Publications by authors named "Xinxin Ding"

144 Publications

Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism.

Mol Metab 2021 Apr 30:101243. Epub 2021 Apr 30.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA; University of Arizona Cancer Center, University of Arizona, Tucson, AZ, 85724, USA. Electronic address:

NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. It is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage. However, we show herein that in contrast to canonical NRF2 activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. Using a combination of wild-type, Nrf2, p62, and Nrf2;p62 mice and an arsenic-induced diabetes model, we demonstrate that NRF2 and p62 are essential for promoting insulin resistance and glucose intolerance. Integrated transcriptomic and metabolomic analyses reveal a p62-and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis through the upregulation of four novel NRF2 target genes. In conclusion, our findings reveal a key pro-diabetic role for non-canonical NRF2 activation.
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http://dx.doi.org/10.1016/j.molmet.2021.101243DOI Listing
April 2021

Novel application of bergapten and quercetin with anti-bacterial, osteogenesis-potentiating, and anti-inflammation tri-effects.

Acta Biochim Biophys Sin (Shanghai) 2021 Mar 27. Epub 2021 Mar 27.

Department of Oral and Maxillo-facial Implantology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.

The bacteria-mediated inflammatory conditions adversely affect the osseointegration process of endosseous implants, which can even lead to implant malfunction or failure. Local drug delivery has been designed to exert anti-inflammatory and antibacterial activities, but whether this strategy has an effect on the compromised osseointegration under inflammation has rarely been studied. The present study focused on the osteoinductive efficacy of two known phytoestrogens (bergapten (BP) and quercetin (QE)) on implant sites under multiple bacteria-infected conditions in situ. Furthermore, the gene expression profiles of rat bone mesenchymal stem cells (rBMSCs) treated with BP and QE in the presence of Porphyromonas gingivalis-derived lipopolysaccharide were identified. The results showed that both drugs, especially QE, had significant potentiating effects on promoting osteogenic differentiation of rBMSCs, resisting multiple pathogens, and reducing inflammatory activity. Meanwhile, RNA sequencing analysis highlighted the enriched gene ontology terms and the differentially expressed genes (Vps25, Il1r2, Csf3, Efemp1, and Ccl20) that might play essential roles in regulating the above tri-effects, which provided the basis for the drug delivery system to be used as a novel therapeutic strategy for integrating peri-implant health. Overall, our study confirmed that QE appeared to outperform BP in osteogenesis and bacterial killing but not in anti-inflammation. Moreover, both drugs possess favorable tri-effects and can serve as the pivotal agents for the drug delivery system to boost osseointegration at inflammatory implant sites.
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http://dx.doi.org/10.1093/abbs/gmab037DOI Listing
March 2021

Breathing exercises in people with COPD: A realist review.

J Adv Nurs 2021 Apr 8;77(4):1698-1715. Epub 2020 Dec 8.

School of Nursing, Jilin University, Changchun, China.

Aims: To determine the theoretical framework that explains the mechanisms of the success of breathing exercise interventions in people with chronic obstructive pulmonary disease.

Design: A realist review.

Data Sources: Seven bibliographic databases and the grey literature were searched from 2015-January 2020 to identify the studies of breathing exercises.

Review Methods: The evaluation criteria of realist review and the mixed method appraisal tool were both used to evaluate the included studies. We extracted and integrated the context-mechanism-outcome strings of each study to form the theoretical framework.

Results: Six theoretical mechanisms that affected the success of the intervention were articulated: Wide acceptance of training methods, Integration of the intervention with life, Self-management of the participants, Confidence in controlling symptoms, Participation and support of practitioners, Motivation for intervention. Conversely, the other two mechanisms including the gap between implementation and training and the duration of the intervention, had negative impacts on the implementation of breathing exercises.

Conclusion: This review updates and expands the previous literature review on the impact of breathing exercises in people and provides researchers and clinical practitioners with theoretical mechanisms to ensure that the interventions achieve expected effects.

Impact: When formulating or selecting breathing exercise interventions, our theoretical framework will guide researchers and clinical practitioners to ensure that the intervention will have practical effects.
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http://dx.doi.org/10.1111/jan.14703DOI Listing
April 2021

Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases.

Br J Pharmacol 2021 Apr 18;178(7):1495-1506. Epub 2021 Feb 18.

Institute for Cardiovascular Physiology, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany.

Background And Purpose: Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here.

Experimental Approach: As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR ) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates.

Key Results: Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR . Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response.

Conclusions And Implications: Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.
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http://dx.doi.org/10.1111/bph.15362DOI Listing
April 2021

Editorial.

Authors:
Xinxin Ding

Drug Metab Dispos 2021 Jan 2;49(1):1-2. Epub 2020 Nov 2.

