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The oral consumption of alcohol (ethanol) has a long tradition in humans and is an integral part of many cultures. The causal relationship between ethanol consumption and numerous diseases is well known. In addition to the well-described harmful effects on the liver and pancreas, there is also evidence that ethanol abuse triggers pathological skin conditions, including acne. In the present study, we addressed this issue by investigating the effect of ethanol on the energy metabolism in human SZ95 sebocytes, with particular focus on qualitative and quantitative lipogenesis. It was found that ethanol is a strong trigger for lipogenesis, with moderate effects on cell proliferation and toxicity. We identified the non-oxidative metabolism of ethanol, which produced fatty acid ethyl esters (FAEEs), as relevant for the lipogenic effect—the oxidative metabolism of ethanol does not contribute to lipogenesis. Correspondingly, using the Seahorse extracellular flux analyzer, we found an inhibition of the mitochondrial oxygen consumption rate as a measure of mitochondrial ATP production by ethanol. The ATP production rate from glycolysis was not affected. These data corroborate that ethanol-induced lipogenesis is independent from oxygen. In sum, our results give a causal explanation for the prevalence of acne in heavy drinkers, confirming that alcoholism should be considered as a systemic disease. Moreover, the identification of key factors driving ethanol-dependent lipogenesis may also be relevant in the treatment of acne vulgaris.

Propofol belongs to a class of molecules that are known to block learning and memory in mammals, including rodents and humans. Interestingly, learning and memory are not tied to the presence of a nervous system. There are several lines of evidence indicating that single-celled organisms also have the capacity for learning and memory which may be considered as basal intelligence. Here, we introduce a new experimental model for testing the learning ability of Physarum polycephalum, a model organism frequently used to study single-celled “intelligence”. In this study, the impact of propofol on Physarum’s “intelligence” was tested. The model consists of a labyrinth of subsequent bifurcations in which food (oat flakes soaked with coconut oil-derived medium chain triglycerides [MCT] and soybean oil-derived long chain triglycerides [LCT]) or propofol in MCT/LCT) is placed in one of each Y-branch. In this setting, it was tested whether Physarum memorized the rewarding branch. We saw that Physarum was a quick learner when capturing the first bifurcations of the maze; thereafter, the effect decreased, perhaps due to reaching a state of satiety. In contrast, when oat flakes were soaked with propofol, Physarum’s preference for oat flakes declined significantly. Several possible actions, including the blocking of gamma-aminobutyric acid (GABA) receptor signaling, are suggested to account for this behavior, many of which can be tested in our new model.

The clinical application of immune checkpoint inhibitors represents a breakthrough progress in the treatment of metastasized melanoma and other tumor entities. In the present study, it was hypothesized that oligonucleotides (ODNs), known as modulators of the immune response, have an impact on the endogenous expression of checkpoint molecules, namely PD-L1 and PD-L2 (PD-L1/2). IFNγ-stimulated melanoma cells (A375, SK-Mel-28) were treated with different synthetically manufactured oligonucleotides which differed in sequence, length and backbone composition. It was found that a variety of different ODN sequences significantly suppressed PD-L1/2 expression. This effect was dependent on length and phosphorothioate (PTO) backbone. In particular, a sequence containing solely guanines (nCpG-6-PTO) was highly effective in downregulating PD-L1/2 at the protein, mRNA and promoter levels. Mechanistically, we gave evidence that ODNs with G-quartet-forming motifs suppress the interferon signaling axis (JAK/STAT/IRF1). Our findings identify a subset of ODNs as interesting pharmacological compounds that could expand the arsenal of targeted therapies to combat the immunological escape of tumor cells.

Although anti-cancer properties of the natural compound curcumin have been reported, low absorption and rapid metabolisation limit clinical use. The present study investigated whether irradiation with visible light may enhance the inhibitory effects of low-dosed curcumin on prostate cancer cell growth, proliferation, and metastasis in vitro. DU145 and PC3 cells were incubated with low-dosed curcumin (0.1–0.4 µg/mL) and subsequently irradiated with 1.65 J/cm2 visible light for 5 min. Controls remained untreated and/or non-irradiated. Cell growth, proliferation, apoptosis, adhesion, and chemotaxis were evaluated, as was cell cycle regulating protein expression (CDK, Cyclins), and integrins of the α- and β-family. Curcumin or light alone did not cause any significant effects on tumor growth, proliferation, or metastasis. However, curcumin combined with light irradiation significantly suppressed tumor growth, adhesion, and migration. Phosphorylation of CDK1 decreased and expression of the counter-receptors cyclin A and B was diminished. Integrin α and β subtypes were also reduced, compared to controls. Irradiation distinctly enhances the anti-tumor potential of curcumin in vitro and may hold promise in treating prostate cancer.

Recent documentation shows that a curcumin-induced growth arrest of renal cell carcinoma (RCC) cells can be amplified by visible light. This study was designed to investigate whether this strategy may also contribute to blocking metastatic progression of RCC. Low dosed curcumin (0.2 µg/mL; 0.54 µM) was applied to A498, Caki1, or KTCTL-26 cells for 1 h, followed by exposure to visible light for 5 min (400−550 nm, 5500 lx). Adhesion to human vascular endothelial cells or immobilized collagen was then evaluated. The influence of curcumin on chemotaxis and migration was also investigated, as well as curcumin induced alterations of α and β integrin expression. Curcumin without light exposure or light exposure without curcumin induced no alterations, whereas curcumin plus light significantly inhibited RCC adhesion, migration, and chemotaxis. This was associated with a distinct reduction of α3, α5, β1, and β3 integrins in all cell lines. Separate blocking of each of these integrin subtypes led to significant modification of tumor cell adhesion and chemotactic behavior. Combining low dosed curcumin with light considerably suppressed RCC binding activity and chemotactic movement and was associated with lowered integrin α and β subtypes. Therefore, curcumin combined with visible light holds promise for inhibiting metastatic processes in RCC.

