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Major advances in scientific discovery and insights that stem from the development and use of new techniques and models can bring remarkable progress to conventional toxicology. Although animal testing is still considered as the "gold standard" in traditional toxicity testing, there is a necessity for shift from animal testing to alternative methods regarding the drug safety testing owing to the emerging state-of-art techniques and the proposal of 3Rs (replace, reduce, and refine) towards animal welfare. This review describes some recent research methods in drug discovery toxicology, including in vitro cell and organ-on-a-chip, imaging systems, model organisms (C. elegans, Danio rerio, and Drosophila melanogaster), and toxicogenomics in modern toxicology testing. [ABSTRACT FROM AUTHOR]

Rice yields are largely influenced by variability in weather. Here, we demonstrate the effect of weather variables viz., maximum and minimum temperatures, rainfall, morning and evening relative humidity, bright sunshine hours on the yield of rice cv. Swarna, grown across five rice ecologies of India through field experiments during kharif (wet) season (Jun-Sept.). Critical thresholds of weather elements were identified for achieving above average, average and below average yield for each ecology. The investigation could determine how different weather elements individually and collectively affect rice yield in different rice ecosystems of India. While a sudden increase in minimum temperature by 8-10 °C (> 30 °C) during reproductive period resulted in 40-50 per cent yield reduction at Mohanpur, a sudden decrease (< 20 °C) caused yield decline at Dapoli. The higher yields may be attributed to a significant difference in bright sunshine hours between reproductive phases of above-average and below-average yield years (ranging from 2.8 to 7.8 hours during P5 stages and 1.7 to 5.1 during P4 stages). Rice cultivar Swarna performed differently at various sowing dates in a location as well as across locations (6650 kg ha-1 at Dapoli to 1101 kg ha-1 at Samastipur). It was also found that across all locations, the above average yield could be associated with higher range of maximum temperature compared to that of below average yield. Principal component analysis explained 77 per cent of cumulative variance among the variables at first growth stage, whereas 70 per cent at second growth stage followed by 74 per cent and 66 per cent at subsequent growth stages. We found that coastal locations, in contrast to inland ones, could maximize the yield potential of the cultivar Swarna, due to the longer duration of days between panicle initiation to physiological maturity. We anticipate that the location-specific thresholds of weather factors will encourage rice production techniques that are climate resilient. [ABSTRACT FROM AUTHOR]

Background: Exposure to chemicals during critical windows of development may re-program liver for increased risk of nonalcoholic fatty liver disease (NAFLD). Bisphenol A (BPA), a plastics component, has been described to impart adverse effects during gestational and lactational exposure. Our work has pointed to nuclear factor E2-related factor 2 (Nrf2) being a modulator of hepatic lipid accumulation in models of NAFLD. OBJECTIVES: To determine if chemical exposure can prime liver for steatosis via modulation of NRF2 and epigenetic mechanisms. Methods: Utilizing BPA as a model exposure, pregnant CD-1 mice were administered 25 [micro]g/kg/day BPA via osmotic minipumps from gestational day 8 through postnatal day (PND)16. The offspring were weaned on PND21 and exposed to same dose of BPA via their drinking water through PND35. Tissues were collected from pups at week 5 (W5), and their littermates at week 39 (W39). RESULTS: BPA increased hepatic lipid content concomitant with increased Nrf2 and pro-lipogenic enzyme expression at W5 and W39 in female offspring. BPA exposure increased Nrf2 binding to a putative antioxidant response element consensus sequence in the sterol regulatory-element binding protein-1c (Srebp-1c) promoter. Known Nrf2 activators increased SREBP-1C promoter reporter activity in HepG2 cells. Methylated DNA immunoprecipitation-PCR and pyrosequencing revealed that developmental BPA exposure induced hypomethylation of the Nrf2 and Srebp-1c promoters in livers of W5 mice, which was more prominent in W39 mice than in others. Conclusion: Exposure to a xenobiotic during early development induced persistent fat accumulation via hypomethylation of lipogenic genes. Moreover, increased Nrf2 recruitment to the Srebp-1c promoter in livers of BPA-exposed mice was observed. Overall, the underlying mechanisms described a broader impact beyond BPA exposure and can be applied to understand other models of NAFLD. https://doi.org/ 10.1289/EHP664, Introduction The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased from 3.9% in 1988-1994 to 10.7% in 2007-2010 (Bedogni et al. 2014). There is evidence that, in addition to [...]

Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups. While the relative heart weights from both the swimming and drug-induced cardiac hypertrophy groups were increased 15% after 28 days of dosing, the serum NT-proANP and NT-proBNP values were only increased in association with cardiac hypertrophy caused by compound administration. Serum natriuretic peptide concentrations did not change in response to adaptive physiologic cardiac hypertrophy induced by a 28-day swimming protocol. These data support the use of natriuretic peptides as fluid biomarkers for the distinction between physiological and drug-induced cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Breast cancer resistance protein (Bcrp/Abcg2) localized at the blood-brain barrier (BBB) limits permeability into the brain of many xenobiotics, including pharmacological agents. Peroxisome proliferator-activated receptor α (Pparα), a ligandactivated transcription factor, primarily involved in lipid metabolism, has been shown to regulate the functional expression of Bcrp in human cerebral microvascular endothelial cells (hCMEC/D3). The aim of this study was to investigate ex vivo and in vivo, the regulation of Bcrp by Ppara in an intact BBB. Ex vivo quantitative real-time PCR and immunoblot analyses showed significant up-regulation of Abcg2/Bcrp mRNA and protein levels in CD-1 mouse brain capillaries incubated with clofibrate, a Pparα ligand. Fluorescence-based transport assays in CD-1 and C57BL/6 brain capillaries showed that exposure to clofibrate significantly increased Bcrp transport activity. This increase was not observed in capillaries isolated from Ppara knockout mice. In vivo, we found: i) significant Bcrp protein up-regulation in clofibratedosed CD-1 and C57BL/6 capillary lysates, but no effect in Pparα knockout capillary lysates, and ii) significantly increased Bcrp transport activity in capillaries isolated from clofibratetreated mice. These results demonstrate an increase in Bcrp functional expression by Ppara in brain capillaries, and suggest that Pparα is another nuclear receptor that can contribute to the regulation of membrane efflux transporters and drug permeability at the BBB. [ABSTRACT FROM AUTHOR]

Objective To evaluate whether Nrf2 deficiency impacts insulin resistance and lipid accumulation in liver and white adipose tissue. Methods Lepob/ob mice (OB) with targeted Nrf2 deletion (OB-Nrf2KO) were generated. Pathogenesis of obesity and type 2 diabetes was measured in C57BL/6J, Nrf2KO, OB, and OB-Nrf2KO mice. Hepatic lipid content, lipid clearance, and very low-density lipoprotein (VLDL) secretion were determined between OB and OB-Nrf2KO mice. Results OB-Nrf2KO mice exhibited decreased white adipose tissue mass and decreased adipogenic and lipogenic gene expression compared with OB mice. Nrf2 deficiency prolonged hyperglycemia in response to glucose challenge, which was paralleled by reduced insulin-stimulated Akt phosphorylation. In OB mice, Nrf2 deficiency decreased hepatic lipid accumulation, decreased peroxisome proliferator-activated receptor γ expression and nicotinamide adenine dinucleotide phosphate (NADPH) content, and enhanced VLDL secretion. However, this observation was opposite in lean mice. Additionally, OB-Nrf2KO mice exhibited increased plasma triglyceride content, decreased HDL-cholesterol content, and enhanced apolipoprotein B expression, suggesting Nrf2 deficiency caused dyslipidemia in these mice. Conclusions Nrf2 deficiency in Lepob/ob mice reduced white adipose tissue mass and prevented hepatic lipid accumulation but induced insulin resistance and dyslipidemia. This study indicates a dual role of Nrf2 during metabolic dysregulation-increasing lipid accumulation in liver and white adipose tissue but preventing lipid accumulation in obese mice. [ABSTRACT FROM AUTHOR]

