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Maklakova, I. Yu, V. V. Bazarniy, and D. Yu Grebnev. "EFFECT OF MMSC AND HSC ON REPARATIVE REGENERATION OF THE LIVER UNDER CONDITIONS OF ITS TOXIC DAMAGE." Journal of Ural Medical Academic Science 17, no. 3 (2020): 243–48. http://dx.doi.org/10.22138/2500-0918-2020-17-3-243-248.
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The aim of this study was to study the effect of combined MMSC and HSC transplantation on liver regeneration under conditions of toxic carbon tetrachloride damage. Materials and methods. The study was performed on white male mice with toxic liver damage by intraperitoneal administration of carbon tetrachloride at a dose of 50 µl per mouse once. An hour after modeling liver damage, placental MMSCs and HSCs were administered intravenously at a dose of 4 million cells/kg and 330 thousand cells/kg, respectively, suspended in 0.2 ml of 0.9% NaCl solution. Control group animals were given 0.9% NaCl solution-0.2 ml intravenously. On days 1, 3, and 7 after cell transplantation, changes in inflammatory activity in the liver were evaluated, and mitotic and apoptotic indices were determined. On the 7th day after the introduction of cells, the activity of DNA repair enzymes of the PARP family was analyzed. Results. Combined MMSC and HSC transplantation leads to a decrease in the index of inflammatory activity in the liver due to a decrease in necrosis, hepatocyte dystrophy, and a decrease in infiltration. As a result of the study, an increase in the activity of PARP repair enzymes was found, which led to a decrease in programmed cell death. Also, cotransplantation of MMSCs and HSCs was accompanied by increased mitotic activity of hepatocytes. Conclusion. Cotransplantation of MMSCs and HSCs under conditions of toxic liver damage reduces the inflammatory response, stimulates the mitotic activity of hepatocytes, and increases the activity of enzymes of the DNA repair system. Activation of the liver's reparative system, in turn, reduces the programmed death of hepatocytes.
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Onishchenko, N. A., E. V. Fomenko, A. O. Nikolskaya, Z. Z. Gonikova, M. Yu Shagidulin, M. V. Balyasin, A. V. Elchaninov, and V. I. Sevastyanov. "Activation of regenerative processes in the liver when using cell-bone marrow total RNA." Russian Journal of Transplantology and Artificial Organs 22, no. 3 (October 6, 2020): 134–42. http://dx.doi.org/10.15825/1995-1191-2020-3-134-142.
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Objective: to study the cellular mechanisms of activation of regenerative processes in the liver when using total RNA (tRNA) of bone marrow cells (BMCs) based on an extended liver resection (ELR) model. Materials and methods. Male Wistar rats (n = 80) with ELR model (70%) were divided into 2 groups: group 1 (control group) had a single saline injection, while group 2 (experimental group) received a single tRNA injection at a 30 μg/100 g dose of animal weight. The biochemical parameters of liver function and weight were monitored over time. Also monitored were microstructural changes in hepatocytes 48 hours after ELR by examining mitotic activity, caspase-9 expression and morphometric parameters. Results. It was found that in group 2, in comparison to group 1, there was faster normalization of biochemical parameters (by 10–14 days), a higher mitotic index of hepatocytes (23.45‰ versus 5.37‰), and initially sharper decrease and then faster recovery of liver mass (by 10–12 days versus 18–20 days). Both groups showed almost total expression of caspase-9, including in mitotically splitting hepatocytes. Group 1 demonstrated decreased values of morphometric parameters of single and binuclear cells, decreased number of binucleated hepatocytes and increased total density of hepatocytes as compared to the intact liver. Intraperitoneal administration of tRNA increased morphometric parameters of mononuclear hepatocytes, did not affect their number, but increased the area of the nuclei of binuclear hepatocytes as compared to the control group. Conclusion. The proven capability of cell-bone marrow total RNA to simultaneously support apoptosis in liver cells after ELR and induce mitotic activity indicates that tRNA can switch activated apoptosis to cell proliferation at the early phase of the regenerative process. This effect may be due to the presence of regulatory RNA molecules in tRNA, including numerous non-coding RNAs.
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Gaboriau, François, Karine Chantrel-Groussard, Nicole Pasdeloup, Hans Peter Nick, Pierre Brissot, and Gérard Lescoat. "Comparative Effect of the Oral Iron Chelators ICL670A and CP20 on Cell Proliferation, Apoptosis and Polyamine Metabolism in Rat and Human Liver Cell Cultures." Blood 106, no. 11 (November 16, 2005): 4448. http://dx.doi.org/10.1182/blood.v106.11.4448.4448.
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Abstract Iron overload increases the mitotic index in rat hepatocyte cultures stimulated by EGF. Iron, implicated in tumoral cell proliferation, promotes the development of the hepatocellular carcinoma. Conversely, iron chelation decreases cell proliferation. Polyamines play also an important role in cell proliferation. The purpose of the present work was to compare the effect of the two oral iron chelators ICL670A and CP20 on cell proliferation, apoptosis and polyamine metabolism in rat and human liver cell cultures. We used three experimental models: the rat hepatoma cell line FAO, the rat liver epithelial cell line RLEC and the human hepatoma cell line HUH7. Chelator cell uptake was analyzed by mass spectrometry. DNA replication and cell viability were measured by thymidine incorporation and mitochondrial succinate dehydrogenase activity. Cytotoxicity was evaluated by extracellular LDH activity. Cell cycle analysis was performed by flow cytometry. Apoptosis was quantified by DNA fragmentation and caspase 3 activity. Polyamine metabolism was analyzed by measuring their intracellular concentrations by mass spectrometry as well as the ornithine decarboxylase (ODC) and spermine-spermidine acetyl transferase (SSAT) mRNAs levels. ICL670A entered the cells four times better than CP20. We observed that ICL670A (20 μM) decreased DNA replication (−75%) and cell viability (−40%) while a comparable CP20 stoechiometric concentration (30 μM) had no significant effect. ICL670A exhibited also a higher cytotoxicity than CP20. The decrease in DNA replication induced by ICL670A was correlated to a cell cycle block in S phase; CP20 (30 μM) increased slightly the cell number in G2/M phase while a higher CP20 concentration (150 μM) blocked clearly cell cycle in G2/M phase. By measuring DNA fragmentation and the activity of the executioner caspase 3, we demonstrated a high apoptotic effect of ICL670A (20 μM) compared to CP20 (30 μM). In the HUH7 human cell line, we observed that ICL670A (20 μM) decreased the intracellular levels of polyamines which was correlated to a drop in ODC and SSAT mRNAs levels. Conversely, an increase in SSAT mRNA level was observed in the presence of CP20 (150 μM) leading to an enhancement of putrescine and spermidine levels. In conclusion, ICL670A and CP20 inhibit cell proliferation by two distinct ways. ICL670A compared to CP20: enters better the cells; exerts a higher antiproliferative and apoptotic effect; modulates polyamine metabolism by inhibiting ODC and SSAT enzyme activities.
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Ledda-Columbano, G. M., A. Perra, M. Pibiri, F. Molotzu, and A. Columbano. "Induction of pancreatic acinar cell proliferation by thyroid hormone." Journal of Endocrinology 185, no. 3 (June 2005): 393–99. http://dx.doi.org/10.1677/joe.1.06110.
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Thyroid hormone is known to elicit diverse cellular and metabolic effects in various organs, including mitogenesis in the rat liver. In the present study, experiments were carried out to determine whether thyroid hormone is able to stimulate cell proliferation in another quiescent organ such as the pancreas. 3,5,3′-l-tri-iodothyronine (T3) added to the diet at a concentration of 4 mg/kg caused a striking increase in nuclear bromodeoxyuridine (BrdU) incorporation of rat acinar cells 7 days after treatment (the labeling index was 46.7% in T3-treated rats vs 7.1% in controls). BrdU incorporation was limited to the acinar cells, with duct cells and islet cells being essentially negative. The increase in DNA synthesis was accompanied by the presence of several mitotic figures. Histological examination of the pancreas did not exhibit any sign of T3-induced toxicity. Determination of the apoptotic index, measurement of the serum levels of α-amylase and lipase, and glycemia determination did not show any increase over control values, suggesting that the enhanced proliferation of acinar cells was a direct effect induced by T3 and not a regenerative response consequent to acinar or β-cell injury. Additional experiments showed that DNA synthesis was induced as early as 2 days after T3 treatment (the labeling index was 9.4 vs 1.9% in controls) and was associated with increased protein levels of cyclin D1, cyclin A and proliferating cell nuclear antigen, with no substantial differences in the expression of the cyclin-dependent kinase inhibitor p27. The mitogenic effect of T3 on the pancreas was not limited to the rat, since extensive acinar cell proliferation was also observed in the pancreas of mice treated with T3 for 1 week (the labeling index was 28% in T3-treated mice vs 1.8% in controls). Treatment with three other ligands of nuclear receptors, ciprofibrate, all-trans retinoic acid and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, induced little or no pancreatic cell proliferation. These results demonstrated that T3 is a powerful inducer of cell proliferation in the pancreas and suggested that pancreatic acinar cell proliferation by selected agents may have potential for therapeutic use.
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Nolan, L. A., and A. Levy. "Temporally Sensitive Trophic Responsiveness of the Adrenalectomized Rat Anterior Pituitary to Dexamethasone Challenge: Relationship between Mitotic Activity and Apoptotic Sensitivity." Endocrinology 144, no. 1 (January 1, 2003): 212–19. http://dx.doi.org/10.1210/en.2002-220241.
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Abstract Depending on timing and dose, exogenous glucocorticoids induce a wave of apoptosis in the adult rat anterior pituitary, a response that is enhanced by adrenalectomy. In this study, we show that the size of the glucocorticoid-sensitive apoptotic population progressively increases during the week following surgical adrenalectomy, plateaus for a further week, then spontaneously declines to levels seen in intact animals by 4 wk. Mitotic activity, in contrast, rises rapidly post adrenalectomy but returns to baseline within 2 wk. Increased mitotic activity precedes the increase in the population of cells that undergo glucocorticoid-induced apoptosis and the subsequent decline in mitotic activity precedes the decline in apoptotic sensitivity despite persistent elevation of hypothalamic CRH and pituitary proopiomelanocortin transcripts. If glucocorticoid exposure is delayed until 4 wk post adrenalectomy when the apoptotic response has returned to baseline, glucocorticoid withdrawal, by transiently increasing mitotic activity, again primes the formation of an expanded glucocorticoid-sensitive apoptotic cell population. These data suggest that apoptotic sensitivity is largely confined to cells that have recently entered the cell cycle. This observation is further corroborated by demonstrating an abrupt glucocorticoid-induced step-down in the bromodeoxyuridine-labeling index to basal levels in rats given daily injections of bromodeoxyuridine during the week following adrenalectomy.
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Gu, Juan, Francisco J. Hernandez-Ilizaliturri, Cory Mavis, Natalie M. Czuczman, Karen E. Thudium, George Deeb, John Gibbs, and Myron S. Czuczman. "Apoptotic and Non-Apoptotic Cellular Pathways Executed by Bortezomib (BTZ) in Rituximab-Resistant Lymphomas." Blood 118, no. 21 (November 18, 2011): 4967. http://dx.doi.org/10.1182/blood.v118.21.4967.4967.
