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Oxidative stress is an undesirable effect of in vitro culture, which requires antioxidant supplementation. This study investigated the analogue of resveratrol (RA33) as an alternative to resveratrol, an antioxidant molecule, for the in vitro culture of in vitro-fertilized bovine embryos. The effect of different concentrations of RA33 on embryo development was evaluated and a comparison between RA33 and resveratrol was performed. The cleavage rate was higher (P < 0.05) with 2.5 μM (69.0 ± 4.4%) than at 0, 0.1 or 0.5 μM RA33 (62.1 ± 2.0%, 60.7 ± 5.9% and 56.7 ± 5.8%, respectively). The blastocyst rates on days 7 and 8 post-fertilization with 2.5 μM RA33 (19.4 ± 3.3% and 24.6 ± 3.3%, respectively) were higher (P < 0.05) than for 0 μM (12.4 ± 2.5% and 15.2±2.5%, respectively). When 2.5 μM RA33 was compared with 0.5 μM resveratrol, similar (P > 0.05) cleavage and blastocyst rates were found between them, but the cleavage rate was higher (P < 0.05) in the control (80.8 ± 3.4%) than for the resveratrol treatment (76.4 ± 3.6%). The numbers of apoptotic cells and the apoptotic index were lower (P < 0.05) with RA33 (6.5 ± 0.6 cells and 6.4 ± 0.7%, respectively) and resveratrol (5 ± 0.8 cells and 5.5 ± 1.0%, respectively) than in the control group (9.8 ± 1.2 cells and 8.9 ± 1.1%, respectively). In conclusion, RA33 can enhance the preimplantation development of in vitro-fertilized bovine embryos and be an alternative to resveratrol in embryo culture medium.
In Chapter 3 we present the first main part of our case for Causal Mechanism, by discussing in detail apoptosis, a central biological mechanism. We examine how John Kerr and his co-workers first introduced apoptosis in 1972. We then present the most important stages in scientific research regarding apoptosis during the last decades that led to its identification as a central biological mechanism, explaining the shift from morphological descriptions to biochemical descriptions of the mechanism. We generalise the molecular definition of a pathway to arrive at a more general notion of a causal pathway. We also show that several distinctions used by biologists in order to differentiate between causal pathways and identify the genuine biological mechanisms (active vs passive, programmed vs non-programmed, physiological vs accidental) do not correspond to internal features of causal pathways, but concern an external feature, that is, the role those processes play within the organism.
In recent years what has come to be called the 'New Mechanism' has emerged as a framework for thinking about the philosophical assumptions underlying many areas of science, especially in sciences such as biology, neuroscience, and psychology. This book offers a fresh look at the role of mechanisms, by situating novel analyses of central philosophical issues related to mechanisms within a rich historical perspective of the concept of mechanism as well as detailed case studies of biological mechanisms (such as apoptosis). It develops a new position, Methodological Mechanism, according to which mechanisms are to be viewed as causal pathways that are theoretically described and are underpinned by networks of difference-making relations. In contrast to metaphysically inflated accounts, this study characterises mechanism as a concept-in-use in science that is deflationary and metaphysically neutral, but still methodologically useful and central to scientific practice.
Lithium is an inhibitor of glycogen synthase kinase 3 beta, which is traditionally used in the treatment of bipolar disorders and has antitumor effects. The aim of the current study was to determine if lithium salt causes autophagy and apoptosis in skin melanoma cells to enhance cell death. Light microscopy, transmission electron microscopy, immunohistochemistry, and immunofluorescence were used to study the mechanism of action of lithium carbonate in B16 melanoma cells in vivo. Proliferating cell nuclear antigen immunofluorescence assay revealed that the proliferation of B16 melanoma cells was suppressed by lithium treatment for 7 days. Electron microscopy demonstrated a significant increase in the number of autophagic vacuoles in lithium-treated cells relative to control. In addition, levels of autophagy markers LC3 beta and LAMP1 found in lithium-treated tumor xenografts were higher than levels of these markers in the control tumors. Lithium induced caspase-3 expression and apoptotic cell death in tumor cells. Thus, lithium carbonate is the compound that inhibits cell proliferation and stimulates cell death in melanoma cells through induction of autophagy and apoptosis. Stimulation of autophagy by lithium could contribute to the development of autophagic cell death in tumor cells.
