Beta-carotene supplementation: a good thing, a bad thing, or nothing?

Available data from several completed large-scale randomized trials indicate that beta-carotene supplementation for durations up to 12 years has no overall benefit in well-nourished populations on the incidence of cardiovascular disease or the middle-to-late stages of carcinogenesis. Several important questions, however, remain unanswered. The post-trial follow-up of completed trials, together with the results of several ongoing trials of beta-carotene supplementation, will contribute reliable information to the totality of evidence from basic research, animal studies, observational epidemiologic studies, and completed trials, thus allowing more rational clinical decisions for individual patients and policy decisions for the health of the general public.     

Urocortin: a beneficial or detrimental agent to endothelium?

As a member of the corticotropin-releasing factor (CRF) family, urocortin (UCN) has been demonstrated to show diverse effects on cardiovascular system. It is commonly considered as a protective agent on vascular function. However, a growing body of evidence suggests that some effects of UCN may lead to endothelial dysfunction (ED) which may be the cause or consequence of vascular disease and a hallmark of known cardiovascular risk factors. The present review is then focused on recent evidence that reveals the beneficial and detrimental effects of UCN on endothelium.     

Revisiting ovarian cancer microenvironment: a friend or a foe?

Development of ovarian cancer involves the co-evolution of neoplastic cells together with the adjacent microenvironment. Steps of malignant progression including primary tumor outgrowth, therapeutic resistance, and distant metastasis are not determined solely by genetic alterations in ovarian cancer cells, but considerably shaped by the fitness advantage conferred by benign components in the ovarian stroma. As the dynamic cancer topography varies drastically during disease progression, heterologous cell types within the tumor microenvironment (TME) can actively determine the pathological track of ovarian cancer. Resembling many other solid tumor types, ovarian malignancy is nurtured by a TME whose dark side may have been overlooked, rather than overestimated. Further, harnessing breakthrough and targeting cures in human ovarian cancer requires insightful understanding of the merits and drawbacks of current treatment modalities, which mainly target transformed cells. Thus, designing novel and precise strategies that both eliminate cancer cells and manipulate the TME is increasingly recognized as a rational avenue to improve therapeutic outcome and prevent disease deterioration of ovarian cancer patients.     

Parkin: a multipurpose neuroprotective agent?

An autosomal recessive juvenile-onset form of Parkinson's disease (AR-JP) is caused by loss-of-function mutations of the parkin gene, which encodes a ubiquitin-protein ligase. Three recent reports demonstrate that parkin can protect neurons from diverse cellular insults, including alpha-synuclein toxicity, proteasomal dysfunction, Pael-R accumulation, and kainate-induced excitotoxicity. These findings suggest a central role for parkin in maintaining dopaminergic neuronal integrity and strengthen the link between AR-JP and the more common sporadic form of Parkinson's disease.     

Gut microbiome in gastrointestinal cancer: a friend or foe?

The impact of the gut microbiome on host health is becoming increasingly recognized. To date, there is growing evidence that the complex characteristics of the microbial community play key roles as potential biomarkers and predictors of responses in cancer therapy. Many studies have shown that altered commensal bacteria lead to cancer susceptibility and progression in diverse pathways. In this review, we critically assess the data for gut microbiota related to gastrointestinal cancer, including esophageal, gastric, pancreatic, colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma. Importantly, the underlying mechanisms of gut microbiota involved in cancer occurrence, prevention and treatment are elucidated. The purpose of this review is to provide novel insights for applying this understanding to the development of new therapeutic strategies in gastrointestinal cancer by targeting the microbial community.     

Mechanisms of vanadium action: insulin-mimetic or insulin-enhancing agent?

The demonstration that the trace element vanadium has insulin-like properties in isolated cells and tissues and in vivo has generated considerable enthusiasm for its potential therapeutic value in human diabetes. However, the mechanisms by which vanadium induces its metabolic effects in vivo remain poorly understood, and whether vanadium directly mimics or rather enhances insulin effects is considered in this review. It is clear that vanadium treatment results in the correction of several diabetes-related abnormalities in carbohydrate and lipid metabolism, and in gene expression. However, many of these in vivo insulin-like effects can be ascribed to the reversal of defects that are secondary to hyperglycemia. The observations that the glucose-lowering effect of vanadium depends on the presence of endogenous insulin whereas metabolic homeostasis in control animals appears not to be affected, suggest that vanadium does not act completely independently in vivo, but augments tissue sensitivity to low levels of plasma insulin. Another crucial consideration is one of dose-dependency in that insulin-like effects of vanadium in isolated cells are often demonstrated at high concentrations that are not normally achieved by chronic treatment in vivo and may induce toxic side effects. In addition, vanadium appears to be selective for specific actions of insulin in some tissues while failing to influence others. As the intracellular active forms of vanadium are not precisely defined, the site(s) of action of vanadium in metabolic and signal transduction pathways is still unknown. In this review, we therefore examine the evidence for and against the concept that vanadium is truly an insulin-mimetic agent at low concentrations in vivo. In considering the effects of vanadium on carbohydrate and lipid metabolism, we conclude that vanadium acts not globally, but selectively and by enhancing, rather than by mimicking the effects of insulin in vivo.     

