Role of the vanins-myeloperoxidase axis in colorectal carcinogenesis

The presence of chronic inflammation in the colonic mucosa leads to an increased risk of cancer. Among proteins involved in the regulation of mucosal inflammation and that may contribute both to structural damage of the intestinal mucosa and to intestinal carcinogenesis, there are myeloperoxidase (MPO) and vanins. The infiltration of colonic mucosa by neutrophils may promote carcinogenesis through MPO, a key enzyme contained in the lysosomes of neutrophils that regulates local inflammation and the generation of reactive oxygen species (ROS) and mutagenic species. The human vanin gene family consists of three genes: vanin-1, vanin-2 and vanin-3. All vanin molecules are pantetheinases, that hydrolyze pantetheine into pantothenic acid (vitamin B5), and cysteamine, a sulfhydryl compound. Vanin-1 loss confers an increased resistance to stress and acute intestinal inflammation, while vanin-2 regulates adhesion and transmigration of activated neutrophils. The metabolic product of these enzymes has a prominent role in the inflammation processes by affecting glutathione levels, inducing ulcers through a reduction in mucosal blood flow and oxygenation, decreasing local defense mechanisms, and in carcinogenesis by damaging DNA and regulating pathways involved in cell apoptosis, metabolism and growth, as Nrf2 and HIF-1α

Attenuated adenomatous polyposis of the large bowel: Present and future

Attenuated adenomatous polyposis (AAP) is a poorly understood syndrome, that can be defined as the presence of 10-99 synchronous adenomas in the large bowel, and it is considered a phenotypic variant of familial adenomatous polyposis (FAP). This definition has the advantage of simplicity, but it may include sporadic multiple adenomas of the large bowel at an extreme, or FAP cases on the other side. AAP shows a milder phenotype than FAP, with an older age of onset of adenomas and cancer, and less frequent extracolonic manifestations. AAP may be diagnosed as a single case in a family or, less frequently, it may be present in other family members, and it shows distinct pattern of inheritance. In less than 50% of cases, it may be caused by adenomatous polyposis coli (APC) or MUTYH mutations, referred to as APC-associated polyposis, inherited as an autosomal dominant trait, or MUTYH - associated polyposis, which shows an autosomal recessive mechanism of inheritance, respectively. Surveillance should rely on colonoscopy at regular intervals, with removal of adenomas and careful histological examination. When removal of polyps is not possible or advanced lesions are observed, the surgical approach is mandatory, being subtotal colectomy with ileo-rectal anastomosis the treatment of choice. Studies on this syndrome are lacking, and controversies are still present on many issues, thus, other clinical and genetic studies are requested

Inflammatory pathways in the early steps of colorectal cancer development

Colorectal cancer is a major cause of cancer-related death in many countries. Colorectal carcinogenesis is a stepwise process which, from normal mucosa leads to malignancy. Many factors have been shown to influence this process, however, at present, several points remain obscure. In recent years some hypotheses have been considered on the mechanisms involved in cancer development, expecially in its early stages. Tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. Chronic inflammation of the large bowel (as in inflammatory bowel diseases), has been associated with the subsequent development of colorectal cancer. In this review we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Indeed, the activation of these pathways establishes an oxidative and anaerobic microenvironment with DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism. Many cellular mechanisms, such as proliferation, apoptosis, and autophagy are altered causing failure to control normal mucosa repair and renewal

Giant reed (Arundo donax L.) as energy crop in Central Italy: A review

In the European Union energy security have been driving the search for economically viable and environmentally sustainable renewable energy sources since the 90’s. Energy crops could represent a good opportunity to combine the energy goals with the conservation of farmer incomes and the global climate change control. Giant reed (Arundo donax L.) is a perennial rhizomatous grass particularly attractive for energy production because of a high yield potential, a generally positive environmental impact and a good attitude to energy conversion. Long-term studies carried out in Central Italy confirmed its high production level, in both fertile and marginal lands (aboveground yields from 38 to 20 t ha–1 year–1). In addition, the crop highlighted a high growth rate at the beginning of the growing season, progressively decreasing in summer when high temperature and low water availability occurred. Giant reed nutrient requirements were generally low and part of nutrient stocks were remobilized from the rhizome to the aboveground biomass over the spring, with the opposite flow occurring in autumn. From an environmental point of view giant reed showed a positive energy balance with a high-energy efficiency. Compared to other energy crops, giant reed showed the lowest GHG emissions per unit of energy and the best performance in terms of cost per ton of dry biomass or per unit of energy. To improve knowledge on giant reed and to favour the diffusion of energy crops in Italian cropping systems, further studies are needed to analyze the long-term effects of giant reed on soil fertility and the optimal soil management after its cultivation. In our researches the environmental impacts of giant reed and its production costs were referred to the production phase. Therefore, there is the need to extend the research activity to the whole energy chain and to identify the most sustainable conversion technologies (e.g. biogas, 2nd generation bioethanol, etc.) for the different environments