Nanomaterials are potentially a nanotoxicity problem. One potential source of nanomaterial toxicity is the large surface-to-volume ratio inherent in materials on the nanoscale size range. Many chemical reactions are aided by surfaces that can bring together different molecules for potential interactions and aid in their reorientations for potential interactions. In this way, small nanoparticles can act as catalysts and like enzymes to amplify the effects of interactions between molecules. Reactivity of nanomaterials also varies widely with size. For all of these reasons, nanotoxicity should be measured using nanoparticles of specific size ranges. The same nanomaterials can be more or less cytotoxic depending on their size. Biocoatings may hide the true nanotoxicity.
The low levels of toxicity and cytoprotective effect attributed to Achyrocline satureioides (Lam.) DC, a medicinal plant native to South America, are of interest for bovine mastitis therapy. This research paper reports the hypothesis that a nanoemulsion of macela extract (Achyrocline satureioides) exerts protective effects on bovine mammary alveolar cells -T (MAC-T) and increases the permeation of flavonoid compounds through mammary epithelium. Extract-loaded nanoemulsions (2.5 mg/ml) (NE-ML) (n = 4) were prepared using high-pressure homogenization with varying concentrations of flaxseed oil and Tween 80. Permeation and retention of free and nanoencapsulated quercetin, 3-O-methylquercetin and luteolin were performed on mammary glandular epithelium using Franz diffusion cells. The cell viability was evaluated on mammary epithelial cells (MAC-T lineage) using the MTT method (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) after exposure to loaded and blank nanoemulsions (NE-ML and NE-BL). Necrotic or apoptotic cell death was evaluated by flow cytometry after exposure to nanoemulsions (NE-ML and NE-BL). Subsequently, the cell death was assessed by previously treating MAC-T cells with NE-ML for 23 h, followed by exposure to H2O2 (2 mM) for 1 h. Higher permeation of quercetin and 3-O-methylquercetin in NE-ML was found compared to that of free extract with a final permeated amount of 50.7 ± 3.2 and 111.2 ± 0.6 μg/cm2 compared to 35.0 ± 0.6 and 48.9 ± 1.2, respectively. For NE-BL, the IC50 was at least 1.3% (v/v), while for the NE-ML, it was at least 2.6% (v/v). After exposure to NE-ML (5 and 1.2%, v/v), the percentage of apoptotic cells was reduced (±30%). For the H2O2 assay, the percentage of cells in necrosis was reduced by 40% after exposure to NE-ML1% (v/v) + H2O2 2 mM. The protective effects and increased permeation of macela nanoemulsion make this a promising new candidate for bovine mastitis therapy.
The current study aimed to investigate the protective effects of dietary thiamine supplementation on the regulation of colonic integrity and mucosal inflammation in goats fed a high-concentrate (HC) diet. Twenty-four Boer goats (live weight of 35·62 (sem 2·4) kg) were allocated to three groups (CON: concentrate/forage = 30:70; HC; concentrate/forage = 70:30 and HCT: concentrate/forage = 70:30 with 200 mg thiamine/kg DMI) for 12 weeks. Results showed that compared with the HC treatment, the HCT group had a significantly higher ruminal pH value from 0 to 12 h after the feeding. The haematoxylin–eosin staining showed that desquamation and severe cellular damage were observed in the colon epithelium of the HC group, whereas the HCT group exhibited more structural integrity of the epithelial cell morphology. Compared with the HC treatment, the HCT group showed a markedly increase in pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes activity. The mRNA expressions in the colonic epithelium of SLC19A2, SLC19A3, SLC25A19, Bcl-2, occludin, claudin-1, claudin-4 and ZO-1 in the HCT group were significantly increased in comparison with the HC diet treatment. Compared with the HC treatment, the HCT diet significantly increased the protein expression of claudin-1 and significantly decreased the protein expression of NF-κB-related proteins p65. The results show that dietary thiamine supplementation could improve the colon epithelial barrier function and alleviate mucosal inflammation injury in goats after lipopolysaccharide and low pH challenge.
Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that develops in or around the throat, larynx, nose, sinuses and mouth, and is mostly treated with a combination of chemo- and radiotherapy (RT). The main goal of RT is to kill enough of the cancer cell population, whilst preserving the surrounding normal and healthy tissue. The mechanisms by which conventional photon RT achieves this have been extensively studied over several decades, but little is known about the cell death pathways that are activated in response to RT of increasing linear energy transfer (LET), including proton beam therapy and heavy ions. Here, we provide an up-to-date review on the observed radiobiological effects of low- versus high-LET RT in HNSCC cell models, particularly in the context of specific cell death mechanisms, including apoptosis, necrosis, autophagy, senescence and mitotic death. We also detail some of the current therapeutic strategies targeting cell death pathways that have been investigated to enhance the radiosensitivity of HNSCC cells in response to RT, including those that may present with clinical opportunities for eventual patient benefit.
Endoparasitoid species devoid of symbiotic viruses inject secretions derived from their reproductive glands into their hosts during parasitism in order to avoid various immune responses of their hosts. Pimpla turionellae L. (Hymenoptera: Ichneumonidae) is an endoparasitoid that lacks polydnaviruses, and its venom has previously been shown to paralyze the host Galleria mellonella (Lepidoptera: Pyralidae) and suppress its immune reactions to ensure the egg survival. The present study demonstrates that another female-injected factor calyx fluid extracted from the P. turionellae ovary is also responsible for the suppression of G. mellonella immunity. The total hemocyte counts of G. mellonella decrease after treatment with calyx fluid in a concentration-dependent manner. Significant reductions in cell viability are also observed at all calyx fluid doses both in vivo and in vitro. The analyses of the beads injected into the insects as encapsulation targets revealed that the number of encapsulated beads reduced significantly compared to controls post-calyx fluid injection. The injection of the highest calyx fluid dose (1 female equivalent calyx) is sufficient to completely inhibit the strong encapsulation and melanization reactions of the last instar larvae 24 h post-injection. These results demonstrate that P. turionellae calyx fluid is required to regulate host immunity for successful parasitization.
An in vitro spermatogonial stem cell (SSC) culture can serve as an effective technique to study spermatogenesis and treatment for male infertility. In this research, we compared the effect of a three-dimensional alginate hydrogel with Sertoli cells in a 3D culture and co-cultured Sertoli cells. After harvest of SSCs from neonatal mice testes, the SSCs were divided into two groups: SSCs on a 3D alginate hydrogel with Sertoli cells and a co-culture of SSCs with Sertoli cells for 1 month. The samples were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays and bromodeoxyuridine (BrdU) tracing, haematoxylin and eosin (H&E) and periodic acid–Schiff (PAS) staining after transplantation into an azoospermic testis mouse. The 3D group showed rapid cell proliferation and numerous colonies compared with the co-culture group. Molecular assessment showed significantly increased integrin alpha-6, integrin beta-1, Nanog, Plzf, Thy-1, Oct4 and Bcl2 expression levels in the 3D group and decreased expression levels of P53, Fas, and Bax. BrdU tracing, and H&E and PAS staining results indicated that the hydrogel alginate improved spermatogenesis after transplantation in vivo. This finding suggested that cultivation of SSCs on alginate hydrogel with Sertoli cells in a 3D culture can lead to efficient proliferation and maintenance of SSC stemness and enhance the efficiency of SSC transplantation.
Many studies have focused on the optimization of the composition of embryo culture medium; however, there are few studies involving the effect of a culture medium changing procedure on the preimplantation development of embryos. In this study, three groups were designed: a non-renewal group, a renewal group and a half-renewal group. The levels of reactive oxygen species (ROS), apoptotic index, blastocyst ratio and blastocyst total cell number were analyzed in each group. The results showed that the ROS level and the apoptotic index of blastocyst in the non-renewal group were significantly higher than in the renewal group and the half-renewal group (P < 0.05). The blastocyst ratio and blastocyst total cell number were significantly higher in the half-renewal group than that in non-renewal group and the renewal group (P < 0.05). These results demonstrated that the procedure of changing the culture medium influenced ROS level, apoptotic index, blastocyst ratio and total cell number of blastocysts. In addition, the result suggested that changing the culture medium may lead to a loss of important regulatory factors for embryos, while not changing the culture medium may lead to the accumulation of toxic substances. Half-renewal can alleviate the defects of both no renewal and renewal, and benefit embryo development. This study will be of high value as a reference for the optimization of embryo culture in vitro, and is very significant for assisted reproduction.
