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Medical Science Monitor : International... Sep 2012Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of...
BACKGROUND
Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of choice but not approved for use in congenital Toxoplasmosis. We hypothesized atovaquone to be safe and effective against feto-maternal Toxoplasmosis.
MATERIAL/METHODS
Programmed pregnant mice were i.p. infected with 50-2400 Tachyzoites from Type II strain (clone PTG). Dams were treated daily with atovaquone or sham and monitored for pain, and complications.
RESULTS
Dams developed pain related abdominal hypersensitivity (allodynia) to mechanical stimuli in a Tachyzoites dose dependent manner. Infected dams were anemic and exhibited ascities and severe hepatitis (score 3.6±0.01 on scale 0--normal to 4--severe) with influx of inflammatory and plasma cells, multinucleated dysplastic hepatocytes and necrosis. In addition, dams expressed mild to severe pancreatitis with mononuclear cell invasion, loss of islets and necrosis. This was consistent with splenomegaly (X3 Fold), and massive infiltration of epithelioid cells and loss of germinal structure. Colon became significantly shortened in length (p<0.01) with semi-normal content. Pathological manifestation included, shortening of crypts with numerous microabscess formations, infiltration of lymphocytes, and macrophages. The severe clinical complications led to abortion (50%), early birth (25%) or still birth (25%) consistent with the high dose of Tachyzoites inoculation. Atovaquone treatment partially but significantly protected the dams from the severity of hepatitis, splenomegaly, colitis, myocarditis, and pain related responses as well as fetal demise.
CONCLUSIONS
This is a valuable model for therapeutic evaluation of feto-maternal Toxoplasmosis and gastrointestinal complications. Atovaquone protects dams and their fetuses against some infectious/inflammatory aspects of the disease.
Topics: Analysis of Variance; Animals; Anti-Infective Agents; Atovaquone; Disease Models, Animal; Female; Gastrointestinal Tract; Hepatitis; Hyperalgesia; Immunohistochemistry; Mice; Pancreatitis; Pregnancy; Toxoplasmosis, Congenital
PubMed: 22936182
DOI: 10.12659/msm.883342 -
International Journal of Clinical... Jan 2014Toxoplasmosis is a common cause of foodborne, gastrointestinal and congenital syndrome with particularly severe or unknown health consequences. There is no safe and...
BACKGROUND
Toxoplasmosis is a common cause of foodborne, gastrointestinal and congenital syndrome with particularly severe or unknown health consequences. There is no safe and effective preventive or therapeutic modality against congenital toxoplasmosis or to eliminate the persistent chronic infection.
HYPOTHESIS
Diclazuril to be safe in pregnancy and effective against gastrointestinal toxoplasmosis.
METHODS
CD1 programmed pregnant mice were divided into groups and administered a diet containing diclazuril, or sham control. Treatments were initiated on Day 5 of pregnancy and continued until Day 16 when dams were euthanatized. On Day 8 of pregnancy dams were infected intraperitoneally with escalating doses of tachyzoites (0, 100, 300, 600) from Type II strain. Dams were monitored daily for distress, pain, and abortion and samples collected at the end of the experiments.
RESULTS
Infected dams developed moderate to severe related complications in tachyzoites dose dependent manner. Animals became anemic and showed hydrothorax, and ascities. Diclazuril effectively protected dams from ascities and anemia (p < 0.05). Infected dams showed splenomegaly, with massive infiltration of epithelioid cells compared with the protective effect of diclazuril in treated animals. Infected dams exhibited severe hepatitis (score 0 to 4 scale = 3.5 ± 0.01) with influx of inflammatory and plasma cells, dysplastic hepatocytes, multinucleated giant cell transformation and hepatic cells necrosis. Diclazuril treatment significantly protected dams from hepatitis, also in tachyzoites dose (100, 300, 600) dependent manner (respectively infected-treated versus infected controls, p < 0.001, p < 0.01 and p < 0.05). Colonic tissues were significantly shortened in length, with infiltration of lymphocytes, and macrophages and microabscess formations in the cryptic structures, with significant improvement in diclazuril treated animals. Additionally, the number of fetuses, fetal length and fetal weight were preserved in diclazuril treated dams.
CONCLUSIONS
This is the first report describing of diclazuril safety in pregnancy as well as efficacy against mild to moderate hepato-gastrointestinal syndrome in dams and fetal toxoplasmosis (Special issue, "Treatment of Liver Diseases").
