In Vivo Identification of H3K9me2/H3K79me3 as an Epigenetic Barrier to Carcinogenesis.

The highly dynamic nature of chromatin's structure, due to the epigenetic alterations of histones and DNA, controls cellular plasticity and allows the rewiring of the epigenetic landscape required for either cell differentiation or cell (re)programming. To dissect the epigenetic switch enabling the programming of a cancer cell, we carried out wide genome analysis of Histone 3 (H3) modifications during osteogenic differentiation of SH-SY5Y neuroblastoma cells. The most significant modifications concerned H3K27me2/3, H3K9me2, H3K79me1/2, and H3K4me1 that specify the process of healthy adult stem cell differentiation. Next, we translated these findings in vivo, assessing H3K27, H3K9, and H3K79 methylation states in biopsies derived from patients affected by basalioma, head and neck carcinoma, and bladder tumors. Interestingly, we found a drastic decrease in H3K9me2 and H3K79me3 in cancer specimens with respect to their healthy counterparts and also a positive correlation between these two epigenetic flags in all three tumors. Therefore, we suggest that elevated global levels of H3K9me2 and H3K79me3, present in normal differentiated cells but lost in malignancy, may reflect an important epigenetic barrier to tumorigenesis. This suggestion is further corroborated, at least in part, by the deranged expression of the most relevant H3 modifier enzymes, as revealed by bioinformatic analysis. Overall, our study indicates that the simultaneous occurrence of H3K9me2 and H3K79me3 is fundamental to ensure the integrity of differentiated tissues and, thus, their combined evaluation may represent a novel diagnostic marker and potential therapeutic target.

Molecular Research on Platelet Activity in Health and Disease 3.0.

Zhao and Devine [...].

Platelet-Derived miR-126-3p Directly Targets AKT2 and Exerts Anti-Tumor Effects in Breast Cancer Cells: Further Insights in Platelet-Cancer Interplay.

Among the surrounding cells influencing tumor biology, platelets are recognized as novel players as they release microvesicles (MVs) that, once delivered to cancer cells, modulate signaling pathways related to cell growth and dissemination. We have previously shown that physiological delivery of platelet MVs enriched in miR-126 exerted anti-tumor effects in different breast cancer (BC) cell lines. Here, we seek further insight by identifying AKT2 kinase as a novel miR-126-3p direct target, as assessed by bioinformatic analysis and validated by luciferase assay. Both ectopic expression and platelet MV-mediated delivery of miR-126-3p downregulated AKT2 expression, thus suppressing proliferating and invading properties, in either triple negative (BT549 cells) or less aggressive Luminal A (MCF-7 cells) BC subtypes. Accordingly, as shown by bioinformatic analysis, both high miR-126 and low AKT2 levels were associated with favorable long-term prognosis in BC patients. Our results, together with the literature data, indicate that miR-126-3p exerts suppressor activity by specifically targeting components of the PIK3/AKT signaling cascade. Therefore, management of platelet-derived MV production and selective delivery of miR-126-3p to tumor cells may represent a useful tool in multimodal therapeutic approaches in BC patients.

Comparative Analysis of Phenolic Composition of Six Commercially Available Chamomile (Matricaria chamomilla L.) Extracts: Potential Biological Implications.

Several phytochemical-containing herbal extracts are increasingly marketed as health-promoting products. In particular, chamomile (Matricaria recutita L.) is well known for its anti-inflammatory, analgesic, and antitumor properties. Here, we evaluated differences in chemical composition among six commercially available products and their potential impact on biological activity in human immortalized colonocytes. Our investigation encompassed: (i) preparation of dry extracts and yield evaluation; (ii) qualitative and quantitative analysis of phenol content; (iii) modulation of redox state; and (iv) bioavailability of main bioactive compounds. We demonstrated that apparently identical products showed huge heterogeneity, in terms of yield extraction, chemical composition, and antioxidant effects. All samples contained high amounts of flavonoids and cinnamic acid derivatives, but differentially concentrated in the six extracts. Depending on polyphenol content, chamomile samples possessed variable antioxidant potential, in terms of decreased radical generation and increased reduced glutathione levels. The observed effects might be ascribed to flavones (apigenin, luteolin, and their glycones) highly represented in the six extracts. Nonetheless, chamomile extracts exerted cytotoxic effects at high concentrations, suggesting that a herbal medicine is not always safe. In conclusion, due to the complexity and variability of plant matrices, studies evaluating effectiveness of chamomile should always be accompanied by preliminary characterization of phytochemical composition.