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Abstract Abstract 4967 Rituximab-chemotherapy relapsed/refractory (r/r) B-cell lymphomas represent an emerging clinical challenge that underlies the need to develop alternative therapeutic strategies. A better understanding of the mechanism(s)-of-action of BTZ and other proteasome inhibitors (PI) is likely to aid in the identification of biomarkers that can be used to determine clinical responsiveness and/or help in the rational development of novel PI-based therapeutic combinations (e.g. incorporating biologics, small molecules and/or chemotherapy) in r/r B-cell lymphoma. Previously we demonstrated that rituximab resistance was associated with increased proteasome activity leading to a de-regulation in the apoptotic threshold of lymphoma cells to multiple chemotherapy agents. Pharmacological and genetic (e.g. siRNA silencing of BAK/BAX) inhibition of apoptosis partially affected BTZ activity in rituximab-resistant (RSCL) but not in rituximab-sensitive cell lines (RSCL) suggesting the existence of alternative pathways of cell death associated with PI exposure. To this end we evaluated the contribution of cellular senescence, cell cycle inhibition, or mitotic catastrophe to the anti-tumor activity of BTZ as a single agent or in combination with chemotherapeutic agents in RSCL, RRCL and in primary tumor cells. Lymphoma cells were exposed to BTZ (10-25nM) for 24–48 hrs. Cell senescence was determined by SA-β-gal staining using a senescence assay kit and inverted phase-contrast microscopy was performed. Changes in cell cycle were analyzed by the FACScan DNA method and changes in cell cycle regulatory proteins (i.e. cdc2, cyclinA/B, p21, CDK2/4/6) were analyzed by Western blotting. Mitotic index was determined by Wright-Giemsa stain and positive cells were counted under a Nikon microscope. Mitotic catastrophe was determined by confocal microscopy by staining with α-tubulin antibody. Finally, changes in ATP content was determined by the Cell Titer Glo assay. Baseline differences were observed between RSCL and RRCL in terms of cell morphology, proliferation rate and senescence. RRCL (Raji2R and Raji4RH) were considerably larger in size, had a slower proliferation rate and an exhibited a 3-fold increase the number of cells in senescence than RSCL. In vitro exposure of RSCL and RRCL to BTZ attenuated the number of cells in senescence by 50–75%. Cell cycle analysis demonstrated that RRCL had more cells in S phase when compared to RSCL. In vitro exposure to BTZ-induced G2/M arrest in RRCL, but not in RSCL. Overexpression of G2/M cell cycle regulatory proteins cyclin B and cdc2 were observed in RRCL and in tumor cells isolated from r/r B-cell lymphoma patients. Mitotic catastrophe with multi-nucleated cells were only detected in RRCLs exposed to BTZ. In vitro and ex vivo exposure of RSCL and RRCL to BTZ potentiated the cytotoxic effects of paclitaxel and overcame the acquired resistance to chemotherapy drugs in RRCL and primary tumor cells isolated from r/r lymphoma patients in a dose-dependent manner. Our results suggested that BTZ activates several death pathways in B-cell lymphoma pre-clinical models. In addition to apoptosis, BTZ is capable in triggering mitotic catastrophe in rituximab-chemotherapy lymphoma cells with decreased levels of pro-apoptotic proteins. Moreover, sensitization of RRCL to drug therapy involves interplay between cellular senescence attenuation, G2/M cell cycle regulation, and mitotic catastrophe. Hence, proteasome inhibition may provide a novel therapeutic approach for treating apoptosis-resistant B-cell lymphoma. Research, supported in part as a subproject of NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute. Disclosures: Hernandez-Ilizaliturri: Genmab: Research Funding; Amgen: Research Funding; Celgene: Consultancy. Czuczman:Millennium: Honoraria, Research Funding.
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Sit, Kwok Hung, and De Lin Chen. "Transient G2M arrest and subsequent release of apoptotic and mitotic cells in vanadyl(4)-prepulsed human Chang liver cells." Cell Death & Differentiation 4, no. 3 (April 1997): 216–23. http://dx.doi.org/10.1038/sj.cdd.4400223.
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Lomovsky, Alexey, Yulia Baburina, Irina Odinokova, Margarita Kobyakova, Yana Evstratova, Linda Sotnikova, Roman Krestinin, and Olga Krestinina. "Melatonin Can Modulate the Effect of Navitoclax (ABT-737) in HL-60 Cells." Antioxidants 9, no. 11 (November 18, 2020): 1143. http://dx.doi.org/10.3390/antiox9111143.
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Melatonin (N-acetyl-5-methoxytryptamine MEL) is an indolamine that has antioxidant, anti-inflammatory and anti-tumor properties. Moreover, MEL is capable of exhibiting both anti-apoptotic and pro-apoptotic effects. In the normal cells, MEL possesses antioxidant property and has an anti-apoptotic effect, while in the cancer cells it has pro-apoptotic action. We investigated the combined effect of MEL and navitoclax (ABT-737), which promotes cell death, on the activation of proliferation in acute promyelocytic leukemia on a cell model HL-60. The combined effect of these compounds leads to a reduction of the index of mitotic activity. The alterations in the level of anti- and pro-apoptotic proteins such as BclxL, Bclw, Mcl-1, and BAX, membrane potential, Ca2+ retention capacity, and ROS production under the combined action of MEL and ABT-737 were performed. We obtained that MEL in combination with ABT-737 decreased Ca2+ capacity, dropped membrane potential, increased ROS production, suppressed the expression of anti-apoptotic proteins such as BclxL, Bclw, and Mcl-1, and enhanced the expression of pro-apoptotic BAX. Since, MEL modulates autophagy and endoplasmic reticulum (ER) stress in cancer cells, the combined effect of MEL and ABT-737 on the expression of ER stress and autophagy markers was checked. The combined effect of MEL and ABT-737 (0.2 μM) increased the expression of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), leading to a decrease in the level of binding immunoglobulin protein (BIP) followed by an increase in the level of C/EBP homologous protein (CHOP). In this condition, the expression of ERO1 decreased, which could lead to a decrease in the level of protein disulfide isomerase (PDI). The obtained data suggested that melatonin has potential usefulness in the treatment of cancer, where it is able to modulate ER stress, autophagy and apoptosis.
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Riwanto, Ignatius, Selamat Budijitno, Edi Dharmana, Djoko Handojo, Sigit Adi Prasetyo, Albert Eko, Dicky Suseno, and Bondan Prasetyo. "Effect of Phaleria Macrocarpa Supplementation on Apoptosis and Tumor Growth of C3H Mice With Breast Cancer Under Treatment With Adriamycin–Cyclophosphamide." International Surgery 96, no. 2 (April 1, 2011): 164–70. http://dx.doi.org/10.9738/1404.1.
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Abstract The objective of this study was to know the response of supplementation of Phaleria macrocarpa (PM) to adriamycin-cyclophosphamide (AC) in the treatment of C3H mice with breast cancer. Twenty-four C3H mice, who were successfully inoculated with breast cancer cells, were randomly allocated into 4 groups: without treatment, treated with AC, treated with AC + PM 0.07 mg/d, and treated with AC + PM 0.14 mg/d. The tumor size was measured using millimeter calipers before and 12 weeks after treatment. The tumor, liver, and kidneys were removed and prepared for pathologic examination using imunohistochemistry staining, and the apoptotic index was counted using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. AC reduce the tumor growth significantly (P < 0.001), whereas supplementation of PM, which significantly reduced the tumor growth compared with AC only, was at the 0.14 mg/d dose (P = 0.007). AC increase the apoptotic index significantly (P < 0.001), and supplementation with PM showed that the higher dose increased the apoptotic index. The correlation between the apoptotic index and the diameter of tumor was significantly negative (r = −0.884; P = 0.020). The apoptotic index of the liver and kidney increased significantly in the AC group (P < 0.001 and P = 0.002, respectively); supplementation with PM decreased significantly the high apoptotic index caused by AC. We conclude that PM supplementation has a synergic effect to AC treatment in reducing the tumor growth, by increasing apoptosis, and protects the liver and kidney from damage caused by AC.
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SMALINSKIENE, A., V. LESAUSKAITE, S. RYSELIS, O. ABDRAKHMANOV, R. KREGZDYTE, I. SADAUSKIENE, L. IVANOV, N. SAVICKIENE, V. ZITKEVICIUS, and A. SAVICKAS. "Assessment of the Effect of Echinacea purpurea (L.) Moench on Apoptotic and Mitotic Activity of Liver Cells during Intoxication by Cadmium." Annals of the New York Academy of Sciences 1095, no. 1 (January 1, 2007): 574–84. http://dx.doi.org/10.1196/annals.1397.062.
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Cai, Jie, Tong Zheng, Rizwan Masood, D. Lynne Smith, David R. Hinton, Caryn Nae Kim, Guofu Fang, Kapil Bhalla, and Parkash S. Gill. "Paclitaxel Induces Apoptosis in AIDS-Related Kaposi's Sarcoma Cells." Sarcoma 4, no. 1-2 (2000): 37–45. http://dx.doi.org/10.1155/s1357714x00000074.
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Paclitaxel is a microtubule stabilizing drug that causes dividing cells to arrest and then undergo apoptosis. It also has antiangiogenic activity because it alters cytoskeletal structure, affecting migration and invasion. Paclitaxel is an effective treatment for AIDS-related Kaposi’s sarcoma (KS). KS is a tumor in which there is marked proliferation of endothelial cells in addition to the tumor cells, which themselves share many markers with activated (proliferating) endothelial cells.We sought to determine the mechanism by which paclitaxel exerts its anti-KS tumor effects.In vitro, KS cells are very sensitive to paclitaxel, with half-maximal growth inhibition observed at 0.8 nM. Inhibition of migration of KS cells was also observed at nanomolar concentrations of the drug. Paclitaxel induced cell cycle arrest with an accumulation of cells in sub-G1.This was accompaniedin vitroby various events typical of apoptosis: phosphorylation of two anti-apoptotic proteins Bcl-2 and Bcl-xL, release of cytochrome c into the cytoplasm, cleavage and activation of caspase-3.In vitroresults were borne out by studies of KS tumor xenografts in nude mice. Paclitaxel (10 mg/kg) inhibited tumor growth by 75% over 21 days. Histological examination of the tumors revealed a decrease in proliferative index, a decrease in the number of mitotic figures and an increase in apoptotic cells compared to tumors from untreated mice.
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Madonna, Rosalinda, Cihan Cevik, Maher Nasser, and Raffaele De Caterina. "Hepatocyte growth factor: Molecular biomarker and player in cardioprotection and cardiovascular regeneration." Thrombosis and Haemostasis 107, no. 04 (2012): 656–61. http://dx.doi.org/10.1160/th11-10-0711.
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SummaryThe liver possesses impressive regenerative capacities. Grafts of embryonic liver explants and liver explant-conditioned media have been shown to enhance the mitotic activity of hepatocytes. Hepatocyte growth factor (HGF), also named scatter factor (SF), has been identified as a primary candidate in promoting and regulating liver regeneration. Although initially thought to be a liver-specific mitogen, HGF was later reported to have mitogenic, motogenic, morphogenic, and anti-apoptotic activities in various cell types. By promoting angiogenesis and inhibiting apoptosis, endogenous HGF may play an important role in cardioprotection as well as in the regeneration of endothelial cells and cardiomyocytes after myocardial infarction. Since serum concentration of HGF increases in the early phase of myocardial infarction and in heart failure, HGF may also play a key role as a prognostic and diagnostic biomarker of cardiovascular disease. Here we discuss the role of HGF as a biomarker and mediator in cardioprotection and cardiovascular regeneration.
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Wilkins, Heather R., Kinuko Ohneda, Temitope O. Keku, A. Joseph D'Ercole, C. Randall Fuller, Kristen L. Williams, and P. Kay Lund. "Reduction of spontaneous and irradiation-induced apoptosis in small intestine of IGF-I transgenic mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 2 (August 1, 2002): G457—G464. http://dx.doi.org/10.1152/ajpgi.00019.2002.
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Insulin-like growth factor I (IGF-I) may promote survival of putative stem cells in the small intestinal epithelium. Mitosis and apoptosis were quantified in crypts of nonirradiated and irradiated IGF-I transgenic (TG) and wild-type (WT) littermates. The mean apoptotic index was significantly greater in WT vs. TG littermates. After irradiation, apoptotic indexes increased, and WT mice showed a more dramatic increase in apoptosis than TG mice at the location of putative stem cells. After irradiation, no mitotic figures were observed in WT crypts, whereas mitosis was maintained within the jejunal epithelium of TG mice. The abundance and localization of Bax mRNA did not differ between nonirradiated littermates. However, there was more Bax mRNA in TG vs. WT mice after irradiation. Bax mRNA was located along the entire length of the irradiated crypt epithelium, but there was less Bax protein observed in the bottom third of TG mouse crypts compared with WT littermates. IGF-I regulates cell number by stimulating crypt cell proliferation and decreasing apoptosis preferentially within the stem cell compartment.
