[Show abstract][Hide abstract] ABSTRACT: Cyanobacterial blooms in aquatic environments are frequently characterized by elevated levels of microcystins, a potent hepatotoxin. Here we exposed the nematode Caenorhabditis elegans with environmentally realistic concentrations of MC-LR to explore its non-hepatic toxicity. Lifespan, reproduction and growth assays confirmed the toxic potential of 100 μg/L MC-LR even in this liver-lacking invertebrate. Whole-genome microarray analysis revealed that a neuromodulating action was the dominant response in nematodes challenged with 100 μg/L MC-LR. Indeed, most of the 201 differentially expressed genes were associated with neurobehavior, neurogenesis, and signaling associated pathways. In addition, a whole-genome miRNA-microarray highlighted that, in particular, members of the let-7 family were differentially regulated. These miRNAs are involved in the developmental timing of cell fates, including neurons, and are probably also part of the stress response system. To conclude, neurological modulation is the main transcriptional stress response in C. elegans exposed to MC-LR.
[Show abstract][Hide abstract] ABSTRACT: Organobromines of natural and artificial origin are omnipresent in aquatic and terrestrial environments. Although it is well established that exposure to high concentrations of organobromines are harmful to vertebrates, few studies have investigated the effect of environmentally realistic concentrations on invertebrates. Here, the nematode Caenorhabditis elegans was challenged with two organobromines, namely dibromoacetic acid (DBAA) and tetrabromobisphenol-A (TBBP), and monitored for changes in different life trait variables and global gene expression patterns. Fifty micromolar DBAA stimulated the growth and lifespan of the nematodes; however, the onset of reproduction was delayed. In contrast, TBBP changed the lifespan in a hormetic fashion, namely it was stimulated at 0.1 μM but impaired at 50 μM. The reproductive performance was even impaired at 2 μM TBBP. Moreover, DBAA could not reduce the toxic effect of TBBP when applied as a mixture. A whole-genome DNA microarray revealed that both organobromines curtailed signalling and neurological processes. Furthermore on the transcription level, 50 μM TBBP induced proteolysis and DBAA up-regulated biosynthesis and metabolism. To conclude, even naturally occurring concentrations of organobromines can influence the biomolecular responses and life cycle traits in C. elegans. The life extension is accompanied by negative changes in the reproductive behaviour, which is crucial for the stability of populations. Thus, this paper highlights that the effects of exposure to moderate, environmentally realistic concentrations of organobromines should not be ignored.
Environmental Science and Pollution Research 05/2014; 21(17). · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stem cell research is a major focus of regenerative medicine, which amalgamates diverse disciplines ranging from developmental cell biology to chemical and genetic therapy. Although embryonic stem cells have provided the foundation of stem cell therapy, they offer an in vitro study system that might not provide the best insight into mechanisms and behaviour of cells within living organisms. Caenorhabditis elegans is a well defined model organism with highly conserved cell development and signalling processes that specify cell fate. Its genetic amenability coupled with its chemical screening applicability make the nematode well suited as an in vivo system in which regenerative therapy and stem cell processes can be explored. Here, we describe some of the major advances in stem cell research from the worm's perspective.
Drug discovery today 02/2014; · 6.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exogenous hydrogen sulfide (H2S) administration and endogenous H2S metabolism were explored in the nematode C. elegans. Chronic treatment with a slow-releasing H2S donor, GYY4137, extended median survival by 17-23% and increased tolerance towards oxidative and endoplasmic reticulum (ER) stress. Also, cysl-2, a sulfhydrylase/cysteine synthase in C. elegans, was transcriptionally upregulated by GYY4137 treatment and the deletion of cysl-2 resulted in a significant reduction in lifespan which was partially recovered by the supplementation of GYY4137. Likewise, a mammalian cell culture system, GYY4137 was able to protect bovine aortic endothelial cells (BAECs) from oxidative stress and (H2O2)-induced cell death. Taken together, this provides further support that H2S exerts a protective function which is consistent with the longevity dividend theory. Overall, this study underlines the therapeutic potential of a slow-releasing H2S donor as regulators of the aging and cellular stress pathways.
