Intro - K.P.A. - Asitopf (CD)

Open in a separate window. Discussion This pilot study demonstrated that acupuncture is feasible as an adjunct treatment for chronic CD, and that this modality might be associated with subjective symptomatic benefits. Conclusions Acupuncture as an adjunctive therapy for CD might be a safe and effective alternative therapy, while decreasing subjective experiences of pain and discomfort. Author Disclosure Statement D. References 1. Effectiveness of acupuncture in cervical dystonia.

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Discovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation. The densely O-glycosylated MUC2 mucin protects the intestine and provides food for the commensal bacteria. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. An ex vivo method for studying mucus formation, properties, and thickness in human colonic biopsies and mouse small and large intestinal explants.

Normalization of host intestinal mucus layers requires long-Term microbial colonization. Colonic mucosa-associated microbiota is influenced by an interaction of crohn disease and FUT2 Secretor genotype.

Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.

The mucin MUC2 limits pathogen burdens and epithelial barrier dysfunction during salmonella enterica serovar typhimurium colitis. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cross-talk between akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.

A purified membrane protein from akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Akkermansia muciniphila improves metabolic profiles by reducing inflammation in chow diet-fed mice. Polysaccharide degradation by the intestinal microbiota and its influence on human health and disease. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. A discrete genetic locus confers xyloglucan metabolism in select human gut bacteroidetes.

Glycan complexity dictates microbial resource allocation in the large intestine. Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism. Molecular dissection of xyloglucan recognition in a prominent human Gut symbiont.

The Sus operon: a model system for starch uptake by the human gut bacteroidetes. Structural basis for nutrient acquisition by dominant members of the human gut microbiota. Unique organization of extracellular amylases into amylosomes in the resistant starch-utilizing human colonic firmicutes bacterium Ruminococcus bromii.

Intraspecific competition drives increased resource use diversity within a natural population. Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon. Understanding the effects of diet on bacterial metabolism in the large intestine. Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product.

Utilisation of mucin glycans by the human Gut symbiont ruminococcus gnavus Is strain-Dependent. The mucin-degradation strategy of ruminococcus gnavus: The importance of intramolecular trans-sialidases. Altered o-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. Microbial pathways in colonic sulfur metabolism and links with health and disease.

Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Culturing of 'unculturable' human microbiota reveals novel taxa and extensive sporulation. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria.

Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Secreted enteric antimicrobial activity localises to the mucus surface layer. Secretory IgA is concentrated in the outer layer of colonic mucus along with gut bacteria. Human secretory immunoglobulin A May contribute to biofilm formation in the gut.

Decreased expression of mannose-specific adhesins by Escherichia coli in the colonic microflora of immunoglobulin A-deficient individuals. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans.

Altered fecal microbiota composition in patients with major depressive disorder. Human gut microbiota community structures in urban and rural populations in russia.

Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens.

Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Akkermansia muciniphila gen. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. The warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms?

The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro. Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods.

Fine-tuning of the mucosal barrier and metabolic systems using the diet-microbial metabolite axis. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota.

Enteric commensal bacteria potentiate epithelial restitution via reactive oxygen species-mediated inactivation of focal adhesion kinase phosphatases. Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of epithelial cell layer. Lactobacillus plantarum ameliorates colonic epithelial barrier dysfunction by modulating the apical junctional complex and PepT1 in IL knockout mice. Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Bacteroides thetaiotaomicron and faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent.

Ruminococcus gnavus E1 modulates mucin expression and intestinal glycosylation. Glycan-modifying bacteria-derived soluble factors from bacteroides thetaiotaomicron and lactobacillus casei inhibit rotavirus infection in human intestinal cells. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Molecular players involved in the interaction between beneficial bacteria and the immune system. Growth and host interaction of mouse segmented filamentous bacteria in vitro.

Intestinal microbiota is a plastic factor responding to environmental changes. Characterization of the gut microbiota in leptin deficient obese mice - correlation to inflammatory and diabetic parameters. Early life treatment with vancomycin propagates akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Low relative abundances of the mucolytic bacterium akkermansia muciniphila and bifidobacterium spp. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics.

Identification of an anti-inflammatory protein from faecalibacterium prausnitzii, a commensal bacterium deficient in crohn's disease.