Molecular Research on Platelet Activity in Health and Disease 2.0.

Hsia and collaborators [...].

Molecular Research on Platelet Activity in Health and Disease.

This editorial summarizes and discusses the themes of eleven articles (five reviews and six original studies) published in the Special Issue "Molecular Research On Platelet Activity in Health and Disease". They give an international picture of the up-to-date understanding of i) platelet signalling under physiological and pathological conditions, ii) novel technologies for monitoring platelet functions and iii) clinical applications of platelet-based-therapy for management of pathological conditions, not directly related to haemostasis and thrombosis.

The "Janus Face" of Platelets in Cancer.

Besides their vital role in hemostasis and thrombosis, platelets are also recognized to be involved in cancer, where they play an unexpected central role: They actively influence cancer cell behavior, but, on the other hand, platelet physiology and phenotype are impacted by tumor cells. The existence of this platelet-cancer loop is supported by a large number of experimental and human studies reporting an association between alterations in platelet number and functions and cancer, often in a way dependent on patient, cancer type and treatment. Herein, we shall report on an update on platelet-cancer relationships, with a particular emphasis on how platelets might exert either a protective or a deleterious action in all steps of cancer progression. To this end, we will describe the impact of (i) platelet count, (ii) bioactive molecules secreted upon platelet activation, and (iii) microvesicle-derived miRNAs on cancer behavior. Potential explanations of conflicting results are also reported: Both intrinsic (heterogeneity in platelet-derived bioactive molecules with either inhibitory or stimulatory properties; features of cancer cell types, such as aggressiveness and/or tumour stage) and extrinsic (heterogeneous characteristics of cancer patients, study design and sample preparation) factors, together with other confounding elements, contribute to "the Janus face" of platelets in cancer. Given the difficulty to establish the univocal role of platelets in a tumor, a better understanding of their exact contribution is warranted, in order to identify an efficient therapeutic strategy for cancer management, as well as for better prevention, screening and risk assessment protocols.

Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications.

Niacin (also known as "vitamin B3" or "vitamin PP") includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial for energy production, but they are also substrates for enzymes involved in non-redox signaling pathways, thus regulating biological functions, including gene expression, cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B3 has long been recognized as a key mediator of neuronal development and survival. Here, we will overview available literature data on the neuroprotective role of niacin and its derivatives, especially focusing especially on its involvement in neurodegenerative diseases (Alzheimer's, Parkinson's, and Huntington's diseases), as well as in other neuropathological conditions (ischemic and traumatic injuries, headache and psychiatric disorders).

Downstream effects of endocannabinoid on blood cells: implications for health and disease.

Endocannabinoids (eCBs), among which N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are the most biologically active members, are polyunsaturated lipids able to bind cannabinoid, vanilloid and peroxisome proliferator-activated receptors. Depending on the target engaged, these bioactive mediators can regulate different signalling pathways, at both central and peripheral levels. The biological action of eCBs is tightly controlled by a plethora of metabolic enzymes which, together with the molecular targets of these substances, form the so-called "endocannabinoid system". The ability of eCBs to control manifold peripheral functions has received a great deal of attention, especially in the light of their widespread distribution in the body. In particular, eCBs are important regulators in blood, where they modulate haematopoiesis, platelet aggregation and apoptosis, as well as chemokine release and migration of immunocompetent cells. Here, we shall review the current knowledge on the pathophysiological roles of eCBs in blood. We shall also discuss the involvement of eCBs in those disorders affecting the haematological system, including cancer and inflammation. Knowledge gained to date underlines a fundamental role of the eCB system in blood, thus suggesting that it may represent a therapeutic promise for a broad range of diseases involving impaired hematopoietic cell functions.

Physical activity and the endocannabinoid system: an overview.

