Dihydrochalcone Derivatives from Populus balsamifera L. Buds for the Treatment of Psoriasis.

Psoriasis is a skin disorder characterized by epidermal hyperplasia, hyperkeratosis, and inflammation. The treatments currently available on the market only improve patients' quality of life and are associated with undesirable side effects. Thus, research leading to the development of new, effective, and safer therapeutic agents is still relevant. Populus balsamifera L. buds were used traditionally by Native Americans to treat various skin pathologies such as eczema and psoriasis. In this study, the antipsoriatic activities of dihydrochalcone derivatives from Populus balsamifera L. buds, known as balsacones, were investigated. The experiments were performed in vitro using a psoriatic skin substitute model. Also, anti-inflammatory and antioxidant activities were investigated. The tested balsacones showed promising antipsoriatic properties by slowing down cell growth and by regulating the expression of involucrin, loricrin, and Ki67 better than methotrexate in psoriatic substitutes. All five tested compounds could be an effective topical treatment for psoriasis, with promising anti-inflammatory and antioxidant actions that may contribute to clinical improvement in patients with psoriasis.

Diphoterine, an amphoteric rinsing solution, reduces hydrofluoric acid injuries in an ex vivo pigskin model.

Hydrofluoric acid (HF) is a ubiquitous industrial chemical that is particularly hazardous because of the potential for systemic effects and the induction of severe cutaneous necrosis after contact with the skin. Minimizing skin injury requires decontaminating the affected area promptly with an emergency rinsing solution. Few experimental studies have objectively characterized rinsing solutions such as Diphoterine (DP). Here we develop an ex vivo pigskin model to study and compare the efficacy of rinsing solutions as initial decontaminating agents to stop the progression of skin lesions after HF splashing. The pigskin model shows an immediate local response to HF at varying concentrations and exposure times. We then exposed the pigskin biopsies to 3.75% HF for 1 min and rinsed them with different solutions, including water, 0.9% NaCl solution (saline), 10% calcium gluconate (CaG), Hexafluorine (HXF), and DP. We found DP to be a more effective agent for decontaminating HF lesions than water, saline, and CaG. DP had a similar efficacy as HXF, an emergency rinsing solution used specifically for decontaminating HF-exposed skin. This study shows that skin exposed to HF must be treated quickly from the first minute of exposure.

A quantitative proteomic approach of the different stages of colorectal cancer establishes OLFM4 as a new nonmetastatic tumor marker.

Expression profiles represent new molecular tools that are useful to characterize the successive steps of tumor progression and the prediction of recurrence or chemotherapy response. In this study, we have used quantitative proteomic analysis to compare different stages of colorectal cancer. A combination of laser microdissection, OFFGEL separation, iTRAQ labeling, and MALDI-TOF/TOF MS was used to explore the proteome of 28 colorectal cancer tissues. Two software packages were used for identification and quantification of differentially expressed proteins: Protein Pilot and iQuantitator. Based on ∼1,190,702 MS/MS spectra, a total of 3138 proteins were identified, which represents the largest database of colorectal cancer realized to date and demonstrates the value of our quantitative proteomic approach. In this way, individual protein expression and variation have been identified for each patient and for each colorectal dysplasia and cancer stage (stages I-IV). A total of 555 proteins presenting a significant fold change were quantified in the different stages, and this differential expression correlated with immunohistochemistry results reported in the Human Protein Atlas database. To identify a candidate biomarker of the early stages of colorectal cancer, we focused our study on secreted proteins. In this way, we identified olfactomedin-4, which was overexpressed in adenomas and in early stages of colorectal tumors. This early stage overexpression was confirmed by immunohistochemistry in 126 paraffin-embedded tissues. Our results also indicate that OLFM4 is regulated by the Ras-NF-κB2 pathway, one of the main oncogenic pathways deregulated in colorectal tumors.

Escape from p21-mediated oncogene-induced senescence leads to cell dedifferentiation and dependence on anti-apoptotic Bcl-xL and MCL1 proteins.

