Evolution of dietary specialization and chemical defense in poison frogs (Dendrobatidae): a comparative analysis

Defensive mechanisms, including noxious or toxic substances, are favored by predation-driven natural selection. The acquisition of noxious/toxic substances can be either endogenous, in which the substances are produced by the organism, or exogenous, in which the substances are produced by another organism and are sequestered. Evidence indicates that the defensive skin alkaloids of Neotropical poison frogs (Dendrobatidae) have an exogenous source: a diet of ants and other small alkaloid-containing arthropods, which we term the diet-toxicity hypothesis. A critical prediction of the diet-toxicity hypothesis is that independent origins of dietary specialization will be found to be correlated with independent origins of skin alkaloids. We tested this prediction in an integrated framework using comparative methods with new and published data on feeding ecology and chemical defense for 15 species of dendrobatids in five genera. We found a significant correlation between alkaloid profiles and degree of dietary specialization. This reveals a recurring association of dietary specialization and alkaloid sequestration in dendrobatids, which suggests parallel evolutionary trends in the origins of defensive mechanisms.     

Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview

The stomach is in a state of continuous exposure to potentially hazardous agents. Hydrochloric acid together with pepsin constitutes a major and serious threat to the gastric mucosa. Reflux of alkaline duodenal contents containing bile and pancreatic enzymes are additional important injurious factors of endogenous origin. Alcohol, cigarette smoking, drugs and particularly aspirin and aspirin-like drugs, and steroids are among exogenous mucosal irritants that can inflict mucosal injury. The ability of the stomach to defend itself against these noxious agents has been ascribed to a number of factors constituting the gastric mucosal defense. These include mucus and bicarbonate secreted by surface epithelial cells, prostaglandins, sulfhydryl compounds and gastric mucosal blood flow. The latter is considered by several researchers to be of paramount importance in maintaining gastric mucosal integrity. The aim of this paper is to review the experimental and clinical data dealing with the role of mucosal blood flow and in particular the microcirculation in both damage and protection of the gastric mucosa.     

Nickel: a review of its occupational and environmental toxicology

Nickel and nickel compounds belong to the classic noxious agents encountered in industry, but is also known to affect non-occupationally exposed individuals, especially those handling stainless-steel and nickel plated articles of everyday use. For plants and some vertebrates, specifically for mammals, nickel is indispensable as one of the essential trace elements. The most important health problems due to exposure to nickel and nickel compounds are allergic dermatitis (nickel itch) and increased incidence of cancers of the lungs and nasal mucosa encountered among the workers after a long-term over-exposure to nickel. In this respect the most hazardous nickel compounds appear to be nickel sulfide and nickel oxide. The monitoring of nickel exposure levels can be based on blood serum and urine analyses, but also on nickel determinations in hair which have proved promising even in groups of non-occupationally exposed individuals. Nickel carbonyl is the most toxic of all of the nickel compounds encountered, but because of its relatively short half-life it does not seem to represent any actual biohazard from the standpoint of environmental pollution. To prevent incidence of malignancies it is recommended to include in the routine plan of the preventive medical examinations also the cytologic analysis supplemented, in the case of cytologic positivity, with the bioptic examination for epithelial dysplasia. A systematic medical surveillance of workers with known long-term exposure to nickel is, of course, essential. At present, a major attention is centered on biochemical interactions of nickel with copper, cadmium, iron, iodine and particularly with manganese known to significantly reduce the experimental carcinogenicity of nickel and nickel compounds.     

How to study placental vascular development?

