Background: In the 20th century, cancer metabolism has been studied from different aspects. In the last decade, the interest in this issue has been renewed and many studies have been carried out on tumor and endothelial metabolism. Although tumor metabolism is well recognized, there are some discrepancies between what we knew and what has been studied lately about the metabolism of endothelial cells. Moreover, cancer and endothelial cells are not alone in their microenvironment. Immune cells and fibroblasts are also present and have a crucial role in tumor-associated inflammation, as well as in tumor progression, metastasis and angiogenesis. Nevertheless, metabolism of these cells is poorly understood. Conclusion: In the present mini-review, information about metabolic characteristics of these cells is summarized and compared with our knowledge about cancer and endothelial cell metabolism. This knowledge could contribute to open up innovative approaches to the treatment of cancer. Keywords: Endothelial cells, fibroblasts, glycolysis, glutaminolysis, immune cells, metabolic reprogramming of cancer, tumor cells, Warburg effect.
Background: Interferons (IFNs) are functional proteins of vertebrate cells that have been conserved throughout evolution. Antiviral response in cells and uncontrolled cell proliferation of lymphocytes and macrophages are influenced by IFNs. B and T cell functions are influenced by these molecules in vitro and in vivo. These facts are confirmed by the effects on different conditions: antibodies production, T cells' cytotoxicity, allograft survival, delayed-type hypersensitivity reactions. Some IFNs are produced as a result of antigen recognition by T cells, and in turn, they modulate Natural Killer (NK) cell and phagocyte activities and functions. On the other hand, there are viral infections without immunological specificity, which involve IFNs and interfere in immune reactions. Some clinical applications of IFNs have been implemented in the recent years, for example for hepatitis B and C treatment. Conclusion: However, in this review, emphasis will be placed on the use of IFNs for the possible treatment of seasonal influenza viruses that have specificity with the upper respiratory tract. IFNs prevent highly pathogenic influenza viruses to disseminate to the lung, assuming their use as an emergency drug against pandemic forms of influenza. Keywords: Interferons, influenza, immune system, lymphocytes, macrophages, phagocyte.
Background and Objective: Thalassemia is one of the most common hereditary disorders in the world, Beta thalassemia is much more diverse than the alpha type; it was estimated that about 4% to 7% of the world's population are carriers of beta thalassemia. In thalassemia, oxidative damage is increased, which causes damage to cellular components and functional disorders in the body. Oxidative injuries and stress are important factors for accelerating the aging process and the immune system response. Such frequent problems may cause local and systemic infections in the patients and financial damages to the society. Therefore, this study was performed to evaluate the strength of the immune response in patients diagnosed with thalassemia. Materials and Methods: This descriptive cross-sectional study was conducted in the Shafa Hospital Ahvaz. Peripheral blood samples were collected from patients with the beta-thalassemia minor (test group) and healthy individuals (control group) have been investigated. Results: Overall, 100 patients (48% female and 52% male) were enrolled and compared with the 100 healthy volunteers (56% femal and 44% male). There was no significant differences in the number of WBC between the case and control groups (P>0.05). In the case group, 94% and 6% of the patients had normal and high WBC, respectively. Conclusion: It can be concluded that patients with thalassemia may be at risk for local and systemic infections due to many resaons, which include increased oxidative stress and decreased antigen presentation by dendritic cells, defects in chemotaxis or phagocytosis, neutrophil and monocytes, impaired natural killer cells activity and the immune response, increasing the dose of iron, lymphocytes, and other immune cells functions. Keywords: Beta thalassemia, hereditary disorders, immune system, leukocytes, red blood cells, Shafa Hospital.
