Melanin is a group of natural pigments that determines the human skin color and provides fundamental protection against the harmful impacts of physical and chemical stimuli. The aim of this study was to establish the regulatory role of aryl hydrocarbon receptor (AhR) in α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis. In the present study, following knockdown of AhR, murine B16F10 cells were treated with α-MSH (200 nM) and tyrosinase activities, cellular melanin content, mRNA levels of several important genes involved in melanogenesis including AhR, CTNNB1, TYR2, and microphthalmia-associated transcription factor ( MITF) were measured as endpoints. Exposure to α-MSH led to elevated expression of AhR, CTNNB1, MITF, and TYR in accordance with increased tyrosinase enzyme activity as well as a significant rise in the total melanin content. Our results suggest that AhR plays a regulatory role in α-MSH-stimulated melanogenesis.
Hyperpigmentation disorders negatively influence an individual's quality of life and may cause emotional distress. Over the years, various melanogenesis inhibitors (mainly tyrosinase inhibitors) have been developed, most of which with low efficacy or high toxicity. Although metabolic engineering by deviation in the flux of substrate is of considerable interest, trials to develop a melanogenesis inhibitor based on L-tyrosine (L-Tyr) restriction are missing. We propose a novel proteinaceous melanogenesis inhibitor called tyrosine ammonia-lyase (TAL), an enzyme that catalyzes the conversion of L-Tyr to p-coumaric acid and ammonia. Since the cell membrane can act as a barrier for intracellular protein delivery, we have covalently conjugated a recombinant TAL enzyme from Rhodobacter sphaeroides (RsTAL) to a trans-activator of transcription (TAT) cell-penetrating peptide (CPP) to afford the intracellular delivery. The heterologously expressed TAT-RsTAL fusion protein was delivered successfully into B16F10 melanocytes as confirmed by the direct fluorescence microscopy with increased intensity from 30 to 180 min. TAT-RsTAL showed sufficient intracellular activity of about 0.83 ± 0.04 and 0.34 ± 0.03 nmol•mg −1 •s −1 for the native and inclusion body-extracted conjugates, respectively. The conjugate inhibited melanin biosynthesis in B16F10 cells in a time-dependent manner. Melanin accumulation was inhibited by 12.7 ± 6.2%, 28.2 ± 5.7%, and 33.9 ± 2.9% compared to the nontreated control groups after 24, 48, and 72 hr of incubation, respectively. L-Tyr restriction had no significant effect on the cell viability up to a concentration of 100 μgml −1 even after 72 hr. According to the observed hypopigmentary effect of the conjugate in this study, TAT-RsTAL can be suggested as a melanogenesis inhibitor for further investigations.
The preservation of the redox homeostasis is critical for cell survival and functionality. Redox imbalance is an essential inducer of several pathological states. CD4+/helper T cells are highly dependent on the redox state of their surrounding milieu. The potential of the aryl hydrocarbon receptor (AhR) engagement in controlling CD4+ T‐cell fate during redox alteration is still challenging. C57BL/6 mice were treated with AhR agonist 6‐formylindolo[3,2‐b]carbazole (FICZ), AhR antagonist CH223191, an inhibitor of glutathione biosynthesis buthionine sulfoximine (BSO), and the antioxidant N‐acetylcysteine (NAC) alone or in combination. Six days later, splenocytes were evaluated for the expression of the redox‐related genes and the possible changes in T‐cell subsets. FICZ like BSO significantly elevated the expression of HMOX1, GCLC, and GCLM genes but it failed to increase the expression of the Nrf2 gene. Moreover, FICZ + BSO increased while FICZ + CH223191 or NAC decreased the expression of these genes. FICZ also significantly increased Th1 cell numbers but decreased Tregs in a dose‐dependent manner. Furthermore, a high dose of FICZ + CH223191 + NAC significantly enhanced Th1, Th17, and Treg cells but its low dose in such a situation increased Th2 and Th17 while decreased Treg cells. AhR engagement during redox alteration can determine the fate of CD4 + T cells, so, AhR agonists or antagonists might be useful in assessing immune responses. However, these results need further verifications in vitro and in animal models of various diseases.
The amyloid beta precursor protein (APP) plays a pathophysiological role in the development of Alzheimer’s disease as well as a physiological role in neuronal growth and synaptogenesis. The aryl hydrocarbon receptor (AhR)/WNT/Catenin Beta 1 (CTNNB1)/Notch signaling pathways stamp in many functions, including development and growth of neurons. However, the regulatory role of AhR-/WNT-/CTNNB1-/Notch-induced APP expression and its influence on hippocampal-dependent learning and memory deficits is not clear. Male BALB/C mice received 6-formylindolo[3,2-b]carbazole (an AhR agonist), CH223191(an AhR antagonist), DAPT (an inhibitor of Notch signaling), and XAV-939 (a WNT pathway inhibitor) at a single dose of 100 μg/kg, 1, 5 , and 5 mg/kg of body weight, respectively, via intraperitoneal injection alone or in combination. Gene expression analyses and protein assay were performed on the 7th and 29th days. To assess the hippocampal-dependent memory, all six mice also underwent contextual fear conditioning on the 28th day after treatments. Our results showed that endogenous ligand of AhR has a regulatory effect on APP gene. Also, the interaction of AhR/WNT/CTNNB1 has a positive regulatory effect, but Notch has a negative regulatory effect on the mRNA and protein expression of APP, which have a correlation with mice’s learning skills and memory.
Background and Objectives: Exposure to lead and its effects on children's health is one of the most important and widespread concerns of human societies today. Therefore, the purpose of this systematic study was to evaluate blood lead levels in Iranian children.
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