PubMed: 24851194
DOI: 10.4236/ijcm.2014.53017 -
BMC Biotechnology Nov 2017The myxomycetes derive their common name (slime molds) from the multinucleate trophic stage (plasmodium) in the life cycle, which typically produces a noticeable amount...
BACKGROUND
The myxomycetes derive their common name (slime molds) from the multinucleate trophic stage (plasmodium) in the life cycle, which typically produces a noticeable amount of slimy materials, some of which is normally left behind as a "slime track" as the plasmodium migrates over the surface of a particular substrate. The study reported herein apparently represents the first attempt to investigate the chemical composition and biological activities of slime tracks and the exopolysaccharides (EPS) which cover the surface of the plasmodia of Physarum polycephalum and Physarella oblonga.
RESULTS
Chemical analyses indicated that the slime tracks and samples of the EPS consist largely of carbohydrates, proteins and various sulphate groups. Galactose, glucose and rhamnose are the monomers of the cabohydrates present. The slime tracks of both species and the EPS of Phy. oblonga contained rhamnose, but the EPS of Ph. polycephalum had glucose as the major monomer. In term of biological activities, the slime tracks displayed no antimicrobial activity, low anticancer activity and only moderate antioxidant activity. However, EPSs from both species showed remarkable antimicrobial activities, especially toward Candida albicans (zone of inhibition ≥20 mm). Minimum inhibitory concentrations of this fungus were found to be 2560 μg/mL and 1280 μg/mL for EPS from Phy. oblonga and Ph. polycephalum, respectively. These EPS samples also showed moderate antioxidant activities. However, they both displayed cytotoxicity towards MCF-7 and HepG2 cancer cells. Notably, EPS isolated from the plasmodium of Phy. oblonga inhibited the cell growth of MCF-7 and HepG2 at the half inhibitory concentration (IC50) of 1.22 and 1.11 mg/mL, respectively.
CONCLUSIONS
EPS from Ph. polycephalum plasmodium could be a potential source of antifungal compounds, and EPS from Phy. oblonga could be a potential source of anticancer compounds.
Topics: Antioxidants; Biological Products; Candida albicans; Cell Proliferation; Hep G2 Cells; Humans; MCF-7 Cells; Microbial Sensitivity Tests; Mycetozoa; Physarum polycephalum; Polysaccharides; Staphylococcus aureus
PubMed: 29121887
DOI: 10.1186/s12896-017-0398-6 -
Scientific Reports Nov 2020Tilapia lake virus (TiLV) causes high mortality and high economic losses in tilapines. We describe an experimental challenge study focusing on early post challenge...
Tilapia lake virus (TiLV) causes high mortality and high economic losses in tilapines. We describe an experimental challenge study focusing on early post challenge innate immune responses. Nile tilapia (Oreochromis niloticus) were infected with 10 TCID/mL TiLV intraperitoneally, followed by virus quantification, histopathology and gene expression analysis in target (brain/liver) and lymphoid (spleen/headkidney) organs at 3, 7, 12, 17, and 34 days post challenge (dpc). Onset of mortality was from 21 dpc, and cumulative mortality was 38.5% by 34 dpc. Liver and kidney histopathology developed over the period 3-17 dpc, characterized by anisocytosis, anisokaryocytosis, and formation of multinucleated hepatocytes. Viral loads were highest at early time (3 dpc) in liver, spleen and kidney, declining towards 34 dpc. In brain, viral titer peaked 17 dpc. Innate sensors, TLRs 3/7 were inversely correlated with virus titer in brain and headkidney, and IFN-ß and Mx showed a similar pattern. All organs showed increased mRNA IgM expression over the course of infection. Overall, high virus titers downplay innate responses, and an increase is seen when viral titers decline. In silico modeling found that TiLV segments 4, 5 and 10 carry nucleolar localization signals. Anti-viral effects of TiLV facilitate production of virus at early stage of infection.
Topics: Animals; Antibodies, Viral; Brain; Cichlids; Fish Diseases; Gene Expression Regulation; Hepatocytes; Host-Pathogen Interactions; Immunity, Innate; Immunoglobulin M; Interferon-beta; Kidney; Liver; Negative-Sense RNA Viruses; Spleen; Survival Analysis; Time Factors; Toll-Like Receptor 3; Toll-Like Receptor 7
PubMed: 33230226
DOI: 10.1038/s41598-020-73781-y -
BMB Reports Jul 2017We previously reported that p53 plays a role as a key regulator in the tetraploid G1 checkpoint, which is activated by actin damage-induced cytokinesis blockade and then...
