Cause Of Cell Death Research Articles

Low-density Lipoprotein Receptor-related Protein-1 (LRP1) Mediates Autophagy and Apoptosis Caused by Helicobacter pylori VacA

In Helicobacter pylori infection, vacuolating cytotoxin (VacA)-induced mitochondrial damage leading to apoptosis is believed to be a major cause of cell death. It has also been proposed that VacA-induced autophagy serves as a host mechanism to limit toxin-induced cellular damage. Apoptosis and autophagy are two dynamic and opposing processes that must be balanced to regulate cell death and survival. Here we identify the low-density lipoprotein receptor-related protein-1 (LRP1) as the VacA receptor for toxin-induced autophagy in the gastric epithelial cell line AZ-521, and show that VacA internalization through binding to LRP1 regulates the autophagic process including generation of LC3-II from LC3-I, which is involved in formation of autophagosomes and autolysosomes. Knockdown of LRP1 and Atg5 inhibited generation of LC3-II as well as cleavage of PARP, a marker of apoptosis, in response to VacA, whereas caspase inhibitor, benzyloxycarbonyl-VAD-fluoromethylketone (Z-VAD-fmk), and necroptosis inhibitor, Necrostatin-1, did not inhibit VacA-induced autophagy, suggesting that VacA-induced autophagy via LRP1 binding precedes apoptosis. Other VacA receptors such as RPTPα, RPTPβ, and fibronectin did not affect VacA-induced autophagy or apoptosis. Therefore, we propose that the cell surface receptor, LRP1, mediates VacA-induced autophagy and apoptosis.

Mitochondria, monoamine oxidase B and Parkinson’s disease

The cause of cell death in Parkinson’s disease (PD) remains unclear but it is multifactorial with a complex interaction between a range of pathogenic mechanisms. However, alterations in mitochondrial function have been clearly linked to nigral dopaminergic loss in sporadic PD and to the effects of gene mutations in familial forms of the illness. These may underlie the onset of oxidative and nitrative stress, a failure of protein degradation and apoptotic degeneration of dopaminergic cells in PD. Perhaps importantly, monoamine oxidase B (MAO-B) is located in the mitochondrial wall and plays a significant role in dopamine degradation in PD. This can explain the symptomatic actions of MAO-B inhibitors, such as selegiline and rasagiline on motor symptoms of PD. However, both selegiline and rasagiline also are associated with neuroprotective and/or disease modifying activities. The second generation MAO-B inhibitor, rasagiline can prevent multiple pathways that lead to apoptotic cell death and it is effective in in vitro and in vivo models of neuronal degeneration. However, there may be contributions from its major metabolite, aminoindan and non-MAO-B mediated actions on mitochondria may also contribute to these effects. It is important to determine whether these actions contribute to the possible disease modifying effect of MAO-B inhibitors in PD in man.

Redox Cycling of 1,2-Naphthoquinone by Thioredoxin1 through Cys32 and Cys35 Causes Inhibition of Its Catalytic Activity and Activation of ASK1/p38 Signaling

1,2-Naphthoquinone (1,2-NQ) is an atmospheric chemical capable of (1) redox cycling with electron donors and (2) covalent modification of nucleophilic groups on proteins. In the present study, we investigated its interaction with the redox protein, thioredoxin1 (Trx1), which led to oxidative stress-dependent cell damage. In experiments with purified wild-type Trx1 and its double mutant (32S/35S Trx1), we found that incubation of Trx1 with 1,2-NQ resulted in a redox cycling reaction, generating superoxide and hydrogen peroxide involving Cys32 and Cys35 and an arylation reaction resulting in covalent modification of Lys85 together with a loss of Trx activity. A significant fraction of the lost Trx1 activity following interaction with 1,2-NQ was restored by dithiothreitol. Exposure of RAW264.7 cells to 1,2-NQ generated reactive oxygen species (ROS) and caused a decrease in Trx activity. Trx is a negative regulator of apoptosis signal-regulating kinase 1 (ASK1), and under the conditions of the experiment, 1,2-NQ activated ASK1 and p38, leading to PARP cleavage and apoptotic cell death that were blocked by pretreatment with polyethylene glycol-catalase. These results suggest that Trx1 readily undergoes oxidative modification by 1,2-NQ through the proximal thiols Cys32 and Cys35. It seems likely that ROS production concomitant with decline in cellular Trx activity plays a role in the activation of ASK1/p38 signaling to promote apoptotic cell death cause by 1,2-NQ exposure.

