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Chemotherapeutic agents; cyclophosphamide (CYC) is used for treatment of cancer and autoimmune diseases. Grievously, CYC is non-selective as it affects both tumor and healthy cells resulting in systemic toxicity including placenta. The present study aimed to evaluate the effect of phosphodiesterase 5 inhibitor, sildenafil (Sild) on CYC-induced placental injury in rats.
Thirty-two female Wister rats were randomly divided into 4 experimental groups. Group 1 control pregnant group; Group 2 Sild-treated pregnant rats; Group 3 pregnant rats received CYC; Group 4 pregnant rats received Sild and CYC. Placental malondialdehyde (MDA), total nitrite/nitrate (NOx), reduced glutathione (GSH), tumor necrosis factor-α (TNF-α), platelet growth factor (PlGF), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase (ERK) and cleaved caspase-3 were measured. Histological changes, Nuclear Factor kappa-light-chain-enhancer of activated B (NF-κB), Connexin 43 (GJA1) and proliferating cell nuclear antigen (PCNA) immuno-expressions were also evaluated.
CYC showed significant decrease in placental GSH, NOx, PlGF, GJA1 and PCNA immuno-expressions but significant increase in placental MDA, TNF-α, JNK, P38MAPK, ERK, caspase-3 and NF-kB immuno-expression. Sild showed significant improvement in all oxidative, inflammatory and apoptotic parameters.
Sild is a promising protective drug against placental injury induced by CYC through antagonizing MAPK (JNK, ERK, and p38) signaling pathway with anti-oxidant, anti-inflammatory and anti-apoptotic effects.
Sild is a promising protective drug against placental injury induced by CYC through antagonizing MAPK (JNK, ERK, and p38) signaling pathway with anti-oxidant, anti-inflammatory and anti-apoptotic effects.
Piwi-like RNA-mediated gene silencing 4 (PIWIL4) or HIWI2, are seen deregulated in human cancers and possibly play critical roles in tumorigenesis. It is unknown what role HIWI2 plays in the regulation of fibrosarcoma, an early metastatic lethal type of soft tissue sarcoma (STS). The present study aimed to investigate the role of HIWI2 in the tumorigenesis of fibrosarcoma.
The expression of HIWI2 in HT1080 fibrosarcoma cells was determined by qRT-PCR and western blotting. The MTT assay, colony formation assay, cell cycle, and PE-AnnexinV/7AAD apoptosis assay using flow cytometry, DNA laddering assay, comet assay, and γH2AX accumulation assay were performed to study the effect of HIWI2 overexpression in HT1080 cells. Further, the effect of silencing of HIWI2 was determined by cell viability assay, transwell migration, and invasion assay.
HIWI2 is under-expressed in STS cell lines and tissues, which is associated with poor disease-free survival, disease-specific survival, and progression-free survival of the patients. https://www.selleckchem.com/products/ti17.html Overexpression of HIWI2 in HT1080 cells causes DNA damage by increasing intracellular ROS by inhibiting the expression of antioxidant genes (SOD1, SOD2, GPX1, GPX4, and CAT). Furthermore, an increase in H2AX phosphorylation was observed, which activates p53 that promotes p21 expression and caspase-3 activation, leading to G2/M phase cell cycle arrest and apoptosis. HIWI2 silencing, on the contrary, promotes cell growth, migration, and invasion by activating MMP2 and MMP9.
These results are the first to show that HIWI2 acts as a tumor suppressor in fibrosarcoma by modulating the ROS/DNA damage/p53 pathway.
These results are the first to show that HIWI2 acts as a tumor suppressor in fibrosarcoma by modulating the ROS/DNA damage/p53 pathway.An increasing number of observations have indicated that the activation of inflammatory processes is involved in the pathogenesis of epilepsy. As an effective adjunctive therapy for medically intractable seizures, vagus nerve stimulation (VNS) is thought to interact with the inflammatory process to play an antiepileptic role. In this study, we examined the levels of multiple cytokine in focal brain tissue and peripheral blood to determine whether the antiepileptic effect of chronic VNS is related to the expression of cytokines. We observed that the frequency and duration of seizures significantly decreased in epileptic rats after two weeks of chronic VNS treatment. Pathological staining showed that the number of neural cells in the hippocampus was higher in the Epi + VNS group than in the Epi group, indicating that chronic VNS had a significant neuroprotective effect on epileptic rats. After comparing the expression of 9 cytokines, we found that the levels of the proinflammatory cytokines IL-6, IL-1β and CXCL-1 in the hippocampus were significantly increased in the Epi group, while these cytokines were significantly decreased in the Epi + VNS group. Moreover, the level of the anti-inflammatory cytokine IL-13 was found to be reduced in Epi rats, while its levels were increased after VNS treatment. However, these changes in cytokine expression were not found in the hypothalamus or peripheral blood. These results suggest that the antiepileptic mechanism of VNS may work by inhibiting the activation of inflammatory processes in the epileptogenic focus.Methylphenidate (MP) is extensively prescribed for attention deficit hyperactivity disorder (ADHD). While MP is effective in ameliorating symptoms of ADHD, MP is also used illicitly among healthy subjects without ADHD for cognitive-enhancing purposes. The deleterious consequences associated with long-term MP use as well as its cessation on brain activity remains to be understood. To address this, we administered either water, low dose MP (LD MP), or high dose MP (HD MP) to healthy adolescent Sprague Dawley rats, with five days on the treatment and two days off for thirteen consecutive weeks. Rats were then abstinent from their respective treatments for four weeks. Using positron emission tomography (PET) and fluorodeoxyglucose [18F] (FDG), we scanned rats at three time points after thirteen weeks of treatment, after one week of abstinence, and after four