Recent studies have proven that Dimethylfumarate (DMF) has a marked anti-proliferative impact on diverse cancer entities e.g., on malignant melanoma. To explore its anti-tumorigenic potential, we examined the effects of DMF on human colon carcinoma cell lines and the underlying mechanisms of action. Human colon cancer cell line HT-29 and human colorectal carcinoma cell line T84 were treated with or without DMF. Effects of DMF on proliferation, cell cycle progression, and apoptosis were analyzed mainly by Bromodeoxyuridine (BrdU)- and Lactatdehydrogenase (LDH)-assays, caspase activation, flowcytometry, immunofluorescence, and immunoblotting. In addition, combinational treatments with radiation and chemotherapy were performed. DMF inhibits cell proliferation in both cell lines. It was shown that DMF induces a cell cycle arrest in G0/G1 phase, which is accompanied by upregulation of p21 and downregulation of cyclin D1 and Cyclin dependent kinase (CDK)4. Furthermore, upregulation of autophagy associated proteins suggests that autophagy is involved. In addition, the activation of apoptotic markers provides evidence that apoptosis is involved. Our results show that DMF supports the action of oxaliplatin in a synergetic manner and failed synergy with radiation. We demonstrated that DMF has distinct anti-tumorigenic, cell dependent effects on colon cancer cells by arresting cell cycle in G0/G1 phase as well as activating both the autophagic and apoptotic pathways and synergizes with chemotherapy.

A hallmark of ageing is the redistribution of body fat. Particularly, subcutaneous fat decreases paralleled by a decrease of skin collagen I are typical for age-related skin atrophy. In this paper, we hypothesize that collagen I may be a relevant molecule stimulating the differentiation of adipose-derived stem cells (ASCs) into adipocytes augmenting subcutaneous fat. In this context lipogenesis, adiponectin, and collagen I receptor expression were determined. Freshly isolated ASCs were characterized by stemness-associated surface markers by FACS analysis and then transdifferentiated into adipocytes by specific medium supplements. Lipogenesis was evaluated using Nile Red staining and documented by fluorescence microscopy or quantitatively measured by using a multiwell spectrofluorometer. Expression of adiponectin was measured by real-time RT-PCR and in cell-free supernatants by ELISA, and expression of collagen I receptors was observed by western blot analysis. It was found that supports coated with collagen I promote cell adhesion and lipogenesis of ASCs. Interestingly, a reverse correlation to adiponectin expression was observed. Moreover, we found upregulation of the collagen receptor, discoidin domain-containing receptor 2; receptors of the integrin family were absent or downregulated. These findings indicate that collagen I is able to modulate lipogenesis and adiponectin expression and therefore may contribute to metabolic dysfunctions associated with ageing.

The anti-cancer properties of curcumin in vitro have been documented. However, its clinical use is limited due to rapid metabolization. Since irradiation of curcumin has been found to increase its anti-cancer effect on several tumor types, this investigation was designed to determine whether irradiation with visible light may enhance the anti-tumor effects of low-dosed curcumin on renal cell carcinoma (RCC) cell growth and proliferation. A498, Caki1, and KTCTL-26 cells were incubated with curcumin (0.1–0.4 µg/mL) and irradiated with 1.65 J/cm2 visible light for 5 min. Controls were exposed to curcumin or light alone or remained untreated. Curcumin plus light, but not curcumin or light exposure alone altered growth, proliferation, and apoptosis of all three RCC tumor cell lines. Cells were arrested in the G0/G1 phase of the cell cycle. Phosphorylated (p) CDK1 and pCDK2, along with their counter-receptors Cyclin B and A decreased, whereas p27 increased. Akt-mTOR-signaling was suppressed, the pro-apoptotic protein Bcl-2 became elevated, and the anti-apoptotic protein Bax diminished. H3 acetylation was elevated when cells were treated with curcumin plus light, pointing to an epigenetic mechanism. The present findings substantiate the potential of combining low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in RCC.

Curcumin—a rhizomal phytochemical from the plant Curcuma longa—is well known to inhibit cell proliferation and to induce apoptosis in a broad range of cell lines. In previous studies we showed that combining low curcumin concentrations and subsequent ultraviolet A radiation (UVA) or VIS irradiation induced anti-proliferative and pro-apoptotic effects. There is still debate whether curcumin induces apoptosis via the extrinsic or the intrinsic pathway. To address this question, we investigated in three epithelial cell lines (HaCaT, A431, A549) whether the death receptors CD95, tumor necrosis factor (TNF)-receptor I and II are involved in apoptosis induced by light and curcumin. Cells were incubated with 0.25⁻0.5 µg/mL curcumin followed by irradiation with 1 J/cm2 UVA. This treatment was combined with inhibitors specific for distinct membrane-bound death receptors. After 24 h apoptosis induction was monitored by quantitative determination of cytoplasmic histone-associated-DNA-fragments. Validation of our test system showed that apoptosis induced by CH11 and TNF-α could be completely inhibited by their respective antagonists. Interestingly, apoptosis induced by curcumin/light treatment was reversed by none of the herein examined death receptor antagonists. These results indicate a mechanism of action independent from classical death receptors speaking for intrinsic activation of apoptosis. It could be speculated that a shift in cellular redox balance might prompt the pro-apoptotic processes.