Rhabdomyoma is the most common cardiac tumour in children. It is usually associated with tuberous sclerosis complex caused by mutations in TSC-1 or TSC-2 genes. This tumour typically regresses by unknown mechanisms; however, it may cause inflow or outflow obstruction that necessitates urgent surgery. Here we investigate the clinical features and the genetic analysis of patients with tuberous sclerosis complex presenting with large rhabdomyoma tumours. We also investigate the potential role of autophagy and apoptosis in the pathogenesis of this tumour.
All the patients with cardiac rhabdomyoma referred to Aswan Heart Centre from 2010 to 2018 were included in this study. Sanger sequencing was performed for coding exons and the flanking intronic regions of TSC1 and TSC2 genes. Histopathological evaluation, immunohistochemistry, and western blotting were performed with P62, LC3b, caspase3, and caspase7, to evaluate autophagic and apoptotic signaling.
Five patients were included and had the clinical features of tuberous sclerosis complex. Three patients, who were having obstructive tumours, were found to have pathogenic mutations in TSC-2. The expression of two autophagic markers, P62 and LC3b, and two apoptotic markers, caspase3 and caspase7, were increased in the tumour cells compared to normal surrounding myocardial tissue.
All the patients with rhabdomyoma were diagnosed to have tuberous sclerosis complex. The patients who had pathogenic mutations in the TSC-2 gene had a severe disease form necessitating urgent intervention. We also demonstrate the potential role of autophagy and apoptosis as a possible mechanism for tumourigenesis and regression. Future studies will help in designing personalised treatment for cardiac rhabdomyoma.
More than 20,000 patients have participated in clinical trials of more than 100 neuroprotective therapies, but no study has provided convincing evidence of benefit. Several improvements to the rigor of preclinical agent qualification have been identified to increase the likelihood of success in human clinical trials: stringent randomization and blinding techniques to mitigate observer bias; assessment in in time periods achievable in the clinical setting; testing in older animals with comorbidities; and robust and reproducible benefit magnitudes. Human clinical trials should start agents hyperacutely, in the first minutes and hours after onset, when treatment effect would be maximal; target enrolment of patients likely to have transient rather than permanent ischaemic exposure; and use factorial and platform trial designs that would permit efficient testing of combinations of agents able to block multiple ischaemic injury-mediating pathways concurrently, including both anti-necrotic and anti-apoptotic interventions. For agents that allow cells to endure ischaemic stress, human trial delivery approaches include: prehospital initiation; initiation immediately upon brain imaging in patients destined for endovascular intervention; and initiation at outside hospitals in patients undergoing transfer to a neurothrombectomy center. For agents that mitigate reperfusion injury, treatment start before or concurrent with reperfusion, including intra-arterial administration via catheter immediately after endovascular thrombectomy, should be pursued.
Nutrition in early life has a long-term influence on later health. In order to the explore effects of in ovo feeding (IOF) of vitamin C on splenic development, splenic metabolism and apoptosis were detected in embryo, adult chickens and in vitro. A total of 360 fertile eggs were selected and randomly assigned to control (CON) and vitamin C (VC) groups which were injected with saline and vitamin C on embryonic day 11, respectively. Functional enrichment of differentially expressed genes by transcriptome on embryonic day 19 suggested that purine nucleotide metabolism might be a potential pathway for the IOF of vitamin C to regulate spleen development. Additionally, the IOF of vitamin C significantly increased splenic vitamin C content on post-hatch day 21. Meanwhile, the splenic expression of adenosine deaminase, serine/threonine kinase 1 and proliferating cell nuclear antigen was down-regulated, whereas the expression of cysteinyl aspartate specific proteinase 9 was up-regulated in the VC group. On post-hatch day 42, the IOF of vitamin C significantly down-regulated the splenic expression of B-cell lymphoma 2 and increased the mRNA level of cysteinyl aspartate specific proteinase 9. The IOF of vitamin C could regulate the expression of genes related to adenylate metabolism and increased the apoptosis rate in vitro, which is consistent with the result in vivo. In conclusion, the IOF of vitamin C regulated splenic development and maturation by affecting purine nucleotide metabolism pathway and promoting apoptosis.