weeks of abstinence. After thirteen weeks of LD and HD MP treatment, increases in brain glucose metabolism (BGluM) were seen in several cortical and subcortical regions associated with sensory and motor functions as well as learning and memory. One-week abstinence from LD MP treatment promoted increased BGluM compared to both water treated and HP MP treated groups. After four weeks of abstinence, little group differences were seen. Longitudinally, we observed contrasting differences on BGluM depending on whether a LD or HD of MP was administered. Our results demonstrate that MP treatment during adolescence can significantly alter BGluM. Moreover, these changes in brain activity do not subside in many areas of the brain after both one and four-week drug abstinence.Reports of ante-mortem diagnosis of cardiovascular diseases in donkeys (Equus asinus) are rare. This case report describes the echocardiographic findings of suspected mitral valve dysplasia in a 3-year-old Nevisian donkey jenny presented for evaluation of a grade III/VI left-sided systolic murmur. Pertinent findings on transthoracic echocardiography included double mitral regurgitant jets and a bridge of tissue between the septal and mural mitral leaflets. Based upon the mild degree of cardiac remodeling and absence of clinical signs, therapeutic intervention was deemed unnecessary, and the jenny was returned to the teaching herd. Repeat echocardiography 10 months later revealed no significant progression of mitral regurgitation or cardiac remodeling. This case reinforces the utility of auscultation and echocardiography in detecting structural heart disease in donkeys.The persistent endocrinological effects of perinatal stress due to gestational immaturity in horses are unknown, although effects have been reported in other livestock species. This pilot study tested the hypothesis that persistent adrenocortical dysregulation is present in horses that were gestationally immature at birth by assessing the salivary cortisol response to exogenous ACTH. Case horses (n = 10) were recruited with histories of gestation length less then 315 d or dysmaturity observable through neonatal signs. Positive controls (n = 7) and negative controls (n = 5) were recruited where possible from related horses at the same locations. Cases and positive controls received an intramuscular, low-dose (0.1 ug/kg) of synthetic ACTH (Tetracosactrin 250 mg/mL, Synacthen); negative controls received no ACTH. Saliva samples were collected from all horses at baseline T = 0 and at 30 min intervals post injection from T = 30 to T = 150. These were assayed for salivary cortisol concentration (SCC) using a commercially available ELISA kit (Salimetrics). All baseline values (T = 0) were within normal published ranges. Peak and AUC values (corrected for baseline) for case horses were significantly different (ANOVA P less then .001) to positive controls, with either higher (H-cases) or lower (L-cases) SCC values, outside the 95% Confidence Interval of the reference population. There was no significant effect of breed, age, sex, test month, or location on results. The results suggest that gestational immaturity may lead to subclinical adrenocortical dysregulation, with affected horses presenting an elevated or blunted response to a low-dose ACTH stimulation, despite normal basal levels.The aim of this study was to evaluate the validity of the SpO2/FiO2 diagram in estimating gas exchange in horses under general anaesthesia. In this prospective, controlled clinical study were included 10 horses under general anaesthesia. FiO2 was progressively reduced with the following steps 0.6, 0.4, 0.3 and 0.21; SpO2 was recorded at each step. An arterial blood sample was collected at the steps of 1.0 and 0.21, to calculate intrapulmonary shunt with the Fshunt formula. The Fshunt value calculated at 0.21 FiO2 was defined as "Fshunt 0.21", the one calculated at 1.0 FiO2 as "Fshunt 1.0". The FiO2 vs SpO2 data points were analyzed using a computer algorithm which uses the haemoglobin and a fixed value for arterial-venous oxygen difference of 3.5 mL/dL. The algorithm estimates a shunt value fitting the obtained data with an ideal SpO2/FiO2 curve. The value of shunt (Sshunt) was considered for the study. Correlation between "Fshunt 1.0", "Fshunt0.21" and SShunt was determined using the Spearman Rank Correlation Coefficient test, the analysis of the regression curve and the coefficient of determination (r2). Values of P less then .05 were considered statistically significant. A significant and strong correlation (P = .0069; r = 0.839; r2=0.6194) and a significant and moderate correlation (P = .0443; r = 0.644; r2=0.2336) was found between Sshunt and "Fshunt 1.0" and between Sshunt and "Fshunt 0.21", respectively. The SpO2/FiO2 diagram proved to be a useful and non-invasive tool to characterize gas exchange in horses under general anaesthesia and mechanical ventilation.Osteochondrosis (OC) is an important skeletal disease causing profound welfare concerns in horses. Although numerous studies have explored the genetics underlying OC in various breeds, the Belgian Warmblood (BW) remains unstudied despite having a concerning prevalence of 32.0%. As a result, this study aimed to conduct genome-wide association (GWA) analyses to identify candidate variants associated with OC in BWs. To achieve this, blood samples and radiographs were collected from 407 Belgian Warmbloods registered to one of two BW studbooks (Belgisch Warmbloedpaard and Zangersheide), and genotyping was performed using the 670K Axiom Equine Genotyping Array. GWA analyses using a principle component approach were then performed on OC status (OCS; presence or absence of OC at any joint), hock OC status (HOC) and stifle OC status (SOC). These analyses yielded significantly associated (P less then .01) SNPs on Equus caballus chromosome (ECA) 3, ECA 12, and ECA 18 for OCS; however, no single nucleotide polymorphisms (SNPs) reached significance for HOC or SOC.
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