Nonlinear Dose-effect Relationship Research Articles

Insights into the enzymatic degradation of DNA expedited by typical perfluoroalkyl acids

Perfluoroalkyl acids (PFAAs) are considered forever chemicals, gaining increasing attention for their hazardous impacts. However, the ecological effects of PFAAs remain unclear. Environmental DNA (eDNA), as the environmental gene pool, is often collected for evaluating the ecotoxicological effects of pollutants. In this study, we found that all PFAAs investigated, including perfluorohexanoic acid, perfluorooctanoic acid, perfluorononanoic acid, and perfluorooctane sulfonate, even at low concentrations (0.02 and 0.05 mg/L), expedited the enzymatic degradation of DNA in a nonlinear dose–effect relationship, with DNA degradation fragment sizes being lower than 1,000 bp and 200 bp after 15 and 30 min of degradation, respectively. This phenomenon was attributed to the binding interaction between PFAAs and AT bases in DNA via groove binding. van der Waals force (especially dispersion force) and hydrogen bonding are the main binding forces. DNA binding with PFAAs led to decreased base stacking and right-handed helicity, resulting in loose DNA structure exposing more digestion sites for degrading enzymes, and accelerating the enzymatic degradation of DNA. The global ecological risk evaluation results indicated that PFAA contamination could cause medium and high molecular ecological risk in 497 samples from 11 contamination-hot countries (such as the USA, Canada, and China). The findings of this study show new insights into the influence of PFAAs on the environmental fates of biomacromolecules and reveal the hidden molecular ecological effects of PFAAs in the environment.

ROS- and Radiation Source-Dependent Modulation of Leukocyte Adhesion to Primary Microvascular Endothelial Cells.

Anti-inflammatory effects of low-dose irradiation often follow a non-linear dose–effect relationship. These characteristics were also described for the modulation of leukocyte adhesion to endothelial cells. Previous results further revealed a contribution of reactive oxygen species (ROS) and anti-oxidative factors to a reduced leukocyte adhesion. Here, we evaluated the expression of anti-oxidative enzymes and the transcription factor Nrf2 (Nuclear factor-erythroid-2-related factor 2), intracellular ROS content, and leukocyte adhesion in primary human microvascular endothelial cells (HMVEC) upon low-dose irradiation under physiological laminar shear stress or static conditions after irradiation with X-ray or Carbon (C)-ions (0–2 Gy). Laminar conditions contributed to increased mRNA expression of anti-oxidative factors and reduced ROS in HMVEC following a 0.1 Gy X-ray and 0.5 Gy C-ion exposure, corresponding to reduced leukocyte adhesion and expression of adhesion molecules. By contrast, mRNA expression of anti-oxidative markers and adhesion molecules, ROS, and leukocyte adhesion were not altered by irradiation under static conditions. In conclusion, irradiation of endothelial cells with low doses under physiological laminar conditions modulates the mRNA expression of key factors of the anti-oxidative system, the intracellular ROS contents of which contribute at least in part to leucocyte adhesion, dependent on the radiation source.

RETRACTED ARTICLE: Receptor tyrosine kinase inhibitor Sunitinib and integrin antagonist peptide HM-3 show similar lipid raft dependent biphasic regulation of tumor angiogenesis and metastasis