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Uyar, J. Hacaloglu, and F. Given the importance of the caspases in mammals, a search for orthologues in plants and other non-metazoan organisms was undertaken by using the primary sequences of caspases, in and around the active site, in a PSI-BLAST Position-Specific Iterative Basic Local Alignment Search Tool search [ 39 ]. In addition, the metacaspases were identified in protozoa, fungi and plants [ 39 ], whereas the paracaspases were found distributed throughout the animal kingdom, from which the metacaspases were notably absent [ 42 ] see Table 1.

Early studies on the metacaspases attempted to draw parallels between possible metacaspase function and the fundamental and well-established processes carried out by the caspases [ 43 — 46 ]. Indeed, the yeast metacaspase Yca1 from Saccharomyces cerevisiae has been implicated in cell death processes [ 43 ], suggesting a degree of functional homology with the caspases. This resulted in similar investigations being carried out on metacaspases from other organisms, and revealed a role for several fungi and plant metacaspases in cell death reviewed in Tsiatsiani et al.

However, a link with cell death mechanisms could not be identified for all metacaspases and a number of other functions have since been established in various cellular processes including cell-cycle progression [ 48 ], cell proliferation [ 49 ], endoplasmic reticulum ER stress [ 50 ], clearance of insoluble aggregates [ 51 ] and virulence [ 52 ].

In addition, multi-functional metacaspases have also been identified, particularly in organisms that have a single metacaspase gene, e. Metacaspases also differ significantly from the caspases in that they are active monomers [ 11 ], for which activation profiling has revealed a widespread, but not universal [ 62 ], requirement for calcium [ 45 , 60 , 63 , 64 ]. The S 1 -binding pockets are highlighted as in Figure 2 and the topologies are based on the PDB codes described in the same Figure.

For direct comparison of structures from different clan CD families throughout the present review, caspase nomenclature is highlighted for the SSEs and loops of all clan CD structures, when they are structurally conserved and similar to those found in the caspases, e. In TbMCA2, L6 is 8 residues long and well ordered , whereas in Yca1 it is 59 residues long and disordered, making L6 a potentially interesting variation between the two enzymes.

In addition, compared with TbMCA2, Yca1 has an extended, non-conserved, N-terminal region as opposed to 70 residues, respectively. The first 68 residues of Yca1 consist of QXXQ repeats involved in targeting Yca1 to insoluble aggregates in yeast [ 51 ] and, although the first 89 residues are absent in the structure, a further 48 N-terminal residues are found to be ordered.

Paracaspases are the second group of enzymes classified in the caspase subfamily C14B and, similar to the metacaspases, these enzymes recognize basic substrates, cleaving after arginine residues see Table 2. To date, the only available paracaspase structures come from the human and murine mucosa-associated lymphoid tissue translocation protein 1 MALT1 [ 10 , 67 ]. MALT1 is a large multi-domain protein, which exhibits functionally important, arginine-specific, proteolytic activity as a result of its paracaspase domain.

The full-length protein comprises an N-terminal death domain DD , followed by two immunoglobin Ig -like domains Ig1 and Ig2 , the paracaspase domain, a further Ig-like domain Ig3 and approximately C-terminal residues with no apparent secondary structure [ 10 ].

Apart from the ordering of L4, the most striking difference in the apo- and inhibitor-bound forms of MALT1 is found within L5, which undergoes a significant structural rearrangement, repositioning an important glutamine residue.

In the ligand-free structure, this residue Gln points directly into the S 1 -binding pocket, blocking access to the active site. However, in the inhibitor-bound form L5 points away from the main body of the enzyme, towards the solvent, and forms an elbow with Gln sitting at the tip [ 69 ].

The conformation of Ig3 also changes on inhibitor binding, leading to the suggestion that MALT1 activation is a two-step process relying on both dimerization and, on substrate binding, release from Ig3-mediated autoinhibition [ 69 ].

Despite this, the structure of MALT1-P has much more similarity with the caspases than the metacaspases. In addition, the metacaspase structures revealed reasonably large and well-ordered N-terminal regions, which have shown good association with the main body of the enzyme [ 11 ].

This differs from the caspases, for which the N-terminal region has never been observed in a crystal structure, suggesting that it is more easily dissociated. In the metacaspases H L5 has not been identified as contributing to the active site because it is disordered in both crystal structures.

This structural family of enzymes, classed as C14, collectively exhibits a variety of substrate specificities, activation mechanisms, potential autoinhibitory machinery and N-terminal functionality. Structurally, the specificity-diverse caspases and paracaspases are almost identical whereas the metacaspases have a different structural topology, and all the family members appear to use analogous structural elements to recognize and bind their substrates.

