דו״ח מאומת

Aging is an inevitable natural process, with gray hair being one of its most visible signs. Hair graying holds psychosocial importance and is an excellent model for studying human pigmentation and aging in an accessible mini-organ. This phenomenon results from decreased melanin production in hair follicles, influenced by genetic, environmental, and lifestyle factors. Gray hair often poses aesthetic concerns and can be accelerated by environmental stressors, lifestyle choices, and nutritional deficiencies. Given the variation in onset and prevalence of gray hair, this study explores the underlying biological factors-namely, genetics, oxidative stress, and hormonal changes-to inform better prevention and treatment strategies. Recent advancements in prevention and treatment, such as topical melanin stimulants, antioxidants, dietary supplements, and low-level laser therapy (LLLT), offer promising approaches to managing gray hair. Understanding gray hair comprehensively-encompassing biological, psychological, and social dimensions-provides valuable insights into the aging process and can enhance overall well-being while addressing the stigma associated with aging. Our comprehensive analysis reveals that while graying correlates with certain health conditions, its primary significance is physiological rather than pathological. This understanding is essential for healthcare providers and the public to approach graying with scientific objectivity rather than social prejudice.…

PMID: 40546989

Premature hair graying (PHG) is the early loss of natural hair color, influenced by genetic, biological, and environmental factors. This review discusses the significant psychological impacts of PHG and explores its underlying mechanisms, related health conditions, and available treatments. The review examines the roles of genetics, oxidative stress, and lifestyle factors such as smoking and diet in premature graying. It also considers associated medical conditions and current and emerging treatment options. This overview aims to improve understanding of PHG and its broader implications.…

PMID: 39697103

Melanins are natural pigments of skin, hair and eyes and can be classified into two main types: brown to black eumelanin and yellow to reddish-brown pheomelanin. Biosynthesis of melanins takes place in melanosomes, which are specialized cytoplasmic organelles of melanocytes - dendritic cells located in the basal layer of the epidermis, uveal tract of the eye, hair follicles, as well as in the inner ear, central nervous system and heart. Melanogenesis is a multistep process and begins with the conversion of amino acid L-tyrosine to DOPAquinone. The addition of cysteine or glutathione to DOPAquinone leads to the intermediates formation, followed by subsequent transformations and polymerization to the final product, pheomelanin. In the absence of thiol compounds DOPAquinone undergoes an intramolecular cyclization and oxidation to form DOPAchrome, which is then converted to 5,6-dihydroksyindole (DHI) or 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Eumelanin is formed by polymerization of DHI and DHICA and their quinones. Regulation of melanogenesis is achieved by physical and biochemical factors. The article presents the intracellular signaling pathways: cAMP/PKA/CREB/MITF cascade, MAP kinases cascade, PLC/DAG/PKCβ cascade and NO/cGMP/PKG cascade, which are involved in the regulation of expression and activity of the melanogenesis-related proteins by ultraviolet radiation and endogenous agents (cytokines, hormones). Activity of the key melanogenic enzyme, tyrosinase, is also affected by pH and temperature. Many pharmacologically active substances are able to inhibit or stimulate melanin biosynthesis, as evidenced by in vitro studies on cultured pigment cells.…

PMID: 27356601

Tyrosinase (EC 1.14.18.1) is a binuclear copper enzyme responsible for the rate-limiting steps of melanogenesis, catalyzing the hydroxylation of L-tyrosine and oxidation of L-DOPA into o-quinones that polymerize melanin. Beyond its physiological role in pigmentation, tyrosinase is also implicated in food browning and oxidative stress-related disorders, making it a key target in cosmetic, food, and biomedical industries. This systematic review, conducted following PRISMA guidelines, aimed to identify and analyze microbial metabolites with tyrosinase inhibitory potential as sustainable alternatives to conventional inhibitors such as hydroquinone and kojic acid. Literature searches in Scopus and Web of Science (March 2025) yielded 156 records; after screening and applying inclusion criteria, 11 studies were retained for analysis. The inhibitors identified include indole derivatives, phenolic acids, peptides, and triterpenoids, mainly produced by fungi (e.g., <i>Ganoderma lucidum</i>, <i>Trichoderma</i> sp.), actinobacteria (<i>Streptomyces</i>, <i>Massilia</i>), and microalgae (<i>Spirulina</i>, <i>Synechococcus</i>). Reported IC₅₀ values ranged from micromolar to milli-molar levels, with methyl lucidenate F (32.23 µM) and <i>p</i>-coumaric acid (52.71 mM). Mechanisms involved competitive and non-competitive inhibition, as well as gene-level regulation. However, methodological heterogeneity, the predominance of mushroom tyrosinase assays, and limited human enzyme validation constrain translational relevance. Computational modeling, site-directed mutagenesis, and molecular dynamics are proposed to overcome these limitations. Overall, microbial metabolites exhibit promising efficacy, stability, and biocompatibility, positioning them as emerging preclinical candidates for the development of safer and more sustainable tyrosinase inhibitors.…