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Poojari, Radhika, Avishkar V. Sawant, Sudarshan Kini, Rohit Srivastava, and Dulal Panda. "Antihepatoma activity of multifunctional polymeric nanoparticles via inhibition of microtubules and tyrosine kinases." Nanomedicine 15, no. 4 (February 2020): 381–96. http://dx.doi.org/10.2217/nnm-2019-0349.
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Aim: Synthesis of poly-L-lactic acid nanoparticles comprising of microtubule-inhibitor docetaxel and tyrosine kinase inhibitor sorafenib (PLDS NPs) for hepatoma treatment. Materials & methods: PLDS NPs were prepared by the emulsion solvent evaporation method and the anticancer activity was evaluated in Huh7 hepatoma cells. Results: Real-time imaging of quantum dots incorporating poly-L-lactic acid nanoparticles showed a rapid internalization of the nanoparticles in Huh7 cells. PLDS NPs exerted stronger antiproliferative, apoptotic and antiangiogenic effects than free single drug counterparts. They strongly promoted microtubule bundling, multinucleation and increased mitotic index in Huh7 cells. They also inhibited the expression of pERK1/2, pAKT and cyclin D1. Conclusion: We developed a single-nanoscale platform for dual drug delivery and high-sensitivity quantum dots imaging for hepatoma treatment. [Formula: see text]
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Domijan, AM, D. Želježić, M. Peraica, G. Kovačević, G. Gregorović, Ž. Krstanac, K. Horvatin, and M. Kalafatić. "Early toxic effects of fumonisin B1 in rat liver." Human & Experimental Toxicology 27, no. 12 (December 2008): 895–900. http://dx.doi.org/10.1177/0960327108100418.
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Mycotoxin fumonisin B1 (FB1) is hepatotoxic and carcinogenic in experimental animals. It is known that long-term exposure of experimental animals to FB1 causes apoptosis and lipid peroxidation. In this study, male adult Wistar rats were treated with single FB1 doses (5, 50, and 500 μg/kg b.w.) and sacrificed 4, 24, and 48 hours after treatment. Parameters of oxidative stress, histopathological changes, and DNA damage were monitored in the liver of treated and control animals. Parameters of oxidative stress were not affected by such treatment. A significant increase in apoptotic cells appeared in animals when 5 μg/kg b.w. dose was given and sacrificed after 24 hours with further increase at higher doses. In contrast to the number of mitotic figures and karyomegaly seen mostly at lower FB1 doses, necrosis was the prominent feature at higher doses. Significant increase in liver cells DNA mobility was observed 48 hours following treatment with 50 and 500 μg/kg b.w. as compared to control (tail length 15.2 ± 0.3, 16.4 ± 0.5, and 13.5 ± 0.1 μm, respectively). Tail intensity appeared to be more sensitive parameter for detecting DNA damage even at 5 μg/kg b.w. after 48 hours (1.69 ± 0.27% DNA; control 0.59 ± 0.11% DNA). This study proved that FB1-induced DNA damage is time- and dose-dependent, and that it could be caused in Wistar rats by a single dose.
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Su, Ting, Xian-Yang Qin, Naoshi Dohmae, Feifei Wei, Yutaka Furutani, Soichi Kojima, and Wenkui Yu. "Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling." Metabolites 11, no. 3 (March 15, 2021): 167. http://dx.doi.org/10.3390/metabo11030167.
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The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important in the organization of the membrane and membrane protein-mediated signal transduction. Ganglioside synthesis is increased in several types of cancers and has been proposed as a promising target for cancer therapy. Here, we provide evidence that ganglioside synthesis was increased in the livers of an animal model recapitulating the features of activation and expansion of liver progenitor-like cells and liver cancer (stem) cells. Chemical inhibition of ganglioside synthesis functionally suppressed proliferation and sphere growth of liver cancer cells, but had no impact on apoptotic and necrotic cell death. Proteome-based mechanistic analysis revealed that inhibition of ganglioside synthesis downregulated the expression of AURKA, AURKB, TTK, and NDC80 involved in the regulation of kinetochore metaphase signaling, which is essential for chromosome segregation and mitotic progression and probably under the control of activation of TP53-dependent cell cycle arrest. These data suggest that targeting ganglioside synthesis holds promise for the development of novel preventive/therapeutic strategies for HCC treatment.
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Eminovic, Izet, Emira Kahrovic, Aner Mesic, Emir Turkusic, Dzenana Kargic, Adnan Zahirovic, and Zana Dolicanin. "Cytogenotoxic effects of two potential anticancer Ruthenium(III) Schiff Bases complexes." Journal of Health Sciences 6, no. 2 (October 3, 2016): 112–20. http://dx.doi.org/10.17532/jhsci.2016.357.
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Introduction: Treatment of cancer has been subject of great interest. Researchers are continuously searching for new medicines. In this sense, ruthenium complexes have big potential. Some evidences suggest that ruthenium compounds possess anticancer activities. We synthesized two recently published ruthenium(III) complexes with bidentate O,N and tridentate O,O,N Schiff bases derived from 5-substituted salicylaldehyde and aminophenol or anilineare. These compounds showed affinity for binding to the DNA molecule, however, insufficient data are available regarding their possible toxic effects on biological systems.Methods: In the present study we evaluated genotoxic, cytotoxic, and cytostatic effects of Na[RuCl2(L1)2] and Na[Ru(L2)2], using the Allium cepa assay.Results: Different toxic effects were observed depending on the substance, tested concentration, and endpoint measured. In general, the tested compounds significantly lowered the root growth and mitotic index values as compared to the control group. Additionally, a wide range of abnormal mitotic stages, both clastogenic and non-clastogenic were observed in the treated cells. Na[RuCl2(L1)2] significantly increased the frequency of sticky metaphases, chromosome bridges, micronuclei, impaired chromosome segregation, as well as number of apoptotic and necrotic cells over the controls. In contrast, Na[Ru(L2)2] did not show significant evidence of genotoxicity with regard to chromosome aberrations and micronuclei, however, significant differences were detected in the number of apoptotic and necrotic cells when the highest concentration was applied.Conclusions: In this study we demonstrated antiproliferative effects of Na[RuCl2(L1)2] and Na[Ru(L2)2]. At clinical level, these results could be interesting for further studies on anticancer potential of the ruthenium(III) complexes using animal models.
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Eferl, Robert, Maria Sibilia, Frank Hilberg, Andrea Fuchsbichler, Iris Kufferath, Barbara Guertl, Rainer Zenz, Erwin F. Wagner, and Kurt Zatloukal. "Functions of c-Jun in Liver and Heart Development." Journal of Cell Biology 145, no. 5 (May 31, 1999): 1049–61. http://dx.doi.org/10.1083/jcb.145.5.1049.
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Mice lacking the AP-1 transcription factor c-Jun die around embryonic day E13.0 but little is known about the cell types affected as well as the cause of embryonic lethality. Here we show that a fraction of mutant E13.0 fetal livers exhibits extensive apoptosis of both hematopoietic cells and hepatoblasts, whereas the expression of 15 mRNAs, including those of albumin, keratin 18, hepatocyte nuclear factor 1, β-globin, and erythropoietin, some of which are putative AP-1 target genes, is not affected. Apoptosis of hematopoietic cells in mutant livers is most likely not due to a cell-autonomous defect, since c-jun−/− fetal liver cells are able to reconstitute all hematopoietic compartments of lethally irradiated recipient mice. A developmental analysis of chimeras showed contribution of c-jun−/− ES cell derivatives to fetal, but not to adult livers, suggesting a role of c-Jun in hepatocyte turnover. This is in agreement with the reduced mitotic and increased apoptotic rates found in primary liver cell cultures derived from c-jun−/− fetuses. Furthermore, a novel function for c-Jun was found in heart development. The heart outflow tract of c-jun−/− fetuses show malformations that resemble the human disease of a truncus arteriosus persistens. Therefore, the lethality of c-jun mutant fetuses is most likely due to pleiotropic defects reflecting the diversity of functions of c-Jun in development, such as a role in neural crest cell function, in the maintenance of hepatic hematopoiesis and in the regulation of apoptosis.
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Kovpak, V., and O. Kovpak. "Cytogenetic analysis of rat pancreatic cell cultures at early passages." Cell and Organ Transplantology 4, no. 1 (May 31, 2016): 66–69. http://dx.doi.org/10.22494/cot.v4i1.8.
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Cell culture obtained from the pancreas can serve as a source of physiologically competent substitute for primary islets of Langerhans in the treatment of diabetes. However, it is possible to obtain the required number of cells only at long-term cultivation in vitro. Therefore, it is necessary to investigate the risks of neoplastic transformation of cells in vitro before transplantation.Materials and methods. Cell culture was obtained by explant method from pancreas of 12-day-old rats. Cell cultures of the first to sixth passages were used for the cytogenetic analysis. In this study the number of cells with altered karyotype, cells with micronuclei, binucleated cells and the cells in a state of apoptosis were considered, mitotic index was calculated.Results. Aneuploid cells were noted at all passages in an amount of 2.2 % (1st) to 16.6 % (4th). Polyploidy manifested in a population of cells from the second (1.1 %) to the sixth passage (4.4 %) with a maximum at passage four (7.8 %). A significant increase in their number was observed since the second passage (0.3 %). We have seen a significant increase in the number of binucleated cells from the first (0.1 %) to the sixth passage (0.8 %). During the study there was a decrease in mitotic index from the first (2.7 %), to the third passage (1.5 %) and its gradual increase in fourth (1.7 %) and sixth (2.0 %) passages. In addition, there was discovered a small percentage of cells in apoptosis, their number gradually increased to the 4th passage (0.5 %). The 5th-6th passages showed decrease in the number of apoptotic cells to 0.1 %.Conclusion. There have been revealed changes in the rat pancreatic cells culture as aneuploidies, polyploidies and micronuclei, the intensity of which varied depending on the passage. However, karyotype variability of mentioned cell did not exceed the level of spontaneous mutations characteristic of mammalians.
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Murali, Mahadevamurthy, Satish Anandan, Mohammad Azam Ansari, Mohammad A. Alzohairy, Mohammad N. Alomary, Sarah Mousa Maadi Asiri, Ahmad Almatroudi, et al. "Genotoxic and Cytotoxic Properties of Zinc Oxide Nanoparticles Phyto-Fabricated from the Obscure Morning Glory Plant Ipomoea obscura (L.) Ker Gawl." Molecules 26, no. 4 (February 8, 2021): 891. http://dx.doi.org/10.3390/molecules26040891.
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The study was undertaken to investigate the antioxidant, genotoxic, and cytotoxic potentialities of phyto-fabricated zinc oxide nanoparticles (ZnO-NPs) from Ipomoea obscura (L.) Ker Gawl. aqueous leaf extract. The UV-visible spectral analysis of the ZnO-NPs showed an absorption peak at 304 nm with a bandgap energy of 3.54 eV, which are characteristics of zinc nanoparticles. Moreover, the particles were of nano-size (~24.26 nm) with 88.11% purity and were agglomerated as observed through Scanning Electron Microscopy (SEM). The phyto-fabricated ZnO-NPs offered radical scavenging activity (RSA) in a dose-dependent manner with an IC50 of 0.45 mg mL−1. In addition, the genotoxicity studies of ZnO-NPs carried out on onion root tips revealed that the particles were able to significantly inhibit the cell division at the mitotic stage with a mitotic index of 39.49%. Further, the cytotoxic studies on HT-29 cells showed that the phyto-fabricated ZnO-NPs could arrest the cell division as early as in the G0/G1 phase (with 92.14%) with 73.14% cells showing early apoptotic symptoms after 24 h of incubation. The results of the study affirm the ability of phyto-fabricated ZnO-NPs from aqueous leaf extract of I. obscura is beneficial in the cytotoxic application.