In addition, this analysis suggests that the metacaspases are sufficiently structurally and functionally diverse to be classed separately from the caspases and paracaspases; to investigate this fully, however, the structure—function relationships for other available clan CD family members need to be considered. The archetypal member of family C11 is clostripain: a cysteine peptidase released by the anaerobic bacterium Clostridium histolyticum.

This family of petidases is reportedly found in most phylogenetic kingdoms but is missing from the Metazoa see Table 1. To date, there are no structures of clostripain available in the PDB, but there is a structure of an unassigned peptidase from family C B A phylogenetic tree based on structure, in which Q H [ 85 ] is a measure of structural homology.

The archetypal member of family C13 is legumain, an asparagine-specific cysteine peptidase, which is found throughout most phylogenetic kingdoms see Table 1 , although it has been most extensively studied in the blood fluke parasite Schistosoma sp. Legumain is synthesized as an inactive zymogen with the first 17 residues consisting of a signal peptide, which is released during secretion. Historically, the remainder of the enzyme has been described as consisting of an eight-residue, N-terminal pro-peptide, a peptidase domain and a large residue, C-terminal prodomain.

However, the N-terminal region of legumain has recently been shown to have no role in the activation of the enzyme [ 75 ], whereas the C-terminal domain has been shown to be instrumental in controlling the zymogen, along with enzyme activation and stability [ 9 ].

Legumain is also distinct from all the C14 enzymes, in that it is activated by pH. This acidification is accompanied by intermolecular trans autoproteolytic processing at Asn , a cleavage site situated in the C-terminal domain.

Cleavage is not required for activity but the reaction rate is much faster when cleavage occurs [ 76 ]. In general, legumain exhibits specificity towards asparagine in P 1 pH optimum 5. Both the AP and the LSAM domains interact extensively with the peptidase domain at the autoprocessing site Asn found at the interface between them.

In addition, Ser from the AP forms hydrogen bonds to Arg 44 and Ser in the P 1 pocket, blocking access to the active site. The interacting surfaces of the C domain and the peptidase domain are complementary positively and negatively charged, respectively and, as the pH is lowered and the peptidase becomes protonated, the interaction between the two surfaces is disrupted in particular several salt bridges , which produces a conformational arrangement that allows substrates to access the active site.

However, the C domain does not dissociate from the enzyme on processing; in fact it becomes markedly unstable if the LSAM domain is removed [ 9 ] and it is not possible to express legumain in the absence of the C domain [ 75 ]. Furthermore, superimposing a copy of pro-legumain on to each monomer in the caspase-7 dimer reveals a steric clash between LSAM domains.

This, together with the fact that there is no biological need for dimerization, suggests that monomeric legumain is a more energetically favourable form. In summary, a change in pH the activation mechanism , followed by trans -autoprocessing and a conformational rearrangement, has a role in producing fully mature legumain. The only structure available from the C25 family of clan CD peptidases is gingipain R RgpB , a virulence factor participating in the infection and survival of Porphyromonas gingivalis in periodontitis.

To date, the RgpB structure has been determined in both its mature and its pro-forms [ 13 , 14 ] see Supplementary Table S1. Trp is also found stacking on top of the P 1 arginine covering the S 1 pocket like a lid. It is interesting that the only functional group involved in hydrogen bonding to the P 1 arginine is the carboxylic acid of Asp , which forms a stable bidentate salt bridge with the guanidino group.

The pro-form of RgpB consists of a residue, N-terminal prodomain, which contains two autoprocessing sites at Arg and Arg proform numbering denoted P Arg and P Arg , respectively.

Cleavage at these sites is required for full activation of the enzyme [ 77 ], with cleavage at P Arg being essential for processing at P Arg and subsequent removal of the prodomain.

The lung is also considered as one of the target organs of Cd toxicity. Cadmium can induce apoptosis in rat lung epithelial cell lines and a possible underlying mechanism is the induction of ROS. This protein is also responsible for GSH secretion to protect lung tissue against damage [ 60 ] and any mutation in this protein can result in low GSH levels in the cell leading to an oxidative stress environment [ 61 ].

This apparent contradiction can be explained by the different exposure conditions time and dose , but needs further investigation. The components of tobacco smoke, aside from nicotine, such as heavy metals and carcinogens can lead to an oxidative stress environment [ 65 ]. Cadmium, a major constituent of cigarettes has proven to cause pulmonary oxidative stress, emphysema and persistent airway inflammation in rat models that mirror the conditions observed in COPD patients [ 10 ].

