CYLD is a deubiquitinating enzyme known for its role as a tumor suppressor whose mutation leads to skin appendages tumors and other cancers. In this manuscript we report that the tumor suppressor CYLD, similarly to other renowned tumor suppressor genes, protects from premature aging and cancer. We have generated transgenic mice expressing the mutant CYLDC/S protein, lacking its deubiquitinase function, under the control of the keratin 5 promoter, the K5-CYLDC/S mice. These mice express the transgene in different organs, including those considered to be more susceptible to aging, such as skin and thymus. Our results show that K5-CYLDC/S mice exhibit epidermal, hair follicle, and sebaceous gland alterations; and, importantly, they show signs of premature aging from an early age. Typically, 3-month-old K5-CYLDC/S mice exhibit a phenotype characterized by alopecia and kyphosis, and, the histological examination reveals that transgenic mice show signs of accelerated aging in numerous organs such as skin, thymus, pancreas, liver and lung. Additionally, they spontaneously develop tumors of diverse origin. Over-activation of the NF-kappa B pathway, along with hyperactivation of Akt, JNK and c-Myc, and chronic inflammation, appear as the mechanisms responsible for the premature aging of the K5-CYLDC/S mice.

NMSC (non-melanoma skin cancer) is a common tumor in the Caucasian population, accounting for 90% of skin cancers. Among them, squamous cell carcinomas (SCCs) can metastasize and, due to its high incidence, constitute a severe health problem. It has been suggested that cutaneous SCCs with more risk to metastasize express high levels of nuclear IKKα. However, the molecular mechanisms that lead to this enhanced aggressiveness are largely unknown. To understand in depth the influence of nuclear IKKα in skin SCC progression, we have generated murine PDVC57 skin carcinoma cells expressing exogenous IKKα either in the nucleus or in the cytoplasm to further distinguish the tumor properties of IKKα in both localizations. Our results show that IKKα promotes changes in both subcellular compartments, resembling EMT (epithelial–mesenchymal transition), which are more pronounced when IKKα is in the nucleus of these tumor cells. These EMT-related changes include a shift toward a migratory phenotype and induction of the expression of proteins involved in cell matrix degradation, cell survival and resistance to apoptosis. Additionally, we have found that apigenin, a flavonoid with anti-cancer properties, inhibits the expression of IKKα and attenuates most of the pro-tumoral EMT changes induced by IKKα in mouse tumor keratinocytes. Nevertheless, we have found that apigenin only inhibits the expression of the IKKα protein when it is localized in the cytoplasm.

Silicon as a functional ingredient of restructured meat (RM) shows antidiabetic and hypocholesterolemic effects in a type 2 diabetes mellitus (T2DM) rat model. The present paper investigated the mechanisms involved in this cholesterol-lowering effect by studying the impact of silicon-RM consumption on bile acid (BA) and cholesterol metabolism. In addition, the main effects of cecal BA and short-chain fatty acids derived from the microbiota on intestinal barrier integrity were also tested. Rats were fed an RM high-saturated-fat, high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection (LD group) and for an 8 wk. period. Silicon-RM was included in the HSFHCD as a functional food (LD-Si group). An early-stage T2DM group fed a high-saturated-fat diet (ED group) was used as a reference. Silicon decreased the BA pool with a higher hydrophilic BA profile and a lower ability to digest fat and decreased the damaging effects, increasing the occludin levels and the integrity of the intestinal barrier. The ileal BA uptake and hepatic BA synthesis through CYP7A1 were reduced by FXR/FGF15 signaling activation. The silicon up-regulated the hepatic and ileal FXR and LXRα/β, improving transintestinal cholesterol (TICE), biliary BA and cholesterol effluxes. The inclusion of silicon in meat products could be used as a new therapeutic nutritional tool in the treatment of diabetic dyslipidemia.

Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.

Silicon included in a restructured meat (RM) matrix (Si-RM) as a functional ingredient has been demonstrated to be a potential bioactive antidiabetic compound. However, the jejunal and hepatic molecular mechanisms by which Si-RM exerts its cholesterol-lowering effects remain unclear. Male Wistar rats fed an RM included in a high-saturated-fat high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection were used as late-stage type 2 diabetes mellitus (T2DM) model. Si-RM was included into the HSFHCD as a functional food. An early-stage TD2M group fed a high-saturated-fat diet (HSFD) was taken as reference. Si-RM inhibited the hepatic and intestinal microsomal triglyceride transfer protein (MTP) reducing the apoB-containing lipoprotein assembly and cholesterol absorption. Upregulation of liver X receptor (LXRα/β) by Si-RM turned in a higher low-density lipoprotein receptor (LDLr) and ATP-binding cassette transporters (ABCG5/8, ABCA1) promoting jejunal cholesterol efflux and transintestinal cholesterol excretion (TICE), and facilitating partially reverse cholesterol transport (RCT). Si-RM decreased the jejunal absorptive area and improved mucosal barrier integrity. Consequently, plasma triglycerides and cholesterol levels decreased, as well as the formation of atherogenic lipoprotein particles. Si-RM mitigated the dyslipidemia associated with late-stage T2DM by Improving cholesterol homeostasis. Silicon could be used as an effective nutritional approach in diabetic dyslipidemia management.