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Introduction: Venlafaxine is one of the most commonly used anti-depressant and antineoplastic drug. Previous studies have predicted venlafaxine as an anti-cancer compound, but the therapeutic effects of venlafaxine in melanoma have not yet been demonstrated. Nur77 is an orphan nuclear receptor that highly expressed in melanoma cells and can interact with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic protein.Method: We examined the effects of venlafaxine in MV3 cells in vitro and MV3 xenograft tumor in nude mice. Western-blot, PCR, TUNEL assay and immunofluorescence were used to reveal the growth of melanoma cells.Results: Here, our data revealed that venlafaxine could reduce the growth, and induce apoptosis of melanoma cells through a Nur77-dependent way. Our results also showed that treatment with venlafaxine (20 mg/kg, i.p.) potently inhibited the growth of melanoma cells in nude mice. Mechanistically, venlafaxine activated JNK1/2 signaling, induced Nur77 expressions and mitochondrial localization, thereby promoting apoptosis of melanoma cells. Knockdown of Nur77 and JNK1/2, or inhibition of JNK1/2 signaling with its inhibitor SP600125 attenuated the anti-cancer effects of venlafaxine.Conclusion: In summary, our results suggested venlafaxine as a potential therapy for melanoma.

Doxorubicin (DOX) is one of the most common chemotherapeutic anti-cancer drugs. However, its clinical use is restricted by serious cardiotoxicity. Oleoylethanolamide (OEA), a structural congener of endocannabinoid anandamide, is the endogenous agonist of peroxisome proliferator activated-receptor α (PPARα) and transient receptor potential cation channel vanilloid-1 (TRPV1), and involved in many physiological processes. The present study aimed to determine whether OEA treatment protects against DOX-induced cytotoxicity (DIC) and gain insights into the underlying mechanism that mediate these effects. Our data revealed that Oleoylethanolamide treatment improved the myocardial structure in DOX-challenged mice by attenuating cardiac oxidative stress and cell apoptosis. OEA also alleviated DOX-induced oxidative stress and apoptosis dysregulation in HL-1 cardiomyocyte. These effects were mediated by activation of TRPV1 and upregulation of PI3K/ Akt signaling pathway. Inhibition of TRPV1 and PI3K reversed the protective effects of OEA. Taken together, our data suggested that OEA protects against DIC through a TRPV1- mediated PI3K/ Akt pathway.

Sleep loss is a key factor associated with dry eye. Use of a “stick over water” mouse model revealed that sleep deprivation induces accumulation of lipids, hypertrophy, and dysfunction of the lacrimal gland. These changes result in decreased tear production and dry eye clinical signs. The specific pathophysiological mechanisms that contribute to dry eye remain unclear. In this study, we found that sleep deprivation decreased endogenous lipid palmitoylethanolamide (PEA) expression in the lacrimal gland. The reduced expression was mainly attributed to the decreased expression of N-acylated phosphatidylethanolamine–phospholipase D, the synthetic enzyme of PEA. Exogenous PEA treatment restored local lipid metabolism homeostasis in the lacrimal gland. This change was accompanied by reduced lipid deposition, maintenance of the endoplasmic reticulum and mitochondrial morphology, and improved acinar cell secretory function. PEA treatment also prevented damage to corneal barrier function and improved the dry eye clinical signs caused by sleep deprivation. The nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) was found to mediate the PEA-associated improvements. We describe here for the first time that PEA is involved in sleep deprivation–induced lacrimal gland pathogenesis and dry eye development. PEA and its metabolizing enzymes may serve as adjunctive therapeutic targets for treatment of dry eye.