We previously reported that p53 plays a role as a key regulator in the tetraploid G1 checkpoint, which is activated by actin damage-induced cytokinesis blockade and then prevents uncoupled DNA replication and nuclear division without cytokinesis. In this study, we investigated a role of Skp2, which targets CDK2 inhibitor p27/Kip1, in actin damage-induced tetraploid G1 arrest. Expression of Skp2 was reduced, but p27/Kip1 was increased, after actin damage-induced cytokinesis blockade. The role of Skp2 repression in tetraploid G1 arrest was investigated by analyzing the effects of ectopic expression of Skp2. After actin damage, ectopic expression of Skp2 resulted in DNA synthesis and accumulation of multinucleated cells, and ultimately, induction of apoptosis. These results suggest that Skp2 repression is important for sustaining tetraploid G1 arrest after cytokinesis blockade and is required to prevent uncoupled DNA replication and nuclear division without cytokinesis. [BMB Reports 2017; 50(7): 379-383].
Topics: Actins; Cyclin-Dependent Kinase Inhibitor p27; Cytokinesis; G1 Phase Cell Cycle Checkpoints; HCT116 Cells; Hep G2 Cells; Humans; S-Phase Kinase-Associated Proteins; Tetraploidy; Tumor Cells, Cultured
PubMed: 28648144
DOI: 10.5483/bmbrep.2017.50.7.063 -
Food Science and Biotechnology Jun 2022Sub-chronic toxicity studies using rats have been conducted for (Maxim.) Hemsley (CW) and Royle ex Wight (CA). CW water extract didn't show any adverse effects whereas...
Sub-chronic toxicity studies using rats have been conducted for (Maxim.) Hemsley (CW) and Royle ex Wight (CA). CW water extract didn't show any adverse effects whereas administering CW powder decreased body weights in complication with decreased food consumptions. In the case of CA water extract, triglyceride and absolute/relative liver weights were elevated and vacuolation was observed in liver. Treated CA powder in male rats increased alanine aminotransferase and aspartate aminotransferase and induced single cell necrosis and multinucleated hepatocyte in liver. As for female rats, increased absolute/relative weights and hypertrophy/vacuolation in adrenal glands and vacuolation in ovaries were observed when administered CA powder. In conclusion, no observed adverse effect level (NOAEL) of CW water extract was over 5000 mg/kg/day, while NOAEL of CW powder was 700 mg/kg/day for female and 150 mg/kg/day for male. In case of CA, NOAEL of water extract was 1500 mg/kg/day for male and 2000 mg/kg/day for female, while NOAEL of powder was 150 mg/kg/day for both gender. To the best of our knowledge, this is the first sub-chronic toxicity study on the adverse effects, target organs and its dose levels of (Maxim.) Hemsley and Royle ex Wight following GLP protocols.
PubMed: 35646417
DOI: 10.1007/s10068-022-01072-5 -
Stem Cell Research & Therapy Dec 2018Adipose tissue is an excellent source for isolation of stem cells for treating various clinical conditions including injuries to the neuromuscular system. Many previous...
BACKGROUND
Adipose tissue is an excellent source for isolation of stem cells for treating various clinical conditions including injuries to the neuromuscular system. Many previous studies have focused on differentiating these adipose stem cells (ASCs) towards a Schwann cell-like phenotype (dASCs), which can enhance axon regeneration and reduce muscle atrophy. However, the stromal vascular fraction (SVF), from which the ASCs are derived, also exerts broad regenerative potential and might provide a faster route to clinical translation of the cell therapies for treatment of neuromuscular disorders.
METHODS
The aim of this study was to establish the effects of SVF cells on the proliferation and differentiation of myoblasts using indirect co-culture experiments. A Growth Factor PCR Array was used to compare the secretomes of SVF and dASCs, and the downstream signaling pathways were investigated.
RESULTS
SVF cells, unlike culture-expanded dASCs, expressed and secreted hepatocyte growth factor (HGF) at concentrations sufficient to enhance the proliferation of myoblasts. Pharmacological inhibitor studies revealed that the signal is mediated via ERK1/2 phosphorylation and that the effect is significantly reduced by the addition of 100 pM Norleual, a specific HGF inhibitor. When myoblasts were differentiated into multinucleated myotubes, the SVF cells reduced the expression levels of fast-type myosin heavy chain (MyHC2) suggesting an inhibition of the differentiation process.
