Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma

Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long‐term diseases including hepatocellular carcinoma (HCC ). Melatonin has been reported to alleviate promotion and progression of HCC , but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN ) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg^?1d^?1 ip beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Liver expression of Bmal1, Clock, Npas2, Rorα, and Sirt1 increased, whereas Cry1, Per1, Per2, Per3, CK 1ε, Rev‐erbα, and Rev‐erbβ decreased following DEN administration. Melatonin treatment prevented changes in the expression of clock genes, and this effect was accompanied by an upregulation of the MT 1 receptor and reduced levels of the hypoxia‐inducible factors Hif‐1α and Hif‐2α. An increased expression of p21, p53, and PARP 1/2, a higher Bax/Bcl‐2 ratio, and a lower expression of Cyclin D1, CDK 6, HSP 70, HSP 90, and GRP 78 proteins were also observed in melatonin‐treated mice. Melatonin significantly potentiated the suppression of proliferation and cell cycle arrest induced by the synthetic REV ‐ERB agonist SR 9009 in human Hep3B cells, and BMAL 1 knocking down attenuated the pro‐apoptotic and antiproliferative effect of melatonin. Results support a contribution of changes in the circadian clock components to the beneficial effects of melatonin in HCC and highlight the usefulness of strategies modulating the circadian machinery in hepatocarcinogenesis.     

In vivo and in vitro evaluation of the use of a newly developed melatonin loaded emulsion combined with UV filters as a protective agent against skin irradiation

BackgroundMelatonin has attracted attention because of their high antioxidant and anticarcinogenic activity. Otherwise, the use of sunscreens is recommended for patients after chemotherapy and radiotherapy treatments or to prevent UV radiation-induced skin damages that may result in pre-cancerous and cancerous skin lesions.ObjectiveTo evaluate the beneficial influence of melatonin in topical sunscreen emulsions combined with three common ultraviolet filters.MethodsAfter the formulation characterization in terms of rheology, stability studies were performed. Release studies let us to evaluate its mechanism of delivery and ex vivo permeation study through human skin, the amount of melatonin retained. The antioxidant activity assay was also carried out, and finally the in vivo photoprotective effect in rats was tested as transepidermal water loss and erythema formation.ResultsThe rheological behaviour of formulations was pseudoplastic fluid, all emulsions had good physical stability. Release studies showed a trend of enhancement in melatonin release from emulsions incorporating UV filters and followed a Weibull model. Melatonin permeation was higher from the emulsion containing melatonin combined with a mixture of three ultraviolet filters (MMIX) formulation. Equally this formulation exhibited the highest radical scavenging activity. Finally the photoprotective assay showed that only skin areas treated with this formulation were statistically equivalent to the unirradiated control area.ConclusionMMIX formulation would be a promising formulation for preventing the undesirable adverse effects of UV skin irradiation because melatonin not only acts as a potent antioxidant itself, but also is capable of activating an endogenous enzymatic protective system against oxidative stress.     

Cytotoxic and estrogenic activity of chlorpyrifos and its metabolite 3,5,6-trichloro-2-pyridinol. Study of marine yeasts as potential toxicity indicators

Chlorpyrifos (CP) is one of the organophosphate insecticides most used worldwide today. Although the main target organ for CP is the nervous system triggering predominantly neurotoxic effects, it has suggested other mechanisms of action as cytotoxicity and endocrine disruption. The risk posed by the pesticide metabolites on non-target organisms is increasingly recognized by regulatory agencies and natural resource managers. In the present study, cytotoxicity and estrogenic activity of CP, and its principal metabolite 3,5,6-trichloro-2-pyridinol (TCP) have been evaluated by in vitro assays, using two mammalian cell lines (HEK293 and N2a), and a recombinant yeast. Results indicate that TCP is more toxic than CP for the two cell lines assayed, being N2a cells more sensitive to both compounds. Both compounds show a similar estrogenic activity being between 2500 and 3000 times less estrogenic than 17β-estradiol. In order to find new toxicity measurement models, yeasts isolated from marine sediments containing CP residues have been tested against CP and TCP by cell viability assay. Of the 12 yeast strains tested, 6 of them showed certain sensitivity, and a concentration-dependent response to the tested compounds, so they could be considered as future models for toxicity tests, although further investigations and proves are necessary.

     

Correction to: Henoch-Schönlein purpura nephritis: initial risk factors and outcomes in a Latin American tertiary center

Clinical Rheumatology - One of the author’s name on this article was incorrectly spelled as “Sylvia C. L. Fahrat” . The correct spelling is “Sylvia C. L. Farhat” and...     

Multisystemic Langerhans Cell Histiocytosis Mimicking Diffuse Neonatal Hemangiomatosis

We report the first case of multisystemic Langerhans cell histiocytes mimicking diffuse neonatal hemangiomatosis clinically. This has been described in patients with congenital self‐healing reticulohistiocytosis but not in patients with acute, disseminated, and multisystemic disease. In our experience, dermoscopic findings did not help to diagnose the condition.