PLoS ONE 11/2013; 8(11):e80135. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although the extraction of an impacted third molar (3M) is a routine procedure, postoperative morbidities typically include swelling, pain, and trismus. The aim of the present study was to investigate whether the application of kinesiologic tape can improve the postoperative morbidities associated with 3M surgery, thereby improving the postoperative well-being of patients.
Forty patients assigned for prospective 3M removal were randomized into two treatment groups (with/without kinesiologic tape). Facial swelling was quantified using a five-line measurement at six specific time points. Pain scores were assessed using a visual analog scale, and mouth opening range was assessed by means of standard calipers. In addition, all patients were asked to evaluate overall satisfaction and swelling (both groups) and the effect of the tape on movement and comfort (taped group only).
The postoperational application of kinesiologic tape reduced significantly all investigated parameters: swelling, pain, and trismus. Furthermore, patients with kinesiologic tape reported a significantly lower morbidity rate.
The application of kinesiologic tape following a 3M surgery is a simple and economical, yet medically relevant approach.
Kinesiologic tape offers patients a less traumatic postoperational experience and therefore holds promise to enhance the quality of life of a large cohort of the population.
[Show abstract][Hide abstract] ABSTRACT: Hormetic lifespan extension is, for obvious reasons, beneficial to an individual. But is this effect really cost-neutral? To answer this question, four tannic polyphenols were tested on the nematode Caenorhabditis elegans. All were able to extend the lifespan, but only some in a hormetic fashion. Additional life trait variables including stress resistance, reproductive behavior, growth, and physical fitness were observed during the exposure to the most life extending concentrations. These traits represent the quality of life and the population fitness, being the most important parameters of a hormetic treatment besides lifespan. Indeed, it emerged that each life-extension is accompanied by a constraining effect in at least one other endpoint, for example growth, mobility, stress resistance, or reproduction. Thus, in this context, longevity could not be considered to be attained for free and therefore it is likely that other hormetic benefits may also incur cost-intensive and unpredictable side-effects.
[Show abstract][Hide abstract] ABSTRACT: Obesity is an ever increasing health concern of global importance. The treatment options for this condition are limited and until recently there was only one FDA approved anti-obesity drug available. The approval of two anti-obesity drugs which have both undergone post-marketing withdrawal undermines consumer confidence and highlights the need for more robust pre-clinical toxicity testing. The nematode Caenorhabditis elegans is an established toxicological model and while it is still in its infancy with regards to the study of obesity, the ease of maintenance and high-throughput assays makes C. elegans an appealing choice. Here, we explore the suitability of C. elegans as an in vivo toxicity model for the mechanistic screening of two anti-obesity drugs. Toxicity profiles identified that a Sibutramine containing drug induced pronounced effects on pharyngeal pumping, defecation, locomotion and reproduction, in concert indicative of a possible neuronal mode of action. Resultant from a drug resistance screen we demonstrate that Sibutramine has non-serotonergic targets, a notion that suggests that serotonin-specific reuptake inhibitors (SSRIs) are less specific than first assumed. These results stress that the interplay between serotonin, dopamine and norepinephrine is not easily dissected. Overall, the data highlight the value of C. elegans as an in vivo toxicity tool in anti-obesity drug research.
[Show abstract][Hide abstract] ABSTRACT: Evidence is emerging that earthworms can evolve tolerance to trace element enriched soils. However, few studies have sought to establish whether such tolerance is determined through adaption or plasticity. Here we report results from a combined analysis of mitochondrial (cytochrome oxidase II, COII), nuclear (amplified fragment length polymorphism, AFLP) variation and DNA methylation in populations of the earthworm Lumbricus rubellus from sites across an abandoned arsenic and copper mine. Earthworms from the mine site population demonstrated clear arsenic tolerance in comparison to a naïve strain. COII and AFLP results suggest that L. rubellus from the unexposed and the adapted populations comprises two cryptic lineages (Linages A and B) each of which was present across all of the sites. AFLP analysis by lineage highlighted variations associated with soil metal/metalloid concentrations (most clearly for Lineage A) suggesting a genetic component to the observed tolerance. The methylation sensitive AFLP (Me-AFLP) identified a high genome methylation content (average 13.5%) in both lineages. For Lineage A, Me-AFLP analysis did not identify a strong association with soil arsenic levels. For Lineage B, however, a clear association of methylation patterns with soil arsenic concentrations was found. This suggests that Lineage B earthworms utilise epigenetic mechanisms to adapt to the presence of contamination. These fundamentally different genetic adjustments in the two clades indicate that the two lineages employ distinct adaptive strategies (genetic or epigenetic) in response to arsenic exposure. Mechanisms driving this variation may be founded within the colonisation histories of the lineages.