Myeloperoxidase expression in human colonic mucosa is related to systemic oxidative balance in healthy subjects

Objectives: To improve understanding of the preclinical stage of colonic inflammation by exploring the existence of a link between early inflammatory changes in the colonic mucosa and the systemic redox balance. Methods: Clinical characteristics, a fasting blood draw, and mucosal biopsies from the right, left, and sigmoid-rectum colonic tracts collected from 28 healthy individuals (14/14 males/females) who underwent colonoscopy. Myeloperoxidase (MPO) positive cells infiltrating colonic mucosa specimens were assessed by immunohistochemistry, and patients divided into high or low MPO expressing cells/optical field groups (MPOhighor MPOlow, respectively).The systemic oxidative balance has been studied through derived-Reactive Oxygen Metabolites (d-ROMs), Biological Antioxidant Potential (BAP), and Lipoperoxide-cholesterol Oxidizing (LP-CHOLOX) tests on serum. Results: MPOhighpatients demonstrated an increased systemic oxidative stress compared to MPOlowindividuals (P = 0.035), especially when MPO is referred to the left-sided colonic mucosa (P = 0.007). MPOlowsubjects in the sigmoid-rectum showed a significant higher antioxidant capacity in the serum (P < 0.02). Sex-specific differences in MPO expression (male and female: 4.6 \ub1 3.2 and 2.6 \ub1 1.5 MPO-positive cells/optical field, respectively, P = 0.044), and a decreasing gradient in MPO expression moving from the cecum to the rectum (ascendant, descendant, and sigmoid-rectum: 3.7 \ub1 2.8, 3.1 \ub1 1.7, and 1.4 \ub1 0.5, respectively, P = 0.012) were also found and discussed. Discussion: The study is the first demonstrating a connection between systemic redox balance and MPO expression in the colonic mucosa, according to the colonic tract and patient gender. Further research evaluating the MPO expression in the human colon and its relationship with pathological conditions could benefit from these results

Metformin induces apoptosis and alters cellular responses to oxidative stress in Ht29 colon cancer cells: Preliminary findings

Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-\u3baB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer

Seasonal nutrient dynamics and biomass quality of giant reed (Arundo donax L.) and miscanthus (Miscanthus x giganteus Greef et Deuter) as energy crops

The importance of energy crops in displacing fossil fuels within the energy sector in Europe is growing. Among energy crops, the use of perennial rhizomatous grasses (PRGs) seems promising owing to their high productivity and their nutrient recycling that occurs during senescence. In particular, nutrient requirements and biomass quality have a fundamental relevance to biomass systems efficiency. The objective of our study was to compare giant reed (Arundo donax L.) and miscanthus (Miscanthus × giganteus Greef et Deuter) in terms of nutrient requirements and cellulose, hemicelluloses and lignin content. This aim was to identify, in the Mediterranean environment, the optimal harvest time that may combine, beside a high biomass yield, high nutrient use efficiency and a good biomass quality for second generation biofuel production. The research was carried out in 2009, in San Piero a Grado, Pisa (Central Italy; latitude 43°41' N, longitude 10°21' E), on seven-year-old crops in a loam soil characterised by good water availability. Maximum above-ground nutrient contents were generally found in summer. Subsequently, a decrease was recorded; this suggested a nutrient remobilisation from above-ground biomass to rhizomes. In addition, miscanthus showed the highest N, P, and K use efficiency, probably related to its higher yield and its C4 pathway. Regarding biomass quality, stable values of cellulose (38%), hemicelluloses (25%) and lignin (8%) were reported from July onwards in both crops. Hence, these components appear not to be discriminative parameters in the choice of the harvest time in the Mediterranean environment. In conclusion, our results highlighted that, in our environment, a broad harvest period (from late autumn to winter) seems suitable for these PRGs. However, further research is required to evaluate the role of rhizomes in nutrient storage and supply during the growing season, as well as ecological and productive performances in marginal lands, in particular those where water availability may be a limiting factor

Expression of Autophagic and Inflammatory Markers in Normal Mucosa of Individuals with Colorectal Adenomas: A Cross Sectional Study among Italian Outpatients Undergoing Colonoscopy