Recognized as a "disease modifier", physical activity (PA) is increasingly viewed as a more holistic, cost-saving method for prevention, treatment and management of human disease conditions. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. Moreover, it is now emerging that PA itself is able to modulate ECS in different ways. Against this background, in the present review we shall discuss evidence of the cross-talk between PA and the ECS, ranging from brain to peripheral districts and highlighting how ECS must be tightly regulated during PA, in order to maintain its beneficial effects on cognition, mood, and nociception, while avoiding impaired energy metabolism, oxidative stress, and inflammatory processes.

Obesity-associated oxidative stress: strategies finalized to improve redox state.

Obesity represents a major risk factor for a plethora of severe diseases, including diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and cancer. It is often accompanied by an increased risk of mortality and, in the case of non-fatal health problems, the quality of life is impaired because of associated conditions, including sleep apnea, respiratory problems, osteoarthritis, and infertility. Recent evidence suggests that oxidative stress may be the mechanistic link between obesity and related complications. In obese patients, antioxidant defenses are lower than normal weight counterparts and their levels inversely correlate with central adiposity; obesity is also characterized by enhanced levels of reactive oxygen or nitrogen species. Inadequacy of antioxidant defenses probably relies on different factors: obese individuals may have a lower intake of antioxidant- and phytochemical-rich foods, such as fruits, vegetables, and legumes; otherwise, consumption of antioxidant nutrients is normal, but obese individuals may have an increased utilization of these molecules, likewise to that reported in diabetic patients and smokers. Also inadequate physical activity may account for a decreased antioxidant state. In this review, we describe current concepts in the meaning of obesity as a state of chronic oxidative stress and the potential interventions to improve redox balance.

The endocannabinoid system and its relevance for nutrition.

Endocannabinoids bind to cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The biological actions of these polyunsaturated lipids are controlled by key agents responsible for their synthesis, transport and degradation, which together form an endocannabinoid system (ECS). In the past few years, evidence has been accumulated for a role of the ECS in regulating food intake and energy balance, both centrally and peripherally. In addition, up-regulation of the ECS in the gastrointestinal tract has a potential impact on inflammatory bowel diseases. In this review, the main features of the ECS are summarized in order to put in better focus our current knowledge of the nutritional relevance of endocannabinoid signaling and of its role in obesity, cardiovascular pathologies, and gastrointestinal diseases. The central and peripheral pathways that underlie these effects are discussed, as well as the possible exploitation of ECS components as novel drug targets for therapeutic intervention in eating disorders.

Anandamide extends platelets survival through CB(1)-dependent Akt signaling.

Platelets are stored at 22 degrees C, since incubation at 37 degrees C results in loss of viability. Nonetheless, in our body (37 degrees C), platelets survive for 8-10 days. This discrepancy has been explained in terms of deprivation of viability factors or accumulation of apoptotic factors during storage. We report that the endocannabinoid anandamide (AEA) may be one of the agents allowing platelet survival. In fact, at 37 degrees C, human platelets enhance the expression of pro-apoptotic proteins (caspases, Bax, Bak) and decrease the expression of Bcl-xL, thus changing the Bcl-xL/Bak ratio, a key platelet biological clock. AEA or its non-hydrolyzable analogue, methanandamide, extend platelet life span, without reversing the changes in Bcl-xL/Bak ratio induced by heat stress. Instead, AEA binding to type-1 cannabinoid receptor activates Akt, which regulates, through phosphorylation of Bad, the interactions among different Bcl-2 family members. These findings could have implications for platelet collection and, potentially, for their clinical use.

Dietary Strategies for Management of Metabolic Syndrome: Role of Gut Microbiota Metabolites.

Metabolic syndrome (MetS) is a complex pathophysiological state with incidence similar to that of a global epidemic and represents a risk factor for the onset of chronic non-communicable degenerative diseases (NCDDs), including cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and some types of cancer. A plethora of literature data suggest the potential role of gut microbiota in interfering with the host metabolism, thus influencing several MetS risk factors. Perturbation of the gut microbiota's composition and activity, a condition known as dysbiosis, is involved in the etiopathogenesis of multiple chronic diseases. Recent studies have shown that some micro-organism-derived metabolites (including trimethylamine N-oxide (TMAO), lipopolysaccharide (LPS) of Gram-negative bacteria, indoxyl sulfate and p-cresol sulfate) induce subclinical inflammatory processes involved in MetS. Gut microbiota's taxonomic species or abundance are modified by many factors, including diet, lifestyle and medications. The main purpose of this review is to highlight the correlation between different dietary strategies and changes in gut microbiota metabolites. We mainly focus on the validity/inadequacy of specific dietary patterns to reduce inflammatory processes, including leaky gut and subsequent endotoxemia. We also describe the chance of probiotic supplementation to interact with the immune system and limit negative consequences associated with MetS.