Soil Biology and Biochemistry 02/2013; 57:524-532. · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The animal model Caenorhabditis elegans was employed to study polyphenol- and humic substances-induced hormetic changes in lifespan. A detailed insight into the underlying mechanism of hormesis was uncovered by applying whole genome DNA microarray experimentation over a range of quercetin (Q), tannic acid (TA), and humic substances (HuminFeed(®), HF) concentrations. The transcriptional response to all exposures followed a non-linear mode which highlighted differential signaling and metabolic pathways. While low Q concentrations regulated processes improving the health of the nematodes, higher concentrations extended lifespan and modulated substantially the global transcriptional response. Over-represented transcripts were notably part of the biotransformation process: enhanced catabolism of toxic intermediates possibly contributes to the lifespan extension. The regulation of transcription, Dauer entry, and nucleosome suggests the presence of distinct exposure dependent differences in transcription and signaling pathways. TA- and HF-mediated transcript expression patterns were overall similar to each other, but changed across the concentration range indicating that their transcriptional dynamics are complex and cannot be attributed to a simple adaptive response. In contrast, Q-mediated hormesis was well aligned to fit the definition of an adaptive response. Simple molecules are more likely to induce an adaptive response than more complex molecules.
[Show abstract][Hide abstract] ABSTRACT: The synthesis of designer solid-state materials by living organisms is an emerging field in bio-nanotechnology. Key examples include the use of engineered viruses as templates for cobalt oxide (Co(3)O(4)) particles, superparamagnetic cobalt-platinum alloy nanowires and gold-cobalt oxide nanowires for photovoltaic and battery-related applications. Here, we show that the earthworm's metal detoxification pathway can be exploited to produce luminescent, water-soluble semiconductor cadmium telluride (CdTe) quantum dots that emit in the green region of the visible spectrum when excited in the ultraviolet region. Standard wild-type Lumbricus rubellus earthworms were exposed to soil spiked with CdCl(2) and Na(2)TeO(3) salts for 11 days. Luminescent quantum dots were isolated from chloragogenous tissues surrounding the gut of the worm, and were successfully used in live-cell imaging. The addition of polyethylene glycol on the surface of the quantum dots allowed for non-targeted, fluid-phase uptake by macrophage cells.
[Show abstract][Hide abstract] ABSTRACT: Bisphosphonate related osteonecrosis of the jaw (BRONJ) is rare but potentially severe, and the etiopathology and risk factors are poorly defined. To date, it has not been possible to induce BRONJ in a large animal model, a shortfall this study aims to redress. Ten two-year-old adult Göttingen minipigs were split into two groups. Five pigs (group 1) were administered intravenously a weekly dose of a bisphosphonate (zoledonate 0.05mg/kg body weight, approximating the oncologic dose in humans) and five pigs (group 2) served as controls. After 6 weeks, tooth extractions were performed in the upper and lower jaw (both groups) and the bisphosphonate administration continued for a further 10 weeks (group 1 only). Clinical and blood parameters were monitored throughout the entire experiment; thereafter, the jaw-bones were subjected to macroscopic, radiological (CT) and histological investigations. Whilst the extraction sites in the control group healed within two weeks, all animals in the bisphosphonate group exhibited exposed bone and impaired wound healing, indicators that are synonymous of macroscopically advanced osteonecrosis. Radiological and in particular histological investigations confirmed the presence of BRONJ in the animals from group 1. This paper demonstrates that the administration of bisphosphonates, in combination with tooth extractions, induces BRONJ in a minipig model. The ability to study BRONJ in miniature pigs, animals with a bone structure not dissimilar to humans, may improve our knowledgebase regarding the etiopathology, the prophylaxis and potentially uncover new therapies of BRONJ.
