The Anticancer Activities of Natural Terpenoids That Inhibit Both Melanoma and Non-Melanoma Skin Cancers.

The prevalence of two major types of skin cancer, melanoma and non-melanoma skin cancer, has been increasing worldwide. Skin cancer incidence is estimated to rise continuously over the next 20 years due to ozone depletion and an increased life expectancy. Chemotherapeutic agents could affect healthy cells, and thus may be toxic to them and cause numerous side effects or drug resistance. Phytochemicals that are naturally occurring in fruits, plants, and herbs are known to possess various bioactive properties, including anticancer properties. Although the effects of phytochemicals are relatively milder than chemotherapeutic agents, the long-term intake of phytochemicals may be effective and safe in preventing tumor development in humans. Diverse phytochemicals have shown anti-tumorigenic activities for either melanoma or non-melanoma skin cancer. In this review, we focused on summarizing recent research findings of the natural and dietary terpenoids (eucalyptol, eugenol, geraniol, linalool, and ursolic acid) that have anticancer activities for both melanoma and non-melanoma skin cancers. These terpenoids may be helpful to protect skin collectively to prevent tumorigenesis of both melanoma and nonmelanoma skin cancers.

Unveiling Prognostic RNA Biomarkers through a Multi-Cohort Study in Colorectal Cancer.

Because cancer is a leading cause of death and is thought to be caused by genetic errors or genomic instability in many circumstances, there have been studies exploring cancer's genetic basis using microarray and RNA-seq methods, linking gene expression data to patient survival. This research introduces a methodological framework, combining heterogeneous gene expression data, random forest selection, and pathway analysis, alongside clinical information and Cox regression analysis, to discover prognostic biomarkers. Heterogeneous gene expression data for colorectal cancer were collected from TCGA-COAD (RNA-seq), and GSE17536 and GSE39582 (microarray), and were integrated with Entrez Gene IDs. Using Cox regression analysis and random forest, genes with consistent hazard ratios and significantly affecting patient survivability were chosen. Predictive accuracy was evaluated using ROC curves. Pathway analysis identified potential RNA biomarkers. The authors identified 28 RNA biomarkers. Pathway analysis revealed enrichment in cancer-related pathways, notably EGFR downstream signaling and IGF1R signaling. Three RNA biomarkers (ZEB1-AS1, PI4K2A, and ITGB8-AS1) and two clinical biomarkers (stage and age) were chosen for a prognostic model, improving predictive performance compared to using clinical biomarkers alone. Despite biomarker identification challenges, this study underscores integration of heterogenous gene expression data for discovery.

OR2AT4, an Ectopic Olfactory Receptor, Suppresses Oxidative Stress-Induced Senescence in Human Keratinocytes.

Olfactory receptors (ORs) are the largest protein superfamily in mammals. Certain ORs are ectopically expressed in extranasal tissues and regulate cell type-specific signal transduction pathways. OR2AT4 is ectopically expressed in skin cells and promotes wound healing and hair growth. As the capacities of wound healing and hair growth decline with aging, we investigated the role of OR2AT4 in the aging and senescence of human keratinocytes. OR2AT4 was functionally expressed in human keratinocytes (HaCaT) and exhibited co-expression with G-protein-coupled receptor signaling components, Golfα and adenylate cyclase 3. The OR2AT4 ligand sandalore modulates the intracellular calcium, inositol phosphate, and cyclic adenosine monophosphate (cAMP) levels. The increased calcium level induced by sandalore was attenuated in cells with OR2AT4 knockdown. OR2AT4 activation by sandalore inhibited the senescent cell phenotypes and restored cell proliferation and Ki-67 expression. Sandalore also inhibited the expression of senescence-associated ß-galactosidase and increased p21 expression in senescent HaCaT cells in response to hydrogen peroxide. Additionally, sandalore activated the CaMKKß/AMPK/mTORC1/autophagy signaling axis and promoted autophagy. OR2AT4 knockdown attenuated the increased in the intracellular calcium level, cell proliferation, and AMPK phosphorylation induced by sandalore. These findings demonstrate that the effects of sandalore are mediated by OR2AT4 activation. Our findings suggest that OR2AT4 may be a novel therapeutic target for anti-aging and anti-senescence in human keratinocytes.