SUSCEPTIBILITY AND PROTECTIVE MECHANISMS OF MOTILE AND NON MOTILE CELLS OF HAEMATOCOCCUS PLUVIALIS (CHLOROPHYCEAE) TO PHOTOOXIDATIVE STRESS(1).

The life cycle of the unicellular green alga Haematococcus pluvialis consists of motile and nonmotile stages under typical growing conditions. In this study, we observed that motile cells were more susceptible than nonmotile cells to high light, resulting in a decrease in population density and photo-bleaching. Using two Haematococcus strains, CCAP 34/12 (a motile cell dominated strain) and SAG 34/1b (a nonmotile cell dominated strain), as model systems we investigated the cause of cell death and the protective mechanisms of the cells that survived high light. The death of motile cells under high light was attributed to the generation of excess reactive oxygen species (ROS), which caused severe damage to the photosynthetic components and the membrane system. Motile cells were able to dissipate excess light energy by nonphotochemical quenching and to relax ROS production by a partially up-regulated scavenging enzyme system. However, these strategies were not sufficient to protect the motile cells from high light stress. In contrast, nonmotile cells were able to cope with and survive under high light by (i) relaxing the over-reduced photosynthetic electron transport chain (PETC), thereby effectively utilizing PETC-generated NADPH to produce storage starch, neutral lipid, and astaxanthin, and thus preventing formation of excess ROS; (ii) down-regulating the linear electron transport by decreasing the level of cytochrome f; and (iii) consuming excess electrons produced by PSII via a significantly enhanced plastid terminal oxidase pathway.

Calpain 2 Regulates Akt-FoxO-p27Kip1 Protein Signaling Pathway in Mammary Carcinoma

Calpain 2 Regulates Akt-FoxO-p27Kip1 Protein Signaling Pathway in Mammary Carcinoma

Abstract 4909: Calcitriol and arsenic trioxide synergistically inhibited proliferation of HL-60 cell line mainly through apoptosis pathway

Abstract Arsenic trioxide (As2O3) has shown substantial efficacy in the treatment of patients with acute promyelocytic leukemia (APL). However, since not all patients could achieve complete remission after As2O3 treatment, it is necessary to investigate a novel treatment method overcoming the resistance of current treatment. However, the therapeutic role of calcitriol against APL has not yet been fully elucidated. In our study, we investigated the anti-leukemic effect of calcitriol in combination with As2O3 on the human APL cell line HL-60. Inhibition of proliferation rate of HL-60 cells was measured by the trypan blue exclusion test was resulted in dose, time- dependent expressions. To evaluate the effects of combination treatment of As2O3 and calcitriol on the cell proliferation, we analyzed the combined effects of As2O3 and calcitriol using CalcuSyn software (BioSoft, Ferguson, MO, USA), which is based on the multiple drug-effect equation of Chou and Talalay (Chou TC, et al. Adv Enzyme Regul 1984): a combination index (CI) of <1, 1, or >1 is defined as synergistic, additive, or antagonistic, respectively. In all combinations, the CI values calculated were less than 1. To investigate the effects of these treatments on the apoptosis pathway, we analyzed the expression of Bax, Caspase-3, Bcl-2 with the Western blot and the RT-PCR. In the Western blot analysis, lower Bcl-2 and higher Bax and Caspase-3 expressions were observed in the As2O3 or calcitriol-treated groups compared to the control group. The combination treatment decreased Bcl-2 expression and increased Bax and Caspase-3 expressions more prominently than the single treatment using either As2O3 or calcitriol. In the RT-PCR analysis, these trends were validated again with the same results. These cells were then labeled with fluorescein-conjugated Annexin V-FITC and propidium iodide (PI), and analyzed with flow cytometry to differentiate whether the main cause of cell death was apoptosis or necrosis. To resultsze, calcitriol in combination with As2O3 synergistically inhibited proliferation of the human APL cell line HL-60. In addition, calcitriol combined with As2O3 more prominently activated the apoptosis pathway than single treatment using either calcitriol or As2O3. The main cause of cell death was also apoptosis. Our results suggest that these novel findings could be applied to improve the therapeutic outcomes of patients with APL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4909. doi:1538-7445.AM2012-4909

Abstract 872: Identification of romidepsin (FK228) and its analogs as HDAC/PI3K dual inhibitors