Both exogenous and endogenous factors during pregnancy may impact placental vascular development and cause different malformations of placental vessels. In humans, consequences of abnormal vascular development have been associated with different pregnancy-related pathologies ranging from miscarriage to intrauterine growth restriction or preeclampsia. Pregnancy-associated exposure to bacterial or viral infections or pharmacologic or toxic agents may also influence vascular development of the placenta and lead to preterm labor and delivery. Several steps of vascular adaptation on both the fetal and maternal side are necessary and include such events as uterine vasodilation, remodeling by extravillous trophoblast, as well as vasculogenesis and angiogenesis within the placenta. Ubiquitous as well as pregnancy-specific angiogenic factors are involved. Morphologic and stereologic approaches, as well as experiments in established laboratory animals, cannot be applied to large domestic animals or humans without hesitation. Thus, further studies into the different aspects of this process will require an appropriate in vitro model of placental vascular development. Reflecting the core of placental vascular development, the in vitro model should facilitate the interactions between trophoblast and stromal cells with endothelial progenitor cells. The effects of viral or bacterial infection as well as pharmacologic or toxic agents may be studied more closely in the process. This report reviews major aspects of vascular development in the placenta and describes the establishment of a three-dimensional in vitro model of human placental vascular development.     

Factors contributing to biomarker responses in exposed workers.

"...[Th]e proper study of mankind is man" (Pope, circa 1733/1734). Human monitoring fits this notion and monitoring after exposure to genotoxic agents is now an established discipline. It is possible in many situations to identify humans exposed to potentially toxic materials in the workplace and the environment. Responses are often measured in peripheral lymphocytes because these cells can be acquired by a generally socially and ethically acceptable, minimally invasive route. In the early 1960s, chromosome damage in these cells was one of the first endpoints to be used as a biomarker and benzene was one of the first chemicals investigated. Although a causal relationship between chromosome damage and cancer has not been proven, it has been suggested to have some prognostic significance for future cancer onset. With other genetic biomarkers this is as yet not the case, but there are now many biomarkers for different areas of toxicology. Other well-established genetic biomarkers include the detection of hprt mutations, micronuclei and sister chromatid exchanges. However, for interpretation of responses, the issue of confounding factors must be addressed. As in most human studies, there tends to be a high degree of interindividual variability in response to chemical insults. Some non-exposed control individuals exhibit as high a level of damage as some exposed individuals and some of these have levels of damage as low as many of the controls. Thus, it is only the mean values of the groups that can substantiate an exposure related-problem; the data on an individual basis are still of limited use. While human lymphocytes remain the most popular cell type for monitoring purposes, sperm, buccal, nasal, epithelial and placental cells are also used. Confounding factors affect responses in all cell types. There are endogenous confounding factors such as age, sex, genetic make-up and exogenous confounding factors including lifestyle habits such as smoking, drinking, etc. There are biomarkers of exposure, effect and susceptibility and the last may be influenced by the genotype and polymorphism genes existing in a population. From our own studies, confounding effects will be considered in relation to workers exposed to vinyl chloride and petroleum emissions. The relationship between the biomarkers and various factors which influence them is complex. Sometimes the variables are not completely independent of one another.     

Detection of risk of cancer to man.

Epidemiology can pick out large-scale determinants of human cancer, such as smoking. Also, epidemiology can pick out carcinogens such as asbestos to which groups of perhaps a few hundred or a few thousand workers have been heavily exposed for decades. However, if highly exposed groups cannot be studied then epidemiology cannot recognize carcinogens which, although perhaps widely distributed, produce only a small percentage increase in particular cancers. Almost all of the environmental pollutants that can affect human cancer incidence will do so only to a very minor extent, at the levels to which we are currently exposed. For this reason, and also because it is often difficult to define an exposed and an unexposed group which do not differ in other ways as well, it will almost always be impossible to do anything epidemiologically except to set a very crude upper limit on their likely hazards. The only way, therefore, to get any direct estimate of these hazards is by laboratory studies of the effects of high doses on various model systems. For this and for other reasons, it would be highly desirable to have good laboratory models for human carcinogenesis. The characteristics required of satisfactory laboratory systems are reviewed, and it is argued that systematic errors may arise unless one studies epithelial cells from large, long-lived species under conditions of chronic, low-dose exposure to noxious test agents in conjunction with standard chronic doses of agents which may be synergistic with the test agents. (Carcinogenic mutagens may be synergistic with carcinogenic non-mutagens.) For reasons of expense and speed, such studies must be done in vitro. If such in-vitro systems can be developed, either by using tissue explants or cell cultures, an important criterion which they will have to satisfy to be trusted will be that under chronic exposure the rate of transformation should be proportional to something like the fourth power of exposure duration. This paper chiefly reviews the reasons for choosing these specifications for a trustworthy in-vitro model for human carcinogenesis.     

