Month: October 2020

Historically, gramicidin was the first antibiotic drug, although its systemic use in clinical practice was prevented by the high toxicity for eukaryotic cells. Comprehensive examination of gA as the first channel with an exactly characterized molecular structure was aimed mostly at elucidating the mechanism of ionic channel operation and peptide interaction with lipid membrane environment. The studies of gA and its engineered analogues have produced a large body of basic knowledge and, moreover, substantially advanced a variety of experimental approaches. In the present work, we described the newly synthesized gA peptide exhibiting very low toxicity towards eukariotic cells, which is obviously associated with suppressed conductivity of the peptide for potassium and sodium ions. Remarkably, the protonophoric activity of gA resulted in mitochondria uncoupling at the peptide concentrations which appeared to be practically nonpoisonous for mammalian cells. Bearing in mind that partial uncoupling is known to protect mitochondria from oxidative stress and produce a beneficial effect on organisms against obesity, gA can be considered as a prototype of a new class of peptide therapeutic agent. Adolescent and adult women of childbearing age in the United States of America have a high prevalence of vitamin D insufficiency. This insufficiency is likely related to diet and is gaining recognition as a public health problem. The prevalence of vitamin D insufficiency is high even in sunny climates, such as Brazil’s, principally in adolescents. Vitamin D is critical for the development of the nervous system and immunological functions during fetal development. Vitamin D during the pregnancy is important to both maternal skeletal preservation and fetal skeletal formation. However, new evidence suggests that vitamin D could be vital to normal fetal development and that vitamin D restriction in this period may affect chronic disease susceptibility post-natal life. Furthermore, recent studies have shown that this restriction can generate “genomic imprinting” in the fetus, which is related to the genesis of chronic diseases in adulthood. Moreover, vitamin D is associated with premature births, obesity and renal dysfunction in adulthood, making it more than an essential fat-soluble vitamin responsible for calcium metabolism. Normal development of the kidney is a highly complex process that requires precise cellular proliferation, differentiation and apoptosis. Among the essential regulators of kidney development are components of the renin-angiotensin system, podocin and the Wilms’ tumor suppressor gene WT1. Vitamin D restriction during pregnancy and throughout lactation in rats is associated with an increased number of glomeruli and decreased renal corpuscle size among offspring, although the causes and GDC-0879 consequences of this abnormal kidney phenotype remain unknown. Therefore, the adverse effects of vitamin D restriction during kidney development need further exploration. This study investigates the effects of maternal vitamin D deficiency on glomerular development in early postnatal life and its effects on renal structure at maturity. This study focuses on the F1 and F2 generations after F0 maternal vitamin D restriction. Micronutrient deficiency during development, such as maternal vitamin D deficiency, is a subject of increasing importance because of the nutritional deficiencies caused by excessive consumption of junk food during pregnancy. However, vitamin D insufficiency is still under-recognized and under-treated, despite its prevalence. A recent study of pregnant women in Europe reported that only 12% had an optimal level of vitamin D.

This finding is consistent with the high renin and AT1r expressions observed in the present study. Activation of the RAS may play a significant role in the development of mechanisms that lead to kidney damage. After kidney damage occurs, chronic renal disease progresses through a cycle that passes the damage from lost or damaged nephrons to healthy nephrons. Two hypotheses are currently proposed to explain the progression of chronic renal disease. The results of the present study are consistent with the “overload hypothesis”. This hypothesis suggests that AB1010 VEGFR/PDGFR inhibitor structural and functional adaptations are associated with glomerular hypertension, hyperfiltration, and hypertrophy partially compensated for nephron losses. Podocin provides the structural organization of the slit diaphragm and the regulation of filtration function and seems to be involved in the alteration of the glomerular basement membrane. Nephrin is expressed late in the process of podocyte differentiation and is a locus for the formation of the slit diaphragm, foot process maintenance and physical integrity in vivo, but it is dispensable for cell survival and has little impact on gene regulation during glomerular development. Nephrin does not affect podocyte apoptosis and gene expression patterns. In the present study, vitamin D restriction during nephrogenesis reduced podocin expression in the F1 generation from weaning until six months of age but not in the F2 generation. Such effects should be evaluated because podocin serves in the structural organization of the slit diaphragm and the regulation of its filtration function. Although the mature animals did not show significant proteinuria, maternal vitamin D deficiency altered podocin expression in the F1 generation from weaning until six months of age, but not in the F2 generation. Intense maternal protein restriction, for example, leads to chronic diseases in adult life, affecting both the F1 and F2 generations, and reaching even the F3 generation. Part of the explanation seems to be decreased global methylation in these offspring. The present study has certain limitations. The major aim of the study was to investigate glomerular development and renal structure at birth, 10 days and adulthood in mice born to mothers fed a diet restricted in vitamin D. Although, we examined other variables, such as body mass and 24 h urine, the present study was not designed to investigate renal functional and metabolic consequences but rather was designed to answer the question of whether there were structural, glomerular alterations or transgenerational effects. Further studies are necessary to clarify the impact of maternal vitamin D restriction on the renal function of offspring. Furthermore, the literature shows some relationship between vitamin D deficiency and adipose tissue development, and other studies should evaluate such effects, and the transgenerational effects. In conclusion, the present findings provide insight into the relationship between maternal vitamin D deficiency and the occurrence of a greater number of glomeruli in offspring. Maternal vitamin D deficiency is accompanied by changes in the renal expression of podocin, renin and AT1 receptors, and it delays the maturity of the glomeruli, by extending nephrogenesis. These findings are more pronounced in F1 progeny, but F2 progeny are also affected. Gastric cancer is the fourth most common malignancy in the world and the second leading cause of cancer death in both sexes worldwide. The highest mortality rates are estimated in Eastern Asia. The 5-year survival rate for gastric cancer is less than 20%–25% in the USA, Europe and China.