[Show abstract][Hide abstract] ABSTRACT: Recent research has highlighted that the polyphenols Quercetin and Tannic acid are capable of extending the lifespan of Caenorhabditis elegans. To gain a deep understanding of the underlying molecular genetics, we analyzed the global transcriptional patterns of nematodes exposed to three concentrations of Quercetin or Tannic acid, respectively. By means of an intricate meta-analysis it was possible to compare the transcriptomes of polyphenol exposure to recently published datasets derived from (i) longevity mutants or (ii) infection. This detailed comparative in silico analysis facilitated the identification of compound specific and overlapping transcriptional profiles and allowed the prediction of putative mechanistic models of Quercetin and Tannic acid mediated longevity. Lifespan extension due to Quercetin was predominantly driven by the metabolome, TGF-beta signaling, Insulin-like signaling, and the p38 MAPK pathway and Tannic acid's impact involved, in part, the amino acid metabolism and was modulated by the TGF-beta and the p38 MAPK pathways. DAF-12, which integrates TGF-beta and Insulin-like downstream signaling, and genetic players of the p38 MAPK pathway therefore seem to be crucial regulators for both polyphenols. Taken together, this study underlines how meta-analyses can provide an insight of molecular events that go beyond the traditional categorization into gene ontology-terms and Kyoto encyclopedia of genes and genomes-pathways. It also supports the call to expand the generation of comparative and integrative databases, an effort that is currently still in its infancy.
Frontiers in Genetics 04/2012; 3:48.
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[Show abstract][Hide abstract] ABSTRACT: Low concentrations of the dissolved leonardite humic acid HuminFeed(®) (HF) prolonged the lifespan and enhanced the thermal stress resistance of the model organism Caenorhabditis elegans. However, growth was impaired and reproduction delayed, effects which have also been identified in response to other polyphenolic monomers, including Tannic acid, Rosmarinic acid, and Caffeic acid. Moreover, a chemical modification of HF, which increases its phenolic/quinonoid moieties, magnified the biological impact on C. elegans. To gain a deep insight into the molecular basis of these effects, we performed global transcriptomics on young adult (3 days) and old adult (11 days) nematodes exposed to two different concentrations of HF. We also studied several C. elegans mutant strains in respect to HF derived longevity and compared all results with data obtained for the chemically modified HF. The gene expression pattern of young HF-treated nematodes displayed a significant overlap to other conditions known to provoke longevity, including various plant polyphenol monomers. Besides the regulation of parts of the metabolism, transforming growth factor-beta signaling, and Insulin-like signaling, lysosomal activities seem to contribute most to HF's and modified HF's lifespan prolonging action. These results support the notion that the phenolic/quinonoid moieties of humic substances are major building blocks that drive the physiological effects observed in C. elegans.
[Show abstract][Hide abstract] ABSTRACT: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side-effect of bisphosphonate therapy. In the majority of cases BRONJ occurs in the mandible. As a consequence a detailed investigation of BRONJ of the maxilla and in particular of involvement of the maxillary sinus has largely so far been neglected. The aim of this study was to analyse the frequency of maxillary sinusitis and oro-antral fistulae in BRONJ of the maxilla.
A retrospective multicentre analysis was carried out in three Departments of Oral and Maxillofacial Surgery focussing on patients suffering from BRONJ in the maxilla. The role of involvement of the maxillary sinus, in particular sinusitis and oro-antral fistula, was analysed.
Out of a total of 170 patients suffering from BRONJ 53 cases (31.2%) with involvement of the maxilla were identified. At least one sign of maxillary sinusitis was present in 43.6% (23/53) and an oro-antral fistula in the course of the disease was detected in 35.8% (19/53) of those patients. The mean length of time of bisphosphonate intake was 36.16±16.32 months. Zoledronate was most frequently associated (60.4%) with symptoms, followed by the combination of Zoledronate/Ibandronate (13.2%), and Zoledronate/Pamidronate or Pamidronate alone (both 7.5%).
Maxillary sinusitis and oro-antral fistulae are associated with a BRONJ manifestation in the upper jaw in approximately 44%. The involvement of the maxillary sinus should be given special attention and three-dimensional imaging modalities might be necessary, not only to evaluate the extent of necrosis, but also to exclude involvement of the maxillary sinus.