Mammary tissue (MT) turnover is characterized by programed cell death and remodeling which might be affected by both feeding level and animal species. Thus, twenty-four dairy goats and the same number of sheep were assigned to three homogenous sub-groups per animal species and fed the same diet in quantities which met 70% (FL70), 100% (FL100) and 130% (FL130) of their daily energy and crude protein requirements. Individual MT samples were taken by biopsy from the animals on the 30th and 60th experimental day. The results showed, in the first sampling time, a significant reduction in the mRNA abundance for selected genes involved in programed cell death in both FL 70 fed goats (STAT3 and BECN1) and sheep (CASPASE8 and BECN1) compared with the respective FL100 groups. The FL130, in comparison with the FL100, caused a significant increase in transcripts accumulation of STAT3 gene in both sampling times and CASPASE8 gene in the second sampling time in goat MT, while the opposite happened for the mRNA expression of CASPASE8 and BECN1 genes in sheep MT, but only in the first sampling time. Moreover, a significant up regulation in the mRNA levels of MMP2 gene in MT of FL130 fed sheep was observed. The FL130, in comparison with the FL70, caused an enhancement in the mRNA expression levels of BECN1, CASPASE8, BAX and STAT3 genes in goat MT only. It was also shown that apoptosis and autophagy can be affected simultaneously by the feeding level. Overfeeding affects MT programed cell death and remodeling by a completely different way in goats than sheep. In conclusion, feeding level and animal species have strong effects on both MT programed cell death (apoptosis and autophagy) and remodeling but the molecular mechanisms need further investigation.
We evaluated whether early-life protein restriction alters structural parameters that affect β-cell mass on the 15th day and 20th day of gestation in control pregnant (CP), control non-pregnant (CNP), low-protein pregnant (LPP) and low-protein non-pregnant (LPNP) rats from the fetal to the adult life stage as well as in protein-restricted rats that recovered after weaning (recovered pregnant (RP) and recovered non-pregnant). On the 15th day of gestation, the CNP group had a higher proportion of smaller islets, whereas the CP group exhibited a higher proportion of islets larger than the median. The β-cell mass was lower in the low-protein group than that in the recovered and control groups. Gestation increased the β-cell mass, β-cell proliferation frequency and neogenesis frequency independently of the nutritional status. The apoptosis frequency was increased in the recovered groups compared with that in the other groups. On the 20th day of gestation, a higher proportion of islets smaller than the median was observed in the non-pregnant groups, whereas a higher proportion of islets larger than the median was observed in the RP, LPP and CP groups. β-Cell mass was lower in the low-protein group than that in the recovered and control groups, regardless of the physiological status. The β-cell proliferation frequency was lower, whereas the apoptosis rate was higher in recovered rats compared with those in the low-protein and control rats. Thus, protein malnutrition early in life did not alter the mass of β-cells, especially in the first two-thirds of gestation, despite the increase in apoptosis.
There is strong evidence that foods containing dietary fibre protect against colorectal cancer, resulting at least in part from its anti-proliferative properties. This study aimed to investigate the effects of supplementation with two non-digestible carbohydrates, resistant starch (RS) and polydextrose (PD), on crypt cell proliferative state (CCPS) in the macroscopically normal rectal mucosa of healthy individuals. We also investigated relationships between expression of regulators of apoptosis and of the cell cycle on markers of CCPS. Seventy-five healthy participants were supplemented with RS and/or PD or placebo for 50 d in a 2 × 2 factorial design in a randomised, double-blind, placebo-controlled trial (the Dietary Intervention, Stem cells and Colorectal Cancer (DISC) Study). CCPS was assessed, and the expression of regulators of the cell cycle and of apoptosis was measured by quantitative PCR in rectal mucosal biopsies. SCFA concentrations were quantified in faecal samples collected pre- and post-intervention. Supplementation with RS increased the total number of mitotic cells within the crypt by 60 % (P = 0·001) compared with placebo. This effect was limited to older participants (aged ≥50 years). No other differences were observed for the treatments with PD or RS as compared with their respective controls. PD did not influence any of the measured variables. RS, however, increased cell proliferation in the crypts of the macroscopically-normal rectum of older adults. Our findings suggest that the effects of RS on CCPS are not only dose, type of RS and health status-specific but are also influenced by age.