In the present meta-analysis, several ocular neovascular diseases, such as age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion, were included. Sensitivity analysis was undertaken to evaluate the variation of the risk of arterial thromboembolic events with anti-VEGF among different diseases. Intravitreal anti-VEGF significantly TH-302 decreased the risk of arterial thromboembolic events by 32% in patients with diabetic macular edema, with the 95% confidence intervals of 6% to 64%; no difference in this risk was detected in patients with neovascular age-related macular degeneration and retinal vein occlusion. In patients with diabetes mellitus, increased VEGF-mediated angiogenesis has been implicated in retinopathy and nephropathy, whereas a defective angiogenic response to ischemia, which might be attributable to a VEGF signaling defect in which there is reduced receptor signaling despite higher ligand expression, could lead to poor clinical outcomes. Therefore, the targets within the system that lead to altered VEGF signaling, such as low dose systemic anti-VEGF, may be beneficial in diabetic patients. The sensitivity analysis according to the type of diseases showed that intravitreal anti-VEGF increased the risks of cerebrovascular accidents by 52% in neovascular age-related macular degeneration, with the 95% confidence intervals of -32% to 83%. However, the point estimates of all three trials were distributed across the 1.0 risk ratio. Two estimates have shown a possible risk of cerebrovascular accidents of intravitreal anti-VEGF. However, a larger epidemiological study found that no statistically significant relationship between intravitreal anti-VEGF use and stroke. Therefore, the small differences of cerebrovascular accidents between intravitreal anti-VEGF and placebo in the two trials might be due to chance finding, but not drug-related. Although we tried to conduct a thorough review of the existing literature, this present analysis has limitations inherent to any systematic review. First, the incidences of arterial thromboembolic events showed significant heterogeneity among the included studies. This may reflect differences in sample sizes, disease types, interventions, concomitant treatment, study durations, and many other factors among these studies. Despite these differences, the risk ratios reported by all of these studies showed remarkable homogeneity. In addition, combination data by using a randomeffects model may be able to achieve more conservative estimates. Second, the included trials were done at various clinical centers, and the ability to detect arterial thromboembolic events and the classification of events might vary among these institutions, which could result in a bias of reported incidence rates. Third, only published studies were included in the present meta-analysis. To avoid the publication bias, we searched in multiple databases. In addition, to find potential publication biases, we explored asymmetry in funnel plots and detect heterogeneity using Egger’s linear regression, and no publication bias was found. Finally, the findings of this meta-analysis are based on the study level, not on patient-level source data, and some confounding factors cannot be properly assessed and incorporated into the results. Despite these limitations, the strength evidence from the present meta-analysis data suggests that the intravitreal use of anti-VEGF agents is not associated with an increased risk of arterial thromboembolic events.