Abstract Activation of phosphatidylinositol 3-kinase (PI3K) signaling is involved in carcinogenesis and cancer progression. Therefore, inhibitors targeting PI3K are considered to be candidate drugs for cancer therapy. Indeed, some PI3K inhibitors have entered clinical trials, but efforts are still underway to develop new PI3K inhibitors. To discover novel PI3K inhibitors, we took advantage of a drug screening system by using the yeast Saccharomyces cerevisiae with deleterious mutations in ATP-binding cassette transporter genes. This is because wild-type yeast employs drug efflux pumps for reducing intracellular drug concentrations. The screening system is based on growth inhibition induced by overexpression of membrane localized p110α in yeast, in which no endogenous p110 homolog is expressed. However, compounds with the ability to inhibit PI3K can rescue cells from p110α induced growth inhibition. Using this system, we screened the deposited chemical library of the Screening Committee of Anticancer Drugs (SCADS). As a result, the histone deacetylase (HDAC) inhibitor romidepsin (FK228) and its novel analogs were isolated. In vitro PI3K activity assays confirmed that these compounds directly inhibit PI3K activity at μM-range concentrations. FK-A5 analog was the most potent inhibitor. Western blotting revealed that these compounds inhibit phosphorylation of v-akt murine thymoma viral oncogene homolog (AKT) and downstream signaling components. Molecular modeling of the PI3K-FK228 complex indicated that FK228 binds to the ATP binding pocket of p110α. At µM range concentrations, FK228 and FK-A5 exhibit potent cytotoxicity even in HDAC inhibitor-resistant cells. Fluorescence activated cell sorting (FACS) and western blotting indicated apoptosis as the cause of cell death. Furthermore, it was suggested that HDAC/PI3K dual inhibitory activity of FK228 and FK-A5 at µM range concentrations contributed to the induction of potent apoptosis because of the following reasons. 1) FK228 or FK-A5 within µM range inhibited AKT phophorylation and acetylated histones simultaneously. 2) The apoptosis induction by FK228 or FK-A5 at µM range concentrations was mimicked by combination of HDAC inhibitor and PI3K inhibitor. In conclusion, we demonstrated that FK228 and its analogs directly inhibited PI3K activity and induce potent apoptosis exhibiting HDAC/PI3K dual inhibition at µM range concentrations. In future, optimizing potency of FK228 and its analogs against PI3K may contribute to the development of novel HDAC/PI3K dual inhibitors for cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 872. doi:1538-7445.AM2012-872

Antimicrobial Mechanism of Monocaprylate

Monoglyceride esters of fatty acids occur naturally and encompass a broad spectrum of antimicrobial activity. Monocaprylate is generally regarded as safe (GRAS) and can function both as an emulsifier and as a preservative in food. However, knowledge about its mode of action is lacking. The aim of this study was therefore to elucidate the mechanism behind monocaprylate's antimicrobial effect. The cause of cell death in Escherichia coli, Staphylococcus xylosus, and Zygosaccharomyces bailii was investigated by examining monocaprylate's effect on cell structure, membrane integrity, and its interaction with model membranes. Changes in cell structure were visible by atomic force microscopy (AFM), and propidium iodide staining showed membrane disruption, indicating the membrane as a site of action. This indication was confirmed by measuring calcein leakage from membrane vesicles exposed to monocaprylate. AFM imaging of supported lipid bilayers visualized the integration of monocaprylate into the liquid disordered, and not the solid ordered, phase of the membrane. The integration of monocaprylate was confirmed by quartz crystal microbalance measurements, showing an abrupt increase in mass and hydration of the membrane after exposure to monocaprylate above a threshold concentration. We hypothesize that monocaprylate destabilizes membranes by increasing membrane fluidity and the number of phase boundary defects. The sensitivity of cells to monocaprylate will therefore depend on the lipid composition, fluidity, and curvature of the membrane.

Mechanical behaviour of in-situ chondrocytes subjected to different loading rates: a finite element study

Experimental findings indicate that in-situ chondrocytes die readily following impact loading, but remain essentially unaffected at low (non-impact) strain rates. This study was aimed at identifying possible causes for cell death in impact loading by quantifying chondrocyte mechanics when cartilage was subjected to a 5% nominal tissue strain at different strain rates. Multi-scale modelling techniques were used to simulate cartilage tissue and the corresponding chondrocytes residing in the tissue. Chondrocytes were modelled by accounting for the cell membrane, pericellular matrix and pericellular capsule. The results suggest that cell deformations, cell fluid pressures and fluid flow velocity through cells are highest at the highest (impact) strain rate, but they do not reach damaging levels. Tangential strain rates of the cell membrane were highest at the highest strain rate and were observed primarily in superficial tissue cells. Since cell death following impact loading occurs primarily in superficial zone cells, we speculate that cell death in impact loading is caused by the high tangential strain rates in the membrane of superficial zone cells causing membrane rupture and loss of cell content and integrity.