Skn-1a/Oct-11 and ΔNp63α exert antagonizing effects on human keratin expression.

The formation of a stratified epidermis requires a carefully controlled balance between keratinocyte proliferation and differentiation. Here, we report the reciprocal effect on keratin expression of ΔNp63, pivotal in normal epidermal morphogenesis and maintenance, and Skn-1a/Oct-11, a POU transcription factor that triggers and regulates the differentiation of keratinocytes. The expression of Skn-1a markedly downregulated ΔNp63-driven K14 expression in luciferase reporter assays. The extent of downregulation was comparable to the inhibition of Skn-1a-mediated K10 expression upon expression of ΔNp63. ΔNp63, mutated in the protein-protein interaction domain (SAM domain; mutated in human ectodermal dysplasia syndrome), was significantly less effecting in downregulating K10, raising the possibility of a direct interaction among Skn-1a and ΔNp63. Immunolocalization in human skin biopsies revealed that the expression of the two transcription factors is partially overlapping. Co-immunoprecipitation experiments did not, however, demonstrate a direct interaction between ΔNp63 and Skn-1a, suggesting that the antagonistic effects of Skn-1a and p63 on keratin promoter transactivation is probably through competition for overlapping binding sites on target gene promoter or through an indirect interaction.

Expression of the endocannabinoid system in the bi-potential HEL cell line: commitment to the megakaryoblastic lineage by 2-arachidonoylglycerol.

The role of the endocannabinoid system in haematopoietic cells is not completely understood. We investigated whether human erythroleukemia (HEL) cells were able to bind, metabolise and transport the main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). We also investigated whether AEA or 2-AG could modulate HEL differentiation. Although able to internalise both endocannabinoids, HEL cells had the machinery to metabolise 2-AG only, since they were devoid of the enzymes needed to synthesise and degrade AEA. Nonetheless, the intracellular transport of exogenous AEA might be required to activate the vanilloid receptors, with yet unknown implications for vascular biology. On the contrary, 2-AG appeared to play a role in lineage determination. Indeed, 2-AG itself drove HEL cells towards megakaryocytic differentiation, as it enhanced expression of beta3 integrin subunit, a megakaryocyte/platelet surface antigen, and glycoprotein VI, a late marker of megakaryocytes; in parallel, it reduced the amount of messenger RNA encoding for glycophorin A, a marker of erythroid phenotype. All these effects were mediated by activation of CB(2) cannabinoid receptors that triggered an extracellular signal-regulated kinase-dependent signalling cascade. In addition, classical inducers of megakaryocyte differentiation reduced 2-AG synthesis (although they did not affect the binding efficiency of CB(2) receptors), suggesting that levels of this endocannabinoid may be critical for committing HEL cells towards the megakaryocytic lineage.

The Impact of Whole Grain Intake on Gastrointestinal Tumors: A Focus on Colorectal, Gastric, and Esophageal Cancers.

Cereals are one of staple foods in human diet, mainly consumed as refined grains. Nonetheless, epidemiological data indicate that whole grain (WG) intake is inversely related to risk of type 2 diabetes, cardiovascular disease, and several cancer types, as well as to all-cause mortality. Particularly responsive to WG positive action is the gastrointestinal tract, daily exposed to bioactive food components. Herein, we shall provide an up-to-date overview on relationship between WG intake and prevention of gastrointestinal tumors, with a particular focus on colorectal, stomach, and esophagus cancers. Unlike refined counterparts, WG consumption is inversely associated with risk of these gastrointestinal cancers, most consistently with the risk of colorectal tumor. Some WG effects may be mediated by beneficial constituents (such as fiber and polyphenols) that are reduced/lost during milling process. Beside health-promoting action, WGs are still under-consumed in most countries; therefore, World Health Organization and other public/private stakeholders should cooperate to implement WG consumption in the whole population, in order to reach nutritionally effective intakes.