Sprague-Dawley rats that received nebulised Cd via inhalation 0. The universal antioxidant transcription factor Nrf2 has been recently implicated in broad range of responses involved in both the initiation and progression of lung injuries caused by smoking [ 65 ]. Mice lacking Nrf2, when exposed to cigarette smoke 7 h per day, 7 days per week, during six months were more susceptible to emphysema, had elevated levels of alveolar DNA oxidation as well as enhanced alveolar oxidative stress that regulates the intensity of alveolar cell inflammation and apoptosis [ 66 ].

Cadmium is an independent novel risk factor for cardiovascular diseases CVDs and induces CVDs in vitro and in vivo [ 11 , 67 ]. The exact role of Cd in CVDs is controversial [ 68 ], but it can alter endothelial gene expression and lead to patho-physiological changes at low levels of exposure [ 11 , 69 ].

Oxidative stress induced by Cd might be one of the reasons for cardiovascular effects as low-density lipoprotein LDL modification by oxidative damage is a key event in development of atherosclerosis and oxidized LDL particles are found in atherosclerotic lesions [ 68 , 70 ].

Male Buffalo rats that were given 50 or ppm Cd in drinking water exhibited increased lipid peroxides and GSH. It also increased arterial blood pressure and blunted the vascular responses to vasoactive agents [ 69 ].

Donpunha et al. Thereby DNA fragmentation, which is the terminal step in apoptosis, is inhibited. However, the authors could not exclude that the inhibition of apoptosis might have been caused by a decreased accumulation of intracellular Cd, when applied together with Zn.

Cadmium cannot penetrate the adult blood brain barrier BBB , although it might diffuse across the BBB with the help of a vehicle such as ethanol [ 73 ]. Cadmium can more effectively pass the BBB during the developmental stage in an organism and is more toxic in newborns [ 74 , 75 ]. Once inside, it accumulates in different areas of the brain, induces lipid peroxidation and weakens the antioxidative defence [ 74 , 76 ].

In battery workers Cd-induced oxidative stress was demonstrated to cause amyotrophic lateral sclerosis due to reduced brain SOD activity [ 77 ]. Cadmium 0. Furthermore, vitamin C was also demonstrated to reverse Cd-induced apoptotic cell death in cortical neurons, while necrotic cell death remained unaltered.

This confirms the involvement of ROS in apoptosis [ 31 ]. In a mouse neuroblastoma cell line HT4, it was shown that cell death mechanisms and pro-inflammatory responses induced upon Cd exposure are redox-dependent. COX2 activation is necessary for Cd-induced pro-inflammatory responses and is mediated by a signalling cascade comprising of PI3K phosphatidylinositide 3-kinase , a flavoprotein and p38 MAPK mitogen-activated protein kinase [ 80 ].

The variable effects of Cd on oxidative stress signature in different experimental set-ups are also reported in brain cells [ 83 ]. A significant reduction in enzymatic activities of SOD, GPx as well as CAT was observed in these cells together with a decline in ascorbic acid content [ 84 ].

Supplementation of vitamin C and E could ameliorate testicular stress to a certain extent. Also in Cd-exposed rats an increase in testicular lipid peroxidation and a decrease in the antioxidant enzyme activities, such as GPx and SOD, were observed. Pretreatment with vitamin C and E reduced testicular ROS production, thereby restoring normal testicular function [ 85 ].

The high membrane lipid content of testicular Leydig cell mitochondria and microsomes makes these cells more susceptible to Cd-induced lipid peroxidation [ 87 ].

Testicular Leydig cells are also the target cell population for Cd carcinogenesis. Atrophy with calcification occurred in 2—3 months and atrophied tissues were regenerated towards the end of 1 year after exposure.

The authors concluded that the Cd doses that compromise cellular defence mechanisms and hence induce oxidative stress, may have an important role in the initiation of carcinogenesis within the target cell population.

As such, the negative effect of Cd on pulmonary tumour formation was indicated in both epidemiological and experimental studies [ 14 , 90 , 91 ]. There is also clear evidence of cancer progression due to Cd toxicity within the prostate [ 92 — 94 ], kidney [ 95 , 96 ], breast [ 97 , 98 ], endometrium [ 99 ], bladder [ — ] and pancreas [ 14 , — ].