PMID: 41596661

The production of pigment in mammalian melanocytes requires the contribution of at least three melanogenic enzymes, tyrosinase and two other accessory enzymes called the tyrosinase-related proteins (Trp1 and Trp2), which regulate the type and amount of melanin. The last two proteins are paralogues to tyrosinase, and they appeared late in evolution by triplication of the tyrosinase gene. Tyrosinase is a copper-enzyme, and Trp2 is a zinc-enzyme. Trp1 has been more elusive, and the direct identification of its metal cofactor has never been achieved. However, due to its enzymatic activity and similarities with tyrosinase, it has been assumed as a copper-enzyme. Recently, recombinant human tyrosinase and Trp1 have been expressed in enough amounts to achieve for the first time their crystallization. Unexpectedly, it has been found that Trp1 contains a couple of Zn(II) at the active site. This review discusses data about the metal cofactor of tyrosinase and Trps. It points out differences in the studied models, and it proposes some possible points accounting for the apparent discrepancies currently appearing. Moreover, some proposals about the possible flexibility of the tyrosinase family to uptake copper or zinc are discussed.…

PMID: 29473882

Copper is a cofactor for many cellular enzymes and transporters. It can be loaded onto secreted and endomembrane cuproproteins by translocation from the cytosol into membrane-bound organelles by ATP7A or ATP7B transporters, the genes for which are mutated in the copper imbalance syndromes Menkes disease and Wilson disease, respectively. Endomembrane cuproproteins are thought to incorporate copper stably on transit through the trans-Golgi network, in which ATP7A accumulates by dynamic cycling through early endocytic compartments. Here we show that the pigment-cell-specific cuproenzyme tyrosinase acquires copper only transiently and inefficiently within the trans-Golgi network of mouse melanocytes. To catalyse melanin synthesis, tyrosinase is subsequently reloaded with copper within specialized organelles called melanosomes. Copper is supplied to melanosomes by ATP7A, a cohort of which localizes to melanosomes in a biogenesis of lysosome-related organelles complex-1 (BLOC-1)-dependent manner. These results indicate that cell-type-specific localization of a metal transporter is required to sustain metallation of an endomembrane cuproenzyme, providing a mechanism for exquisite spatial control of metalloenzyme activity. Moreover, because BLOC-1 subunits are mutated in subtypes of the genetic disease Hermansky-Pudlak syndrome, these results also show that defects in copper transporter localization contribute to hypopigmentation, and hence perhaps other systemic defects, in Hermansky-Pudlak syndrome.…

PMID: 18650808

<h4>Background</h4>Copper deficiency is an under-recognized complication after metabolic and bariatric surgery (MBS) with hematologic and neurologic sequelae. Comparative evidence between one-anastomosis gastric bypass (OAGB) and Roux-en-Y gastric bypass (RYGB) is limited. We compared time-dependent copper trends and deficiency prevalence after OAGB versus RYGB and identified associated factors.<h4>Methods</h4>We conducted a single-center retrospective cohort study of consecutive adults undergoing primary OAGB or RYGB (January 2020-December 2022). Serum copper was measured preoperatively and at 6 months and 12 months. Copper deficiency was defined as serum copper < 75 µg/dL. Multivariable logistic regression assessed associations of age, sex, procedure type, and 6-month percent total weight loss (%TWL) with deficiency; receiver operating characteristic (ROC) analysis explored a 6-month %TWL threshold.<h4>Results</h4>Among 294 patients (OAGB n = 107; RYGB n = 187; mean age 38.8 ± 9.9 years; 83% women), deficiency prevalence across 6, and 12 months did not differ between procedures. Mean serum copper declined from baseline to 6 months in both groups and remained below baseline at 12 months. In adjusted analyses, female sex and greater 6-month %TWL were independently associated with copper deficiency at 6 months; age and procedure type were not. ROC analysis suggested an exploratory 6-month %TWL threshold of ~ 29% for identifying higher-risk patients (AUC 0.64). No consistent between-group differences were observed in hematologic or iron indices by copper status.<h4>Conclusion</h4>Copper deficiency rates through 12 months were comparable after OAGB and RYGB; however, mean serum copper declined after both procedures. Greater early weight loss was associated with deficiency, supporting targeted biochemical surveillance-particularly within the first postoperative year-and reinforcement of supplementation adherence.…

PMID: 41353140