Biochemical effects of diquat and paraquat. Disturbance of the control of corticosteroid synthesis in rat adrenal and subsequent effects on the control of liver glycogen utilization.
Ontology highlight
ABSTRACT:
SUBMITTER: Rose MS
PROVIDER: S-EPMC1166229 | biostudies-other | 1974 Mar
REPOSITORIES: biostudies-other
Similar Datasets
Project description:ObjectiveThis study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency.DesignTwenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies.Patients and measurementsPatients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC-MS/MS RESULTS: Compared to controls, progressively lower concentrations of the glucocorticoid precursors 11-deoxycortisol, 11-deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11-deoxycortisol, 11-deoxycorticosterone and corticosterone conce ntrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11-deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24-hour free cortisol excretion in urine.ConclusionsAdrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined.
| S-EPMC6851705 | biostudies-literature
Project description:BackgroundParaquat (PQ) is a herbicide that is used globally in the agriculture sector to eradicate unwanted weeds, however it also induces significant damages in various organs of the body such as testes. Tectochrysin (TEC) is an important flavonoid that shows versatile therapeutic potentials. Currently, there is no established antidote to cure PQ-induced testicular toxicity.ObjectiveThe present study was conducted to evaluate the ameliorative effects of TEC against PQ prompted testicular damage.MethodsSprague-Dawley rats (n = 48) were used to conduct the trial. Rats were allocated in to 4 groups i.e., Control, PQ administrated group (5 mgkg-1), PQ + TEC co-administrated group (5 mgkg-1 + 2.5 mgkg-1) and TEC only administrated group (2.5 mgkg-1). The trial was conducted for 8 weeks. The activity of anti-oxidants and the levels of MDA and ROS were determined by spectrophotometric method. Steroidogenic enzymes as well as apoptotic markers expressions were evaluated by qRT-PCR. The level of hormones and inflammatory indices was quantified by enzyme-linked immunosorbent assay.ResultsPQ exposure markedly (P < 0.05) disturbed the biochemical, spermatogenic and histological profile in the rats. Nevertheless, TEC treatment considerably (P < 0.05) increased CAT, GPx GSR and SOD activity, besides decreasing MDA and ROS contents. TEC administration also increased sperm viability, count and motility. 17β-HSD, 3β-HSD, StAR and Bcl-2 expressions were also increased following TEC administration. The supplementation of TEC substantially (P < 0.05) decreased Bax, Caspase-3 expression and the levels of inflammatory markers i.e., interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) activity. Additionally, the levels of plasma testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were increased following TEC supplementation. Furthermore, TEC supplementation considerably decreased sperm structural abnormalities and histomorphological damages of the testes. The mitigative role of TEC might be due to its anti-inflammatory, anti-apoptotic, androgenic and anti-oxidant potentials.ConclusionTaken together, it is concluded that TEC can be used as a potential candidate to treat testicular toxicity.
| S-EPMC10865255 | biostudies-literature
Project description:BackgroundA serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression.MethodsWe enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing.FindingsBetween November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10-6), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7·32, 95% CI 3·15-16·99; p=5·8 × 10-8). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3·86, 95% CI 1·19-12·50; p=0·02) and adult COPD (2·41, 1·10-5·28; p=0·03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5·89, 95% CI 2·97-11·68; p=4·3 × 10-9; and 4·05, 2·00-8·21; p=3·5 × 10-10).InterpretationOur findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively.FundingDepartment of Health Chair in Pharmacogenetics.
| S-EPMC5971210 | biostudies-literature
Project description:Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that causes severe infections in humans and the swine industry. Acquisition and utilization of available carbon sources from challenging host environments is necessary for bacterial pathogens to ensure growth and proliferation. Glycogen is abundant in mammalian body and may support the growth of SS2 during infection in hosts. However, limited information is known about the mechanism between the glycogen utilization and host adaptation of SS2. Here, the pleiotropic effects of exogenous glycogen on SS2 were investigated through transcriptome sequencing. Analysis of transcriptome data showed that the main basic metabolic pathways, especially the core carbon metabolism pathways and virulence-associated factors, of SS2 responded actively to glycogen induction. Glycogen induction led to the perturbation of the glycolysis pathway and citrate cycle, but promoted the pentose phosphate pathway and carbohydrate transport systems. Extracellular glycogen utilization also promoted the mixed-acid fermentation in SS2 rather than homolactic fermentation. Subsequently, apuA, a gene encoding the unique bifunctional amylopullulanase for glycogen degradation, was deleted from the wild type and generated the mutant strain ΔapuA. The pathogenicity details of the wild type and ΔapuA cultured in glucose and glycogen were investigated and compared. Results revealed that the capsule synthesis or bacterial morphology were not affected by glycogen incubation or apuA deletion. However, extracellular glycogen utilization significantly enhanced the hemolytic activity, adhesion and invasion ability, and lethality of SS2. The deletion of apuA also impaired the pathogenicity of bacteria cultured in glucose, indicating that ApuA is indeed an important virulence factor. Our results revealed that exogenous glycogen utilization extensively influenced the expression profile of the S. suis genome. Based on the transcriptome response, exogenous glycogen utilization promoted the carbon adaption and pathogenicity of SS2.