Evidence for the involvement of Cd in the development of stomach, liver and hematopoietic cancers, however, is not very convincing [ 14 , ]. Cadmium-induced carcinogenesis is a well-discussed topic recently reviewed by several independent researchers [ 25 , — ]. Both, oxidative stress and inhibition of repair of oxidative DNA damage undoubtedly influence this process, although some papers state that the role of ROS in the process of cancer formation is minimal [ 50 , ].

Several studies discuss the impact of induced adaptation mechanisms upon chronic Cd exposure, where diminished ROS levels were detected as a result of increased antioxidant levels such as GSH and MTs [ 22 , 50 ]. As a consequence, a condition of increased apoptotic resistance is created where DNA damaged cells can escape from elimination through apoptosis, and proliferate with inherent DNA lesions, eventually progressing to a malignant phenotype.

Nevertheless, multiple studies indicate Cd-induced ROS formation, which affect different pathways in the development of malignancies, thereby inducing or strengthening Cd-provoked carcinogenesis. Within the perspective of the current review, carcinogenic processes will be highlighted in function of their sensitivity to redox disturbances induced by Cd based on relevant literature that supports the role of ROS in the formation of cancer tissue Figure 2.

Schematic overview of Cd-induced carcinogenesis. Both Cd and ROS interfere with the activation of oncogenes, the inhibition of tumour suppressor genes and influence signal transduction processes via the modulation of transcription factors. One of the affected pathways involves the activation of c-fos and c-jun transcription factors, which together form AP This transcription factor is responsible for the activation of proto-oncogenes involved in cell growth and division [ ].

However, care should be taken, as Cd-induced redox alterations not always provoke identical responses concerning the MAPK cascade. Also the phosphatidylinositide 3-kinases PI3K pathway, responsible for inhibition of apoptosis and stimulation of proliferation through protein kinase B AKT and mammalian target of rapamycin mTOR , is affected after Cd exposure in a ROS-dependent way.

HIF-1 is a promoting factor in tumour formation. They are involved in maintaining the balance between proliferation and apoptosis and when disrupted by Cd, hyperproliferation or apoptotic resistance can be induced. The involvement of ROS herein, however, still remains to be elucidated.

A lot of proteins involved in DNA repair systems have Zn-binding proteins that can directly be disrupted by Cd [ , ]. Critical cysteine residues on 8-oxoguanine DNA glycosylase OGG1 , one of the compounds of the BER system, can be indirectly oxidized by Cd, thereby inhibiting proper functioning of this enzyme [ , ].

An association between Cd and the formation of 8-OHdG was also seen in glass production workers [ ]. On the other hand, the link between the progression of cancer tissue and the presence of 8-OHdGs has been proven in both human and animal tumour models [ — ].

These data combined could give an indication that the formation of 8-OHdGs as a result of Cd-induced ROS formation is an important element in the progression of cells towards cancer. The epigenetic state of the genome determines the gene expression profile of an organism without changing the DNA sequence, and is determined by the function of different proteins such as DNA methyltransferases DNMTs , histone deacetylases HDACs , histone acetylases, histone methyltransferases and the methyl-binding domain protein MECP2 [ ].

Cadmium interferes with the epigenome, thereby changing gene expression profiles in favour of carcinogenesis [ ]. Either way the result is hypomethylation or hypermethylation of respectively oncogenes and tumour suppressor genes, which could induce altered gene expression patterns that lead to carcinogenic events. Huang et al. This could indicate that hypomethylation or hypermethylation is the result of direct interference by Cd and not ROS [ ].

However direct exposure to ROS without the involvement of Cd has shown to induce epigenetic changes as well, so mechanisms through Cd-induced ROS can still apply [ , ]. In the previous part, we discussed how the redox balance contributes to the transition of normal cells to cancer cells. Carcinogenic processes 1 can be initiated in specialized cells, which often result in dedifferentiation, or 2 can start in undifferentiated cells [ ]. Undifferentiated cells or stem cells are characterized by their high capacity of self-renewal and differentiation.

They are highly resistant to many stressors such as chemical compounds, ultraviolet light, radiation and oxidative stress [ , ], a property that makes them unique for studying cellular maintenance and protection. Stem cells wield two main defence strategies, quiescence and damage control, which are discussed below in function of their responses to redox-related changes.

Quiescent cells are cells that are kept in a G 0 resting phase, a process that is critical to preserve successful self-renewal [ , ]. The defence strategy of quiescent cells resides in the fact that they have a low metabolic status, a high efflux capacity of cytotoxic compounds through ATP-dependent transporters such as MDR1 [ ] and an extensive network of scavengers [ , , ].