Journal of cranio-maxillo-facial surgery: official publication of the European Association for Cranio-Maxillo-Facial Surgery 11/2011; 40(7):568-71. · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metallobiologists have, at large, neglected soil dwelling invertebrates; exceptions are the nematode (Caenorhabditis elegans) and snails (Helix pomatia and Cantareus aspersus). This review aims to compare and contrast the molecular, protein and cellular mechanisms of the multifunctional nematode and snail metallothioneins (MTs). The C. elegans genome contains two MT genes, mtl-1, which is constitutively expressed in the pharynx and likely to act as an essential and/or toxic metal sensor, and mtl-2, which plays a negligible role under normal physiological conditions but is strongly induced (as mtl-1) in intestinal cells upon metal exposure. It has been possible to follow the intricate phenotypic responses upon the knockdown/knockout of single and multiple MT isoforms and we have started to decipher the multifunctional role of C. elegans MTs. The snails have contributed to our understanding regarding MT evolution and diversity, structure and metal-specific functionality. The H. pomatia and C. aspersus genomes contain at least three MT isoform genes. CdMT is responsible for cadmium detoxification, CuMT is involved in copper homeostasis and Cd/CuMT is a putative ancestral MT possibly only of minor importance in metal metabolism. Further investigations of nematode, snail and other invertebrate MTs will allow the development of alternative biomarker approaches and lead to an improved understanding of metallobiology, protein evolution and toxicogenomics.
European Journal of Biochemistry 08/2011; 16(7):1057-65. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The model organism Caenorhabditis elegans was utilized to determine, in vivo, the mode(s) of action of four plant polyphenols, namely, tannic acid (TA), gallic acid (GA), ellagic acid (EA), and catechin (CT). The determination of lifespan, stress resistance, growth, reproduction, eating-related behaviors, antioxidative capacities, and lifespan assays with the mev-1 and the eat-2 mutants as well as in the presence of dead bacteria provided new insights into their action. All four compounds prolonged lifespan, but only TA and CT mediated distinct stress protection. Longevity is unlikely the result of antioxidant capacities but rather due to calorie restriction imitating and hormetic properties in the case of TA and EA or antimicrobial capacities of GA and EA. Furthermore, the prominent "disposable soma theory" is only partly reflected by these polyphenols. In summary, this study underlines the diversity of polyphenolic phytochemicals and their mechanistic background.
Journal of Natural Products 08/2011; 74(8):1713-20. · 3.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteonecrosis of the jaw (ONJ) is a serious side-effect of intravenous nitrogen-containing bisphosphonate therapy frequently used in the treatment of malignant diseases. Despite numerous case series published so far studies with detailed investigations into risk factors, the precise localization of ONJ and impact of ONJ on the oncological treatment remain sparse.
This single-centre study collated medical records (2003-2009) of all patients that suffered from ONJ within the Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians-University of Munich, Germany. In total, 126 patients fulfilled the case criteria of ONJ and were examined clinically. The complete medical history including detailed questionnaires was collected of 66 patients, focussing in particular on the identification of underlying risk factors, clinical features, ONJ localization as well as the impact on the oncological treatment.
The majority of ONJ cases occurred in patients suffering from malignant diseases (n=117; 92.8%), in particular breast cancer (n=57; 45.2%), multiple myeloma (n=37; 29.4%) and prostate cancer (n=13; 10.3%), all received nitrogen-containing bisphosphonates intravenously. ONJ was also diagnosed in 9 patients (7.1%) suffering from osteoporosis or rheumatoid arthritis. The most prevalent clinical feature was exposed necrotic bone (93.9%) in the oral cavity which was accompanied in 78.8% of cases by pain. A predilection for the mandible and in particular for molar and premolar regions in both jaws was shown. Although no recommendation concerning the oncologic treatment was made, the manifestation of ONJ resulted (in a significant proportion of the patients) in a change of medication and schedule. The most frequent co-medications were steroids and anti-angiogenetic drugs, such as thalidomide.
The predilection for mandibular molar and premolar regions, and the infectious conditions that often precede the onset of ONJ support recent pathogenesis theories stating that local inflammation and associated pH-changes may trigger the release and activation of nitrogen-containing bisphosphonates ultimately resulting in necrosis.
The development of ONJ has a multi-factorial aetiology and the clinical presentation can vary markedly. ONJ cannot only impair the quality of life but also the treatment of the underlying disease.
Journal of cranio-maxillo-facial surgery: official publication of the European Association for Cranio-Maxillo-Facial Surgery 06/2011; 40(4):303-9. · 1.25 Impact Factor