Modulation of Neuronal Survival Factor MEF2 by Kinases in Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder due to selective death of neurons in the substantia nigra pars compacta. The cause of cell death remains largely unknown. Myocyte enhancer factor 2 (MEF2) is a group of transcriptional factors required to regulate neuronal development, synaptic plasticity, as well as survival. Recent studies show that MEF2 functions are regulated in multiple subcellular organelles and suggest that dysregulation of MEF2 plays essential roles in the pathogenesis of PD. Many kinases associated with transcription, translation, protein misfolding, autophagy, and cellular energy homeostasis are involved in the neurodegenerative process. Following the first demonstration that mitogen-activated protein kinase p38 (p38 MAPK) directly phosphorylates and activates MEF2 to promote neuronal survival, several other kinase regulators of MEF2s have been identified. These include protein kinase A and extracellular signal regulated kinase 5 as positive MEF2 regulators, and cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β as negative regulators in response to diverse toxic signals relevant to PD. It is clear that MEF2 has emerged as a key point where survival and death signals converge to exert their regulatory effects, and dysregulation of MEF2 function in multiple subcellular organelles may underlie PD pathogenesis. Moreover, several other kinases such as leucine-rich repeat kinase 2 and PTEN-induced putative kinase 1 (PINK1) are of particular interest due to their potential interaction with MEF2.

The scaffold protein MEK Partner 1 is required for the survival of estrogen receptor positive breast cancer cells

MEK Partner 1 (MP1 or MAPKSP1) is a scaffold protein that has been reported to function in multiple signaling pathways, including the ERK, PAK and mTORC pathways. Several of these pathways influence the biology of breast cancer, but MP1’s functional significance in breast cancer cells has not been investigated. In this report, we demonstrate a requirement for MP1 expression in estrogen receptor (ER) positive breast cancer cells. MP1 is widely expressed in both ER-positive and negative breast cancer cell lines, and in non-tumorigenic mammary epithelial cell lines. However, inhibition of its expression using siRNA duplexes resulted in detachment and apoptosis of several ER-positive breast cancer cell lines, but not ER-negative breast cancer cells or non-tumorigenic mammary epithelial cells. Inhibition of MP1 expression in ER-positive MCF-7 cells did not affect ERK activity, but resulted in reduced Akt1 activity and reduced ER expression and activity. Inhibition of ER expression did not result in cell death, suggesting that decreased ER expression is not the cause of cell death. In contrast, pharmacological inhibition of PI3K signaling did induce cell death in MCF-7 cells, and expression of a constitutively active form of Akt1 partially rescued the cell death observed when the MP1 gene was silenced in these cells. Together, these results suggest that MP1 is required for pro-survival signaling from the PI3K/Akt pathway in ER-positive breast cancer cells.

Rapamycin Induces Cell Death of Hepatoma Cells via Upregulation of Beclin 1

Objective To investigate the rapamycin-induced cell death and the time and dose-effect relationship.Methods Cell death ratio was analyzed by using trypan blue exclusion assay.The rapamycin-induced cell death fashion was detected by TEM in SMMC7721.Furthermore,Beclin 1 was detected by using Western blot.Results Rapamycin significantly induces liver cell death,and has significant time and dose-effect dependence.Rapamycin can induce both apoptosis and autophagy in SMMC7721.Beclin 1 was upregulated by rapamycin.Conclusion Rapamycin can induce apoptosis and autophagic cell death in hepatoma cells,Beclin 1 upregulation may be the direct cause for rapamycin-induced cell death in HCC cells.

Population‐based modeling of the progression of apoptosis in mammalian cell culture

The production of biopharmaceuticals from mammalian cell culture is hindered by apoptosis, which is the primary cause of cell death in these cultures. As a tool for optimization of culture yield, this study presents a population-based model describing the progression of apoptosis in a monoclonal antibody (mAb)-producing Chinese hamster ovary (CHO) cell culture. Because mAb production does not cease when apoptosis begins, the model was designed to incorporate subpopulations at various stages in the progression of apoptosis. The model was validated against intracellular measurements of caspase activity as well as cell density, nutrient levels, and toxic metabolites. Since the specific details of apoptotic mechanisms have not been elucidated in this cell line, we employed a model comparison analysis that suggests the most plausible pathways of activation.

