scholarly journals Acute and Subchronic Toxic Effects of the Fruits ofPhysalis peruvianaL.

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Basak Ozlem Perk ◽  
Sinem Ilgin ◽  
Ozlem Atli ◽  
Hale Gamze Duymus ◽  
Basar Sirmagul
Keyword(s):  
Fruit Juice ◽  
Troponin I ◽  
Troponin T ◽  
Qualitative Content Analysis ◽  
Toxic Effects ◽  
Control Group ◽  
Subchronic Toxicity ◽  
Male Group ◽  
Toxicity Studies

The fruit ofPhysalis peruvianaL. (PPL) has been traditionally used as antispasmodic, diuretic, antiseptic, sedative, and analgesic all over the world. We aimed to perform qualitative content analysis of the fruits of PPL and to clarify thein vitrogenotoxicity andin vivoacute and subchronic toxicity of the fruit. Lyophilized fruit juice does not induce genetic damage. In the acute toxicity studies, LD50 value of the fruit was found to be more than 5000 mg kg−1for both sexes. According to the subchronic toxicity studies, hepatic, renal, and hematological toxic effects were not induced in both sexes. Plasma troponin I (only in the group treated with 5000 mg kg−1of lyophilized fruit juice) and troponin T levels were significantly increased in male groups treated with lyophilized fruit juice compared to the control group. Furthermore, potassium level was significantly increased in the male group treated with 5000 mg kg−1of lyophilized fruit juice. These findings were considered to indicate the myocardial damage particularly in the male group treated with 5000 mg kg−1of lyophilized fruit juice. In conclusion, lyophilized fruit juice of PPL is shown to induce cardiac toxicity only at high doses and in male gender.

Abstract 14201: The Application of Hipsc-derived Cardiomyocytes Paced by Re-entrant Waves for Drug Assessment

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Junjun Li ◽  
Itsunari Minami ◽  
Shigeru Miyagawa ◽  
Xiang Qu ◽  
YING HUA ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Troponin T ◽  
Field Potential ◽  
Electrical Signal ◽  
Assessment System ◽  
K Channel ◽  
Control Group ◽  
Culture Dish ◽  
Robust Response

Introduction: How to precisely evaluate response in newly developed medications in vitro may be a great concern in drug screening. We modified normal low-attachment culture dish and created closed-loop tissue ring from single hiPSC-CMs. We hypothesized that the re-entrant wave (ReW) could originate and pace the cardiac tissue ring, and the CMs under pacing could be matured and used for drug assessment. Methods: PDMS wells and pillars were mounted in low-attachment petri dishes (Figure 1A). 4 х 10 5 hiPSC-CMs were plated into the wells to form tissue ring where the ReW could spontaneously originate. After cultivation for 14 days, the hiPSC-CMs were evaluated by immunostaining and gene expression. Micro electrode array (MEA) were used to evaluating the CM response to different drugs. Results: The electrical signal recorded by MEA indicated that the ReWs could make the CMs beat at a much higher rate than the Control group (Figure 1B, 123.26 ± 10.36 bpm vs. 14.08 ± 4.53 bpm, p<0.0001). After 14 day culture, the ReW group demonstrated significantly higher expression of Troponin T (TnT2), myosin heavy chain 7 (β-MHC), and α-actinin. Interestingly, the α-actinin staining indicated alignment of CMs within the ReW group (Figure 1C). The CMs under ReW pacing showed robust response to several cardiac compounds including E4031, (hERG K+ channel blocker, Figure 1D and E), isoproterenol (β adrenoceptor agonist) and propranolol (beta-blocker). Both the field potential as well as the Ca 2+ transients showed correlated dose-dependent change and the recovering after washout of the drugs. Conclusions: The ReWs could spontaneously originate in the cultured cardiac tissue ring with enhancement of the maturation in the hiPSC-CMs and robust response to various drugs, indicating the system as a robust drug assessment system with multiple read-out methods.