BackgroundAnti-angiogenesis remains an attractive strategy for cancer therapy. Some anti-angiogenic reagents have bell-shape dose-response curves with higher than the effective doses yielding lower anti-angiogenic effects. In this study, two different types of anti-angiogenic reagents, a receptor tyrosine kinase inhibitor Sunitinib and an integrin antagonist peptide HM-3, were selected and their effects on tumor angiogenesis and metastasis were compared. The involved molecular mechanisms were investigated.MethodsThe effect of high dose Sunitinib and HM-3 on tumor angiogenesis and metastasis was investigated with two animal models: metastasis of B16F10 cells in syngeneic mice and metastasis of human MDA-MB-231 cells in nude mice. Furthermore, mechanistic studies were performed with cell migration and invasion assays and with biochemical pull-down assays of intracellular RhoGTPases. Distribution of integrin αvβ3, α5β1, VEGFR2 and the complex of integrin αvβ3 and VEGFR2 inside or outside of lipid rafts was detected with lipid raft isolation and Western-blot analysis.ResultsBoth Sunitinib and HM-3 showed a bell-shape dose-response curve on tumor angiogenesis and metastasis in both animal models. The effects of Sunitinib and HM-3 on endothelial cell and tumor cell proliferation and migration were characterized. Activation of intracellular RhoGTPases and actin stress fiber formation in endothelial and cancer cells following Sunitinib and HM-3 treatment correlated with cell migration analysis. Mechanistic studies confirmed that HM-3 and Sunitinib regulated distribution of integrin αvβ3, α5β1, VEGFR2 and αvβ3-VEGFR2 complexes, both inside and outside of the lipid raft regions to regulate endothelial cell migration and intracellular RhoGTPase activities.ConclusionsThese data confirmed that a general non-linear dose-effect relationship for these anti-angiogenic drugs exists and their mechanisms are correlative. It also suggests that the effective dose of an anti-angiogenic drug may have to be strictly defined to achieve its optimal clinical effects.

Interrelationships among common predictors of cardiovascular diseases in patients of OSA: A large-scale observational study

Background and aimsThe apolipoprotein B/apolipoprotein A-I (ApoB/ApoA-I) and insulin resistance has been recognized as common cardiovascular diseases (CVD) risk factors. However, whether they were biomarkers for 10-year CVD risk in obstructive sleep apnea (OSA) had been rarely studied. Besides, interrelationships between the ApoB/ApoA-I, insulin resistance and OSA remain unclear. Methods and resultsA total of 4010 subjects were finally included. Anthropometric, fasting biochemical, and polysomnographic parameters were collected. 10-year Framingham CVD risk score (FRS) was calculated for each subjects. The relationships between insulin resistance, OSA risk and the ApoB/ApoA-I was evaluated through logistic regressions analysis, restricted cubic spline (RCS) analysis and mediation analysis. ApoB/ApoA-I, HOMA-IR and AHI were all risk factors for high10-year CVD risk as assessed by FRS (odds ratios (OR) = 5.365, 1.094, 1.010, respectively, all P < 0.001)). The fully adjusted OR (95% confidence intervals) for both OSA [1 (reference), 1.308 (1.027–1.665), 1.517 (1.178–1.953), and 1.803 (1.371–2.372)] and insulin resistance [1 (reference), 1.457 (1.173–1.711), 1.701 (1.369–2.113), 2.051(1.645–2.558)] increased from the first to the fourth quartiles of the ApoB/ApoA-I. The RCS mapped a nonlinear dose–effect relationship between the ApoB/ApoA-I and risk of insulin resistance and OSA. Mediation analyses showed HOMA-IR explain 9.7%, 4.7% and 10.8% of the association between apnea-hypopnea index, oxygen desaturation index, micro-arousal index and ApoB/ApoA-I, respectively. ConclusionsOur study revealed that ApoB/ApoA-I, insulin resistance and OSA were risk factors for CVD. Insulin resistance may serve as a potential mediator in OSA-related lipoprotein disorders and further increase CVD risk.

Interrelationships Among Apolipoprotein B/Apolipoprotein A-I Ratio, Insulin Resistance and Obstructive Sleep Apnea: A Large-Scale Observational Study