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Vranic, Andrej. "Caspase-3 and Survivin Expression in Primary Atypical and Malignant Meningiomas." ISRN Neuroscience 2013 (December 19, 2013): 1–5. http://dx.doi.org/10.1155/2013/626290.
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Objective. Information about possible prognostic factors of the survival of patients with atypical and malignant meningiomas (AMM) is sparse. The aim of our study was to evaluate prognostic significance of apoptotic marker caspase-3 and apoptotic inhibitor survivin in a series of primary AMM. Methods. 86 AMM (76 atypical and 10 malignant) were analyzed. Caspase-3 and survivin expression was evaluated immunohistochemically. The correlation between caspase-3, survivin, and other possible factors of meningioma recurrence was evaluated. Uni- and multivariate recurrence-free survival (RFS) and overall survival (OS) analyses were performed. Results. The intensity of caspase-3 expression correlated with the tumor grade (P=0.004), the proliferation index (P=0.019), and the mitotic count (P=0.013). Survivin tended to be more expressed in female patients (P=0.072). Survivin expression was stronger in malignant compared to atypical meningiomas, however, the difference was not statistically important (P=0.491). Neither survivin nor caspase-3 expression significantly predicted OS or RFS in patients with AMM. Conclusions. Strong caspase-3 expression on AMM cells could reflect a cellular attempt at the homeostatic autoregulation of the tumor size. Survivin expression on AMM cells is similar to the survivin expression reported on benign meningiomas. Caspase-3 and survivin expression has no prognostic significance on the survival of patients with AMM.
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Shafigullina, Z. A., S. Yu Medvedeva, and I. G. Danilova. "ROLE OF THE STROMAL CELLULAR COMPONENT IN COMPENSATORY PROCESSES IN DIFFUSE LIVER DAMAGE." Toxicological Review, no. 3 (June 28, 2018): 32–37. http://dx.doi.org/10.36946/0869-7922-2018-3-32-37.
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The aim of the study was to assess the role of the cellular component of the stroma in liver regeneration after its toxic damage. The experimental model of toxic hepatitis caused by intraperitoneal administration of tetrachloromethane (CCl4) showed that regeneration processes in the liver on the 3rd day are manifested in an increase in binuclear hepatocytes, Ki-67 + cells and hepatocytes dividing by mitosis. The reaction of the stromal component is expressed in an increase in the number of CD45 +, mast and sinusoidal cells (SC). On the 7th day of the development of toxic hepatitis the hepatocyte alteration increases, that is accompanied by a sharp decrease in the mitotic index and the number of Ki-67 + cells. In the stromal component there is a decrease in the number of sinusoidal cells, CD45 + and a significant increase in mast cells with a high secretion granule content.
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Kim, Edward Jae-hoon, Danielle C. Chinn, Thomas John Semrad, and Philip C. Mack. "Aurora kinase A inhibition in combination with proapoptotic BH3-mimetic for treatment of pancreatic cancer." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 316. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.316.
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316 Background: BH3-mimetics were designed to inhibit the anti-apoptotic members of the Bcl-2 family of proteins. BH3-mimetics in clinical development do not inhibit the Bcl-2 protein Mcl1, which is often active in pancreatic cancer. However, Mcl1 level can be decreased by mitotic arrest. Therefore, drugs that cause mitotic arrest may augment apoptosis induced by BH3-mimetics. Aurora Kinase A (AKA), also commonly overexpressed in pancreatic cancer, regulates mitotic spindle assembly and centrosome maturation and its inhibition leads to M-phase arrest. We hypothesized that inhibiting AKA would increase sensitivity of pancreatic cancer cells to BH3-mimetic-induced apoptosis. Methods: Pancreatic cancer cell lines (AsPC-1, PANC-1, MIA PaCa-2, HPAF-II) were evaluated for AKA protein expression by Western blot (WB). Baseline cell cycle distribution was evaluated by flow cytometry. All four cell lines were treated with a BH3-mimetic (ABT-263) alone, an AKA inhibitor (MLN8237) alone, or the combination in comparison to untreated controls. Cell viability was measured using the Celltiter-Fluor assay. Apoptosis was evaluated by WB for cleaved PARP and caspase 3. Percentage of cells undergoing apoptosis was quantitated using flow cytometry of annexin V and propidium iodide stained cells. Results: AKA expression varied between cell lines but correlated with percentage of cells in G2/M. Level of AKA expression did not appear to correlate with response to MLN8237. However, MLN8237 did induce mitotic arrest resulting in an increase in the G2/M fraction. Cell viability assays revealed limited sensitivity to MLN8237 or ABT-263 alone. MIA PaCa-2 cells were the most sensitive to MLN8237 with IC50 ~0.09µM and HPAF-II cells were the most sensitive to ABT-263 with IC50 0.6µM. MLN8237 lowered the IC50of ABT-263 in all 4 cell lines. Chou-Talalay plots exhibited a combination index < 1 in each cell line, confirming synergy. WB for cleaved PARP and caspase 3 showed increased apoptosis with the combination. The percentage of cells undergoing apoptosis also increased with the combination in each cell line. Conclusions: Inhibition of AKA synergistically augments BH3-mimetic-induced apoptosis in pancreatic cancer cells.
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Journal, Baghdad Science. "Study of cytotoxic Effects Alcoholic Nerium Oleander L. Extract on female Albino mice." Baghdad Science Journal 8, no. 2 (June 5, 2011): 359–65. http://dx.doi.org/10.21123/bsj.8.2.359-365.
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This study involved the evaluation of Alcoholic extract of Nerium Oleander L. plant that have a promising anticancer cell. This extract was compared to the well known anticancer drug Cis – Platinum by utilizing an in vivo system in female Albino mice. The first direction was cytogenetically using the mitotic Index of bone marrow cells as a parameter for the cytotoxic effect of this extract. The second direction was enzymatical using a widely distributed enzyme GOT in the different organs of mice: Liver , kidney , spleen and lung . Animals were treated with three doses of Cis-platin , 50 , 200 and 350 Mg/mouse for three days . The same doses were used for the other extract . This study showed that the extract have a promising anticancer cell as could be seen from these effect on mitotic Index (MI) of mice bone marrow , (MI) decreased in animals treated with different doses of extract , mitotic index was reduced to 78% on day three in animals treated with 350 ?g/mouse . These effects were similar to the effect of Cis-platin at the same doses. Comparing the effect of this extract on GOT enzyme showed that Cis-platin was more effective on activating the spleen GOT enzyme of about 95% than the extract while the extract is more effective in Lung , The extract activated GOT enzyme activity in the all organs.
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Duy Binh, Tran, Tuan L. A. Pham, Taisei Nishihara, Tran Thanh Men, and Kaeko Kamei. "The Function of Lipin in the Wing Development of Drosophila melanogaster." International Journal of Molecular Sciences 20, no. 13 (July 4, 2019): 3288. http://dx.doi.org/10.3390/ijms20133288.
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Lipin is evolutionarily conserved from yeast to mammals. Although its roles in lipid metabolism in adipocyte tissue, skeletal muscle, and the liver, and as a transcriptional co-activator are known, its functions during development are still under investigation. In this study, we analyzed the role of Drosophila lipin (dLipin) in development. Specifically, we showed that the tissue-selective knockdown of dLipin in the wing pouch led to an atrophied wing. Elevated DNA damage was observed in the wing imaginal disc of dLipin-knockdown flies. dLipin dysfunction induced accumulation of cells in S phase and significantly reduced the number of mitotic cells, indicating DNA damage-induced activation of the G2/M checkpoint. Reduced expression of cyclin B, which is critical for the G2 to M transition, was observed in the margin of the wing imaginal disc of dLipin-knockdown flies. The knockdown of dLipin led to increased apoptotic cell death in the wing imaginal disc. Thus, our results suggest that dLipin is involved in DNA replication during normal cell cycle progression in wing development of Drosophila melanogaster.
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Samiec, M., M. Skrzyszowska, M. Bochenek, R. Slomski, and D. Lipinski. "50 FLOW CYTOMETRY-MEDIATED DETECTION OF LATE-APOPTOTIC HYPODIPLOID CELL FRACTIONS IN LIPOFECTED PORCINE ADULT DERMAL FIBROBLAST CELL LINES SELECTED FOR SOMATIC CELL NUCLEAR TRANSFER." Reproduction, Fertility and Development 21, no. 1 (2009): 125. http://dx.doi.org/10.1071/rdv21n1ab50.
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Analysis of nuclear DNA (nDNA) content of in vitro cultured somatic cells undergoing apoptosis became one of the most common methods for single-parameter flow cytometric measurement of this process. Apoptosis assessment is performed by quantification of hypodiploid cells. The cell fractions with hypodiploid (<2C) nDNA molecule number, which involve the so-called sub-G1 peak in DNA histograms are identified as late-apoptotic subpopulations. Advantage of this method is the possibility of simultaneous cell cycle measurement. The present study was conducted to investigate the preimplantation developmental outcome of porcine transgenic NT embryos reconstituted with non-apoptotic gilt ear skin-derived fibroblast cells that had been lipofected with pWAPhGH-GFPBsd gene construct. The nuclear donor cells were derived from such cell line populations whose representative random samples had been analyzed on both cell cycle and apoptosis through the non-vital nDNA fluorescent dyeing and subsequent flow cytometry (FACS). Frozen/thawed fibroblast cells, which had been cultured up to a total confluency after 2–3 passages, were used for the diagnostics. The fixed dermal fibroblasts were exposed to nDNA extraction buffer for 5 min and incubated in DNA staining solution (propidium iodide and RNAse) for 30 min. After fluorescent labeling, the cells were analyzed in the flow cytometer by reading nDNA fluorescence in the red band. Somatic cell cloned embryos, which had been created by simultaneous fusion and electrical activation, followed by delayed chemical activation of reconstructed oocytes, were cultured in NCSU-23/FBS medium for 6 to 7 days up to morula/blastocyst stages (Skrzyszowska et al. 2008 Theriogenology 70, 248–259). The FACS analysis revealed that out of all the fibroblast cells diagnosed, 94.9% were cycling and 5.1% were late-apoptotic. In turn, from among the non-apoptotic cells, an average of 92.7% were at G1/G0 stages of cell cycle, 3.1% were at S stage and 4.2% were at G2/M stages. A total of 294/348 (84.5%) enucleated oocytes were successfully fused with non-apoptotic nuclear donor cells. Out of 294 cultured NT embryos, 199 (67.7%) were cleaved. The rates of cloned embryos that reached the morula and blastocyst stages yielded 165/294 (56.1%) and 57/294 (19.4%), respectively. In conclusion, the FACS analysis for mitotic cycle of 100%-confluent lipofected adult dermal fibroblasts confirmed that the cell cycle synchronization at G1/G0 phases was highly efficient, while the frequency of late-apoptotic cells was low. It was also found that the relatively high percentages of pWAPhGH-GFPBsd transgenic blastocysts developed in vitro from NT embryos reconstructed with fibroblast cells undergoing lipofection. Furthermore, porcine cloned blastocysts exhibited approximately 100% index of reporter eGFP transgene expression, which was visually confirmed by their live-fluorescent evaluation. This work was supported by the Scientific Net of Animal Reproduction Biotechnology.
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Tsvirenko, Sergey, Leonid Saveliev, and Sergey Sazonov. "Features of regenerative processes in case of extreme factors influencing the body." BIO Web of Conferences 22 (2020): 02012. http://dx.doi.org/10.1051/bioconf/20202202012.