Respiratory findings in art students

Art students are exposed to many noxious agents during their training. We studied respiratory findings in a cohort of the 117 art students in order to investigate the potential effects of these toxic agents in the art student's environment. A group of 88 medical students matched for age, sex and smoking, not exposed to known environmental pollutants were studied as controls for respiratory symptoms. Respiratory symptoms acute and chronic were evaluated by modifying the British Medical Research Council questionnaire. Lung function studies were performed with a spirometer (Jaeger, Germany) measuring maximum expiratory flow-volume (MEFV) curves. Significantly higher prevalences of most of the chronic respiratory symptoms were recorded in art compared to medical students (p < 0.05). Art students who were smokers had significantly higher prevalences of many of the chronic respiratory symptoms than nonsmoking art students. High prevalences of acute symptoms related to the study environment were recorded for art students. Odds ratios in male art students were significant for chronic cough, chronic phlegm and chronic bronchitis for the risk factors of exposure and smoking. Significantly decreased lung function was recorded for FVC, FEF50 and FEF25 in male and FVC, and FEF25 in female art students. Smokers and nonsmokers had similar reductions of lung function. Our data indicate that art students may be at risk of developing chronic respiratory symptoms and lung function changes as a result of their exposure and their smoking habits.     

Inflammation in neurodegenerative disease--a double-edged sword

Inflammation is a defense reaction against diverse insults, designed to remove noxious agents and to inhibit their detrimental effects. It consists of a dazzling array of molecular and cellular mechanisms and an intricate network of controls to keep them in check. In neurodegenerative diseases, inflammation may be triggered by the accumulation of proteins with abnormal conformations or by signals emanating from injured neurons. Given the multiple functions of many inflammatory factors, it has been difficult to pinpoint their roles in specific (patho)physiological situations. Studies of genetically modified mice and of molecular pathways in activated glia are beginning to shed light on this issue. Altered expression of different inflammatory factors can either promote or counteract neurodegenerative processes. Since many inflammatory responses are beneficial, directing and instructing the inflammatory machinery may be a better therapeutic objective than suppressing it.     

Induction of the cytoplasmic 'petite' mutation by chemical and physical agents in Saccharomyces cerevisiae.

A range of physical and chemical agents induce the mitochondrial 'petite' mutation in the yeast Saccharomyces cerevisiae. DNA intercalating agents as well as chemicals which can interfere with DNA synthesis induce this mutation, but only in growing cells. Many chemical or physical agents that produce a DNA lesion which is not simply reversed can induce various levels of the petite mutation, and may be more effective in non-growing cells. A limited number of chemicals act like ethidium bromide, inducing a high frequency of petites which is partially reversible with increasing concentration or time. The ability of a specific compound to be transported into mitochondria or its affinity for AT base pairs in DNA may determine whether it acts primarily as a nuclear or mitochondrial mutagen. In mammalian cells, some neoplastic changes occur at the mitochondrial level. Analogies between yeast and mammalian mitochondria suggest that agents which increase petite mutagenesis in yeast may have some carcinogenic potential. Although some types of petite inducer may have potential as antitumour drugs, those which are very effective antimitochondrial agents appear to be too toxic for therapeutic use. A process comparable to early stages in petite mutagensis occurs in human degenerative diseases and it seems possible that a consequence of exposure to petite mutagens could be an increase in the rate of degenerative diseases or of the aging process.     