Objective: Recent studies have demonstrated the importance of Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) gene variants in inflammatory conditions, including Type 1 diabetes mellitus. However, to date, no large prospective, genetic-epidemiological data are available on the relevance of ERAP1 genetic variation in the risk of non-insulin dependent diabetes. Methods: The association between 33 tag-SNPs (tSNPs) of ERAP1 and incident Type 2 Diabetes mellitus (T2D) was investigated in 22,718 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cancer, cardiovascular disease, and diabetes mellitus at baseline. During an 18-year follow-up period, 1,927 newly diagnosed first ever T2D were identified. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk assuming an additive genetic model. Results: None of the gene variants evaluated were associated with T2D risk. Conclusions: If corroborated in other large prospective studies, the present findings suggest that genetic variation within the ERAP1 gene locus may not be useful prognostic indicators for risk assessment of type 2 diabetes mellitus. Keywords: Type 2 Diabetes Mellitus, genetic epidemiology, single nucleotide polymorphisms, ERAP1, risk assessment, gene Variation.
Background: Coffee intake represents an essential tradition in many people's lives all around the world: the success of this beverage is mainly due to its unique flavour and its well-known characteristic of reducing sleep. Coffee is usually associated with caffeine, nevertheless, hundreds of other molecules are involved in the very heterogeneous composition of the beans. Many studies revealed that several of these compounds can influence our health, because of their bioactive activities. Coffee appears as an antioxidant, antidiabetic, anticancer, and antidepressant agent and the data about these properties have been already reviewed. Conclusion: In the present work, the antimicrobial and the antiviral activities will be discussed. Attention will also be focused on single compounds present in beans: some coffee constituents appear as valid candidates to develop new efficient drugs and the available data show that more efforts are needed to fully investigate the potential of coffee against pathogens. Keywords: Coffee, caffeine, polyphenols, chlorogenic acids, antimicrobial, antiviral.
Background: Polyethylene Glycols (PEGs) or macrogols are reputed to be inert and nonimmunogenic substances, however they are reported to induce immediate type hypersensitivity reactions. Due to their widespread use in extensively consumed products as cosmetics and drugs, the attention towards these substances is still low. Conclusion: Therefore, it may be useful to focus clinician's attention on possible adverse reactions caused by these polymers. Keywords: Anaphylaxis, excipients, hypersensitivity, immediate-type reaction, macrogols, polyethylene glycols.
Background: Abdominal obesity in adolescents has been identified as a risk factor for occurrence of cardiovascular and metabolic diseases. Objective: To monitor abdominal obesity in Roman adolescents through a five years-period. Method: A total of 410 adolescents aged 14.5-17.9 years, living in the city of Rome, were selected from two cross-sectional studies conducted during 2006-2007 (HELENA Study) (n=198) and 2011-2012 (ALIADO Study) (n=212). Anthropometric measurements such as weight, height and Waist Circumference (WC) were taken in both surveys using the same methodology and trained staff. Overweight and obesity were defined by both the latest IOTF (International Obesity Task Force) and WHO (World Health Organization) references, abdominal obesity as a Waist-to-Height Ratio (WtHR) ≥0.5. Smoking data were collected by questionnaire and socio-economic status was assessed using the education level of both parents. Results: A significant decrease in the mean value of WC in males (p=0.001) and of WtHR in females (p=0.002) was observed from 2006-2007 to 2011-2012. A decrease of abdominal obesity proportion was observed in female. Lower proportions of overweight and obese females were observed in 2011-12 than in 2006-07 using both criteria, IOTF and WHO. It was not found that smokers were more likely to have abdominal obesity. Conclusion: There is a decrease of abdominal obesity and a significant trend towards lower WtHR values in female adolescents from Rome (Italy). In males, despite a trend towards lower waist circumference values, the prevalence of abdominal obesity leveled- off. Keywords: Abdominal, adolescence, gender, obesity, smokers, trend.
Green tea has been consumed for thousands of years, and has been known to have many medicinal properties such as, anti-cancerous, anti-atherogenic, anti-oxidative, anti-inflammatory and anti-bacterial. With the increasing emergence of cardiovascular disease (CVD), and its major risk factor, obesity, there has been increasing interest in green tea as a potential anti-obesity therapy. Evidence has demonstrated that green tea decreases body weight. However it remains unclear through which pathway and mechanism green tea exerts its anti-obesity properties. The metabolic adipose tissue hormones, adipocytokines, leptin and adiponectin have been studied extensively as a potential target for green tea and its main catechin, epigallacatechin gallate (EGCG). It has been demonstrated that green tea consumption decreases leptin levels which may directly decrease body weight through increasing energy expenditure and fat oxidation. Furthermore, ingestion of green tea or its catechins has been associated with increased adiponectin levels which may indirectly reduce body weight through insulin sensitivity.