: Colorectal cancer (CRC) ranks among the three most common cancers in terms of both cancer incidence and cancer-related deaths in Western industrialized countries. Lifetime risk of colorectal cancer may reach 6% of the population living in developed countries. In the current era of personalized medicine, CRC is no longer considered as a single entity. In more recent years many studies have described the distinct differences in epidemiology, pathogenesis, genetic and epigenetic alterations, molecular pathways and outcome depending on the anatomical site. The aim of our study is to assess in a multidimensional model the association between metabolic status and inflammatory and autophagic changes in the normal colorectal mucosa classified as right-sided, left-sided and rectum, and the presence of adenomas. One hundred and sixteen patients undergoing colonoscopy were recruited and underwent a complete serum lipid profile, immunofluorescence analysis of colonic biopsies for MAPLC3 and myeloperoxidase expression, matched with clinical and anthropometric characteristics. Presence of adenomas correlated with cholesterol (total and LDL) levels, IL-6 levels, and MAPLC3 tissue expression, especially in the right colon. In conclusion, serum IL-6 amount and autophagic markers could be good predictors of the presence of colorectal adenomas

Proposed roles of the immune response regulator-ThPOK in human colorectal cancer progression

Solid tumours are commonly infiltrated by several immune cells [1-3]. In cancer, immune cells play conflicting roles with both the potentials to eliminate or to promote malignancy. In contrast to infiltration of cells responsible for chronic inflammation, the presence of high numbers of lymphocytes, especially T cells, has been reported to be important as indicator of good prognosis in many types of cancer [4-7]. The thorough knowledge of both manners and pathways with which tumors are able to evade immune-mediated attack, once established, is therefore of crucial importance. The strategies to escape anti-tumor immune responses include the limited priming or differentiation of antitumor T cells and the role of tumor microenvironment in order to prevent infiltration or activation of effector phase functions. We proposed to evaluate the role of Th inducing POZ-Kruppel Factor (ThPOK), a transcriptional regulator of T cell fate, in tumour-induced immune system plasticity during colorectal carcinogenesis. Data were collected on the amounts of CD4+, CD8+ and CD56+ as well as on ThPOK+ cells infiltrated in normal colorectal mucosa (NM), in dysplastic aberrant crypt foci (microadenomas, MA, the earliest detectable lesions in colorectal carcinogenesis) and in colorectal carcinomas (CRC); moreover, the colocalization of ThPOK with the above-mentioned markers of immune cells was evaluated using confocal microscopy. Interestingly, ThPOK showed a prominent increase since MA. A strong colocalization of ThPOK with CD4 both in NM and in MA was observed, weaker in carcinomas. Surprisingly, there was a peak in the colocalization levels of ThPOK with CD8 in MA, which was evident, although to a lesser extent, also in carcinomas. In conclusion, according to the data of the present study, ThPOK may be considered a central regulator of the earliest events in the immune system during colorectal cancer development. The novelty of the present study is the proposed role of ThPOK in influencing the immune response against cancer cells. References [1] Dunn et al. (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21: 137-148. [2] Knaapen et al. (2006) Neutrophils and respiratory tract DNA damage and mutagenesis: a review. Muta-genesis 21: 225-236. [3] Coussens and Werb (2002) Inflammation and cancer. Nature 420: 860-867. [4] Watt and House (1978) Colonic carcinoma: a quantitative assessment of lymphocyte infiltration at the periphery of colonic tumors related to prognosis. Cancer 41: 279-282. [5] Galon et al. (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313: 1960-1964. [6] Pagès et al. (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27: 5944-5951. [7] Mlecnik et al. (2010) Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal. Gastroenterology 138: 1429-1434

Double row spacing and drip irrigation as technical options in energy sorghum management

The effect of two row spacing configurations and four water supply levels was investigated on sweet and fibre sorghum in Central Italy for two consecutive years. Results highlighted the influence of both irrigation and row spatial configuration on crop productivity. Indeed, several studies have pointed out the positive response of sorghum to irrigation in Mediterranean climate, as in this environment water stress represents one of the main limiting factors on crop productivity. On the other hand, few attempts have been made to explore the role of row spacing on energy sorghum productivity. Results outlined an average increase in sorghum dry biomass yield ranging from +23% to +79% at variable rates of water supply as compared to rainfed control. The positive effect of irrigation was also observed on leaf area index and radiation use efficiency. Moreover, we observed a crop yield increase, from 9% to 20%, under double row spacing compared to the standard planting pattern ( i.e. single row spacing). Finally, it was confirmed the efficient use of water by sorghum and the great ability of sorghum to increase its biomass yield in response to increasing volumes of water supplied. Therefore, this work suggests how row spacing configuration and drip irrigation could be feasible technical options to increase sorghum biomass yields in Mediterranean environments. These techniques should be experienced by farmers towards a sustainable intensification of current cropping systems