Approaches for the development of occupational exposure limits for man-made mineral fibres (MMMFs)

Occupational exposure limits (OELs) are an essential tool in the control of exposure to hazardous chemical agents, and serve to minimise the occurrence of occupational diseases associated with such exposure. The setting of OELs, together with other associated measures, forms an essential part of the European Community's strategy on health and safety at work, upon which the legislative framework for the protection of workers from risks related to chemical agents is based. The European Commission is assisted by the Scientific Committee on Occupational Exposure Limits (SCOEL) in its work of setting OELs for hazardous chemical agents. The procedure for setting OELs requires information on the toxic mechanisms of an agent that should allow to differentiate between thresholded and non-thresholded mechanisms. In the first case, a no-observed adverse effect level (NOAEL) can be defined, which can be the basis for a derivation of an OEL. In the latter case, any exposure is correlated with a certain risk. If adequate scientific data are available, SCOEL estimates the risk associated with a series of exposure levels. This can then be used for guidance, when setting OELs at European level. Man-made mineral fibres (MMMFs) are widely used at different worksites. MMMF products can release airborne respirable fibres during their production, use and removal. According to the classification of the EU system, all MMMF fibres are considered to be irritants and are classified for carcinogenicity. EU legislation foresees the use of limit values as one of the provisions for the protection of workers from the risks related to exposure to carcinogens. In the following paper, the research requirements identified by SCOEL for the development of OELs for MMMFs will be presented.     

Intracellular proteolytic systems may function as secondary antioxidant defenses: An hypothesis

In recent years it has become clear that various free radicals and related oxidants can cause serious damage to intracellular enzymes and other proteins. Several investigators have shown that in extreme cases this can result in an accumulation of oxidatively damaged proteins as useless cellular debris. In other instances, proteins may undergo scission reactions with certain radicals/oxidants, resulting in the direct formation of potentially toxic peptide fragments. Data has also been gathered (recently) demonstrating that various intracellular proteolytic enzymes or systems can recognize, and preferentially degrade, oxidatively damaged proteins (to amino acids). In this hypothesis paper I present evidence to suggest that proteolytic systems (of proteinases, proteases, and peptidases) may function to prevent the formation or accumulation of oxidatively damaged protein aggregates. Proteolytic systems can also preferentially degrade peptide fragments and may thus prevent a wide variety of potentially toxic consequences. I propose that many proteolytic enzymes may be important components of overall antioxidant defenses because they can act to ameliorate the consequences of oxidative damage. A modified terminology is suggested in which the primary antioxidants are such agents as vitamin E, β-carotene, and uric acid and such enzymes as Superoxide dismutase, glutathione peroxidase, and DT-diaphorase. In this classification scheme, proteolytic systems, DNA repair systems, and certain lipolytic enzymes would be considered as secondary antioxidant defenses. As secondary antioxidant defenses, proteolytic systems may be particularly important in times of high oxidative stress, during periods of (primary) antioxidant insufficiency, or with advancing age.     

Endocrine Disruption and Developmental Abnormalities of Female Reproduction

The developing organism is particularly sensitive to exposureto estrogenic chemicals during a critical period in the inductionof longterm changes in female reproductive organs, and persistentmolecular alterations induced by the perinatal estrogenic agents.The perinatal mouse model can be utilized as an indicator ofpossible longterm consequences of exposure to exogenous estrogeniccompounds including environmental endocrine disruptors. Attentionshould be paid to abnormalities in female genital organs exposedto estrogenic endocrine disruptors during fetal and early postnataldevelopment in mammals including humans.     

A baseline study using Plantwise information to assess the contribution of extension services to the uptake of augmentative biological control in selected low- to lower- middle- income countries

The uptake of augmentative biological control agents (BCAs) is still limited, particularly in many low- to lower- middle- income countries. This study focuses on factors that affect the uptake of BCAs for arthropod pests by national extension partners (NEPs) in Plantwise—an agricultural development programme facilitating the establishment of plant clinics where farmers can obtain diagnosis and plant health advice. Using data generated by NEPs, BCA recommendations in extension material and given by extension workers in Ghana, Kenya, Zambia, India, Nepal and Pakistan were analysed. The rate of BCA recommendation ranged from 13.0 (Zambia) to 61.1% (India) in extension materials and from 0.0 (Zambia) to 18.2% (India) in recommendations given by extension workers. Knowledge, availability and price were identified as the main factors affecting the uptake of BCAs by NEPs. This baseline study gives novel insight into the potential of NEPs to facilitate the use of BCAs.     