scholarly journals Atomic resolution probe for allostery in the regulatory thin filament

2016 ◽  
Vol 113 (12) ◽  
pp. 3257-3262 ◽  
Author(s):  
Michael R. Williams ◽  
Sarah J. Lehman ◽  
Jil C. Tardiff ◽  
Steven D. Schwartz
Keyword(s):  
Binding Site ◽  
Human Disease ◽  
Calcium Binding ◽  
Cardiac Troponin ◽  
Thin Filament ◽  
Troponin I ◽  
Troponin T ◽  
Calcium Binding Site

Calcium binding and dissociation within the cardiac thin filament (CTF) is a fundamental regulator of normal contraction and relaxation. Although the disruption of this complex, allosterically mediated process has long been implicated in human disease, the precise atomic-level mechanisms remain opaque, greatly hampering the development of novel targeted therapies. To address this question, we used a fully atomistic CTF model to test both Ca2+ binding strength and the energy required to remove Ca2+ from the N-lobe binding site in WT and mutant troponin complexes that have been linked to genetic cardiomyopathies. This computational approach is combined with measurements of in vitro Ca2+ dissociation rates in fully reconstituted WT and cardiac troponin T R92L and R92W thin filaments. These human disease mutations represent known substitutions at the same residue, reside at a significant distance from the calcium binding site in cardiac troponin C, and do not affect either the binding pocket affinity or EF-hand structure of the binding domain. Both have been shown to have significantly different effects on cardiac function in vivo. We now show that these mutations independently alter the interaction between the Ca2+ ion and cardiac troponin I subunit. This interaction is a previously unidentified mechanism, in which mutations in one protein of a complex indirectly affect a third via structural and dynamic changes in a second to yield a pathogenic change in thin filament function that results in mutation-specific disease states. We can now provide atom-level insight that is potentially highly actionable in drug design.

scholarly journals Acute and Subchronic Toxicity Studies of Combretum collinum Methanol Root Extract in Albino Rats

2020 ◽  
pp. 9-28
Author(s):  
S. W. Hassan ◽  
A. N. Ukwuani-Kwaja ◽  
U. D. Nuhu ◽  
R. D. Jabaka
Keyword(s):  
Oral Administration ◽  
Histopathological Examination ◽  
Lethal Dose ◽  
Research Work ◽  
Control Group ◽  
Albino Rats ◽  
Root Extract ◽  
Acute Administration ◽  
Subchronic Toxicity ◽  
Toxicity Studies

Combretum collinum root extract has been recognized long ago as traditional medicinal plant in curing several diseases among the indigenous people of Alela-land (Zuru), Kebbi State, Nigeria. This research work was carried out to evaluate the toxicological effects of Combretum collinum methanol root extract (CCME) in albino rats. Acute toxicity was performed by a fixed single oral administration at a dose of 10, 100, 1000 mg/Kg and 1600, 2900, 5000 mg/Kg. Subchronic toxicity studies of CCME was conducted at doses of 32, 63, 126 and 253 mg/Kg for 28 days. The result showed that acute administration of CCME resulted at mortality and general behavioral changes at 1000 to 5000 mg/Kg. Therefore, the estimated lethal dose (LD50) of CCME was 316.23 mg/Kg. Subchronic oral administration of CCME revealed a significant (P<0.01) decrease in body weight in rats receiving 63 to 253 mg/Kg throughout the study period compared with the control group. The results also showed a significant (P<0.01) increase in serum ALT, AST, creatinine, potassium and bicarbonate in rats administered with 126 and 253 mg/Kg of the extract. Haematological analysis of the same extract revealed a significant (P<0.01) increase in WBC, HCT, MCV, MCH, MCHC, PLT, LYM and NEUT in rats receiving 126 and 253 mg/Kg only. Histopathological examination of liver revealed severe periportal inflammation, hypertrophy, areas of hydropic changes, cancerous tumor, areas of infiltration and necrosis of the hepatic cells while the kidney showed a mild mesengial hyperplasia, compressed blood vessels, glomerular degeneration, tubular degeneration and tubular widened lumen in rats treated with 63 to 253 mg/Kg. Therefore, caution should be applied as C. collinum root extract has a low mean lethal dose and would be toxic at higher concentrations.