Moreover, quiescence is characterized by a strict regulation of the redox balance in which ROS levels are kept low [ , ]. In some conditions, damage is inevitable, and damage control mechanisms are activated. Depending on the level and type of damage inflicted, stem cells can repair damaged DNA, drive the cells into cellular senescence or induce apoptosis [ , , ].

Stem cells are designed to maintain low levels of ROS [ ]. Within these cells, Cd will raise the levels of ROS concomitantly with several defence mechanisms. Despite the limited data available on this topic, a few strategies of stem cells coping with Cd-induced oxidative stress are hypothesized Figure 3.

On one hand, increased levels of ROS can be removed directly through activation of anti-oxidative mechanisms. On the other hand, ROS levels are indirectly controlled via signalling mechanisms during the quiescent stem cell mode, to maintain low ROS levels. A third way of responding is the induction of apoptosis to prevent an accumulation of damaged stem cells. Schematic overview of Cd toxicity in stem cells in general.

Intoxication of stem cells by Cd could indirectly induce oxidative stress by impairment of the redox balance. The reaction of stem cells to Cd-induced toxicity is ambiguous. Increased levels of ROS can either be removed directly through induction of antioxidative mechanisms or indirectly through induction of the quiescent stem cell model.

On the other hand the increased levels of ROS will trigger signalling cascades that induce apoptosis to prevent the accumulation of damaged stem cells by ROS. Cadmium induces ageing-like effects via oxidative stress, a process that was counteracted in murine fertilized zygotes after treatment with antioxidants [ ].

A direct removal of Cd-induced ROS was also observed in alveolar type II epithelial stem cells that are able to differentiate into type I cells [ ]. The impact of antioxidative defence mechanisms in the coping strategy of a stem cell was also demonstrated in the pluripotent stem cells of planaria organisms capable of extreme regeneration. Planarian stem cells, also known as neoblasts, showed an increased expression of heat shock proteins HSP60 and HSP70 when exposed to 2.

In this manuscript, the authors hypothesize an important role for HSPs in the stem cell defence, guiding survival and proliferation during Cd stress. The involvement of other antioxidative enzymes important in somatic cell defence [ 15 ], is not yet clear for Cd-exposed undifferentiated cells.

However, based on the studies described above, a degree of similarity can be concluded. Overall, among different types of stem cells, an increased number of quiescent cells is observed during Cd stress. All these temporary proliferation stops indicate that a large amount of stem cells goes into a quiescent mode or dies to protect them from further Cd-induced stress.

A decrease in cell proliferation not only coincides with cell death, but is also associated with the induction of cell differentiation. As such, undifferentiated neural precursors were forced into astate of active differentiation after exposure to Cd [ ] and references herein. All of these findings are in contrast with the number of mitotic divisions measured in the planarian Schmidtea mediterranea , which increased when exposed to 2.

This result is not totally unexpected since the stem cells of these organisms are pluripotent and powerful towards stress and ageing [ , ]. However the elevation in mitotic divisions can also be explained by the fact that the cells were measured via histochemical visualization in the M-phase, which could indicate that dividing cells still need to enter the G 0 phase.

Contradictory responses on stem cell proliferation after Cd exposure were also observed in neural precursor cells, an effect that appeared to be concentration-dependent [ ]. This corresponds with somatic cell responses, where increased proliferation during low Cd exposure is often classified as an hormesis effect [ — ]. When defence strategies fail, damage is inevitable, even in stem cells. A cellular defence mechanism against extreme molecular damage is apoptosis.

Genomic instability not only induces cell death, but as described earlier, Cd-induced genomic instability also leads to neoplastic transformation. Evidence for stem cells involved in Cd-induced cancer, was reported by Hart et al [ ]. Also the reprogramming and transformation of prostate stem cells and early stage progenitor cells into cancer cells by Cd was reviewed recently [ ]. Nevertheless, more information is needed to further elucidate a clear role for stem cells in Cd-induced carcinogenesis.

Overall, stem cell responses to Cd stress are ambiguous. Thanks to their extensive defence strategies, among which quiescence, damaging processes can be overcome more easily. If damage does occur and accumulates after Cd intoxication, stem cells can be triggered into apoptosis. Cadmium-induced damage such as genomic instability, however, is not always re-balanced, and can give rise to neoplastic transformations. In general, it might be of interest to compare the Cd exposure levels in vivo to those in vitro , though comparisons between experiments should be done with caution.

This is true in case of cell lines as they are generally more resistant to stress.

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