Background: Previous experimental and clinical studies have shown that lactate concentrations of 10 mM and more in solid malignant tumors may inactivate cytotoxic T cells as a major component of the immune defense of the tumor host. Additionally, it has been demonstrated recently that glucose depletion within cancerous tissue to concentrations of 1 mM and less may inhibit the T cellmediated immune response, as well. To evaluate the significance of lactate accumulation compared to glucose depletion in cancers, we have revisited previous data using the technique of induced metabolic Bioluminescence Imaging (imBI) in various entities of human tumor xenografts and tumors in the clinic. These tumor entities comprise squamous cell carcinomas of the cervix and of the head and neck, ovarian cancer metastases, rectal adenocarcinomas, glioblastomas, and melanomas. Tissue lactate levels in metastatic primary tumors were 1.5- to 2-times higher than those in non-metastatic primaries, and this was true for both patient cancers and corresponding tumor xenografts. Immunologically relevant lactate accumulation (≥ 10 mM) occurred in a large majority of all tumors investigated. In contrast, tumors with average glucose concentrations of 1 mM and less were rarely found in general with the striking exception of rectal adenocarcinomas, where 67 % of all tumors were low glucose malignancies. Conclusion: lactate accumulation in malignant tissue may be quantitatively more relevant for the immune escape compared to glucose depletion. However, in rectal adenocarcinomas both high lactate and low glucose concentrations may substantially contribute to the inhibition of the immune defense. Keywords: Induced metabolic Bioluminescence Imaging (imBI), various human tumor entities, Warburg metabolism, lactate accumulation, glucose depletion, inhibition of cytotoxic T cells, Natural Killer (NK) cells.
Background: The discovery of fullerene by the end of 20th century has revolutionized nanoscience and nanotechnology. Since the inception of fullerene it has been one of the most attractive natural carbon molecules for the researchers from biological, biomedical fields and other varied industries. Fullerene is one of the allotropic forms of carbon. The physical and photo-electro-chemical properties of fullerene make nanomaterials suitable for biological and biomedical applications. Observations: Fullerene and its related compounds exhibit quite intense interaction with free radicals and it is considered as "radical sponge". Fullerene molecules have the capacity to undergo chemical reactions and most of the interactions are related to either donate and/or accept the electron. Pristine fullerene is hydrophobic in nature and it gets agglomerated in aqueous medium resulting in the formation of its suspension. The interaction between fullerene and water is basically related to their specific properties like spatial, orientational dynamics, surface properties etc. Its utility is enhanced by its ability of forming water soluble derivatives. The existing derivatives of fullerene have become a significant research tool in the current scenario due to the enhanced multifaceted properties. Result: In almost all cases there exists correlation between the physicochemical properties of the product and the interacting biosystem. The impact or effect of the product may be toxic, neutral or good in nature to the organism. Fullerene and its derivatives exhibit various efficacies as generator and scavenger of ROS, RNS, antimicrobial, imaging agent, antiviral, toxic, drug delivery agents, etc. Fullerene and its derivatives interact with various biomolecules. These interactions may interfere with cell signaling process and cell functioning. This natural carbon allotropic form exhibits dual behavior that is related to the degree of efficacy of 'covalently functionalized' water soluble form of fullerene. Conclusion: In this article, an effort is made to survey the impact of this multifaceted allotropic form of carbon with reference to biosystem. Keywords: Astrochemistry, buckminster fullerene, fullerene, fullerenol, hydrophobic and hydrophilic forms, oxidase en-zyme, radical sponge, scavenger for ROS and RNS.