Is there any relationship between platelet indices and myocarditis in children?

2021 ◽  
pp. 1-5
Author(s):  
Damla Geçkalan Soysal ◽  
Rahmi Özdemir
Keyword(s):  
Troponin I ◽  
Low Voltage ◽  
Troponin T ◽  
Control Group ◽  
Study Group ◽  
C Reactive Protein ◽  
Distribution Width ◽  
Platelet Indices ◽  
Reactive Protein ◽  
Significant Difference

Abstract Background: Platelet indices are used to evaluate platelet activation and function which change in inflammatory diseases. We hypothesise that platelet indices such as plateletcrit, mean platelet volume, and platelet distribution width may be more useful as prognostic indicators for myopericarditis in children. Methods: A total of 60 children were included in this study. Group 1 consists of children with myopericarditis, Group 2 is those with respiratory infections, and Group 3 consists of control group children of similar age and gender with the patient groups. Complete blood count parameters, C-reactive protein, and troponin values of the whole study group were recorded. Myopericarditis was diagnosed based on acute chest pain, dyspnea, palpitations, heart failure signs, arrhythmia symptoms and ST/T wave change, low voltage, supraventricular tachycardia/ventricular tachycardia on ECG, or elevated troponin T/troponin I levels or functional abnormalities on echocardiography. A comparison of the platelet indices made during diagnosis and 2 weeks after treatment was done for the myopericarditis patients. Results: There was no statistically significant difference in platelet indicies values. However, the increase in platelets and plateletcrit values after the treatment of myopericarditis was statistically significant. This study pointed out that there was a negative correlation between platelet–plateletcrit values and the troponin I–C-reactive protein. Conclusion: We found that platelet count and plateletcrit values increased after treatment. This is important as it is the first study in children to investigate the possible role of platelet indications for myopericarditis in children.

P2585Cardiac dysfunction after myocardial infarction: role of pro-inflammatory extracellular vesicles

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
V Biemmi ◽  
G Milano ◽  
A Ciullo ◽  
E Cervio ◽  
M Dei Cas ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Extracellular Vesicles ◽  
Acute Phase ◽  
Troponin I ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Coronary Artery Ligation ◽  
Cytotoxic Effects