Neurotoxocariasis (NT) is a serious condition that has been linked to reduced cognitive function, behavioural alterations and neurodegenerative diseases. Unfortunately, the available drugs to treat toxocariasis are limited with unsatisfactory results, because of the initiation of treatment at late chronic stages after the occurrence of tissue damage and scars. Therefore, searching for a new therapy for this important disease is an urgent necessity. In this context, cytotherapy is a novel therapeutic approach for the treatment of many diseases and tissue damages through the introduction of new cells into the damaged sites. They exert therapeutic effects by their capability of renewal, differentiation into specialized cells, and being powerful immunomodulators. The most popular cell type utilized in cytotherapy is the mesenchymal stem cells (MSCs) type. In the current study, the efficacy of MSCs alone or combined with albendazole was evaluated against chronic brain insults induced by Toxocara canis infection in an experimental mouse model. Interestingly, MSCs combined with albendazole demonstrated a healing effect on brain inflammation, gliosis, apoptosis and significantly reduced brain damage biomarkers (S100B and GFAP) and T. canis DNA. Thus, MSCs would be protective against the development of subsequent neurodegenerative diseases with chronic NT.
Schistosoma mansoni is the most common species causing schistosomiasis. It has a complex life cycle involving a vertebrate definitive host and a snail intermediate host of the genus Biomphalaria. Each stage encounters a plethora of environmental stresses specially heat stress. Another sort of stress arises from repeated exposure of the parasite to praziquantel (PZQ), the only drug used for treatment, which leads to the development of resistance in the fields and the labs. Heat shock protein 70 (Hsp70) is found in different developmental stages of S. mansoni. It is immunogenic and regulate cercarial invasion besides its chaperone function. In the Biomphalaria/S. mansoni interaction, epigenetic modulations of the Hsp70 gene underscore the susceptibility phenotype of the snail. Hsp70 is up-regulated in adult S. mansoni with decreased sensitivity to PZQ. This could be due to the induction of oxidative and endoplasmic reticulum stress, induction of apoptosis, exposure to the stressful drug pressure and increase influx of calcium ions. Up-regulation of Hsp70 might help the worm to survive the schistosomicidal effect of the drug mainly by dealing with misfolded proteins, inhibition of apoptosis, induction of autophagy, up-regulation of the P-glycoprotein transporter and attenuation of the signalling from G protein coupled receptors.
Connexin 43 (CX43) is a component of gap junctions. The lack of functional CX43 induces oxidative stress, autophagy, and apoptosis in somatic cells. However, the role of CX43 in the early development of porcine embryos is still unknown. Thus, the aim of this study was to investigate the role of CX43, and its underlying molecular mechanisms, on the developmental competence of early porcine embryos. We performed CX43 knockdown by microinjecting dsRNA into parthenogenetically activated porcine parthenotes. The blastocyst development rate and the total number of cells in the blastocysts were significantly reduced by CX43 knockdown. Results from FITC-dextran assays showed that CX43 knockdown significantly increased membrane permeability. ZO-1 protein was obliterated in CX43 knockdown blastocysts. Mitochondrial membrane potential and ATP production were significantly reduced following CX43 knockdown. Reactive oxygen species (ROS) levels were significantly increased in the CX43 knockdown group compared to those in control embryos. Moreover, CX43 knockdown induced autophagy and apoptosis. Our findings indicate that CX43 is essential for the development and preimplantation of porcine embryos and maintains mitochondrial function, cell junction structure, and cell homeostasis by regulating membrane permeability, ROS generation, autophagy, and apoptosis in early embryos.