Background: The apolipoprotein B/apolipoprotein A-I (ApoB/ApoA-I) ratio has been recognized as a new predictor of cardiovascular diseases (CVD). However, the interrelationships between the ApoB/ApoA-I ratio and common CVD risk factor [insulin resistance, obstructive sleep apnea (OSA)] remain unclear. Methods: A total of 6,433 suspected OSA consecutively admitted to our sleep center were screened and 4,813 were included. Anthropometric, fasting biochemical, and polysomnographic parameters were collected. The relationships between insulin resistance, OSA risk, and the ApoB/ApoA-I ratio were evaluated through logistic regressions analysis and restricted cubic spline (RCS) analysis. Mediation analyses were qualified to assess the interrelationships. Results: Patients with OSA had a lower level of ApoA-I and a higher ApoB and ApoB/ApoA-I ratio. The fully adjusted odds ratios (95% confidence intervals) for both OSA [1 (reference), 1.406 (1.129-1.751), 1.556 (1.236-1.958), and 1.943 (1.508-2.505)] and insulin resistance [1 (reference), 1.424 (1.176-1.725), 1.948 (1.359-1.998), 2.019(1.658-2.459)] increased from the first to the fourth quartiles of the ApoB/ApoA-I ratio. Finally, the RCS mapped a nonlinear dose-effect relationship between the ApoB/ApoA-I ratio and risk of insulin resistance and OSA. OSA was also independently associated with insulin resistance. Mediation analyses showed insulin resistance explain 7.4%, 3.6% and 10.8% of the association between apnea-hypopnea index, oxygen desaturation index, micro-arousal index and ApoB/ApoA-I ratio, respectively. Conclusions: Our study revealed that ApoB/ApoA-I ratio was positively associated with an increased risk for insulin resistance and OSA severity. Insulin resistance may serve as a potential mediator in OSA-related lipoprotein disorders and further increase CVD risk. Funding Statement: This study was supported by grants-in-aid from National Key R&D Program of China (2017YFC0112500), National Natural Science Foundation of China (81770987), Shanghai Sailing Program (17YF1414300), multi-center clinical research project from school of medicine, Shanghai Jiao Tong University (DLY201502) and Shanghai Shen-Kang Hospital Management Center Project of Shanghai (SHDC12015101). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The ethics committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital approved this study according to Helsinki Declaration II. All the participants have given the informed consent before taking part in the study.

Distinct severity stages of obstructive sleep apnoea are correlated with unique dyslipidaemia: large-scale observational study

BackgroundDyslipidaemia is an intermediary exacerbation factor for various diseases but the impact of obstructive sleep apnoea (OSA) on dyslipidaemia remains unclear.MethodsA total of 3582 subjects with suspected OSA consecutively admitted...

Non-linear dose effect relationship in anxiolytic and nootropic activity of lithium carbonate and Nardostachys jatamansi in rats

There is increasing use of traditional remedies with modern medicine. It needs to be evaluated whether such integration will be useful or otherwise. We studied interaction between lithium carbonate and Nardostachys jatamansi extract (NJE), given separately and together, both on acute administration and repeated administration in rats with respect to anxiolytic and nootropic activities. Acute administration of lithium carbonate NJE (100 and 200 mg/kg i. p.) given separately, significantly increased time spent in the open arm indicating reduced anxiety. Lithium carbonate (10 mg/kg i. p.) significantly reduced anxiolytic activity of NJE. Rats receiving lithium carbonate (10 mg/kg i.p. for 21 days) and NJE (100 and 200 mg/kg) acutely on 21st day, showed significantly diminished anxiolytic activity of NJE. NJE (100 and 200 mg/kg) used alone, exhibited nootropic activity in the elevated plus maze and object recognition test. In the elevated plus maze, acute administration of lithium carbonate (10 mg/kg) and NJE (100 mg/kg) showed significant improvement in nootropic activity and diminished nootropic response to NJE (200 mg/kg). Similar biphasic effect was observed when rats received lithium carbonate for 21 days and NJE on 21st day. In the object recognition test, acute administration of lithium carbonate and NJE improved nootropic activity but in rats receiving lithium for 21 days, NJE (100 mg/kg) improved and (200 mg/kg) reduced nootropic activity. Thus there is a non-linear dose effect relationship between lithium carbonate and NJE suggesting necessity of careful selection of doses to avoid loss of activity.