Lipopolyamine-Mediated Transfection Allows Gene Expression Studies in Primary Neuronal Cells

A simple and efficient transfection technique based on lipopolyamine-coated DNA that can be used for gene transfer in cerebellar granular neurons is described. Gene transfer is achieved by exposure of cells to a DNA/lipid complex obtained by simple mixing of lipopolyamine and plasmid DNA. This procedure may represent a general tool of physiological investigations in primary cells. We show that the promoters of the introduced chimera genes are regulated by their respective trans-acting factors and may be modulated via membrane receptors and second messengers. This procedure has no noticeable toxic effects, nor does it seem to interfere with complex physiological behavior like neuronal differentiation.     

Effect of cigarette smoke extract on the polymorphonuclear leukocytes chemiluminescence: influence of a filter containing glutathione.

Cigarette smoking is known to be a risk factor for several chronic and neoplastic diseases. Many compounds formed by cigarette burning, ranging from particulate materials to water solutes and gaseous extracts, are considered to be noxious agents, and many biochemical and molecular mechanisms have been proposed for the toxic effects of cigarette smoke. The oral cavity and the upper respiratory tract represent the first contact areas for smoke compounds; even a single cigarette can produce marked effects on some components of the oral cavity, either chemical compounds, such as glutathione and enzymes, or cellular elements, such as polymorphonuclear leukocytes. Several studies suggest a protective role of glutathione against the noxious effects of tobacco smoke; the sulphydril groups of glutathione, in fact, could react with some smoke products, such as unsaturated aldehydes, leading to the formation of harmless intermediate compounds and simultaneously preventing the inactivation of metabolically essential molecules, such as some enzymes. In this paper we analyse the effect of a filter containing glutathione on the respiratory burst of polymorphonuclear leukocytes exposed to aqueous extract of cigarette smoke, measuring their chemiluminescence activity. The results of this paper indicate that the GSH-containing filter has a likely protective effect against the inhibition of cigarette smoke extract on polymorphonuclear leukocyte activity.     

A yeast-based model of alpha-synucleinopathy identifies compounds with therapeutic potential

We have developed a yeast-based model recapitulating neurotoxicity of alpha-synuclein fibrilization. This model recognized metal ions, known risk factors of alpha-synucleinopathy, as stimulators of alpha-synuclein aggregation and cytotoxicity. Elimination of Yca1 caspase activity augmented both cytotoxicity and inclusion body formation, suggesting the involvement of apoptotic pathway components in toxic alpha-synuclein amyloidogenesis. Deletion of hydrophobic amino acids at positions 66-74 in alpha-synuclein reduced its cytotoxicity but, remarkably, did not lower the levels of insoluble alpha-synuclein, indicating that noxious alpha-synuclein species are different from insoluble aggregates. A compound screen aimed at finding molecules with therapeutic potential identified flavonoids with strong activity to restrain alpha-synuclein toxicity. Subsequent structure-activity analysis elucidated that these acted by virtue of anti-oxidant and metal-chelating activities. In conclusion, this yeast-cell model as presented allows not only fundamental studies related to mechanisms of alpha-synuclein-instigated cellular degeneration, but is also a valid high-throughput identification tool for novel neuroprotective agents.     