Jasmonate in plant defence: sentinel or double agent?

Plants and their biotic enemies, such as microbial pathogens and herbivorous insects, are engaged in a desperate battle which would determine their survival–death fate. Plants have evolved efficient and sophisticated systems to defend against such attackers. In recent years, significant progress has been made towards a comprehensive understanding of inducible defence system mediated by jasmonate (JA), a vital plant hormone essential for plant defence responses and developmental processes. This review presents an overview of JA action in plant defences and discusses how microbial pathogens evade plant defence system through hijacking the JA pathway.     

Sulfur signaling: is the agent sulfide or sulfane?

Triplex-forming oligonucleotides (TFOs) are sequence-dependent DNA binders that may be useful for DNA targeting and detection. A sensitive and convenient method to monitor triplex formation by a TFO and its target DNA duplex is required for the application of TFO probes. Here we describe a novel design by which triplex formation can be monitored homogeneously without prelabeling the target duplex. The design uses a TFO probe tagged with a fluorophore that undergoes fluorescence resonance energy transfer with fluorescent dyes that intercalate into the target duplex. Through color compensation analysis, the specific emission of the TFO probe reveals the status of the triple helices. We used this method to show that triple helix formation with TFOs is magnesium dependent. We also demonstrated that the TFO probe can be used for detection of sequence variation in melting analysis and for DNA quantitation in real-time polymerase chain reaction.     

N-acetyl-cysteine: protective agent or promoter of gastric damage?

N-acetyl-cysteine (NAC), when given orally, has been shown to prevent gastric damage induced by ethanol, but when administered intraperitoneally, it appears to potentiate such damage. In an effort to resolve these seemingly discordant findings, fasted rats (six per group) received 1 ml of saline or 20% NAC orally or intraperitoneally (ip). Two hours or 15 min later, they received 1 ml of 100% ethanol orally. At sacrifice 5 min later, rats receiving oral pretreatment with 20% NAC at both 15 and 120 min prior to ethanol exposure demonstrated a significant reduction in the magnitude of gastric injury when compared with saline controls. In contrast, actual promotion of ethanol damage was noted when NAC was given intraperitoneally, but was more pronounced when NAC was administered 15 min prior to exposing the mucosa to 100% ethanol. In all animals receiving intraperitoneal NAC, large amounts of peritoneal fluid (4-6 ml/rat) were recovered at the time of sacrifice, most of which occurred within 15 min of NAC administration; these more pronounced peritoneal effects at 15 min after NAC correlated with the more severe injury from ethanol at this time period compared to 120 min after intraperitoneal NAC. Saline controls had no peritoneal fluid. Mucosal glutathione (GSH) levels generally paralleled these results in that a significant decrease in tissue GSH occurred at 15 min following intraperitoneal NAC when compared with controls; at 120 min after intraperitoneal NAC, GSH levels were similar to control values. Additional experiments demonstrated that within 15 min following NAC administration, systemic blood pressure dropped by approximately 20% and basically remained unchanged over the next 2 hr; intraperitoneal saline had no sustained adverse effects on blood pressure. It was concluded that the inability of NAC to prevent ethanol injury when given intraperitoneally in contrast to orally is related to the drop in blood pressure secondary to NAC's peritoneal irritant effects, which presumably altered gastric mucosal blood flow, thus obivating its ability to prevent ethanol damage under these conditions. Furthermore, the decreased levels in mucosal GSH following the hypotension induced by intraperitoneal NAC suggest that perturbations in GSH metabolism may also have contributed to the decreased resistance to ethanol injury.     

Fibulins and cancer: friend or foe?

The fibulins are a family of secreted glycoproteins, which are characterised by repeated epidermal-growth-factor-like domains and a unique C-terminal structure. Six distinct fibulin genes, encoding at least nine protein products generated by alternative splicing, have been identified. Considerable evidence is available pointing towards a structural role for fibulins within the extracellular matrix. Fibulins have been shown to modulate cell morphology, growth, adhesion and motility. The dysregulation of certain fibulins occurs in a range of human disorders, including cancer. Indeed, both tumour suppressive and oncogenic activities have been proposed for members of the fibulin family. Herein, we discuss the possible roles of fibulins in cancer, in addition to their diagnostic and therapeutic potential.     

Oxidative DNA damage in cancer patients: a cause or a consequence of the disease development?

A wide variety of oxidative DNA lesions are present in living cells. One of the best known lesions of this type is 8-oxoguanine (8-oxoGua) which has been shown to have mutagenic properties. An influence of antioxidative vitamins and labile iron pool on the background level of 8-oxoGua in cellular DNA is discussed and oxidative damage to free nucleotide pool as a possible source of 8-oxo-2'-deoxyguanosine in DNA and urine is described. An involvement of 8-oxoGua in the origin and/or progression of cancer is reviewed. It is concluded that a severe oxidative stress manifested as a high level of 8-oxoGua in cellular DNA as well as in urine of cancer patients is a consequence of development of many types of cancer. Although at present it is impossible to answer directly the question concerning involvement of oxidative DNA damage in cancer etiology it is likely that oxidative DNA base modifications may serve as a source of mutations that initiate carcinogenesis (i.e. they may be causal factors responsible for the process).     

