Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes. Although melanoma has long been regarded as a cancerous malignancy with few therapeutic options, increased biological understanding and unprecedented innovations in therapies targeting mutated driver genes and immune checkpoints have substantially improved the prognosis of patients. However, the low response rate and inevitable occurrence of resistance to currently available targeted therapies have posed the obstacle in the path of melanoma management to obtain further amelioration. Therefore, it is necessary to understand the mechanisms underlying melanoma pathogenesis more comprehensively, which might lead to more substantial progress in therapeutic approaches and expand clinical options for melanoma therapy. In this review, we firstly make a brief introduction to melanoma epidemiology, clinical subtypes, risk factors, and current therapies. Then, the signal pathways orchestrating melanoma pathogenesis, including genetic mutations, key transcriptional regulators, epigenetic dysregulations, metabolic reprogramming, crucial metastasis-related signals, tumor-promoting inflammatory pathways, and pro-angiogenic factors, have been systemically reviewed and discussed. Subsequently, we outline current progresses in therapies targeting mutated driver genes and immune checkpoints, as well as the mechanisms underlying the treatment resistance. Finally, the prospects and challenges in the development of melanoma therapy, especially immunotherapy and related ongoing clinical trials, are summarized and discussed.

Mitochondrial dysregulation has been implicated in oxidative stress-induced melanocyte destruction in vitiligo. However, the molecular mechanism underlying this process is merely investigated. Given the prominent role of nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase Sirtuin3 (SIRT3) in sustaining mitochondrial dynamics and homeostasis and that SIRT3 expression and activity can be influenced by oxidative stress-related signaling, we wondered whether SIRT3 could play an important role in vitiligo melanocyte degeneration by regulating mitochondrial dynamics. Methods: We initially testified SIRT3 expression and activity in normal and vitiligo melanocytes via PCR, immunoblotting and immunofluorescence assays. Then, cell apoptosis, mitochondrial function and mitochondrial dynamics after SIRT3 intervention were analyzed by flow cytometry, immunoblotting, confocal laser microscopy, transmission electron microscopy and oxphos activity assays. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), immunoblotting and immunofluorescence assays were performed to clarify the upstream regulatory mechanism of SIRT3. Finally, the effect of honokiol on protecting melanocytes and the underlying mechanism were investigated via flow cytometry and immunoblotting analysis. Results: We first found that the expression and the activity of SIRT3 were significantly impaired in vitiligo melanocytes both in vitro and in vivo . Then, SIRT3 deficiency led to more melanocyte apoptosis by inducing severe mitochondrial dysfunction and cytochrome c release to cytoplasm, with Optic atrophy 1 (OPA1)-mediated mitochondrial dynamics remodeling involved in. Moreover, potentiated carbonylation and dampened peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) activation accounted for SIRT3 dysregulation in vitiligo melanocytes. Finally, we proved that honokiol could prevent melanocyte apoptosis under oxidative stress by activating SIRT3-OPA1 axis. Conclusions: Overall, we demonstrate that SIRT3-dependent mitochondrial dynamics remodeling contributes to oxidative stress-induced melanocyte degeneration in vitiligo, and honokiol is promising in preventing oxidative stress-induced vitiligo melanocyte apoptosis.

The CC chemokines macrophage inflammatory protein-1␣ (MIP-1␣) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis. Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had K i values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitrite), was further evaluated. The directed migration of select populations of leukocytes from the circulation to sites of inflammation is an integral part of the immune response. The chemokines are a diverse group of proteins that play an important role in this process (1). They are classified into two major groups, CXC and CC, based on the position of the first two of their four invariant cysteines (2). Each of the chemokines recognizes and induces the chemotaxis of a particular subset of leukocytes. For example, the CXC chemokines, like IL-8 1 and melonoma growth stimulatory activity, mainly chemoattract and activate neutrophils, in contrast to the CC chemokines, like RANTES and monocyte chemoattractant protein, which preferentially attract T lymphocytes and monocytes and induce their activation by producing changes in cellular morphology, transient increases in cellular calcium concentration, and the up-regulation of surface adhesion proteins.The chemokines produce their biologic effects by interacting with specific receptors on the cell surface of their target cells (3). To date, 14 different chemokine receptors including eight CC chemokine receptors have been identified by cloning (4, 5). All of these receptors are characterized by a heptahelical structure and belong to a superfamily of serpentine receptors that are coupled to guanine nucleotide-binding proteins (G-proteins) (6).Occasionally the immune system can turn upon its host, giving rise to chronic inflammation and disease. Given their important role in this process, chemokines have been implicated in the pathophysiology of autoimmune diseases like multiple sclerosis and rheumatoid arthritis. For example a recent study by Karpus et al. (7) provides strong in vivo concept validation for a role of MIP-1␣ in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. These investigators were able to show that antibodies to MIP-1␣ prevented the development of both acute and relapsing paralytic disease as well as infiltration of mononuclear cells into the central nervous system. Treatment with MIP-1␣ antibody was also able to ameliorate the severity of ongoing clinical disease. These results led the authors to conclude that MIP-1␣ plays an important role in this T-cell me...

Background: Keratinocytes can function as innate immune cells under oxidative stress and aggravate the cutaneous T-cell response that undermines melanocytes in the setting of vitiligo. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a regulator of innate immunity that exists in keratinocytes. However, the role of the NLRP3 inflammasome in the pathogenesis of vitiligo has not been investigated. Objective: We sought to explicate the contribution of the activated NLRP3 inflammasome in keratinocytes to the autoimmune response in patients with vitiligo.Methods: Perilesional and serum samples from patients with vitiligo were collected to examine the status of the NLRP3 inflammasome in the setting of vitiligo. Cultured keratinocytes were treated with H 2 O 2 to investigate the mechanism for NLRP3 inflammasome activation under oxidative stress. Peripheral blood T cells were extracted from patients with vitiligo to explore the influence of the NLRP3 inflammasome on the T-cell response in patients with vitiligo. Results: Expressions of NLRP3 and downstream cytokine IL-1b were consistently increased in perilesional keratinocytes of patients with vitiligo. Notably, serum IL-1b levels were From a