In 2009, Chinese authority granted biosafety certificates for two insect-resistant rice lines containing a Bt transgene, meaning that GE rice may enter commercial production in near future. Transgene spread from insect-resistant GE rice to its coexisting weedy rice populations through gene flow becomes a major environmental biosafety concern. Weedy rice is a noxious weed that causes significant losses of rice yield and quality worldwide. The introgression of transgenes with selective advantages may largely enhance the spread of the weedy rice, causing more serious weed problems. Weedy rice is an annual weed conspecific to cultivated rice, and transgene flow from cultivated rice to weedy rice cannot be avoided owing to their similar flowering phenology. It is therefore valid to determine the fitness effect of insect-resistance transgenes on weedy rice populations under different insect pressure for risk assessment. Fitness of an insect-resistance transgene is largely associated with the environment in which insect pressure can largely be variable. The relationship between fitness effect brought by an insect-resistance transgene and the ambient insect pressure has not been well described. A number of studies of crop-weed hybrids showed variable fitness effect brought by insect-resistant transgenes under different insect occurrences. It is apparent based on these studies that the enhanced fitness benefit of insect-resistant transgenes was always associated with the high target herbivore pressure, whereas under low herbivore pressure the benefit brought by the insect-resistant transgenes was reduced. Therefore, to analyzed fitness effect brought by an insectresistance transgene under designed experimental conditions with different insect pressure should be the key to detect the fitness effect of such a transgene. Studies have already revealed the effects of Bt transgene in cropwild or crop-weed hybrid progeny under different environments. Our previous studies of F1–F3 crop-weed hybrids and their derived lineages from insect-resistant rice revealed increased fecundity brought by Bt/CpTI transgenes when target insects were abundant. However, the relationship between variation in different insect pressure and the corresponding fitness change was not well addressed by a properly designed experiment. In this study, we intended to address the following questions: Are the insect-resistant transgenes still effective on resisting rice target ASP1517 herbivores in the transgenic F4 populations derived from a GE crop-weed hybrid under natural insect pressure? Does the transgenic F4 population have significantly higher fitness than the nontransgenic F4 population and weedy rice parent under natural insect pressure? Does the mixed planting of transgenic plants significantly reduce the ambient insect pressure of the nontransgenic plants, and consequently, reduce the potential fitness benefit brought by insect-resistance transgenes in the experimental fields? The answer of above questions is essential for assessing the long-term ecological impacts caused by insect-resistant transgene flow from to its weedy rice populations. The key point of assessing potential ecological risks caused by an insect-resistant transgene introgressed to weedy populations is to analyze the increased fitness of transgenic plants in comparison with their nontransgenic counterparts derived from the same cropweed hybridization under controlled environmental conditions. Our data from this study indicated significant differences in insect pressure between the two rice planting environments with natural vs. low insect pressure.

These results indicate the effectiveness of insect control in our experiment. In addition, as indicated by the insect damage on weedy parents and transgenenegative plants, significantly higher insect index was also detected in pure planting plots than in the mixed-planting plots of nontransgenic plants with transgenic plants under natural insect. In contrast, the mixed-planting plots with transgenic plants did not show such significant differences in insect index under low insect pressure. All together, these results demonstrate that the differential environment allowed us to analyze the fitness effect of insect-resistance transgenes in weedy rice plants against their nontransgenic counterparts, and that the mixed planting of transgenic plants in a field plot can significantly reduce the ambient insect pressure. In pure planting, transgene-positive crop-weed F4 plants showed significantly greater values of fecundity-related traits, such as the number of panicles and well-filled seeds and the ratio of seed set than their transgene-negative plants under natural insect pressure. Particularly, the number of panicles and filled seeds of transgene-positive F4 plants showed significantly higher values than the weedy rice parents. However, such significant differences between the transgenic plants and nontransgenic plants were not detected in these traits under the low insect pressure. The increased fecundity of transgenic crop-weed F4 plants is most likely brought by the introgression of insect-resistance transgenes that significantly reduced insect attack to the plants. The increased fecundity in the transgenic F4 plants demonstrates that the introgressed insect-resistant transgenes are still effective on controlling rice target herbivores in the advanced generation of crop-weed hybrid populations. This result is consistent with our previous study in which the F2–F3 lineages derived from the crop-weed hybrids with the same transgenic event showed effective control of insect damages to the hybrid lineage NVP-BEZ235 compared with both transgenenegative hybrid lineages and the weedy parents, under a high level of insect pressure. Many previous studies on cropweed and crop-wild hybrid lineages also demonstrated that insect-resistance transgenes can dramatically reduce the target herbivores and increase the fecundity in hybrids and their advanced generation of hybrid populations. These findings are consistent with our results in this study. It seems possible to make a conclusion from the field experimental data of above studies including ours that the introgressed insectresistance transgenes will maintain their strong ability to control herbivores and increase fecundity of transgenic populations derived from crop-weed or crop-wild transgene introgression. The transgenic plants may have a strong ability to compete with their nontransgenic counterparts including nontransgenic hybrid and parental populations. However, it is necessary to point out that in the mixedplanting plots the fecundity traits of the transgene-positive plants did not show significantly increased values, compared to the transgene-negative plants and weedy rice parents under natural insect pressure. This result suggests apparent losses of fitness benefit that should have been brought by the insect-resistance transgenes in mixed planting under natural insect pressure. The similar phenomenon was also observed in a number of studies in which the fitness benefit and cost of insect-resistant GE rice lines and their nonGE parental lines was analyzed under natural and low insect pressure, respectively. Associated with the data of insect index from this study where significantly lower insect pressure was recorded.