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Changes in the specific liver mass, number of single and binucleate cells of different ploidy, mitotic index and alteration index, DNA content and inclusion of 3H-thymidine in DNA of Wistar rats and CBA mice in the following conditions: at 0°C for 3, 7, 14 days for 23 hours per day, and in the highlands conditions (3, 200 m above sea level) for 3 and 30 days. Activation of regenerative processes has been established — proliferation of hepatocytes (mainly diploid) in combination with polyploid cell share reduction, as well as cellular hypertrophy development. Cell dynamics shifts persisted throughout the observation duration and were opposite in direction when growing up and aging.
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Song, Ying, Jian-Gang Wang, Rui-Fang Li, Yan Li, Zhao-Chu Cui, Leng-Xin Duan, and Fei Lu. "Gecko Crude Peptides Induce Apoptosis in Human Liver Carcinoma CellsIn Vitroand Exert Antitumor Activity in a Mouse Ascites H22 Xenograft Model." Journal of Biomedicine and Biotechnology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/743573.
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Aim. To investigate the anti-tumor effects and mechanisms of gecko crude peptides (GCPs)in vitroandin vivo.Methods. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay was applied to measure the effects of GCPs on the HepG2 cell viability. Fluorescence morphology was used to identify apoptotic cells. A xenograft H22 liver cancer model was established in Kunming mice. The tumor-bearing mice were treated with daily intraperitoneal injections of normal saline (NS group) or GCPs (80, 40 or 20 mg/kg) for 10 days, or once per two days with 2 mg/kg doxorubicin (ADR group;n=10each). Serum tumor necrosis factor (TNF-α) and interleukin (IL)-6 were quantified using ELISA assay.Results. GCPs significantly inhibited the growth of HepG2 cells and induced typical apoptotic morphological features through increasing bcl-2/bax ratio in a dose- and time-dependent mannerin vitro. The tumor weights of the ADR group, GCPs (H) group, GCPs (M) group, GCPs (L) group were smaller compared to the NS group. While the white blood cell count, thymus index, spleen index were higher in the high dose GCPs group than the NS group (P<0.05), the VEGF expression in tumor tissue and serum TNF-αand IL-6 levels in the GCPs groups were lower than the NS group (P<0.05).
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Chai, Louis F., John C. Hardaway, Kara R. Heatherton, Kyle P. O’Connell, Mikayla C. Lopes, Benjamin A. Rabinowitz, Chandra C. Ghosh, et al. "Regional Delivery of Anti-PD-1 Agent for Colorectal Liver Metastases Improves Therapeutic Index and Anti-Tumor Activity." Vaccines 9, no. 8 (July 21, 2021): 807. http://dx.doi.org/10.3390/vaccines9080807.
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Metastatic liver tumors have presented challenges with the use of checkpoint inhibitors (CPIs), with only limited success. We hypothesize that regional delivery (RD) of CPIs can improve activity in the liver and minimize systemic exposure, thereby reducing immune-related adverse events (irAE). Using a murine model of colorectal cancer liver metastases (LM), we confirmed high levels of PD-L1 expression on the tumor cells and liver myeloid-derived suppressor cells (L-MDSC). In vivo, we detected improved LM response at 3 mg/kg on PTD7 via portal vein (PV) regional delivery as compared to 3 mg/kg via tail vein (TV) systemic delivery (p = 0.04). The minimal effective dose at PTD7 was 5 mg/kg (p = 0.01) via TV and 0.3 mg/kg (p = 0.02) via PV. We detected 6.7-fold lower circulating CPI antibody levels in the serum using the 0.3 mg/kg PV treatment compared to the 5 mg/kg TV cohort (p < 0.001) without increased liver toxicity. Additionally, 3 mg/kg PV treatment resulted in increased tumor cell apoptotic signaling compared to 5 mg/kg TV (p < 0.05). Therefore, RD of an anti-PD-1 CPI therapy for CRCLM may improve the therapeutic index by reducing the total dose required and limiting the systemic exposure. These advantages could expand CPI indications for liver tumors.
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Cristofolini, A., C. Merkis, M. Fiorimanti, A. Magnoli, M. Caverzan, and L. Cavaglieri. "Saccharomyces cerevisiae RC016 modulates the apoptotic pathways in rat livers treated with aflatoxin B1." World Mycotoxin Journal 12, no. 4 (December 4, 2019): 387–97. http://dx.doi.org/10.3920/wmj2019.2472.
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The aim was to study the effect of probiotic Saccharomyces cerevisiae RC016 on the expression of apoptotic protein Bax, Bcl-2, DR4 and c-FLIP, in liver of rats exposed to aflatoxin B1 (AFB1). Four treatments were applied to inbred male Wistar rats: uncontaminated feed control, S. cerevisiae RC016 control, contaminated feed with 100 μg/kg AFB1 and contaminated feed with 100 μg/kg AFB1 + daily oral dose 108 viable S. cerevisiae RC016 cells. Histological technique and high-resolution light microscopy (HRLM) were performed to the study of tissue morphology, the TUNEL assay was used to determine the apoptosis cellular and the expression of Bax, Bcl-2, DR4 and c-FLIP was determinate through immunohistochemistry. In liver the necrotic lesions observed with AFB1 treatment were reduced with the addition of yeast. The highest apoptotic index (IAp) was found in the yeast control, with AFB1 decrease significantly the IAp, while with the addition of yeast increase the IAp of liver cells. This was confirmed by HRLM. DR4 receptor was not present in any of the treatments. The immunolabeling of c-FLIP showed a statistically significant increase in the treatments with S. cerevisiae. The extrinsic pathway of apoptosis through the FAS-receptors would neither be active in the apoptotic process observed in rat livers in the treatments with yeast. Significant differences between proteins Bax and Bcl-2 and effect of treatments on the immunolabeling of Bax were determinate. The exposure to AFB1 decreased the IAp in the livers; while the addition of the yeast produced a significant statistically increase of IAp. In this study it was determined that the apoptosis in liver would be induced by the intrinsic pathway through Bax. These suggest that the incorporation of the autocrine strain S. cerevisiae RC016 increases the apoptosis in liver, counteracting the adverse effect of aflatoxin B1 and favouring the tissue remodulation.
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Martín-Burriel, Inmaculada, Nigel O. Roome, Olivier Dorchies, and Annick Prenez. "Histopathological and Molecular Changes During Apoptosis Produced by 7H-Dibenzo[c,g]-Carbazole in Mouse Liver." Toxicologic Pathology 32, no. 2 (February 2004): 202–11. http://dx.doi.org/10.1080/01926230490274353.
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The topical administration of 7H-dibenzo[c,g]carbazole (7H-DBC) at very low but repeated doses causes genotoxic effects such as DNA adduct formation and produces hepatocellular apoptosis in mouse liver. The purpose of this work was to investigate the alterations in gene expression and protein levels of biomarkers associated with the p53 pathway in mouse liver after exposure to cumulative low doses of 7H-DBC by skin paint applications. The compound was administered topically at the dose of 13.35 μg per animal every 2 days to give either 6, 8, 10, or 12 applications. Animals were sacrificed 48 hours after the different treatments. The apoptotic index increased with the number of applications, with a major proportion of apoptotic cells in the periportal areas. A significant increase of Bax mRNA and protein expression was observed after the 8th application whereas the expression of mRNA levels of Fas and p53 did not show significant differences between treated and control animals. Nuclear staining of p53 was detected in hepatocyte nuclei showing the activation of this protein. Later in the apoptosis process we observed the up-regulation of TGF- β1 in parenchymal cells. In addition to the induction of the p53 apoptosis pathway in vivo by 7H-DBC, we have observed molecular changes related to cell proliferation such as the overexpression of the antiapoptotic gene Bcl-2.
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QUINN, Carmel M., Katarina KÅGEDAL, Alexei TERMAN, Uri STROIKIN, Ulf T. BRUNK, Wendy JESSUP, and Brett GARNER. "Induction of fibroblast apolipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis." Biochemical Journal 378, no. 3 (March 15, 2004): 753–61. http://dx.doi.org/10.1042/bj20031352.
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Apolipoprotein E (apoE) mediates the hepatic clearance of plasma lipoproteins, facilitates cholesterol efflux from macrophages and aids neuronal lipid transport. ApoE is expressed at high levels in hepatocytes, macrophages and astrocytes. In the present study, we identify nuclear and cytosolic pools of apoE in human fibroblasts. Fibroblast apoE mRNA and protein levels were up-regulated during staurosporine-induced apoptosis and this was correlated with increased caspase-3 activity and apoptotic morphological alterations. Because the transcription of apoE and specific pro-apoptotic genes is regulated by the nuclear receptor LXR (liver X receptor) α, we analysed LXRα mRNA expression by quantitative real-time PCR and found it to be increased before apoE mRNA induction. The expression of ABCA1 (ATP-binding cassette transporter A1) mRNA, which is also regulated by LXRα, was increased in parallel with apoE mRNA, indicating that LXRα probably promotes apoE and ABCA1 transcription during apoptosis. Fibroblast apoE levels were increased under conditions of serum-starvation-induced growth arrest and hyperoxia-induced senescence. In both cases, an increased nuclear apoE level was observed, particularly in cells that accumulated lipofuscin. Nuclear apoE was translocated to the cytosol when mitotic nuclear disassembly occurred and this was associated with an increase in total cellular apoE levels. ApoE amino acid sequence analysis indicated several potential sites for phosphorylation. In vivo studies, using 32P-labelling and immunoprecipitation, revealed that fibroblast apoE can be phosphorylated. These studies reveal novel associations and potential roles for apoE in fundamental cellular processes.
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Nolan, LA, and A. Levy. "Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures." Journal of Endocrinology 169, no. 2 (May 1, 2001): 263–70. http://dx.doi.org/10.1677/joe.0.1690263.
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Glucocorticoid withdrawal, depending on the dose and duration of treatment, results in a transient but sometimes prolonged reduction in hypothalamo-pituitary-adrenal (HPA) axis secretory responsiveness. As the anatomic basis of HPA axis suppression remains uncertain, we have directly examined changes in trophic activity within the rat anterior pituitary gland following dexamethasone withdrawal and re-treatment. Treatment of adrenalectomised, male Wistar rats with dexamethasone results in a discrete, highly significant burst of apoptosis in the anterior pituitary with concurrent suppression of mitosis. Despite a surge in mitotic activity immediately after dexamethasone withdrawal, calculated total anterior pituitary cell populations remain below that seen in untreated adrenalectomised controls. Repeated exposures to dexamethasone show that the dexamethasone-sensitive cell population that is deleted by apoptosis is partially but not completely restored. As the amplitude of apoptotic bursts induced by second and third dexamethasone exposures are similar but smaller than that induced by initial exposure, it appears that the very first exposure to dexamethasone deletes a subset of anterior pituitary cells that are either not restored at all, or are only replaced very slowly. The reduced proportion of corticotrophs contributing to the increase in mitotic index after dexamethasone withdrawal corroborates this. Although continued cell turnover within the pituitary predicts that the absolute cellular deficit would diminish with time, the effects seen may contribute to the delayed recovery of pituitary axis function following cessation of glucocorticoid treatment.
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Kovpak, V. V., and O. S. Kovpak. "Порівняльна характеристика генетичної стабільності культур клітин жирової тканини та кісткового мозку щурів на ранніх пасажах." Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 19, no. 73 (February 2, 2017): 95–100. http://dx.doi.org/10.15421/nvlvet7320.