BACKGROUND:Sepsis is a clinical condition due to an infectious event which leads to an early hyper-inflammatory phase followed by a status of tolerance or immune paralysis. Hyper-inflammation derives from a massive activation of immune (neutrophils, monocytes/macrophages, dendritic cells and lymphocytes) and non-immune cells (platelets and endothelial cells) in response to Gram-negative and Gram-positive bacteria and fungi.DISCUSSION:A storm of pro-inflammatory cytokines and reactive oxygen species accounts for the systemic inflammatory response syndrome. In this phase, bacterial clearance may be associated with a severe organ failure development. Tolerance or compensatory anti-inflammatory response syndrome (CARS) depends on the production of anti-inflammatory mediators, such as interleukin-10, secreted by T regulatory cells. However, once triggered, CARS, if prolonged, may also be detrimental to the host, thus reducing bacterial clearance.CONCLUSION:In this review, the description of pathogenic mechanisms of sepsis is propaedeutic to the illustration of novel therapeutic attempts for the prevention or attenuation of experimental sepsis as well as of clinical trials. In this direction, inhibitors of NF-κB pathway, cell therapy and use of dietary products in sepsis will be described in detail.
BACKGROUND:T cell tolerance both at thymic and peripheral levels is a mechanism of protection finalized to eradicate autoreactive T cell clones and/or to maintain immune homeostasis, especially, postnatally. Central tolerance occurs in the thymic medulla via a mechanism of negative selection which leads to the eradication of autoreactive T cell clones. Mechanisms of Action: Such a tolerogenic event relies on Fas-mediated apoptosis of autoreactive T cell clones operated by thymic dendritic cells (DCs), on the one hand. On the other hand, activated thymic T regulatory (Treg) cells in cooperation with medullary thymic epithelial cells and DCs suppress autoreactive T cell clones. Peripherally, different types of Treg cells exert the so-called peripheral tolerance towards autoreactive T cell clones which may have escaped from negative selection mechanisms. At the same time, peripheral Treg cells activated by tolerogenic DC have antiinflammatory activities, especially in the intestine towards food and microbial antigens. Drug Targeting: Various natural and dietary products, such as vitamins (A, C, D), lactobacilli and polyphenols will be described for their tolerogenic capacity to attenuate the inflammatory pathway, as observed in preclinical and clinical studies.
Background: Secondary lymphoid organs (SLO) are distributed in many districts of the body and, especially, lymph nodes, spleen and gut-associated lymphoid tissue are the main cellular sites. On the other hand, tertiary lymphoid organs (TLO) are formed in response to inflammatory, infectious, autoimmune and neoplastic events. Developmental Studies: In the present review, emphasis will be placed on the developmental differences of SLO and TLO between small intestine and colon and on the role played by various chemokines and cell receptors. Undoubtedly, microbiota is indispensable for the formation of SLO and its absence leads to their poor formation, thus indicating its strict interaction with immune and non immune host cells. Furthermore, food antigens (for example, tryptophan derivatives, flavonoids and byphenils) bind the aryl hydrocarbon receptor on innate lymphoid cells (ILCs), thus promoting the development of postnatal lymphoid tissues. Also retinoic acid, a metabolite of vitamin A, contributes to SLO development during embryogenesis. Vitamin A deficiency seems to account for reduction of ILCs and scarce formation of solitary lymphoid tissue. Translational Studies: The role of lymphoid organs with special reference to intestinal TLO in the course of experimental and human disease will also be discussed. Future Perspectives: Finally, a new methodology, the so-called “gut-in-a dish”, which has facilitated the in vitro interaction study between microbe and intestinal immune cells, will be described.