Measles virus: a future therapeutic agent in oncology?

Measles is a potential lethal disease, justifying large immunization campaigns. Attenuated strains are used in immunization with very good safety records. Interestingly, following clinical observations of tumor regressions after measles infection, preclinical and clinical studies have highlighted the therapeutic potential of attenuated strains of measles. The aim of this review is to explain how these viruses can selectively infect and kill cancer cells, and how this selectivity can be improved. We will detail the therapeutic strategies under development, in particular the combination of viruses with chemotherapy and radiation therapy. Furthermore, the engineering of measles viruses encoding the sodium/iodide symporter could enable virus-directed radio-isotope therapy. Antiviral immunity could be a limit of measles therapy. We will highlight the promising combinations with immunosuppressive drugs and innovative strategies using infected cell carriers, aiming at circumventing the immune response and paving the way to future clinical trials.     

Non-target plant use by a weed biocontrol agent in idaho: host expansion or opportunistic behavior?

Larinus curtus Hochhuth (Coleoptera: Curculionidae) was first introduced into the western United States from Greece for the biological control of yellow starthistle (YST), Centaurea solstitialis L., in 1992. The discovery of L. curtus adults in the open flowerheads of safflower (SF), Carthamus tinctorius L., near Lewiston, Idaho in 2007 suggested this weevil might be expanding its host range to include a non-target crop species closely related to YST. In 2008 field plots near the 2007 observation site, 92 L. curtus adults fed in open SF flowerheads (pollen feeding and minor feeding on corolla tubes). No eggs were found in the ovarioles of 19 pollen-feeding females. No eggs, larvae, or evidence of larval feeding were detected in 39 tagged SF capitula, and no adults emerged from approximately 7,135 post-flowering SF capitula. These collective results are not indicative of an expanding developmental host-range of L. curtus. Also, they are consistent with pre-release host-specificity test results.     

Barrett's esophagus: treatment or observation of a major precursor factor of esophageal cancer?

Barrett's esophagus (BE) is a major precursor factor of esophageal cancer (EC). The appropriate management of patients with BE depends on the presence or not of dysplasia and the type of dysplasia that occurs. Due to the small proportion of BE patients that progress to cancer, the value of surveillance programs are a matter of debate. On the contrary, in high risk group of patients surveillance programs have significant impact. Large prospective trials are needed to define the optimal management strategy. Elucidation of carcinogenesis' steps and signal transduction pathways could reveal potential biomarkers in the order of early prediction for a highly malignant neoplasm with dismal prognosis. An efficacious tailored-made manner focusing to the safety profile and associated costs should be practised for less severe disease. In this review a thorough investigation of all available methods dealing with the clinical management of BE is provided.     

Aurora kinases, aneuploidy and cancer, a coincidence or a real link?

As Aurora kinases are overexpressed in a large number of cancers, and ectopic expression of Aurora generates polyploid cells containing multiple centrosomes, it has been tempting to suggest that Aurora overexpression provokes genetic instability underlying the tumorigenesis. However, examination of the evidence suggests a more complex relationship. Overexpression of Aurora-A readily transforms rat-1 and NIH3T3 cells, but not primary cells, whereas overexpression of Aurora-B induces metastasis after implantation of tumors in nude mice. Why do polyploid cells containing abnormal centrosome numbers induced by Aurora not get eliminated at cell-cycle checkpoints? Does this phenotype determine the origin of cancer or does it only promote tumor progression? Would drugs against Aurora family members be of any help for cancer treatment? These and related questions are addressed in this review (which is part of the Chromosome Segregation and Aneuploidy series).     

Changing T-cell enigma: Cancer killing or cancer control?

Data from different laboratories and theoretical considerations challenge our current view on anticancer immunity. Immune cells are capable of destroying cancer cells under in vitro and in vivo conditions. Therefore, cellular immunity is considered to control cancers through mechanisms that kill cancers. Yet, therapeutic anticancer immune responses rarely delete cancers. If efficient, they rather establish a life with stable disease. This raises the question of whether killing is the sole mechanism by which immune therapy attacks cancers. Here, we show that, besides cancer eradication by cytotoxic lymphocytes, other modes of action are operative and strictly required for cancer control. We show that T helper-1 cells arrest cancer growth by driving cancers into a state of stable or permanent growth arrest, called senescence. Such immune cells establish cytokine-producing walls around developing cancers. When producing interferon-γ and tumor necrosis factor, this cytokine-induced tumor immune-surveillance keeps the cancer cells in a permanently non-proliferating state. Simultaneously, antiangiogenic chemokines cut their connections to the surrounding tissues. This strategy significantly reduces tumor burden and prolongs life of cancer-bearing animals. As human cancers also undergo senescence, the current data suggest tumor-immune surveillance through cytokine-induced senescence, instead of tumor eradication, as the more realistic and primary goal of cancer control.