Essential oils and their main chemical components: the past 20 years of preclinical studies in melanoma

The last two decades have seen the development of effective therapies, which have saved the lives of a large number of melanoma patients. However, therapeutic options are still limited for patients without BRAF mutations or in relapse from current treatments, and severe side effects often occur during therapy. Thus, additional insights to improve treatment efficacy with the aim to decrease the likelihood of chemoresistance, as well as reducing side effects of current therapies, are required. Natural products offer great opportunities for the discovery of antineoplastic drugs, and still represent a useful source of novel molecules. Among them, essential oils, representing the volatile fraction of aromatic plants, are always being actively investigated by several research groups and show promising biological activities for their use as complementary or alternative medicine for several diseases, including cancer. In this review, we focused on studies reporting the mechanism through which essential oils exert antitumor action in preclinical wild type or mutant BRAF melanoma models. We also discussed the latest use of essential oils in improving cancer patients’ quality of life. As evidenced by the many studies listed in this review, through their effect on apoptosis and tumor progression-associated properties, essential oils can therefore be considered as potential natural pharmaceutical resources for cancer management

RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivoConclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention

Study Projectile Motion With Different Initial Conditions Using Digital Image

The aim of this research is building algorithms to study projectile motion in tow dimension  and tracking the object in sequence frames of digital image . Computer program has written in visual basic language (version 6) depend on mathematical models to detect a motion of object in two–dimensions (2-D)with different initial conditions like initial velocity, the height of object from the earth and the angle of motion, to calculate important variables in motion such as distance, displacement, velocity, speed and the energy (kinetic and potential). Color digital images of type (bmp) and (RGB) color model were used in the study for easy handling them, after determining the center of the image on the x-axis, and y-axis and tracking movement on the basis of the center, and the results were expected to conform to the movement of the body. Key words: Projectile, Motion, Digital Image

Resting metabolic rate and respiratory quotient in human longevity

Significant changes in body composition, body fat distribution, and resting metabolic rate (RMR) occur with aging. Interestingly, studies on human longevity pointed out that long-lived subjects are less prone to the anthropometrics and metabolic derangement normally observed in the elderly. Indeed, the relationship between energy expenditure and longevity has been poorly investigated. Thus, energy expenditure parameters of 28 long-lived subjects were assessed and compared with those of 26 adults and 27 younger elderly. All subjects enrolled were female. In the whole population, RMR was negatively correlated with age (P < 0.05), waist to hip ratio (WHR) (P < 0.001), fat mass (P < 0.001), and percent body fat (P < 0.03); respiratory quotient (Rq) displayed an age-related decrease (P < 0.001) and was negatively correlated with WHR (P < 0.001) and fat-free mass (FFM) (P < 0.006). In multivariate analysis, both RMR and Rq had FFM, WHR, but not body mass index as significant and independent determinants. Splitting the whole study group into subgroups according to age, long-lived subjects had oxygen volume, carbon dioxide volume, and Rq significantly higher than aged subjects but lower than adult subjects. In addition, long-lived subjects had total volume of expired air and RMR greater than aged subjects but not different from ones found in adults. In long-lived subjects, Rq was negatively correlated with percent body fat (P < 0.02), plasma glucose (P < 0.05), free fatty acid (P < 0.05), and WHR (P < 0.05), whereas RMR was negatively correlated with WHR (P < 0.05). No significant associations of RMR and Rq with FFM were found. In conclusion, our data demonstrate that human longevity seems protected toward an age-related decline. It is likely that the lack of the anthropometrics derangement may preserve long-lived subjects from the age-related decrease in energy metabolism

Probing host pathogen cross-talk by transcriptional profiling of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages

This study provides the proof of principle that probing the host and the microbe transcriptomes simultaneously is a valuable means to accessing unique information on host pathogen interactions. Our results also underline the extraordinary plasticity of host cell and pathogen responses to infection, and provide a solid framework to further understand the complex mechanisms involved in immunity to M. tuberculosis and in mycobacterial adaptation to different intracellular environments

Genomic history of the Italian population recapitulates key evolutionary dynamics of both Continental and Southern Europeans