Estimation of the levels of radiation-induced P-element transposition in Drosophila melanogaster experimental populations and laboratory strains

When experimental P + M populations were exposed to chronic gamma-irradiation (0.31 mGy/h), the highest instability level of the singed-weak (sn(w)) locus was observed in F3-F10 with a subsequent decrease and stabilization of the mutation rate. The sn(w) mutation rate was within the range of spontaneous variation in conditions of P-M hybrid dysgenesis and irradiation of males of the Harwich laboratory strain with active P elements at 1.61 mGy/h. The instability of the sn(w) locus was significantly higher at lower dose rates (0.23 and 0.31 mGy/h), suggesting a nonlinear dose-effect relationship.

Cytogenetic effect of low dose γ-radiation in Hordeum vulgare seedlings: non-linear dose–effect relationship

Cytogenetic effect of low dose γ-radiation in Hordeum vulgare seedlings: non-linear dose–effect relationship

Cytogenetic effect of low dose γ-radiation in Hordeum vulgare seedlings: non-linear dose–effect relationship

The induction of chromosome aberrations in Hordeum vulgare germinated seeds was studied after ionizing irradiation with doses in the range of 10-1,000 mGy. The relationship between the frequency of aberrant cells and the absorbed dose was found to be nonlinear. A dose-independent plateau in the dose range from about 50 to 500 mGy was observed, where the level of cytogenetic damage was significantly different from the spontaneous level. The comparison of the goodness of the experimental data fitting with mathematical models of different complexity, using the most common quantitative criteria, demonstrated the advantage of a piecewise linear model over linear and polynomial models in approximating the frequency of cytogenetical disturbances. The results of the study support the hypothesis of indirect mechanisms of mutagenesis induced by low doses. Fundamental and applied implications of these findings are discussed.

A comparitive study between the coal-biomass briquette and raw coal in SO2 pollution and adverse effects in rabbits

This study was conducted to evaluate the adverse health effects on rabbits exposed to SO2 emitted indoors from burning coals, and compare differences between coal-biomass briquette (B.B.) and raw coal (R.C.). Thirty-six male rabbits were divided equally into three groups at random, and then exposed to burning R.C., B.B., and the third without burning coal (Control) for 90 days. Data showed that the average concentration of SO2 in 24 h in R.C. was 13.04 mg m−3, which was 5-fold greater than B.B. (2.68 mg m−3) and 31-fold higher than control (0.41 mg m−3). After 45 days, the numbers of rabbits, with increased frequency of Comet cell was highest in R.C. After 90 days, the % positive Comet cell was significant at 10.36% in R.C., 5.42% in B.B., and 1.73% in Control. There was a nonlinear dose–effect relationship between % positive Comet cell and the concentration of SO2. The incidence of interstitial pneumonia was 6/12 in R.C. and 4/12 in B.B. showing severe squamous metaplasia with atypical hyperplasia in bronchial epithelia in R.C. animals. The results of study indicate that use of B.B. reduced the emission of SO2; but the smoke emitted from burning coal still produced DNA damage.

Microscale Spatial Variation in Forest Litter Phytotoxicity

The spatial variation (within a 100 × 100 m plot) in the pollution of forest litter with heavy metals (Cu, Cd, Pb, and Zn), its acidity, and phytotoxicity (measured by the results of the root test using seedlings from a genetically homogeneous sample of common dandelion (Taraxacum officinale s.l.) have been estimated. Forest litter has been sampled in three zones differing in the toxic impact of long-term polymetal pollution by emissions from a copper-smelting plant emissions in the Middle Urals. The phytotoxicity variation is maximum in a moderately polluted plot, where both very high and very low pollution levels were observed, which determines a substantially nonlinear dose–effect relationship. The litter phytotoxicity is mainly accounted for by exchangeable forms of metals. Biological testing of samples from the most polluted plot has demonstrated marked antagonism between heavy metals and acidity.