Abstract Background Myocardial infarction (MI) is associated with significant loss of cardiomyocytes (CM), which are replaced by a fibrotic scar. Necrotic CM release damage-associated proteins that stimulate innate immune pathways and macrophages (MΦ) tissue infiltration, which drives to the progression of inflammation and myocardial remodeling process. Both, loss of CM and inflammatory response are determinants of the long term ventricle remodeling and heart failure. Circulating inflammatory extracellular vesicles (EV) play a crucial role in the acute and chronic phases of MI, in terms of inflammatory progression. In this study we examined whether reducing the generation of inflammatory EV within few hours from the ischemic event may ameliorate cardiac outcome at short and long time-point in LAD rat model. Methods Before coronary artery ligation, rats were injected IP with a chemical inhibitor of neutral sphingomyelinase (nSMase) which is essential for the biogenesis and release of EVs. The number and size profile of plasma-derived EV was assessed by NTA analysis at baseline and 24hrs after MI. Multiple EV cytokine levels were simultaneously determined using enzyme-linked immunosorbent assay (ELISA)-based protein array technology. Heart global function was assessed by echocardiography and hemodynamic analysis performed at 7, 14 and 28 days after MI. Cytotoxic effects of circulating EV were evaluated ex-vivo in a Langedorff, system by measuring the level of cardiac troponin I (cTnI) in the perfusate. Mechanisms undergoing cytotoxic effects of EV derived from pro-inflammatory MΦ (MΦM1) were studied in vitro into primary rat neonatal CM. Results The induction of MI and the consequent inflammation, dramatically increase the number of circulating EV carrying inflammatory cytokines such as IL1α, ILβ and Rantes. Preventive inhibition nSMase significantly reduced the boost of inflammatory EV and cytokines in treated group as compared to control animals. The reduction of circulating EV post MI results in preserved LV ejection fraction at 7 and 28 days post-MI as compared to control group. Hemodynamic analysis confirmed functional recovery by displaying a higher velocity of LV relaxation and an improved contractility capacity in treated versus control group. The number of infiltrating CD68+ monocytes/macrophages in the infarct area was significantly reduced. Post-MI circulating EV induce cell death in adult CM when added to the perfusate of Langendorff, as assessed by the incresed level of cTnI into media. In vitro MΦM1-EV activated nuclear translocation of NF-kB. Specific inhibition of TLR4 receptor activity abrogated NF-kB translocation and reduced cell death. Indicating that the axis TRL4-NF-kB is essential in EV-mediated CM death. Conclusions Systemic inhibition of EV release during the acute phase of MI preserves heart function in an animal model of LAD. These findings suggest detrimental effects of exosomes in the acute phase of MI.

scholarly journals Mavacamten rescues increased myofilament calcium sensitivity and dysregulation of Ca2+ flux caused by thin filament hypertrophic cardiomyopathy mutations

2020 ◽  
Vol 318 (3) ◽  
pp. H715-H722 ◽  
Author(s):  
Alexander J. Sparrow ◽  
Hugh Watkins ◽  
Matthew J. Daniels ◽  
Charles Redwood ◽  
Paul Robinson
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Cardiac Troponin ◽  
Thin Filament ◽  
Troponin I ◽  
Troponin T ◽  
Thick Filament ◽  
Calcium Sensitivity ◽  
Calcium Handling ◽  
Cellular Models

Thin filament hypertrophic cardiomyopathy (HCM) mutations increase myofilament Ca2+ sensitivity and alter Ca2+ handling and buffering. The myosin inhibitor mavacamten reverses the increased contractility caused by HCM thick filament mutations, and we here test its effect on HCM thin filament mutations where the mode of action is not known. Mavacamten (250 nM) partially reversed the increased Ca2+ sensitivity caused by HCM mutations Cardiac troponin T (cTnT) R92Q, and cardiac troponin I (cTnI) R145G in in vitro ATPase assays. The effect of mavacamten was also analyzed in cardiomyocyte models of cTnT R92Q and cTnI R145G containing cytoplasmic and myofilament specific Ca2+ sensors. While mavacamten rescued the hypercontracted basal sarcomere length, the reduced fractional shortening did not improve with mavacamten. Both mutations caused an increase in peak systolic Ca2+ detected at the myofilament, and this was completely rescued by 250 nM mavacamten. Systolic Ca2+ detected by the cytoplasmic sensor was also reduced by mavacamten treatment, although only R145G increased cytoplasmic Ca2+. There was also a reversal of Ca2+ decay time prolongation caused by both mutations at the myofilament but not in the cytoplasm. We thus show that mavacamten reverses some of the Ca2+-sensitive molecular and cellular changes caused by the HCM mutations, particularly altered Ca2+ flux at the myofilament. The reduction of peak systolic Ca2+ as a consequence of mavacamten treatment represents a novel mechanism by which the compound is able to reduce contractility, working synergistically with its direct effect on the myosin motor. NEW & NOTEWORTHY Mavacamten, a myosin inhibitor, is currently in phase-3 clinical trials as a pharmacotherapy for hypertrophic cardiomyopathy (HCM). Its efficacy in HCM caused by mutations in thin filament proteins is not known. We show in reductionist and cellular models that mavacamten can rescue the effects of thin filament mutations on calcium sensitivity and calcium handling although it only partially rescues the contractile cellular phenotype and, in some cases, exacerbates the effect of the mutation.

scholarly journals The subchronic toxic effects of Mosla Chinensis Maxim in normal rats.