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From literary sources, we received a number of controversial data regarding the risks of neoplastic transformation of stem cells in vitro. Inasmuch as today bone marrow has been sufficiently studied as a source of adult donor stem cells, and adipose tissue is an alternative source for obtaining cell material (from which it may be obtained using less invasive methods and in much greater quantity), determination of genetic stability of these particular cell cultures currently is the most relevant issue. Comparison of genetic stability of rat bone marrow and adipose cell cultures from the first to the sixth passages. Materials and methods: 3 non-linear 4 months old male rats and 9 non-linear 12 days old infant rats were used in the experiment. Adipose cell culture was obtained from subcutaneous fat using the standardized method in our own modification. Bone marrow cell culture was obtained from the rat femurs, tibiae, and humeri using the standardized method. Obtained cell mass was cultivated in a standard culture medium in a СО2 incubator at 37 ºС and with 5% СО2 concentration. Cytogenetic analysis was carried out on 30 metaphase plates from each passage. Cells from the first to the sixth passage we used in the research. A modification of the standard cytogenetic method was used to obtain chromosome preparations. In the preparations prepared in an aforementioned way, numerical chromosome abnormalities, like aneuploidy, polyploidy, were determined, as well as the number of binucleate cells, micronucleus cells, mitotic and apoptotic indexes. Here, we provide the comparison of genetic stability indicators for rat bone marrow and adipose cell cultures throughout the in vitro cultivation thereof. Changes in the genetic apparatus were identified in both bone marrow and adipose tissue cell cultures. Karyotype analysis of rat bone marrow and adipose cell cultures showed that, given the conditions that we used for the cultivation, the number of aneuploidies and polyploidies varies from one passage to another; however it does not go beyond the limits of spontaneous mutagenesis typical for mammals. Based on the results of cytogenetic evaluation of the culture, it was determined that the number of cells with micronuclei and the binucleate cell remains within the normal range from the first to the sixth passages. The number of cells with aneuploidy and micronuclei in adipose cell culture on all passages was lower than in bone marrow cell culture; this indicates its higher genetic stability in terms of these indicators. The highest mitotic index was determined on the first passage with its following decrease throughout the cultivation in inverse proportion to apoptotic index. The obtained data on the genetic stability of both adipose and bone marrow cell cultures are within normal range typical for mammals in terms of all studied indicators. This allows for the following studies relating to the transplantation with minimal risk of neoplastic transformation of the said cultures.
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Beasley, Michael A., Vibha Singhal, Aloysius J. Klingelhutz, Ike Akabogu, and Frederick D. Goldman. "Association of Telomere Length in Dyskeratosis Congenita Lymphocytes with Increased Sensitivity to Radiation and Anti-Mitotic Agents." Blood 104, no. 11 (November 16, 2004): 2833. http://dx.doi.org/10.1182/blood.v104.11.2833.2833.
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Abstract Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have recently described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). Importantly, we have noted progressive shortening of telomeres in lymphocytes from the most recent generation, correlating with earlier onset of severe cytopenias in some of these patients. While telomere shortening is a normal consequence of the aging process, DC patients display accelerated telomere shortening in many somatic cell types. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents. To test this hypothesis, we characterized lymphocytes from nine AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol. Cell proliferation and viability were quantitated by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. CD57 and CD95, markers of cellular senescence and apoptosis, were significantly upregulated on DC T lymphocytes after two weeks in culture relative to controls. In addition to DC lymphocytes having a decreased proliferative capacity, an increased sensitivity to Taxol was noted, with an average decrease of 21% in cell growth relative to similarly treated control cells. This effect was also noted in irradiated DC cells. Finally, DC lymphocytes displayed an increased apoptotic index in the presence of varying doses of Taxol. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients.
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van der Weyden, Louise, Peter Caldwell, Liesl van Rooyen, Emily P. Mitchell, and Nicolize O’Dell. "Metastatic Cutaneous Melanoma in a White African Lioness (Panthera leo)." Veterinary Sciences 8, no. 8 (August 1, 2021): 154. http://dx.doi.org/10.3390/vetsci8080154.
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Malignant melanomas tend to be locally destructive, aggressive tumours commonly associated with recurrence and/or metastasis. In this report, a 13-year-old captive white African lioness (Panthera leo), with a recent history of intermittent bouts of lethargy and inappetence, presented with a distended abdomen (due to ascites) and a small, round crusty lesion on the ear. An abdominal ultrasound showed the presence of masses on the liver and an exploratory laparotomy revealed multiple pale lesions on the liver and omentum. Histopathology revealed sheets of pleomorphic neoplastic cells compressing the non-neoplastic liver tissue. Similar neoplastic cells had multifocally expanded and effaced omentum adipose tissue, as well as formed a well-circumscribed mass in the ear sample, extending from close to the epidermis to the lateral and deep margins of the section. All three tissue samples had a high mitotic index (15 per 10 HPF), and critically, in the ear sample, there were rafts of neoplastic cells in the lymphatics, indicating lymphovascular invasion. Immunohistochemistry for the melanoma marker, PNL-2, showed strong positivity in all three tissue samples. Thus, the diagnosis was of malignant melanoma with metastasis to the liver and omentum. This is the first report of metastatic cutaneous melanoma in a lion.
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Rai, R. M., S. Q. Yang, C. McClain, C. L. Karp, A. S. Klein, and A. M. Diehl. "Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 6 (June 1, 1996): G909—G918. http://dx.doi.org/10.1152/ajpgi.1996.270.6.g909.
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Although previous work suggests that tumor necrosis factor-alpha (TNF) promotes liver regeneration after partial hepatectomy (PH), the source of TNF is unknown. If Kupffer cells release TNF after PH, then Kupffer cell depletion by gadolinium chloride (GdCl) should inhibit liver regeneration. To test this hypothesis, cytokine expression and regenerative events were compared in GdCl-treated and control rats. Functional assays and Northern blot analysis of a Kupffer cell-specific mRNA confirmed that GdCl depleted Kupffer cells. Despite this, semiquantitative reverse transcription-polymerase chain reaction analysis of total hepatic RNA showed six- to eightfold higher levels of TNF transcripts in GdCl-treated rats. In this group, PH caused 12-to 16-fold greater induction of interleukin-6, a TNF-inducible cytokine, and two- to threefold greater induction of several cytokine-regulated genes (c-jun, C/EBP-beta, and C/EBP-delta). GdCl also amplified regeneration-associated increases in the DNA binding activity of AP-1, a growth regulatory transcription factor. Furthermore, hepatic incorporation of [3H]thymidine, expression of the S-phase antigen, proliferating cell nuclear antigen, and the hepatocyte mitotic index were each significantly greater in GdCl-treated rats. Thus, although GdCl causes Kupffer cell depletion, it does not decrease liver TNF and actually enhances liver regeneration after PH.
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Маклакова, И. Ю., Д. Ю. Гребнев, В. Ч. Юсупова, and Е. М. Петрунина. "THE EFFECT OF MULTIPOTENT MESENCHYMAL STROMAL CELLS TRANSPLANTATION ON LIVER MORPHOMETRIC PARAMETERS OF MATURE AND OLD LABORATORY ANIMALS WITH TOXIC HEPATITIS." Морфология, no. 1 (March 26, 2020): 55–60. http://dx.doi.org/10.34922/ae.2020.157.1.009.
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Цель - изучение влияния трансплантации мультипотентных мезенхимальных стромальных клеток (ММСК) на морфометрические показатели печени зрелых и старых лабораторных животных в условиях токсического гепатита. Материал и методы. Эксперименты выполнены на зрелых и старых мышах-самцах. Токсический гепатит вызывали путем внутрибрюшинного введения CClв дозе 50 мкг/кг. Трансплантация клеток осуществлялась в хвостовую вену через 1 ч после введения четыреххлористого углерода однократно. Исследовалось влияние ММСК на морфометрические показатели печени в физиологических условиях и условиях токсического гепатита на 1-, 3-, 7-е сутки после трансплантации клеток. Результаты. У зрелых лабораторных животных на 3-и сутки после введения ММСК на фоне токсического гепатита обнаружено увеличение митотической активности, повышение количества гепатоцитов, площади ядра гепатоцитов и ядерноцитоплазматического индекса. В то же время, у старых лабораторных животных выявлено лишь увеличение площади ядра гепатоцитов и ядерно-цитоплазматического индекса. На 7-е сутки после введения ММСК на фоне токсического гепатита в обеих возрастных группах выявлены активация митотической активности, повышение количества гепатоцитов, увеличение площади ядра гепатоцитов и ядерно-цитоплазматического индекса. Выводы. Изменение морфометрических показателей печени у зрелых и старых лабораторных животных реализуется через механизмы как клеточной, так и внутриклеточной регенерации. При этом у старых лабораторных животных на 3-и сутки после введения ММСК выявлена активация лишь внутриклеточной регенерации, в то время как у зрелых лабораторных животных имеет место повышение клеточной и внутриклеточной регенерации гепатоцитов. В более поздние сроки в обеих изучаемых возрастных группах изменение основных морфометрических показателей печени реализуется через активацию как клеточной, так и внутриклеточной регенерации. Objective - to study the influence of multipotent mesenchymal stromal cells (MMSC) transplantation on morphometric parameters of the liver of mature and old laboratory animals with toxic hepatitis. Material and methods. The experiments were performed on mature and old male mice. Toxic hepatitis was caused by intraperitoneal administration of CCl4 at a dose of 50 μg/kg. The cells were transplanted via the tail vein 1 hour after administration of a single dose of carbon tetrachloride. The effect of MMSC on liver morphometric parameters in physiological conditions and after toxic hepatitis development was studied on days 1, 3, 7 after cell transplantation. Results. An increase in mitotic activity, an increase in the number of hepatocytes, hepatocyte nucleus area, and nuclear cytoplasmic index were found in mature laboratory animals with toxic hepatitis on the 3 day after the introduction of MMSC. At the same time, only an increase in the area of hepatocyte nucleus and nuclear cytoplasmic index was revealed in old laboratory animals. On the 7 day after the introduction of MMSC to the animals with toxic hepatitis, both age groups demonstrated activation of mitotic activity, an increase in the number of hepatocytes, an increase in the area of hepatocyte nucleus and nuclear cytoplasmic index. Conclusions. Changes in liver morphometric parameters in mature and old laboratory animals are realized through mechanisms of both cellular and intracellular regeneration. In addition, the activation of only intracellular regeneration was found in old laboratory animals on the 3rd day after the introduction of MMSC, while in mature laboratory animals there was an increase in cellular and intracellular regeneration of hepatocytes. In later periods in both studied age groups, the change in the main liver morphometric parameters is realized through the activation of both cellular and intracellular regeneration.
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Gerber, H. P., K. J. Hillan, A. M. Ryan, J. Kowalski, G. A. Keller, L. Rangell, B. D. Wright, F. Radtke, M. Aguet, and N. Ferrara. "VEGF is required for growth and survival in neonatal mice." Development 126, no. 6 (March 15, 1999): 1149–59. http://dx.doi.org/10.1242/dev.126.6.1149.
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We employed two independent approaches to inactivate the angiogenic protein VEGF in newborn mice: inducible, Cre-loxP- mediated gene targeting, or administration of mFlt(1–3)-IgG, a soluble VEGF receptor chimeric protein. Partial inhibition of VEGF achieved by inducible gene targeting resulted in increased mortality, stunted body growth and impaired organ development, most notably of the liver. Administration of mFlt(1–3)-IgG, which achieves a higher degree of VEGF inhibition, resulted in nearly complete growth arrest and lethality. Ultrastructural analysis documented alterations in endothelial and other cell types. Histological and biochemical changes consistent with liver and renal failure were observed. Endothelial cells isolated from the liver of mFlt(1–3)-IgG-treated neonates demonstrated an increased apoptotic index, indicating that VEGF is required not only for proliferation but also for survival of endothelial cells. However, such treatment resulted in less significant alterations as the animal matured, and the dependence on VEGF was eventually lost some time after the fourth postnatal week. Administration of mFlt(1–3)-IgG to juvenile mice failed to induce apoptosis in liver endothelial cells. Thus, VEGF is essential for growth and survival in early postnatal life. However, in the fully developed animal, VEGF is likely to be involved primarily in active angiogenesis processes such as corpus luteum development.
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Bayram, D., ES Çetin, M. Kara, M. Özgöçmen, and IA Candan. "The apoptotic effects of silibinin on MDA-MB-231 and MCF-7 human breast carcinoma cells." Human & Experimental Toxicology 36, no. 6 (July 10, 2016): 573–86. http://dx.doi.org/10.1177/0960327116658105.