Mechanisms of Aging and the Preventive Effects of Resveratrol on Age-Related Diseases.

Aging gradually decreases cellular biological functions and increases the risk of age-related diseases. Cancer, type 2 diabetes mellitus, cardiovascular disease, and neurological disorders are commonly classified as age-related diseases that can affect the lifespan and health of individuals. Aging is a complicated and sophisticated biological process involving damage to biochemical macromolecules including DNA, proteins, and cellular organelles such as mitochondria. Aging causes multiple alterations in biological processes including energy metabolism and nutrient sensing, thus reducing cell proliferation and causing cellular senescence. Among the polyphenolic phytochemicals, resveratrol is believed to reduce the negative effects of the aging process through its multiple biological activities. Resveratrol increases the lifespan of several model organisms by regulating oxidative stress, energy metabolism, nutrient sensing, and epigenetics, primarily by activating sirtuin 1. This review summarizes the most important biological mechanisms of aging, and the ability of resveratrol to prevent age-related diseases.

A dietary anthocyanin cyanidin-3-O-glucoside binds to PPARs to regulate glucose metabolism and insulin sensitivity in mice.

We demonstrate the mechanism by which C3G, a major dietary anthocyanin, regulates energy metabolism and insulin sensitivity. Oral administration of C3G reduced hepatic and plasma triglyceride levels, adiposity, and improved glucose tolerance in mice fed high-fat diet. Hepatic metabolomic analysis revealed that C3G shifted metabolite profiles towards fatty acid oxidation and ketogenesis. C3G increased glucose uptake in HepG2 cells and C2C12 myotubes and induced the rate of hepatic fatty acid oxidation. C3G directly interacted with and activated PPARs, with the highest affinity for PPARα. The ability of C3G to reduce plasma and hepatic triglycerides, glucose tolerance, and adiposity and to induce oxygen consumption and energy expenditure was abrogated in PPARα-deficient mice, suggesting that PPARα is the major target for C3G. These findings demonstrate that the dietary anthocyanin C3G activates PPARs, a master regulators of energy metabolism. C3G is an agonistic ligand of PPARs and stimulates fuel preference to fat.

Mussel adhesive Protein-conjugated Vitronectin (fp-151-VT) Induces Anti-inflammatory Activity on LPS-stimulated Macrophages and UVB-irradiated Keratinocytes.

BACKGROUND: Skin inflammation and dermal injuries are a major clinical problem because current therapies are limited to treating established scars, and there is a poor understanding of healing mechanisms. Mussel adhesive proteins (MAPs) have great potential in many tissue engineering and biomedical applications. It has been successfully demonstrated that the redesigned hybrid type MAP (fp-151) can be utilized as a promising adhesive biomaterial. The aim of this study was to develop a novel recombinant protein using fp-151 and vitronectin (VT) and to elucidate the anti-inflammatory effects of this recombinant protein on macrophages and keratinocytes. METHODS: Lipopolysaccharide (LPS) was used to stimulate macrophages and UVB was used to stimulate keratinocytes. Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were analyzed by Western Blot. Inflammatory cytokines and NO and ROS production were analyzed. RESULT: In macrophages stimulated by LPS, expression of the inflammatory factors iNOS, COX-2, and NO production increased, while the r-fp-151-VT-treated groups had suppressed expression of iNOS, COX-2, and NO production in a dose-dependent manner. In addition, keratinocytes stimulated by UVB and treated with r-fp-151-VT had reduced expression of iNOS and COX-2. Interestingly, in UVB-irradiated keratinocytes, inflammatory cytokines, such as interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a, were significantly reduced by r-fp-151-VT treatment. CONCLUSIONS: These results suggest that the anti-inflammatory activity of r-fp-151-VT was more effective in keratinocytes, suggesting that it can be used as a therapeutic agent to treat skin inflammation.