Oncogene-induced senescence (OIS) is a tumor suppressor response that induces permanent cell cycle arrest in response to oncogenic signaling. Through the combined activation of the p53-p21 and p16-Rb suppressor pathways, OIS leads to the transcriptional repression of proliferative genes. Although this protective mechanism has been essentially described in primary cells, we surprisingly observed in this study that the OIS program is conserved in established colorectal cell lines. In response to the RAS oncogene and despite the inactivation of p53 and p16(INK4), HT29 cells enter senescence, up-regulate p21(WAF1), and induce senescence-associated heterochromatin foci formation. The same effect was observed in response to B-RAF(v600E) in LS174T cells. We also observed that p21(WAF1) prevents the expression of the CDC25A and PLK1 genes to induce cell cycle arrest. Using ChIP and luciferase experiments, we have observed that p21(WAF1) binds to the PLK1 promoter to induce its down-regulation during OIS induction. Following 4-5 weeks, several clones were able to resume proliferation and escape this tumor suppressor pathway. Tumor progression was associated with p21(WAF1) down-regulation and CDC25A and PLK1 reexpression. In addition, OIS and p21(WAF1) escape was associated with an increase in DNA damage, an induction of the epithelial-mesenchymal transition program, and an increase in the proportion of cells expressing the CD24(low)/CD44(high) phenotype. Results also indicate that malignant cells having escaped OIS rely on survival pathways induced by Bcl-xL/MCL1 signaling. In light of these observations, it appears that the transcriptional functions of p21(WAF1) are active during OIS and that the inactivation of this protein is associated with cell dedifferentiation and enhanced survival.

Antioxidant, Anti-Inflammatory, and Anti-Aging Potential of a Kalmia angustifolia Extract and Identification of Some Major Compounds.

Skin aging is the most visible element of the aging process, giving rise to a major concern for many people. Plants from the Ericaceae family generally have antioxidant and anti-inflammatory properties, making them potential anti-aging active ingredients. This study aimed to evaluate the safety and anti-aging efficacy of a Kalmia angustifolia extract using reconstructed skin substitutes. The safety evaluation was performed using a 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, while the efficacy was determined by assessing antioxidant and anti-inflammatory activity and analyzing skin substitutes reconstructed according to the self-assembly method by histology and immunofluorescence staining (elastin, collagen-1, collagen-3, aquaporin-3). The cell viability assay established the safety of the extract at a concentration up to 200 µg/mL. The Oxygen Radical Absorbance Capacity (ORAC) assay and a cell-based assay using 2',7'-dichlorofluorescein-diacetate (DCFH-DA) revealed a strong antioxidant activity with an ORAC value of 16 µmol Trolox Equivalent/mg and a half-maximal inhibitory concentration (IC50) of 0.37 ± 0.02 µg/mL, while an interesting anti-inflammatory activity was found in the inhibition of NO production, with an inhibition percentage of NO production of 49 ± 2% at 80 µg/mL. The isolation and characterization of the extract allowed the identification of compounds that could be responsible for these biological activities, with two of them being identified for the first time in K. angustifolia: avicularin and epicatechin-(2ß-O-7, 4ß-6)-ent-epicatechin. Histological analyses of skin substitutes treated with the extract showed an increase in dermal thickness compared with the controls. K. angustifolia extract enhanced the expression of elastin and collagen-1, which are usually decreased with skin aging. These results suggest that K. angustifolia has promising antioxidant efficacy and anti-aging potential.

STAT3 as a new autophagy regulator.

Signal transducers and activators of transcription 3 (STAT3) proteins are cytoplasmic transcription factors that translocate into the nucleus to induce transcription following growth factor or cytokine stimulation. Besides their normal functions, these proteins play an important role in cancer cells through the abnormal activation of cell cycle progression and the deregulation of survival and senescence pathways. New data obtained from the laboratory of Guido Kroemer identifies STAT3 as a new autophagy regulator. In the cytoplasm, in the absence of conventional phosphorylation on the tyrosine 705 residue, STAT3 interacts with the PKR kinase to inhibit eIF2A phosphorylation and so reduce autophagic pathways. This new and nonconventional function of STAT3 has an important role in normal cells but we suggest that it might also affect cancer cells and the response to chemotherapy treatment.