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Background: Silibinin is a bioactive flavonolignan extracted from milk thistle, known as Silybum marianum. Silibinin exerts strong antiproliferative, proapoptotic, and anti-inflammatory effects. Many studies have shown that silibinin inhibits experimentally induced malignancies of the liver, prostate, skin, and colon as well as promotes inhibition of the proliferation of cancer cell lines in vitro. This study aimed to investigate the effects of silibinin on the human breast carcinoma cell lines MDA-MB-231 and MCF-7 in monolayer and spheroid cultures. Method: The MDA-MB-231 and MCF-7 cell lines were cultured in both monolayer and spheroid cultures. Cells were treated with silibinin at 24, 48, and 72 h of incubation. The 5-bromo-2′-deoxyuridine labeling index was used to determine the cells of the synthesis phase. Poly-ADP-ribose-polimerase immunohistochemical staining and the terminal deoxynucleotidyl transferase dUTP nick and labeling assay were used to determine the death of cells in both the monolayer and spheroid cultures. Results: An half maximal inhibitory concentration dose of silibinin in MDA-MB-231 and MCF-7 cells was 100 µM/mL at 24, 48, and 72 h of incubation. Terminal deoxynucleotidyl transferase dUTP nick and labeling positive cells and active poly-ADP-ribose-polimerase were detected after treatment with silibinin in both the monolayer and spheroid cultures. The dead cell count was higher in the MDA-MB-231 and MCF-7 cell lines with silibinin applied than in the controls. Conclusions: Our study demonstrated that silibinin applications enhanced terminal deoxynucleotidyl transferase dUTP nick and labeling positive cells and active poly-ADP-ribose-polimerase in comparison to the control in both the monolayer and spheroid cultures.
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Schiffer, D., A. Dutto, P. Cavalla, I. Bosone, A. Chiò, R. Villani, and C. Bellotti. "Prognostic Factors in Oligodendroglioma." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 24, no. 04 (November 1997): 313–19. http://dx.doi.org/10.1017/s0317167100032984.
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ABSTRACT:Background:A reliable marker for tumor oligodendroglial cells is not yet available, so that the histological recognition of the tumor still encounters uncertainties. There is no general agreement also on prognostic factors in oligodendroglioma. The inconsistency concerns mainly the histopathological factors. The aim of the study was recognition of prognostic factors in oligodendroglioma.Methods:In a series of ninety-eight oligodendrogliomas, including twenty mixed oligoastrocytomas, clinical [sex, age at surgery, tumor location, symptoms at presentation], therapeutic [extent of resection, year of surgery, post-operative Karnofsky score, post-operative radiotherapy, post-operative chemotherapy], histological [cell density, nuclear pleomorphism, vascular endothelial proliferation, necrosis, microcysts, mitoses, mitotic index (MI), apoptosis, apoptotic index (AI)] and immunohistochemical parameters [MIB-1 and PCNA Labeling Indexes (Lis), staining for GFAP, positivity for p53] were correlated with survival in uni- and multivariate analysis in order to identify their prognostic significance.Results:Age at surgery, extent of surgical resection, year of surgery, postoperative Karnofsky score and MIB-1 LI were associated with survival in both uni- and multivariate analysis. Location, symptoms at presentation, mitoses, MI, AI, and PCNA LI showed a significant correlation with survival in uni- but not in multivariate analysis. The twenty cases of oligoastrocytomas did not show any difference in survival from pure oligodendrogliomas.Conclusions:Some clinical and therapeutic factors together with MIB-1 LI play a prognostic role. MIB-1 LI is prognostic with a cutoff of 8%. Histology gives a limited contribution to the prognosis. Oligoastrocytomas had the same outcome and prognostic factors as pure oligodendrogliomas.
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Diniz, Paulo Henrique Costa, Marcone Loiola dos Santos, Andressa França, Antônio Carlos Melo Lima Filho, Paula Vieira Teixeira Vidigal, Teresa Cristina de Abreu Ferrari, and Maria de Fátima Leite. "Expression of the type 3 inositol 1, 4, 5-trisphosphate receptor according to the chronic liver disease etiology in hepatocellular carcinoma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16604-e16604. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16604.
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e16604 Background: The expression of type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR-3), an intracellular calcium (Ca2+) channel reported in liver cancer cells, is important in the Ca2+ signalling. Thus, it may be involved in the many events of hepatocarcinogenesis. Here, we investigated the ITPR-3 expression in hepatocellular carcinoma (HCC) and its association with clinicopathological parameters and long-term outcomes, according to the etiology of underlying chronic liver disease (CLD). Methods: Clinical and laboratory data from patients (n = 53) who underwent orthotopic liver transplantation for HCC treatment in a Brazilian referral center were retrospectively collected. After pathological reviewing of their explanted liver samples, ITPR-3 expression in both tumor and underlying cirrhosis were assessed by immunohistochemistry, and quantified using density histograms in the ImageJ software. Event (tumor recurrence or death from any cause) occurrence and event-free survival (EFS) were analysed. Results: Hepatitis C virus (HCV) (n = 31), alcohol abuse (n = 16) and cryptogenic cirrhosis (n = 6) were the underlying CLD etiology, and the groups were, in general, well balanced regarding clinicopathological indices. Median EFS was 78.9 months (range, 63.6-94.1). The ITPR-3 expression profile was cytoplasmatic, predominantly perinuclear, and was stronger in tumor than in adjacent cirrhosis, considering all etiologies together (intensity 9.1% higher in tumors, p < 0.001) However, analyzing each etiologic group, the cryptogenic was the only one in which there was no difference between tumor and underlying CLD. Comparing the ITPR-3 expression only in tumors, there was no difference regarding the etiology of CLD. The tumor ITPR-3 higher intensity was correlated with higher serum aspartate alanine-transferases (ALT) levels (p = 0.018) and lower mitotic index ( < 5 per 10 high power fields) (p = 0.009). There was no association between receptor expression and event occurrence or EFS. Conclusions: The ITPR-3 was expressed in HCC, regardless of the underlying CLD etiology. Its correlation with mitotic index, a cell proliferation marker, was demonstrated, but there were no associations with clinical outcomes. Apart from cryptogenic cirrhosis, ITPR-3 expression was more intense in tumors than in underlying cirrhosis. These findings suggest that ITPR-3 could have a role in carcinogenesis. However, the prognostic and therapeutic implications need to be investigated.
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El-Garawani, Islam, Mahmoud Emam, Waill Elkhateeb, Hesham El-Seedi, Shaden Khalifa, Salwa Oshiba, Shaimaa Abou-Ghanima, and Ghoson Daba. "In Vitro Antigenotoxic, Antihelminthic and Antioxidant Potentials Based on the Extracted Metabolites from Lichen, Candelariella vitellina." Pharmaceutics 12, no. 5 (May 24, 2020): 477. http://dx.doi.org/10.3390/pharmaceutics12050477.
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Lichens have recently received great attention due to their pharmacological potentials. The antigenotoxic potential of C. vitellina extract (25 and 50 µg/mL) was assessed in normal human peripheral blood lymphocytes (HPBL) against Mitomycin C (MMC) co-treatments. Flow cytometric analyses of cell cycle distribution, as well as apoptosis (Annexin V/PI), revealed that the extract had significantly (p ≤ 0.05) ameliorated the MMC toxicity by reducing the apoptotic cells and normalized the cell cycle phases. C. vitellina exhibited antigenotoxicity by ameliorating the diminished mitotic index and DNA single-strand breaks caused by MMC. Herein, the hydromethanolic extract (80%) of Candelariella vitellina (Japan) lichen, exhibited very low cytotoxicity towards normal human peripheral lymphocytes (HPBL) with IC50 >1000 µg/mL. In order to explore the antihelminthic effect, Echinococcus granulosus protoscoleces were used in vitro. Eosin staining revealed significant (p ≤ 0.05) dose and time-dependent scolicidal effects of the extract confirmed by degenerative alterations as observed by electron scan microscopy. Furthermore, primary and secondary metabolites were investigated using GC-MS and qualitative HPLC, revealing the presence of sugars, alcohols, different phenolic acids and light flavonoids. Significant antioxidant capacities were also demonstrated by DPPH radical-scavenging assay. In conclusion, the promising antigenotoxic, antihelminthic and antioxidant potentials of C. vitellina extract encourage further studies to evaluate its possible therapeutic potency.
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Shrayer, D., H. J. Wanebo, and M. Resnick. "Apoptosis signal ceramide c6 synergizes anti-tumor effects of paclitaxel oxaliplatin & cisplatin on growth of pancreatic cancer in SCID mice." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13135. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13135.
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13135 Background: Ceramide (C6) is an analog of endogenous ceramides, which are a major signaling pathway for apoptosis in cells undergoing stress, exposure to chemotherapy. Current report documents in vivo anti tumor effects combining C6 with oxaliplatin & cisplatin on L3.6 human pancreatic adenocarcinoma implanted in the SCID mouse. Correlative histologic studies provide additional mechanistic insights. Methods: SCID/Beige/ Taconicmale mice were inoculated subcutaneously (S.C.) w/2×106 L3.6 pancreatic cells. Chemotherapy doses were based on clinical & in vitro data. Treatment began 4 days post tumor implant with 3 weekly 3×/wk) intraperitoneal (IP) injections of Paclitaxel (P) 3.0 m/kg, oxaliplatin (OX) 2.5 mg/kg, cisplatin (CP) 2.5 mg/kg, with/without ceramide 10 mg/kg. Mice were observed for 6 weeks & were autopsied when near death, or at 6 week level. (All controls died by 3rd week). Data recovered included maximum tumor volume, tumor weight, body weight & survival. Histopathology studies were carried out in a separate group of 40 mice treated by the same drug dose levels & autopsied at 4 hours & 24 hours. Tumors were bi-valved & fixed in buffered formalin or frozen in hexane/acetone bath. Major focus was effects on tumor necrosis, apoptosis, mitotic index & Apoptosis (caspase 3 expression) index. Results: Combination w/C6 ceramide augmented the tumor reduction obtained by chemotherapy alone by 57% (while preserving body weight), & increased 6 wk survival from 0% (Chemotherapy alone) to 60% w/combined therapy. Mean survival was increased from 25 to 37 days. Preliminary short term immunohisto chemical studies showed enhancement of apoptotic index by increased and caspase 3 expression at 4 & 24 hr by ceramide combinations. Conclusion: Combination therapy w/C6 Ceramide significantly enhanced anti tumor response to Paclitaxel, Oxaliplatin & Cisplatin in SCID Mice bearing L3.6 pancreatic tumor implants. Early development of enhanced apoptosis by caspase 3 expressions was shown in preliminary short term exposure experiments. No significant financial relationships to disclose.
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Nazarchuk, Oleksandr A., Ihor L. Chereshniuk, and Halyna H. Nazarchuk. "THE RESEARCH OF ANTIMICROBIAL EFFICACY OF ANTISEPTICS DECAMETHOXIN, MIRAMISTIN AND THEIR EFFECT ON NUCLEAR DNA FRAGMENTATION AND EPITHELIAL CELL CYCLE." Wiadomości Lekarskie 72, no. 3 (2019): 374–80. http://dx.doi.org/10.36740/wlek201903111.
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Introduction: Nowadays, the study of biological safety of modern cationic surface-active antiseptics with a wide antimicrobial spectrum has acquired particular importance. The aim was to study antimicrobial effectiveness of antiseptics decamethoxin, miramistin and their influence on nuclear DNA fragmentation and cellular cycle. Materials and methods: A comparative microbiological study of antimicrobial efficacy and a cytometric study of the effect of decamethoxin 0,02% and miramistin 0,01% on the cellular cycle were carried out. Antimicrobial activity of decamethoxin and miramistin was estimated by their minimal inhibitory and minimal microbicidal concentrations against opportunistic microorganisms using serial double dilution technique. Decamethoxin and miramistin cytotoxicity on anterior corneal epithelial cells, after their two-week daily instillation into the eyes of a Vistar line male rats was studied using flow cytometry. The parameters of epithelial cellular cycle, nuclear DNA fragmentation and apoptosis under the influence of antiseptics were registered. Results: High antimicrobial effect of decamethoxin and miramistin against Gram-positive, Gram-negative bacteria with the significant advantages of decamethoxin were found (р<0,001). Decamethoxin caused minimal influence on anterior corneal epithelial cells, the insignificant decrease of their proliferation index, low increase of apoptosis (0.68%), no difference of mitotic activity (p>0.05). But the use of miramistin resulted in the significant increase of nuclear DNA fragmentation, decrease of proliferative activity (р<0.05). Conclusions: Higher antimicrobial effect against a wide range of opportunistic pathogens is proved in decamethoxin 0,02% comparably to miramistin 0,01% (р<0,001). In prolonged antiseptic use of the first one there were found no cytotoxic and no pro-apoptotic effects on the epithelium (р<0,05).