The study herein determined the role of nuclear factor erythoid 2-related factor 2 (Nrf2) in the pathogenesis of hepatic steatosis, insulin resistance, obesity, and type 2 diabetes. Lepob/ob-Keap1- knockdown (KD) mice, which have increased Nrf2 activity, were generated. Markers of obesity and type 2 diabetes were measured in C57Bl/6J, Keap1-KD, Lepob/ob, and Lepob/ob-Keap1-KD mice. Lepob/ob-Keap1-KD mice exhibited less lipid accumulation, smaller adipocytes, decreased food intake, and reduced lipogenic gene expression. Enhanced Nrf2 activity impaired insulin signaling, prolonged hyperglycemia in response to glucose challenge, and induced insulin resistance in Lepob/ob background. Nrf2 augmented hepatic steatosis and increased lipid deposition in liver. Next, C57Bl/6J and Keap1-KD mice were fed a high-fat diet (HFD) to determine whether Keap1 and Nrf2 impact HFD-induced obesity. HFD-induced obesity and lipid accumulation in white adipose tissue was decreased in Keap1-KD mice. Nrf2 activation via Keap1-KD or sulforaphane suppressed hormone-induced differentiation and decreased peroxisome proliferator-activated receptor-γ, CCAAT/enhancer-binding protein α, and fatty acid- binding protein 4 expression in mouse embryonic fibroblasts. Constitutive Nrf2 activation inhibited lipid accumulation in white adipose tissue, suppressed adipogenesis, induced insulin resistance and glucose intolerance, and increased hepatic steatosis in Lepob/ob mice. [ABSTRACT FROM AUTHOR]

Introduction: Bronchial Asthma is one of the most extensively studied respiratory diseases and its genetic basis is well established. Dermatoglyphic traits are formed under genetic control early in development but may be affected by environmental factors during first trimester of pregnancy. These patterns may represent the genetic makeup of an individual and therefore his/her predisposition to certain diseases. Patterns of dermatoglyphics have been studied in various congenital disorders like Down's syndrome, Klinefelter's syndrome and also in chronic diseases like Hypertension, Diabetes Mellitus etc. Epidermal ridge patterns of finger tips in bronchial asthma patients were studied to find out fingertip pattern as Dermatoglyphic features in patients of Bronchial Asthma; it's comparison and association if exists between normal and bronchial asthma patients and also to find use of fingertip pattern in early childhood as non-invasive anatomical marker for bronchial asthma in adulthood. Methods: The study was conducted on clinically diagnosed all bronchial asthma patients attending OPD of Dr Ulhas Patil Medical College, Jalgaon. Matched controls were selected without any respiratory problem or any symptoms related to asthma from medical students, staff members and paramedical staff of hospital after taking the informed consent and permission from the institutional ethical committee. Data collection and fingertip prints were taken by ink and rolling finger method. Prints taken were analysed and tabulated; data was analysed by using statistical tests. Results: Study shows that decrease in number of arches, increase in AFRC in patients as compared with controls. Also there were increased ulnar loops in male patients and increased Whorls and radial loops in female patients. Conclusion: The fingerprints can represent a non-invasive anatomical marker of bronchial asthma risk and facilitate early detection and effective management which is vital for selecting appropriate agents for treating infections. [ABSTRACT FROM AUTHOR]

Introduction: Bronchial Asthma is one of the most extensively studied respiratory diseases and its genetic basis is well established. Dermatoglyphic traits are formed under genetic control early in development but may be affected by environmental factors during first trimester of pregnancy. These patterns may represent the genetic makeup of an individual and therefore his/her predisposition to certain diseases. Patterns of dermatoglyphics have been studied in various congenital disorders like Down's syndrome, Klinefelter's syndrome and also in chronic diseases like Hypertension, Diabetes Mellitus etc. Epidermal ridge patterns of finger tips in bronchial asthma patients were studied to find out fingertip pattern as Dermatoglyphic features in patients of Bronchial Asthma; it's comparison and association if exists between normal and bronchial asthma patients and also to find use of fingertip pattern in early childhood as non-invasive anatomical marker for bronchial asthma in adulthood., Methods: The study was conducted on clinically diagnosed all bronchial asthma patients attending OPD of Dr Ulhas Patil Medical College, Jalgaon. Matched controls were selected without any respiratory problem or any symptoms related to asthma from medical students, staff members and paramedical staff of hospital after taking the informed consent and permission from the institutional ethical committee. Data collection and fingertip prints were taken by ink and rolling finger method. Prints taken were analysed and tabulated; data was analysed by using statistical tests., Results: Study shows that decrease in number of arches, increase in AFRC in patients as compared with controls. Also there were increased ulnar loops in male patients and increased Whorls and radial loops in female patients., Conclusion: The fingerprints can represent a non-invasive anatomical marker of bronchial asthma risk and facilitate early detection and effective management which is vital for selecting appropriate agents for treating infections.