Cyclic deformation-induced injury and differentiation of rat alveolar epithelial type II cells

The injury and differentiation of alveolar epithelial type II cells induced by alveolar epithelial deformation play important roles in the pathophysiology of ventilator-induced lung injury and repair of the lung injury, respectively. We developed an in vitro rat model to investigate the effects of deformation amplitude, peak deformation, and minimum deformation on the viability and differentiation of type II cells. Rat primary alveolar epithelial type II cells were exposed to a variety of equibiaxial cyclic stretch protocols, and deformation-induced cell survival and differentiation were analyzed. Cell death increased when deformation consisted of change in cell surface area (ΔSA) of 0-37%, 0-50%, 12-50%, 37-50% (P=0.001, P<0.001, P<0.001, and P=0.003, respectively). When ΔSA was at 12-37% and 12-50%, mRNA transcription (P=0.034 and P=0.036) and protein expressions (P=0.008 and P=0.001) of caveolin-1 (a marker for the type I phenotype) increased, in contrast to the decrease of their mRNA transcription of surfactant protein C (a marker for the type II phenotype) (P=0.011, 0.002). These results suggest that amplitude or minimum deformation ≥ 37% ΔSA is an important cause of cell death, and amplitude ≥ 25% ΔSA promotes cell differentiation. Appropriate amplitude (25% ΔSA) can not only avoid cell death but also promote cell differentiation.

Dynamic modelling of cell death during biofilm development

Biofilms are currently recognised as the predominant bacterial life-style and it has been suggested that biofilm development is influenced by a number of different processes such as adhesion, detachment, mass transport, quorum sensing, cell death and active dispersal. One of the least understood processes and its effects on biofilm development is cell death. However, experimental studies suggest that bacterial death is an important process during biofilm development and many studies show a relationship between cell death and dispersal in microbial biofilms. We present a model of the process of cell death during biofilm development, with a particular focus on the spatial localisation of cell death or cell damage. Three rules governing cell death or cell damage were evaluated which compared the effects of starvation, damage accumulation, and viability during biofilm development and were also used to design laboratory based experiments to test the model. Results from model simulations show that actively growing biofilms develop steep nutrient gradients within the interior of the biofilm that affect neighbouring microcolonies resulting in cell death and detachment. Two of the rules indicated that high substrate concentrations lead to accelerated cell death, in contrast to the third rule, based on the accumulation of damage, which predicted earlier cell death for biofilms grown with low substrate concentrations. Comparison of the modelling results with experimental results suggests that cell death is favoured under low nutrient conditions and that the accumulation of damage may be the main cause of cell death during biofilm development.

2-Deoxyglucose Induces Noxa-Dependent Apoptosis in Alveolar Rhabdomyosarcoma

Alveolar and embryonal rhabdomyosarcomas are childhood tumors that do not respond well to current chemotherapies. Here, we report that the glycolytic inhibitor 2-deoxyglucose (2-DG) can efficiently promote cell death in alveolar, but not embryonal, rhabdomyosarcoma cell lines. Notably, 2-DG also induced cell differentiation accompanied by downregulation of PAX3/FOXO1a, the chromosome translocation-encoded fusion protein that is a central oncogenic driver in this disease. Cell death triggered by 2-DG was associated with its ability to activate Bax and Bak. Overexpression of the antiapoptotic Bcl-2 homologues Bcl-x(L) and Mcl-1 prevented apoptosis, indicating that cell death proceeds through the mitochondrial pathway. Mechanistic investigations indicated that Mcl-1 downregulation and Noxa upregulation were critical for 2-DG-induced apoptosis. In addition, 2-DG promoted eIF2α phosphorylation and inactivation of the mTOR pathway. Mcl-1 loss and cell death were prevented by downregulation of the endoplasmic reticulum (ER) stress-induced protein ATF4 and by incubating cells in the presence of mannose, which reverted 2-DG-induced ER stress but not ATP depletion. Thus, energetic stresses created by 2-DG were not the primary cause of cell death. Together, our findings suggest that glycolysis inhibitors such as 2-DG may be highly effective in treating alveolar rhabdomyosarcoma and that Noxa could offer a prognostic marker to monitor the efficacy of such agents.

