blast fungus <Emphasis Type="Italic">Magnaporthe oryzae</Emphasis> in osmotic stress response,fungicide action,and pathogenicity

Rice blast fungus (Magnaporthe oryzae) has ten histidine kinases (HKs), one histidine-containing phosphotransfer protein (HPt), and three response regulators (RRs) as putative components of the two-component signal transduction system (TCS). Here, we constructed knockout mutants of two putative RR genes (MoSSK1, MoSKN7) and a RR homolog gene (MoRIM15) to analyze the roles of TCS in environmental adaptation and pathogenicity. The DeltaMossk1 strain had increased sensitivity to high osmolarity and decreased sensitivity to fludioxonil. The DeltaMoskn7 strain had slightly decreased sensitivity to fludioxonil. The involvement of MoSkn7 in the osmoresponse was obvious only on the DeltaMossk1 background. These results show that MoSsk1 and MoSkn7 are major and minor contributors, respectively, in the high osmolarity response and fludioxonil action. The DeltaMossk1 strain was more osmosensitive than the predicted upstream HK gene disruptant Deltahik1, which shows sugar-specific high osmolarity sensitivity. The DeltaMossk1 and DeltaMoskn7 strains showed enhanced hyphal melanization, suggesting that RRs regulate hyphal melanization. MoSsk1 and MoRim15 are required for full virulence, because the DeltaMossk1 and DeltaMorim15 strains exhibited reduced virulence. These results suggest that the putative RRs of the rice blast fungus are involved in the osmotic stress response, fludioxonil action, and pathogenicity.     

Identification and antioxidant activity of melanin isolated from Hypoxylon archeri, a companion fungus of Tremella fuciformis

Melanin produced by Hypoxylon archeri, a companion fungus of Tremella fuciformis, was purified from the submerged culture medium and designated as HM. Ultraviolet-visible and FTIR spectra of the purified HM showed significant similarities with those of the synthesized melanin derived from tyrosine. Thus, the HM melanin was identified to be derived from the precursor molecule of tyrosine or dihydroxyphenylalanine (DOPA). The antioxidant activity of HM melanin, synthetic melanin and vitamin C were compared by inhibition of the oxidation of 5-thio-2-nitrobenzoic acid (TNB) caused by hypochlorous acid (HOCl) and hydrogen peroxide (H(2)O(2)). The HM melanin is likely to be more efficient eliminating oxygen free radicals generated by H(2)O(2) than by HOCl. At a concentration of 100 mg x l(-1), the HM melanin protected 80.95% of TNB oxidation by H(2)O(2), slightly higher than the synthetic melanin. Inhibition curves as a function of time also revealed the HM melanin was a more efficient inhibitor of H(2)O(2) oxidation with an average TNB (TNB(acr)) consumption rate of 0.0553 mmol l(-1 ) x min(-1 )during the inhibition phase. Therefore, HM melanin is an efficient scavenger of peroxide free radicals.