Background: Drugs of abuse affect both central nervous system (CNS) and peripheral immune function. Besides the involvement of dopamine and glutamate systems, chronic exposure to drugs of abuse alters immune homeostasis, promoting a pro-inflammatory status. At the same time, impaired peripheral immunity leads to an increased susceptibility to infections in drug abusers. Discussion: There is evidence that certain drugs, such as opioids, activate microglial cells and astrocytes which, in turn, provoke central neuroinflammation. Particularly, opioids bind the Toll-like receptor (TLR)-4 with increased expression of nuclear factor kappa-light-chain-enhancer of activated B cells and release of pro-inflammatory cytokines. Peripheral mediators released by immune cells also contribute to aggravate central neuroinflammation. Conclusion: These are based either on the inhibition of TLR-4 activation by drugs of abuse or on the correction of dopamine and glutamate pathways. Finally, a hypothetic nutraceutical intervention with polyphenols in view of their anti-inflammatory and anti-oxidant properties will be outlined as an adjuvant treatment for drugs of abuse-related disorders.
Cystic fibrosis (CF) lung disease is nowadays appreciated as a complex trait, characterised by dysfunction of the CF Transmembrane Conductor (CFTR) protein, opportunistic bacterial infections, chronic inflammation and remodelling of the airways. In this review, we have analysed the usefulness of biomarkers of inflammation and remodelling for their ability in predicting and assessing the onset of a pulmonary exacerbation, its evolution with time and its response to therapeutic interventions. Studies concerning sputum, bronchoalveolar lavage fluid, exhaled breath condensate and blood were considered. Our conclusions are: I) although their validity has been proven across different clinical settings, presently there is no biomarker which can be “promoted” to the status of surrogate end-point; II) longitudinal studies at different ages will be needed for assessing this issue; and III) different therapies should consider not only one biomarker but a constellation of them aiding in the evaluation of the complex pathogenesis of CF lung disease. Keywords: Bronchoalveolar lavage, cystic fibrosis, cytokines, exhaled breath condensate, growth factors, oxidative stress, sputum.
Cystic fibrosis pulmonary disease is caused by dysfunctional electrolytes transport that severely impacts the lung environment. Abnormal chloride and carbonate transport by the CFTR favours recurrent bacterial infections which in turn stimulate an immune response that, while inadequate to eradicate infection, contributes to lung failure. Many different cell types are affected by dysfunctional CFTR including epithelial cells and macrophages; the latter being involved in the elimination of foreign particles and microbes and orchestration of the inflammatory response. Sputa and BAL of CF patients are characterized by large amount of proinflammatory mediators, ROS and proteases that contribute to lung failure. Macrophages express CFTR and show functional deficiencies at different levels. First, defective intracellular bacteria killing has been reported in the murine model and in humans; disproportional inflammatory response resulting in high level of cytokine production and defective removal of cellular debris has been documented as well. Microbicidal deficiency against CF pathogens such as Burkholderia cenocepacia or Pseudomonas aeruginosa was ascribed to defective autophagy and phagolysosome pH, respectively. Looking at the causes of inflammation, a hyper responsiveness to LPS has been ascribed to defective AKT/miR-199a-5p/CAV1 pathway governing the feedback loop that shuts down TLR4 signalling. Moreover, abnormal activation of the IRE1a/XBP-1 arm of the unfolded protein response was shown to contribute to inflammation. Overall it appears that bacteria clearance and hyperinflammation may be improved by targeting CF macrophage deficiencies. Keywords: Macrophages, hyper-inflammation, Pseudomonas aeruginosa, microbial killing, reactive oxygen species, autophagy, celecoxib, roscovitine.
Cystic fibrosis (CF) is a multiorgan genetic disease caused by defective function of CFTR, a plasma membrane chloride channel particularly expressed in epithelial cells. CF mutations have been grouped in six classes according to the mechanism through which they affect CFTR function: premature translation termination, impaired folding and stability, altered channel gating, reduced single channel conductance, aberrant RNA splicing, reduced persistence on cell surface. Each type of CFTR defect can be targeted by specific small molecules (correctors, potentiators, or readthrough agents) in order to restore CFTR function. Novel in vitro assays, based on intestinal organoids or nasal epithelial cells, can be used to identify the most appropriate treatment for each genotype. This approach paves the way for the development of personalized treatments for CF patients. Keywords: Cystic fibrosis, CFTR, personalized medicine, in vitro, CF mutations, CF patients.