Origanum vulgare induces apoptosis in human colon cancer caco2 cells.

Oregano spice is widely used in the Mediterranean diet, which is associated with a low risk for colon cancer. Although the medicinal benefits of oregano, such as the anti-inflammatory and antimicrobial activities, are well known; nonetheless, only few data are available on its effect in cancer prevention, especially concerning the mechanism of action. Here, we investigated the effect of Origanum vulgare ethanolic extracts on redox balance, cell proliferation, and cell death in colon adenocarcinoma Caco2 cells. Oregano extract leads to growth arrest and cell death in a dose- and time-dependent manner. Changes in glutathione content, as well as the increase in its oxidized form, may be involved in oregano-triggered death. Both extrinsic and intrinsic apoptotic pathways appear to be activated by spice extract. Our findings suggest that oregano amounts found in the Mediterranean diet can exert proapoptotic effects, which are selective for cancer cells. Moreover, whole extract, instead of a specific component, can be responsible for the observed cytotoxic effects.

Nutrition and Breast Cancer: A Literature Review on Prevention, Treatment and Recurrence.

Breast cancer (BC) is the second most common cancer worldwide and the most commonly occurring malignancy in women. There is growing evidence that lifestyle factors, including diet, body weight and physical activity, may be associated with higher BC risk. However, the effect of dietary factors on BC recurrence and mortality is not clearly understood. Here, we provide an overview of the current evidence obtained from the PubMed databases in the last decade, assessing dietary patterns, as well as the consumption of specific food-stuffs/food-nutrients, in relation to BC incidence, recurrence and survival. Data from the published literature suggest that a healthy dietary pattern characterized by high intake of unrefined cereals, vegetables, fruit, nuts and olive oil, and a moderate/low consumption of saturated fatty acids and red meat, might improve overall survival after diagnosis of BC. BC patients undergoing chemotherapy and/or radiotherapy experience a variety of symptoms that worsen patient quality of life. Studies investigating nutritional interventions during BC treatment have shown that nutritional counselling and supplementation with some dietary constituents, such as EPA and/or DHA, might be useful in limiting drug-induced side effects, as well as in enhancing therapeutic efficacy. Therefore, nutritional intervention in BC patients may be considered an integral part of the multimodal therapeutic approach. However, further research utilizing dietary interventions in large clinical trials is required to definitively establish effective interventions in these patients, to improve long-term survival and quality of life.

Polyunsaturated fatty acids modulate the delivery of platelet microvesicle-derived microRNAs into human breast cancer cell lines.

Breast cancer is one of the most frequent and malignant types of cancer in women, with an increasing morbidity and mortality rate; in particular, treatment of triple negative breast cancer remains a challenge, since the efforts made with targeted therapies were ineffective. Among surrounding cells influencing the biology of cancer cells, platelets are recognizing as novel players. Activated platelets release microvesicles (MVs) that, once delivered to cancer cells, modulate signaling pathways related to cell growth and dissemination; among factors contained in platelet-derived MVs, microRNAs are highly involved in cancer development. The growing interest in ω3 and ω6 polyunsaturated fatty acids (PUFAs) as adjuvants in anti-cancer therapy prompted us to investigate the ability of arachidonic acid (AA) and docosahexaenoic acid (DHA) to modulate MV biological functions. AA induced differential enhancement of platelet-specific microRNAs (miR-223 and miR-126), an effect further enhanced by the presence of DHA. MVs can be delivered to and microRNAs internalized by breast cancer cells, although with different efficiency; analysis of kinetics of MV delivery, indeed, suggested that tumor cells fine-tune the uptake of specific microRNA. Finally, we demonstrated that physiological delivery of platelet miR-223 and miR-126 induced cellular effects in breast cancer cells, including cell cycle arrest, inhibition of migration and sensitivity to cisplatin. These results have been confirmed by exogenous expression of miR-223 and miR-126 through transient transfection experiments. Our preliminary data suggest that ω6/ω3-PUFA supplementation, by modulating microRNA delivery, enhances platelet anti-tumor activities, thus opening new avenues for add-on therapies in cancer patients.