A yeast-based model of α-synucleinopathy identifies compounds with therapeutic potential

We have developed a yeast-based model recapitulating neurotoxicity of α-synuclein fibrilization. This model recognized metal ions, known risk factors of α-synucleinopathy, as stimulators of α-synuclein aggregation and cytotoxicity. Elimination of Yca1 caspase activity augmented both cytotoxicity and inclusion body formation, suggesting the involvement of apoptotic pathway components in toxic α-synuclein amyloidogenesis. Deletion of hydrophobic amino acids at positions 66–74 in α-synuclein reduced its cytotoxicity but, remarkably, did not lower the levels of insoluble α-synuclein, indicating that noxious α-synuclein species are different from insoluble aggregates. A compound screen aimed at finding molecules with therapeutic potential identified flavonoids with strong activity to restrain α-synuclein toxicity. Subsequent structure–activity analysis elucidated that these acted by virtue of anti-oxidant and metal-chelating activities. In conclusion, this yeast-cell model as presented allows not only fundamental studies related to mechanisms of α-synuclein-instigated cellular degeneration, but is also a valid high-throughput identification tool for novel neuroprotective agents.     

Marine-terrestrial contrasts in the ecology of plant chemical defenses against herbivores

Small marine herbivores that live on the plants they consume often selectively eat seaweeds that are chemically defended from fishes. Their feeding is unaffected or stimulated by the plant metabolites that deter fishes, and these small herbivores dramatically reduce their susceptibility to predation by associating with host plants that are noxious to fishes. Ecological similarities between these small marine herbivores and numerous terrestrial insects suggest that herbivorous insects also may have evolved a preference for toxic plants because this diminishes their losses to predators, parasites and pathogens. Although marine and terrestrial plants and herbivores evolved in strikingly different environments, the ease of experimentation in some marine systems makes them ideal for addressing certain questions of fundamental importance to both terrestrial and marine workers.     

Review of Oral Cholecystographic Agents for the Management of Hyperthyroidism

ObjectiveAlthough the use of oral cholecystographic agents (OCAs) had declined due to limited availability, there is literature to suggest it is an effective medication for thyrotoxicosis in appropriate clinical situations.MethodsThe authors performed a PubMed search and systematically reviewed all the English written case reports, original studies and reviews from 1953 to 2012. Additional information was supplemented from available online pharmacologic databases.ResultsThe off-label use of OCAs was reviewed for the management of neonatal and adult Graves’ disease, subacute thyroiditis, amiodarone-induced thyroiditis (AIT), exogenous hyperthyroidism, toxic multinodular goiter (TMNG), thyrotropinoma, thyrotoxicosis during pregnancy, rapid pre-operative control of hyperthyroidism, and thyroid storm. Adverse effects were also reviewed.ConclusionOCAs generally are effective agents in treating thyrotoxicosis in the etiologies reviewed. OCAs are clinically relevant in patients who require rapid control, such as in the pre-operative state or patient who cannot tolerate a thyrotoxicosis state. OCA may also be beneficial in situations where other anti-thyroidal medication would be hazardous or ineffective, such as thionamide allergy or exogenous thyrotoxicosis. Given concern for long-term relapse, OCAs should be considered a short-term bridge to definitive therapy. OCAs are limited in TMNG and should be second line after glucocorticoids in AIT II. OCAs do not preclude the use of radioactive iodine, which can be performed one week after OCA therapy. (Endocr Pract. 2014;20:1084-1092)     

The effect of reducing and other agents on the motility of Treponema pallidum in an acellular culture medium.

The maintenance of Treponema pallidum motility was investigated in an acellular medium based on T. pallidum immobilization test medium. The acellular medium contained cysteine, glutathione, thioglycollate and dithiothreitol as reducing agents and had a redox potential of -275 +/- 25 mV at pH 7.3. In an atomosphere containing 3% O2, motile treponemes survived four times longer when calf serum and bovine serum albumin were added to the medium. The selective omission of glutathione and, particularly, thioglycollate prolonged the survival of motile treponemes almost fivefold. In addition, stored medium, in which thioglycollate had become inactive, sustained motile treponemes for longer than did freshly prepared medium. Thus, thioglycollate is toxic for the organisms. It may be omitted from the medium because low redox potentials can be achieved without it.