Background: The cline of human genetic diversity observable across Europe is recapitulated at a micro-geographic scale by variation within the Italian population. Besides resulting from extensive gene flow, this might be ascribable also to local adaptations to diverse ecological contexts evolved by people who anciently spread along the Italian Peninsula. Dissecting the evolutionary history of the ancestors of present-day Italians may thus improve the understanding of demographic and biological processes that contributed to shape the gene pool of European populations. However, previous SNP array-based studies failed to investigate the full spectrum of Italian variation, generally neglecting low-frequency genetic variants and examining a limited set of small effect size alleles, which may represent important determinants of population structure and complex adaptive traits. To overcome these issues, we analyzed 38 high-coverage whole-genome sequences representative of population clusters at the opposite ends of the cline of Italian variation, along with a large panel of modern and ancient Euro-Mediterranean genomes. Results: We provided evidence for the early divergence of Italian groups dating back to the Late Glacial and for Neolithic and distinct Bronze Age migrations having further differentiated their gene pools. We inferred adaptive evolution at insulin-related loci in people from Italian regions with a temperate climate, while possible adaptations to pathogens and ultraviolet radiation were observed in Mediterranean Italians. Some of these adaptive events may also have secondarily modulated population disease or longevity predisposition. Conclusions: We disentangled the contribution of multiple migratory and adaptive events in shaping the heterogeneous Italian genomic background, which exemplify population dynamics and gene-environment interactions that played significant roles also in the formation of the Continental and Southern European genomic landscapes

Photosensitive drugs: a review on their photoprotection by liposomes and cyclodextrins.

Nowadays, an exciting challenge in the drug chemistry and technology research is represented by the development of methods aimed to protect molecular integrity and therapeutic activity of drugs from effects of light. The photostability characterization is ruled by ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), which releases details throughout basic protocols of stability tests to be performed on new medicinal products for human use. The definition of suitable photoprotective systems is fundamental for pharmaceutical manufacturing and for human healthy as well, since light exposure may affect either drugs or drug formulations giving rise even to allergenic or mutagenic by-products. Here, we summarize and discuss the recent studies on the formulation of photosensitive drugs into supramolecular systems, capable of entrapping the molecules in a hollow of their structure by weak noncovalent interactions and protecting them from light. The best known supramolecular matrices belong to the 'auto-assembled' structures, of which liposomes are the most representative, and the 'host-guest' systems, of which cyclodextrins represent the most common 'host' counterpart. A relevant number of papers concerning the use of both liposomes and cyclodextrins as photoprotection systems for drugs has been published over the last 20 years, demonstrating that this topic captures interest in an increasing number of researchers

Microfluidic Fabricated Liposomes for Nutlin-3a Ocular Delivery as Potential Candidate for Proliferative Vitreoretinal Diseases Treatment

Elisabetta Esposito,1 Elena Pozza,2 Catia Contado,1 Walter Pula,1 Olga Bortolini,3 Daniele Ragno,1 Sofia Toldo,3 Fabio Casciano,4 Agnese Bondi,1 Enrico Zauli,2 Paola Secchiero,4 Giorgio Zauli,3 Elisabetta Melloni4 1Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, I-44121, Italy; 2Department of Translational Medicine, University of Ferrara, Ferrara, I-44121, Italy; 3Department of Environmental Sciences and Prevention, University of Ferrara, Ferrara, I-44121, Italy; 4Department of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, I-44121, ItalyCorrespondence: Elisabetta Esposito; Elisabetta Melloni, Tel +39 0532 455230 ; +39 0532 455936, Email [email protected]; [email protected]: Proliferative vitreoretinal diseases (PVDs) represent a heterogeneous group of pathologies characterized by the presence of retinal proliferative membranes, in whose development retinal pigment epithelium (RPE) is deeply involved. As the only effective treatment for PVDs at present is surgery, we aimed to investigate the potential therapeutic activity of Nutlin-3a, a small non-genotoxic inhibitor of the MDM2/p53 interaction, on ARPE-19 cell line and on human RPE primary cells, as in vitro models of RPE and, more importantly, to formulate and evaluate Nutlin-3a loaded liposomes designed for ophthalmic administration.Methods: Liposomes were produced using an innovative approach by a microfluidic device under selection of different conditions. Liposome size distribution was evaluated by photon correlation spectroscopy and centrifugal field flow fractionation, while the liposome structure was studied by transmission electron microscopy and Fourier-transform infrared spectroscopy. The Nutlin-3a entrapment capacity was evaluated by ultrafiltration and HPLC. Nutlin-3a biological effectiveness as a solution or loaded in liposomes was evaluated by viability, proliferation, apoptosis and migration assays and by morphological analysis.Results: The microfluidic formulative study enabled the selection of liposomes composed of phosphatidylcholine (PC) 5.4 or 8.2 mg/mL and 10% ethanol, characterized by roundish vesicular structures with 150– 250 nm mean diameters. Particularly, liposomes based on the lower PC concentration were characterized by higher stability. Nutlin-3a was effectively encapsulated in liposomes and was able to induce a significant reduction of viability and migration in RPE cell models.Conclusion: Our results lay the basis for a possible use of liposomes for the ocular delivery of Nutlin-3a. Keywords: Nutlin-3a, liposomes, microfluidic, PVDs, CFF

Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL

Background and Purpose—White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease. Methods—We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background. Results—Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance. Conclusions—We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general