2020 ◽  
Author(s):  
Dan Lei ◽  
Longxue Li ◽  
Shenghong Huang ◽  
Li Liu ◽  
Pingdong Cai ◽  
...  
Keyword(s):  
Dose Group ◽  
Intestinal Flora ◽  
Female Rats ◽  
Toxic Effects ◽  
Fixed Dose ◽  
Control Group ◽  
Subchronic Toxicity ◽  
Male And Female ◽  
Sd Rats

Abstract Background: The aim of this work was to study the toxic effects and target organs of Mosla Chinensis Maxim (MCM) in rats and provide theoretical basis for clinical medication.Methods: The subchronic toxicity study was conducted on 60 male and female SD rats using the fixed-dose method for the treatment group and 20 male and female SD rats for the control. At the subchronic toxicity study, the water extract of MCM with fixed-dose of 0.2g/kg/day, 2g/kg/day and 20g/kg/day was administered for 90 days intragastric, and the control group was given the same amount of distilled water. After 90 days, the general conditions of the rats were observed. Assesment on safety of the extract was conducted by a subchronic toxicity test which mainly examined alteration occured in gut flora and urine metabolism. Results: The results showed that there were no significant toxic effects observed at all doses on physical sign and reactivity and fecal property of rats in the treatment groups had no obvious difference from those in control group. The results of routine blood test showed that the number of red blood cells in the male medium dose group and the female low dose group were significantly different from those in the control group (P<0.05). The results of serum biochemical indicators test showed that MCM had influence on the indicators of liver and kidney function, but it had no toxicological significance. In terms of glucose and lipid metabolism, the LDL level of male rats was lower than that of the control group (P<0.05). Compared with the control group, GLU level of female rats in the low, medium and high dose groups was significantly increased (P<0.05), indicating that long-term administration of MCM would affect the glucose level of female rats. The results of intestinal flora diversity showed that feeding MCM for 90 days had an impact on the distribution of intestinal flora. The content of lactobacillus increased and the ratio of Firmicutes and Bacteroidetes (F/B) was also affected, but there was no significant difference. Conclusions: These findings showed that the long-term intragastric administration of the MCM is safe to use within its dose recommendation. But it could have slight affect the metabolism of uric acid by changing the composition of intestinal flora and affecting the metabolism of tryptophan.

scholarly journals Subchronic Toxicity Studies of Cortex Dictamni Extracts in Mice and Its Potential Hepatotoxicity Mechanisms in Vitro

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2486 ◽  
Author(s):  
Qiongyin Fan ◽  
Baosheng Zhao ◽  
Chunguo Wang ◽  
Jingxuan Zhang ◽  
Jinying Wu ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Clinical Signs ◽  
Cell Membrane Permeability ◽  
Dependent Manner ◽  
Subchronic Toxicity ◽  
Chinese Herbal ◽  
Toxicity Studies ◽  
Potential Hepatotoxicity ◽  
Toxic Components