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Ahmed, Sherif G., Ahmed Abdelnabi, Casey A. Maguire, Mohamed Doha, Jessica E. Sagers, Rebecca M. Lewis, Alona Muzikansky, et al. "Gene therapy with apoptosis-associated speck-like protein, a newly described schwannoma tumor suppressor, inhibits schwannoma growth in vivo." Neuro-Oncology 21, no. 7 (April 12, 2019): 854–66. http://dx.doi.org/10.1093/neuonc/noz065.
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Abstract Background We evaluated apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) as a schwannoma tumor suppressor and explored its utilization in a schwannoma gene therapy strategy that may be translated to clinical use. Methods ASC protein expression and mRNA level were assessed in human schwannoma by immunohistochemistry and quantitative PCR, respectively. Methylation- specific PCR was used to assess ASC promoter methylation. The effect of ASC overexpression in schwannoma cells was evaluated through ATP-based viability, lactate dehydrogenase release, and apoptosis staining. Western blotting and colorimetric assay were used to test the effect of ASC overexpression on endogenous pro-apoptotic pathways. Bioluminescence imaging, behavioral testing, and immunohistochemistry in human xenograft and murine allograft schwannoma models were used to examine the efficacy and toxicity of intratumoral injection of adeno-associated virus (AAV) vector encoding ASC. Results ASC expression was suppressed via promoter methylation in over 80% of the human schwannomas tested. ASC overexpression in schwannoma cells results in cell death and is associated with activation of endogenous caspase-9, caspase-3, and upregulation of BH3 interacting-domain death agonist. In a human xenograft schwannoma model, AAV1-mediated ASC delivery reduced tumor growth and resolved tumor-associated pain without detectable toxicity, and tumor control was associated with reduced Ki67 mitotic index and increased tumor-cell apoptosis. Efficacy of this schwannoma gene therapy strategy was confirmed in a murine schwannoma model. Conclusion We have identified ASC as a putative schwannoma tumor suppressor with high potential clinical utility for schwannoma gene therapy and generated a vector that treats schwannomas via a novel mechanism that does not overlap with current treatments.
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Neppalli, Vishala T., Siegfried Janz, Sebastian Rutsch, and Hartmut Goldschmidt. "IL-6 and Tumor Susceptibility Alleles of Strain BALB/C Cause Phenotypic Shift of MYC-Driven Lymphomas in Mice from Diffuse Large B-Cell Lymphoma (DLBCL) to Plasmacytoma (PCT)." Blood 112, no. 11 (November 16, 2008): 5316. http://dx.doi.org/10.1182/blood.v112.11.5316.5316.
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Abstract Aims: Deregulation of cellular oncoprotein MYC (c-Myc) and the plasma cell growth, differentiation and survival cytokine, interleukin-6 (IL-6), are key pathogenetic factors in human high grade B-cell lymphomas (Burkitt lymphoma and DLBCL) and PCT respectively. Genomic instability, as a consequence of this deregulation, is poorly understood. Transgenic expression of these factors in the B-cell lineage, in mice, generates a pre-clinical model system of great relevance for human B-cell lymphoma counterparts. In this study we evaluated for the incidence of lymphomas in transgenic mouse models, with deregulated CMYC and IL-6. We performed a morphologic classification and correlation of the malignant lymphoid proliferations with the underlying genetic lesions. Materials & Methods: Deregulation of CMYC was observed in gene-targeted C57BL/6 mice that harbor a His6-tagged mouse Myc cDNA gene in themouse immunoglobulin heavy-chain locus (B6.iMyc mice). A double transgenic mouse model, using BALB/c mice, carry the same gene insertion, in addition to a widely expressed human IL-6 transgene (C.iMyc/IL-6 mice). Tumor tissue from the mice was processed by formalin fixation and embedded in paraffin. Sections from the paraffin blocks were stained with hematoxylin and eosin and evaluated for morphology. The morphologic evaluation of the lymphomas was performed blind to the genetic make up of the host, followed by genetic correlation with morphology. Results: B6.iMyc mice developed nodal and extranodal lymphomas. Tumor incidence was 50% (70/140) at 18 months of age. The lymphomas demonstrated sheets of large cells with centroblastic morphology, consistent with diffuse large B-cell lymphoma. The mitotic index was high, with the presence of frequent atypical mitotic figures and apoptotic debris laden macrophages, giving a starry sky pattern. C.iMyc/IL-6 mice developed nodal and extra nodal plasma cell tumors (PCT). Tumor incidence was 100% (20/20) at 4–5 months of age. PCT demonstrated sheets of monotonous and atypical plasma cells with prominent nucleoli. In lymphoid tissue containing germinal centers, the sheets of plasma cells were located in the interfollicular areas. There was no bone marrow involvement. Conclusions: Our findings demonstrate that B6.iMyc mice with CMYC deregulation develop high grade B-cell lymphomas similar to human DLBCL. The activity of deregulated IL-6 appears to enhance and accelerate the oncogenic potential of deregulated CMYC, in the pathogenesis of lymphoid malignancy. IL-6 and/or tumor susceptibility alleles of strain BALB/c cause a remarkable shift in the phenotype of MYC-driven lymphomas from DLBCL to PCT.
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Mathewos, Mesfin. "Pathological and Cytological Studies on Hepatocellular Carcinoma in Cattle Slaughtered at Bishoftu Elfora Abattoir, Central Ethiopia." Veterinary Medicine International 2021 (May 5, 2021): 1–6. http://dx.doi.org/10.1155/2021/6649172.
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Hepatocellular carcinoma (HCC) is one of the most common neoplasms that has been described in many domestic animal species. Hence, the disease has significant economic importance; thus, this study aimed to describe the cytopathological characteristics of hepatocellular carcinomas in cattle slaughtered at Bishoftu Elfora Abattoir, Central Ethiopia. A cross-sectional study design with a purposive sampling technique was performed from October 2017 to May 2018 using macroscopic, histopathologic, and cytological methods. For that matter, a total of sixty cattle were assessed for the presence of a hepatic tumor; however, only 1/60 (0.6%) case was found to be affected by hepatocellular carcinomas. On gross examination, hepatocellular carcinomas exhibited soft, white, multifocal nodules (10–40 mm in diameter) on different lobes of the liver. On the cut surface, the tumor revealed a sharply circumscribed border and was divided into lobules by thin connective tissue. The central zone of the tumors exhibited depression with a whitish fibrous area. Moreover, on histopathology, the tumors divulged unencapsulated carcinomatous lesions consisting of a thick, compact, somewhat ambiguous trabecular pattern of arrangement that was unglued by thin collagenous stroma. Cytological studies suggest that the tumor cells showed anisocytosis, anisokaryosis, prominent nucleoli, multinuclearity, palisading arrangements of neoplastic cells, increased N : C ratios, light eosinophilic cytoplasm, high mitotic index, and cytoplasmic and intranuclear vacuoles. In conclusion, cytopathological findings support a diagnosis of HCC in the liver; thus, further studies with a large sample size and use of immunohistochemistry are important for further characterization of hepatocellular carcinomas in cattle.
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Choi, Hyuk Soon, Hoon Jai Chun, In Kyung Yoo, Jae Min Lee, Seung Han Kim, Eun Sun Kim, Bora Keum, Yoon Tae Jeen, Hong Sik Lee, and Chang Duck Kim. "The therapeutic effect of irreversible electroporation ablation in mouse model of gastrointestinal cancer." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 62. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.62.
Full textAbstract:
62 Background: Irreversible electroporation (IRE) is a promising novel technique for the ablation of tumors. IRE has an advantage over other ablation technique in its mechanism to remove undesired cells by affecting the cell membrane without thermally destructing blood vessels, nerves and the surrounding tissues. Studies regarding the clinical application of IRE have been performed in humans, as well as in animals, for organs such as the liver, kidney, prostate, etc. and IRE is now accepted as a novel anti-cancer ablation modality. The aim of this study was to evaluate the therapeutic effect of IRE in mouse model of gastrointestinal cancer for the first time. Methods: The Caco2 cells (ATCC) were cultured in petri-dishes. Male nude mice (Immunodeficient (CAnN.Cg-Foxn1 nu/CrljBgi) 6 weeks old, Orient Inc., Korea) were introduced. Caco2 cells were each visually injected at 1.0 x 107cells/ml into both flakes (one for control, the other for IRE). We performed in vivo IRE procedures in the tumors of nude mouse model. Electrical pulses were applied to the tumor of nude mouse using a DC generator at 1~2kV/cm amplitude, 20~50 pulses, 100 µA length, with 1mm separation between two needle type electrodes. We analyzed the tissues with H&E staining and TUNEL assay immediately afterwards, and then 10 hours, 24 hours. Results: All mice were preserved during the experiment without significant complications. There was complete cell death within the IRE lesions without intervening live cells in 2KV after 24 hours. H& E statin and Tunnel stain at 10hr after 2KV IRE ablation revealed more severe apoptotic cell death comparing with control group. Apoptotic index peaks at 10 hours after IRE ablation, and decreases in 24hours. The framework of extracellular matrix and blood vessels were not affected by IRE. Conclusions: The present study demonstrated that IRE ablated colon cancer tissue very effectively through the induction of cellular apoptosis. This study suggests that IRE has the potentiality in treatment of gastrointestinal cancer patients.
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Huang, Shiang, Ping Law, Karl Francis, Bernhard O. Palsson, and Anthony D. Ho. "Symmetry of Initial Cell Divisions Among Primitive Hematopoietic Progenitors Is Independent of Ontogenic Age and Regulatory Molecules." Blood 94, no. 8 (October 15, 1999): 2595–604. http://dx.doi.org/10.1182/blood.v94.8.2595.420k37_2595_2604.
Full textAbstract:
We have developed a time-lapse camera system to follow the replication history and the fate of hematopoietic stem cells (HSC) at a single-cell level. Combined with single-cell culture, we correlated the early replication behavior with colony development after 14 days. The membrane dye PKH26 was used to monitor cell division. In addition to multiple, synchronous, and symmetric divisions, single-sorted CD34+/CD38− cells derived from fetal liver (FLV) also gave rise to a daughter cell that remained quiescent for up to 8 days, whereas the other daughter cell proliferated exponentially. Upon separation and replating as single cells onto medium containing a cytokine cocktail, 60.6% ± 9.8% of the initially quiescent cells (PKH26 bright) gave rise again to colonies and 15.8% ± 7.8% to blast colonies that could be replated. We have then determined the effects of various regulatory molecules on symmetry of initial cell divisions. After single-cell sorting, the CD34+/CD38− cells derived from FLV were exposed to flt3-ligand, thrombopoietin, stem cell factor (SCF), or medium containing a cytokine cocktail (with SCF, interleukin-3, interleukin-6, granulocyte-macrophage colony-stimulating factor, and erythropoietin). Whereas mitotic rate, colony efficiency, and asymmetric divisions could be altered using various regulatory molecules, the asymmetric division index, defined as the number of asymmetric divisions versus the number of dividing cells, was not altered significantly. This observation suggests that, although lineage commitment and cell proliferation can be skewed by extrinsic signaling, symmetry of early divisions is probably under the control of intrinsic factors.