Mutagenic Analysis of an Adeno-Associated Virus Variant Capable of Simultaneously Promoting Immune Resistance and Robust Gene Delivery.

In addition to the ability to boost gene delivery efficiency in many therapeutically relevant cells, the capability of circumventing neutralizing antibody (NAb) inactivation is a key prerequisite that gene carriers must fulfill for their extensive applications as therapeutic agents in many gene therapy trials, especially for cancer treatments. This study revealed that a genetically engineered adeno-associated virus (AAV) variant, AAVr3.45, inherently possesses dual beneficial properties as a gene carrier: (i) efficiently delivering therapeutic genes to many clinically valuable cells (e.g., stem or cancer cells) and (ii) effectively bypassing immunoglobulin (IgG) neutralization. Detailed interpretation of the structural features of AAVr3.45, which was previously engineered from AAV2, demonstrated that the LATQVGQKTA peptide at the heparan sulfate proteoglycan binding domain, especially the presence of cationic lysine on the peptide, served as a key motif for dramatically enhancing its gene delivery capabilities, ultimately broadening its tropisms for many cancer cell lines. Furthermore, the substitution of valine on the AAV2 capsid at the amino acid 719 site to methionine functioned as a coordinator for promoting viral resistance against IgG inactivation. The NAb-resistant characteristics of AAVr3.45 were possibly associated with the LATQVGQKTA sequence itself, indicating that its synergistic cooperation with the point mutation (V719M) is required for maximizing its ability to evade NAb inactivation. The potential of AAVr3.45 as a cancer gene therapy agent was confirmed by provoking apoptosis in breast adenocarcinoma by efficiently delivering a pro-apoptotic gene, BIM (Bcl-2-like protein 11), under high titers of human IgG. Thus, the superior aspects of the NAb-resistant AAVr3.45 as a potential therapeutic agent for systemic injection approaches, especially for cancer gene therapy, were highlighted in this study.

Development of efficient adeno-associated virus (AAV)-mediated gene delivery system with a phytoactive material for targeting human melanoma cells.

We exploited the emerging potential of gene therapy strategies to design a powerful therapeutic system that combines two key components-AAV vector and [6]-gingerol. In this study, we created an AAV2 construct expressing the proapoptotic protein BIM, which uses HSPG as its primary receptor, to target HSPG-overexpressing melanoma cells. This combination treatment showed promising results in vitro, inducing apoptosis in human melanoma cells. This new platform technology will make a significant contribution to numerous therapeutic applications, most notably for melanoma, including overcoming resistance to conventional anticancer therapies.

Multifunctional Self-Adhesive Fibrous Layered Matrix (FiLM) for Tissue Glues and Therapeutic Carriers.

Tissue adhesives, which inherently serve as wound sealants or as hemostatic agents, can be further augmented to acquire crucial functions as scaffolds, thereby accelerating wound healing or elevating the efficacy of tissue regeneration. Herein, multifunctional adherent fibrous matrices, acting as self-adhesive scaffolds capable of cell/gene delivery, were devised by coaxially electrospinning poly(caprolactone) (PCL) and poly(vinylpyrrolidone) (PVP). Wrapping the building block PCL fibers with the adherent PVP layers formed film-like fibrous matrices that could rapidly adhere to wet biological surfaces, referred to as fibrous layered matrix (FiLM) adhesives. The inclusion of ionic salts (i.e., dopamine hydrochloride) in the sheath layers generated spontaneously multilayered fibrous adhesives, whose partial layers could be manually peeled off, termed derivative FiLM (d-FiLM). In the context of scaffolds/tissue adhesives, both FiLM and d-FiLM demonstrated almost identical characteristics (i.e., sticky, mechanical, and performances as cell/gene carriers). Importantly, the single FiLM-process can yield multiple sets of d-FiLM by investing the same processing time, materials, and labor required to form a single conventional adhesive fibrous mat, thereby highlighting the economic aspects of the process. The FiLM/d-FiLM offer highly impacting contributions to many biomedical applications, especially in fields that require urgent aids (e.g., endoscopic surgeries, implantation in wet environments, severe wounds).