Explanation of protective effects of low doses of γ -radiation with a mechanistic radiobiological model

Purpose : To test whether data that show protective effects of low doses against spontaneous neoplastic transformation of C3H 10T1/2 cells can be explained with a biomathematical model that includes radioprotective mechanisms. To link important features of the model to known biological processes. Materials and methods : The model simulates double-strand break formation in transcriptionally active and in bulk DNA, translocation of DNA segments, and the fixation of damage at mitosis; promotion is also included. The model equations were solved numerically using a stiff solver. Results : The data were successfully simulated by the model: cell transformation-reducing effects of low doses of γ-radiation delivered at low dose-rates are explained by radiation-inducible DNA repair and enzymatic scavenging. Conclusions : The model successfully simulates experimental data. The highly nonlinear features of the data point to a nonlinear dose-effect relationship at low doses and indicate that linear extrapolation from moderate (or high) to low doses and dose-rates may not be justified for in vitro studies of the cell line under consideration.

Significance of cell-cycle delay, multiple initiation pathways, misrepair and replication errors in a model of radiobiological effects

Purpose : To advance a biomathematical model of radiocarcinogenesis by describing multiple pathways for initiation, a radiologically induced cell-cycle delay, misrepair and spontaneous DNA damages caused by replication. It was investigated whether the incorporation of these biological features would improve the fit of the model to data showing plateaus in in vitro irradiations of different cell lines and whether the fit parameters were then more biologically realistic. Materials and methods : A biomathematical submodel was developed based on a previous State-Vector Model that mathematically described enhanced DNA repair and radical scavenging following irradiation. Results : With the two initiation pathways and cell-cycle delay, the simulations better explained the mouse data but not the rat data, and for both data sets the fit parameters were biologically more realistic than previously assumed. Inclusion of misrepair and replicational errors did not significantly affect the fit. Conclusions : A plateau in the dose-effect relationship for in vitro irradiation of different cell lines can be explained by radioprotective mechanisms. The plateau-type dose-response relationships point to a non-linear dose-effect relationship at low doses and indicate that linear extrapolation from moderate (or high) to low doses may not be justified for in vitro studies of these cell lines.

Radiation exposures and risks due to airtightening of homes in an alpine area with high radon emanation

Radon and its short-lived decay products in the indoor environment are the most important single source of exposure to ionizing radiation in Switzerland. Modifications in the construction of dwellings implemented to reduce energy consumption may change indoor pollutant levels and cause substantial long term hazards to the general public (1). The following estimate of additional exposure of humans to the ionizing radiation from radon and its short-lived progeny in the indoor air of energy efficient dwellings, i.e. homes showing low air exchange rates, is based on radon measurements in Swiss alpine regions with high terrestrial radiation. Differences in the indoor radon levels between new or retrofitted dwellings are derived from a matched pair study of single family homes in Switzerland (2). Risk factors for lung cancer induction from radon exposure have to rely mostly on occupational exposures in mines. However, the integral dose over the human life span from radon and its progeny in the indoor air in high background areas may approach or even exceed the values of miner populations showing significant increases in the incidence of malignant lung diseases. Although confounding factors such as poor control of smoking habits and additional chemihal toxicants in mine air do not permit a direct comparison of environmental and occupational exposure risks, both radiobiological considerations and the results from human epidemiology point to a linear dose effect relationship. This is in clear contrast to the case of formaldehyde, where no human data exist and where nasal carcinomas in rats follow a non-linear dose-effect relationship.

Effect of gamma-aminobutyric acid on pulmonary stretch receptors in the cat.

Studies on the effect of γ-aminobutyric acid (GABA) on slowly adapting pulmonary stretch receptors of the cat revealed a decrease in sensitivity to stretch, as evidenced by a reduction in firing during inflation of the lungs following drug administration. This phenomenon was characterized by a nonlinear dose effect relationship, a definite effect being observed at 0.1 mg/kg i.v. While immediate respiratory responses to GABA were clearly unrelated to its effect on afferent impulses from the lungs, the increase in depth of respiration following the initial apnea is consistent with desensitization of pulmonary stretch receptors. Further characterization of the effects observed were attempted by studying antagonism of GABA to protoveratrine.