| S-EPMC9683343 | biostudies-literature
Project description:The synthesis of glycogen represents a key pathway for the disposal of excess glucose while its degradation is crucial for providing energy during exercise and times of need. The importance of glycogen metabolism is also highlighted by human genetic disorders that are caused by mutations in the enzymes involved. In this review, we provide a basic summary on glycogen metabolism and some of the clinical aspects of the classical glycogen storage diseases. Disruptions in glycogen metabolism usually result in some level of dysfunction in the liver, muscle, heart, kidney and/or brain. Furthermore, the spectrum of symptoms observed is very broad, depending on the affected enzyme. Finally, we briefly discuss an aspect of glycogen metabolism related to the maintenance of its structure that seems to be gaining more recent attention. For example, in Lafora progressive myoclonus epilepsy, patients exhibit an accumulation of inclusion bodies in several tissues, containing glycogen with increased phosphorylation, longer chain lengths and irregular branch points. This abnormal structure is thought to make glycogen insoluble and resistant to degradation. Consequently, its accumulation becomes toxic to neurons, leading to cell death. Although the genes responsible have been identified, studies in the past two decades are only beginning to shed light into their molecular functions.
| S-EPMC6050127 | biostudies-literature
Project description:BackgroundThis study was designed to investigate differences in biochemical parameters between mouse and humans after paraquat (PQ) poisoning and develop a suitable animal model for studying organ damage after PQ poisoning. The prognostic factors of PQ-poisoned patients were further analyzed.MethodsThirty C57BL/6J mice were randomly divided into five groups (control, sham, and 3 PQ doses), and the mouse model was established by intragastric administration of PQ. Physiological indexes such as the body weight, mental state, and mortality rate were observed. Biochemical parameters were analyzed 24 h after PQ poisoning. We also performed a retrospective analysis of clinical data from 29 patients with PQ poisoning admitted to the Emergency Department of the Affiliated Hospital of Taishan Medical College between April 2016 and February 2018. Biochemical parameters were compared between the mouse model and patients with PQ poisoning.ResultsIn the PQ poisoning mouse model, the lethal dose group PQ360 showed remarkable increases in serum levels of potassium (K+), carbon dioxide (CO2), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) compared with the nonlethal dose PQ100 and PQ200 groups. The biochemical results of the patients showed that K+ and Cl- levels were significantly reduced in the death group compared to the survival group. Levels of ALT, AST, blood urea nitrogen (BUN), and amylase were higher, and the neutrophil-to-lymphocyte ratio (NLR) was increased in the death group compared with the survival group.ConclusionsThe combination of age, PQ dosage, K+, Cl-, BUN, ALT, AST, amylase, and NLR can be used to more accurately predict the outcome of patients with PQ poisoning. C57 mice are an appropriate animal model to study liver and kidney functions following PQ exposure.