Antifungal action of human cathelicidin fragment (LL13–37) on Candida albicans

Human cathelicidin LL37 and its fragments LL13–37 and LL17–32 exhibited similar potencies in inhibiting growth of the yeast Candida albicans. After treatment with 0.5μM and 5μM LL13–37, the hyphae changed from a uniformly thick to an increasingly slender appearance, with budding becoming less normal in appearance and cell death could be detected. Only the yeast form and no hyphal form could be observed following exposure to 50μM LL13–37. LL13–37 at a concentration of 5μM was able to permeabilize the membrane of yeast form as well as hyphal form of C. albicans since the nuclear stain SYTOX Green was localized in both forms. Mycelia treated with LL13–37 stained with SYTOX Green, but did not stain with MitoTracker deep red, indicating that the mitochondria were adversely affected by LL13–37. Bimane-labeled LL13–37 was able to enter some of the hyphae, but not all hyphae were affected, suggesting that LL37impaired membrane permeability characteristics in some of the hyphae. Reactive oxygen species was detectable in the yeast form of C. albicans cells after treatment with LL13–37 but not in the untreated cells. The results suggest that the increased membrane permeability caused by LL13–37 might not be the sole cause of cell death. It might lead to the uptake of the peptide, which might have some intracellular targets.

Mammalian Cell Viability in Electrospun Composite Nanofiber Structures

Incorporation of mammalian cells into nanofibers (cell electrospinning) and multilayered cell-nanofiber structures (cell layering) via electrospinning are promising techniques for tissue engineering applications. We investigate the viability of 3T3-L1 mouse fibroblasts after incorporation into poly(vinyl alcohol) nanofibers and multilayering with poly(caprolactone) nanofibers and analyze the possible factors that affect cell viability. We observe that cells do not survive cell electrospinning but survive cell layering. Assessing the factors involved in cell electrospinning, we find that dehydration and fiber stretching are the main causes of cell death. In cell layering, the choice of solvent is critical, as residual solvent in the electrospun fibers could be detrimental to the cells.

Cell Arrest and Cell Death in Mammalian Preimplantation Development: Lessons from the Bovine Model

BackgroundThe causes, modes, biological role and prospective significance of cell death in preimplantation development in humans and other mammals are still poorly understood. Early bovine embryos represent a very attractive experimental model for the investigation of this fundamental and important issue.Methods and FindingsTo obtain reference data on the temporal and spatial occurrence of cell death in early bovine embryogenesis, three-dimensionally preserved embryos of different ages and stages of development up to hatched blastocysts were examined in toto by confocal laser scanning microscopy. In parallel, transcript abundance profiles for selected apoptosis-related genes were analyzed by real-time reverse transcriptase-polymerase chain reaction. Our study documents that in vitro as well as in vivo, the first four cleavage cycles are prone to a high failure rate including different types of permanent cell cycle arrest and subsequent non-apoptotic blastomere death. In vitro produced and in vivo derived blastocysts showed a significant incidence of cell death in the inner cell mass (ICM), but only in part with morphological features of apoptosis. Importantly, transcripts for CASP3, CASP9, CASP8 and FAS/FASLG were not detectable or found at very low abundances.Conclusions In vitro and in vivo, errors and failures of the first and the next three cleavage divisions frequently cause immediate embryo death or lead to aberrant subsequent development, and are the main source of developmental heterogeneity. A substantial occurrence of cell death in the ICM even in fast developing blastocysts strongly suggests a regular developmentally controlled elimination of cells, while the nature and mechanisms of ICM cell death are unclear. Morphological findings as well as transcript levels measured for important apoptosis-related genes are in conflict with the view that classical caspase-mediated apoptosis is the major cause of cell death in early bovine development.

Parkinson's: symptoms, treatments and research

Parkinson's is a incurable progressive neurological condition caused by a degeneration of dopamine-producing cells. The most common symptoms of the condition include slowness of movement, tremor and muscle stiffness; other symptoms include sleep difficulties, depression and anxiety. Parkinson's is usually controlled by medication but other treatments and therapies, such as occupational therapy, physiotherapy and speech and language therapy, can also be effective in controlling and managing symptoms. The timing of this medication is key to the successful management of Parkinson's. Delays to initiating medication or missed doses can have serious consequences, and it can take some time for symptoms to stabilize. Research into treatments for Parkinson's and, ultimately, finding a cure for the condition, is ongoing. Parkinson's UK researchers are working on projects to identify the causes of cell death and tests to detect the condition at its earliest possible stage. Current treatments can help to ease the symptoms but none can repair the damage in the brain or slow the progress of the condition; now, Parkinson's UK researchers are working to develop new treatments that can.