CONCLUSIONS
In summary, this study shows the importance of HGF as a mediator of the SVF effects on myoblasts and provides further evidence for the importance of the secretome in cell therapy and regenerative medicine applications.
Topics: Adipose Tissue; Animals; Cell Differentiation; Cell Proliferation; Female; Humans; Mice; Myoblasts; Rats; Rats, Sprague-Dawley; Stromal Cells
PubMed: 30572954
DOI: 10.1186/s13287-018-1096-6 -
Aging Aug 2018Anillin (ANLN) is an actin-binding protein essential for assembly of cleavage furrow during cytokinesis. Although reportedly overexpressed in various human cancers, its...
Anillin (ANLN) is an actin-binding protein essential for assembly of cleavage furrow during cytokinesis. Although reportedly overexpressed in various human cancers, its role in hepatocellular carcinoma (HCC) is unclear. To address this issue, we confirmed that in 436 liver samples obtained from surgically removed HCC tissues, higher ANLN expression was detected in tumor tissues than in adjacent non-tumor tissues of HCC as measured by immunohistochemistry, quantitative real-time PCR and western blotting. Correlation and Kaplan-Meier analysis revealed that patients with higher ANLN expression were associated with worse clinical outcomes and a shorter survival time, respectively. Moreover, ANLN inhibition resulted in growth restraint, reduced colony formation, and a lower sphere number in suspension culture. Mechanistically, ANLN deficiency induced an increasing number of multinucleated cells along with the activation of apoptosis signaling and DNA damage checkpoints. Furthermore, HBV infection increased ANLN expression by inhibiting the expression of microRNA (miR)-15a and miR-16-1, both of which were identified as ANLN upstream repressors by targeting its 3' untranslated region. Thus, we conclude that ANLN promotes tumor growth by ways of decreased apoptosis and DNA damage. Expression level of ANLN significantly influences the survival probability of HCC patients and may represent a promising prognostic biomarker.
Topics: Adult; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cloning, Molecular; Contractile Proteins; DNA Damage; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Hepatitis B; Hepatitis B virus; Hepatocytes; Humans; Liver Neoplasms; Male; Mice; MicroRNAs; Middle Aged; Neoplasms, Experimental; RNA, Messenger; Random Allocation; Up-Regulation
PubMed: 30103211
DOI: 10.18632/aging.101510 -
Hepatology (Baltimore, Md.) May 2018Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular...
UNLABELLED
Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein α (C/EBPα) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples, and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that dephosphorylated C/EBPα creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPα-dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta-like 1 homolog-positive intranuclear inclusions. We further isolated C/EBPα-dependent multinucleated hepatocytes and found that they possess characteristics of tumor-initiating cells, including elevation of stem cell markers. C/EBPα-dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer.
CONCLUSION
The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBPα into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer. (Hepatology 2018;67:1857-1871).
Topics: Animals; Blotting, Western; CCAAT-Enhancer-Binding Protein-alpha; Carcinogenesis; Carcinoma, Hepatocellular; Child; Chromatography, High Pressure Liquid; Flow Cytometry; Hepatoblastoma; Hepatocytes; Humans; Liver; Liver Neoplasms; Mice; Mice, Knockout; Neoplastic Stem Cells; Real-Time Polymerase Chain Reaction
PubMed: 29159818
DOI: 10.1002/hep.29677 -
The Korean Journal of Parasitology Oct 2014This study reports the first case of Capillaria hepatica infection in a nutria in Korea. Ten nutrias, captured near the Nakdong River, were submitted to our laboratory...
This study reports the first case of Capillaria hepatica infection in a nutria in Korea. Ten nutrias, captured near the Nakdong River, were submitted to our laboratory for necropsy. White-yellowish nodules were found in the liver of 1 of the nutrias at necropsy. Histologically, the lesions were granulomatous, and infiltrations of lipid-laden macrophages, eosinophils, and several multinucleated giant cells were observed. The lesions consisted of numerous eggs and necrotic hepatocytes. The eggs were lemon-shaped and had polar plugs at the ends of both long sides. The eggs were morphologically identified as those of C. hepatica. Worldwide, C. hepatica infection in nutrias is very rare. Nutrias are a kind of livestock, as well as wildlife; therefore, an epidemiological study for parasitic infections needs to be conducted.
Topics: Animals; Capillaria; Enoplida Infections; Female; Male; Republic of Korea; Rodent Diseases; Rodentia
PubMed: 25352702
DOI: 10.3347/kjp.2014.52.5.527