| S-EPMC8816545 | biostudies-literature
Project description:The fluctuation of temperature affects many physiological responses in ectothermic organisms, including feed intake, growth, reproduction, and behavior. Changes in environmental temperatures affect the acquisition of energy, whereas hepatic glycogen plays a central role in energy supply for the homeostasis of the entire body. Glycogen phosphorylase (GP), which catalyzes the rate-limiting step in glycogenolysis, is also an indicator of environmental stress. Here, we examined the effects of salinity on glycogen metabolism in milkfish livers under cold stress. A reduction of feed intake was observed in both freshwater (FW) and seawater (SW) milkfish under cold adaptation. At normal temperature (28°C), compared to the FW milkfish, the SW milkfish exhibited greater mRNA abundance of the liver isoform of GP (Ccpygl), higher GP activity, and less glycogen content in the livers. Upon hypothermal (18°C) stress, hepatic Ccpygl mRNA expression of FW milkfish surged at 3 h, declined at 6 and 12 h, increased again at 24 h, and increased significantly after 96 h. Increases in GP protein, GP activity, and the phosphorylation state and the breakdown of glycogen were also found in FW milkfish livers after 12 h of exposure at 18°C. Conversely, the Ccpygl transcript levels in SW milkfish were downregulated after 1 h of exposure at 18°C, whereas the protein abundance of GP, GP activity, and glycogen content were not significantly altered. Taken together, under 18°C cold stress, FW milkfish exhibited an acute response with the breakdown of hepatic glycogen for maintaining energy homeostasis of the entire body, whereas no change was observed in the hepatic glycogen content and GP activity of SW milkfish because of their greater tolerance to cold conditions.
| S-EPMC5816346 | biostudies-literature
Project description:Cerebral radiation necrosis is a common complication of the radiotherapy of brain tumours that can cause significant mortality. Corticosteroids are the standard of care, but their efficacy is limited and the consequences of long-term steroid therapy are problematic, including the risk of adrenal insufficiency (AI). Off-label treatment with the vascular endothelial growth factor A antibody bevacizumab is highly effective in steroid-resistant radiation necrosis. Both the preservation of neural tissue integrity and the cessation of steroid therapy are key goals of bevacizumab treatment. However, the withdrawal of steroids may be impossible in patients who develop AI. In order to elucidate the frequency of AI in patients with cerebral radiation necrosis after treatment with corticosteroids and bevacizumab, we performed a retrospective study at our institution's brain tumour centre. We obtained data on the tumour histology, age, duration and maximum dose of dexamethasone, radiologic response to bevacizumab, serum cortisol, and the need for hydrocortisone substitution for AI. We identified 17 patients with cerebral radiation necrosis who had received treatment with bevacizumab and had at least one available cortisol analysis. Fifteen patients (88%) had a radiologic response to bevacizumab. Five of the 17 patients (29%) fulfilled criteria for AI and required hormone substitution. Age, duration of dexamethasone treatment, and time since radiation were not statistically associated with the development of AI. In summary, despite the highly effective treatment of cerebral radiation necrosis with bevacizumab, steroids could yet not be discontinued due to the development of AI in roughly one-third of patients. Vigilance to spot the clinical and laboratory signs of AI and appropriate testing and management are, therefore, mandated.
| S-EPMC6832264 | biostudies-literature
Project description:The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment.
| S-EPMC9350737 | biostudies-literature
Project description:BackgroundOral corticosteroid (OCS) dependence among patients with severe eosinophilic asthma can cause adverse outcomes, including adrenal insufficiency. PONENTE's OCS reduction phase showed that, following benralizumab initiation, 91.5% of patients eliminated corticosteroids or achieved a final dosage ≤5 mg·day-1 (median (range) 0.0 (0.0-40.0) mg).MethodsThe maintenance phase assessed the durability of corticosteroid reduction and further adrenal function recovery. For ∼6 months, patients continued benralizumab 30 mg every 8 weeks without corticosteroids or with the final dosage achieved during the reduction phase. Investigators could prescribe corticosteroids for asthma exacerbations or increase daily dosages for asthma control deteriorations. Outcomes included changes in daily OCS dosage, Asthma Control Questionnaire (ACQ)-6 and St George's Respiratory Questionnaire (SGRQ), as well as adrenal status, asthma exacerbations and adverse events.Results598 patients entered PONENTE; 563 (94.1%) completed the reduction phase and entered the maintenance phase. From the end of reduction to the end of maintenance, the median (range) OCS dosage was unchanged (0.0 (0.0-40.0) mg), 3.2% (n=18/563) of patients experienced daily dosage increases, the mean ACQ-6 score decreased from 1.26 to 1.18 and 84.5% (n=476/563) of patients were exacerbation free. The mean SGRQ improvement (-19.65 points) from baseline to the end of maintenance indicated substantial quality-of-life improvements. Of patients entering the maintenance phase with adrenal insufficiency, 32.4% (n=104/321) demonstrated an improvement in adrenal function. Adverse events were consistent with previous reports.ConclusionsMost patients successfully maintained maximal OCS reduction while achieving improved asthma control with few exacerbations and maintaining or recovering adrenal function.
| S-EPMC9791910 | biostudies-literature