Cortex Dictamni is a commonly-used traditional Chinese herbal medicine for the treatment of skin inflammation, tinea, and eczema. Recently, some studies reported that Cortex Dictamni might induce liver injury, suggesting more attention to its safety. The current study was designed to investigate subchronic toxicity of Cortex Dictamni aqueous extract (CDAE) and ethanol extract (CDEE) in mice and the potential hepatotoxicity mechanisms in vitro. Firstly, CDAE or CDEE groups were administrated with varying dosages (2.3, 4.6, or 9.2 g/kg/day, p.o.) in mice for 28 days in subchronic toxicity studies. General clinical signs and biochemical parameters were examined, and morphological analyses were conducted. Secondly, we identified the different constituents of CDAE and CDEE using HPLC-MS/MS and chose major components for further study. In order to determine the toxic components, we investigated the cytotoxicity of extracts and chosen components using CCK-8 assay in HepG2 cells. Furthermore, we explored the possible hepatotoxicity mechanisms of Cortex Dictamni using a high content analysis (HCA). The results showed that no significant differences of general clinical signs were observed in mice. Aspartate alanine aminotransferase (ALT) and aminotransferase (AST) were significantly increased in the high-dose CDAE and CDEE groups compared to the control group. Meanwhile, the absolute and relative liver weights and liver/brain ratio were significantly elevated, and histological examination of liver demonstrated cellular enlargement or nuclear shrinkage. In UPLC analysis, we compared the chemical constituents between CDAE and CDEE, and chose dictamnine, obakunone, and fraxinellone for hepatotoxicity evaluation in the in vitro studies. In the CCK-8 assay, CDAE, CDEE, dictamnine, obakunone, and fraxinellone decreased the cell viability in a dose-dependent manner after treatment for 48 h. Furthermore, the cell number decreased, while the nuclear intensity, cell membrane permeability, and concentration of reactive oxygen species were shown to increase, meanwhile, mitochondrial membrane potential was also changed in HepG2 cells following 48 h of compounds treatment using HCA. Our studies suggested that CDAE and CDEE have potential hepatotoxicity, and that the alcohol extraction process could increase toxicity. Dictamnine, obakunone, and fraxinellone may be the possible toxic components in Cortex Dictamni with dictamnine as the most potentially hepatotoxic component, whose potential hepatotoxicity mechanism may be associated with cell apoptosis. Moreover, this study could provide valuable data for clinical drug safety research of Cortex Dictamni and a good example for safety study of other Chinese herbal medicines.

scholarly journals Subchronic Toxicity Test of Indian Almond (Terminalia catappa) Leaves Water Extract on The Liver Histology of Mice (Mus musculus)

BIOEDUSCIENCE ◽  
2020 ◽  
Vol 4 (2) ◽  
pp. 177-182
Author(s):  
Nugroho Rudy ◽  
Ni Cening Sri Puspa ◽  
Retno Aryani ◽  
Widha Prahastika ◽  
Rudianto ◽  
...  
Keyword(s):  
Toxic Effect ◽  
Water Extract ◽  
Leaf Water ◽  
Liver Histology ◽  
Toxic Effects ◽  
Cell Swelling ◽  
Control Group ◽  
Subchronic Toxicity ◽  
Water Extracts ◽  
Terminalia Catappa

Background: Indian almond (Terminalia catappa) is used as an alternative medicine by the community to treat various diseases. However, limited research has been conducted on the subchronic toxicity of Indian almond water extracts on the liver. Present study aimed to determine the subchronic toxic effects of Indian almond leaf water extract on the liver histology of mice and to evaluate the safe dose of Indian almond  leaf water extract with various doses (125, 250, 500, 750 and 1000 mg/kg). Methods: In total of 33 male mice were randomly divided into 11 groups, each group consisting of three mice as replication. For 30 days, mice in five treatment groups were orally treated every day with water extracts of green Indian almond leaf while other five groups were given water extracts of brown Indian almond leaves and compare with control group. At the end of day 30, all mice were sacrificed, and hepar was taken out for histological preparations. The histopathological changes in the liver was observed and assessed based on histological damage in the term of degeneration and necrosis. Results: The administration of green and brown Indian almond water extract at doses of 125, 250, 500, 750 and 1000 mg / kg BB showed a toxic effect on the liver of mice. The toxic effect was due to the high doses, causing a cell swelling damage and increased liver necrosis. Conclusion: Indian almond leaf water extract can cause toxic effects on the liver of mice at the doses implemented.  

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