Editor

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http://dx.doi.org/10.1124/dmd.120.000298DOI Listing
January 2021

Lung injury induced by pyrrolizidine alkaloids depends on metabolism by hepatic cytochrome P450s and blood transport of reactive metabolites.

Arch Toxicol 2021 01 8;95(1):103-116. Epub 2020 Oct 8.

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People's Republic of China.

Pyrrolizidine alkaloids (PAs) are common phytotoxins with both hepatotoxicity and pneumotoxicity. Hepatic cytochrome P450 enzymes are known to bioactivate PAs into reactive metabolites, which can interact with proteins to form pyrrole-protein adducts and cause intrahepatic cytotoxicity. However, the metabolic and initiation biochemical mechanisms underlying PA-induced pneumotoxicity remain unclear. To investigate the in vivo metabolism basis for PA-induced lung injury, this study used mice with conditional deletion of the cytochrome P450 reductase (Cpr) gene and resultant tissue-selective ablation of microsomal P450 enzyme activities. After oral exposure to monocrotaline (MCT), a pneumotoxic PA widely used to establish animal lung injury models, liver-specific Cpr-null (LCN) mice, but not extrahepatic Cpr-low (xh-CL) mice, had significantly lower level of pyrrole-protein adducts in the serum, liver and lungs compared with wild-type (WT) mice. While MCT-exposed LCN mice had significantly higher blood concentration of intact MCT, compared to MCT-exposed WT or xh-CL mice. Consistent with the MCT in vivo bioactivation data, MCT-induced lung injury, represented by vasculature damage, in WT and xh-CL mice but not LCN mice. Furthermore, reactive metabolites of MCT were confirmed to exist in the blood efflux from the hepatic veins of MCT-exposed rats. Our results provide the first mode-of-action evidence that hepatic P450s are essential for the bioactivation of MCT, and blood circulating reactive metabolites of MCT to the lung causes pneumotoxicity. Collectively, this study presents the scientific basis for the application of MCT in animal lung injury models, and more importantly, warrants public awareness and further investigations of lung diseases associated with exposure to not only MCT but also different PAs.
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http://dx.doi.org/10.1007/s00204-020-02921-0DOI Listing
January 2021

Contribution of Pulmonary CYP-mediated Bioactivation of Naphthalene to Airway Epithelial Injury in the Lung.

Toxicol Sci 2020 10;177(2):334-346

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.

Previous studies have established that cytochrome P450 enzymes (CYPs) in both liver and lung are capable of bioactivating naphthalene (NA), an omnipresent air pollutant and possible human carcinogen, in vitro and in vivo. The aim of this study was to examine the specific contribution of pulmonary CYPs in airway epithelial cells to NA-induced airway toxicity. We used a lung-Cpr-null mouse model, which undergoes doxycycline-induced, Cre-mediated deletion of the Cpr (a redox partner of all microsomal CYPs) gene specifically in airway epithelial cells. In 2-month-old lung-Cpr-null mice, Cpr deletion occurred in 75%-82% of epithelial cells of conducting airways. The extent of NA-induced acute lung toxicity (as indicated by total protein concentration and lactate dehydrogenase activity in bronchoalveolar lavage fluid collected at 24-h after initiation of a 4-h, nose-only, 10-ppm NA inhalation exposure) was substantially lower (by 37%-39%) in lung-Cpr-null mice, compared with control littermates. Moreover, the extent of cellular proliferation (as indicated by 5-bromo-2'-deoxyuridine incorporation) was noticeably lower in both proximal and distal airways (by 59% and 65%, respectively) of NA-treated lung-Cpr-null mice, compared with control littermates, at 2-day post-NA inhalation exposure. A similar genotype-related difference in the extent of postexposure cell proliferation was also observed in mice exposed to NA via intraperitoneal injection at 200 mg/kg. These results directly validate the hypothesis that microsomal CYP enzymes in airway epithelial cells play a large role in causing injury to airway epithelia following exposure to NA via either inhalation or intraperitoneal route.
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http://dx.doi.org/10.1093/toxsci/kfaa114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548286PMC
October 2020

RNA-Seq Reveals Sub-Zones in Mouse Adrenal Zona Fasciculata and the Sexually Dimorphic Responses to Thyroid Hormone.

Endocrinology 2020 09;161(9)

Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama.

The sex-specific prevalence of adrenal diseases has been known for a long time. However, the reason for the high prevalence of these diseases in females is not completely understood. Mouse studies have shown that the adult adrenal gland is sexually dimorphic at different levels such as transcriptome, histology, and cell renewal. Here we used RNA-seq to show that in prepubertal mice, male and female adrenal glands were not only sexually dimorphic but also responded differently to the same external stimulus. We previously reported that thyroid hormone receptor β1 (TRβ1) in the adrenal gland is mainly expressed in the inner cortex and the fate of this TRβ1-expressing cell population can be changed by thyroid hormone (triiodothyronine; T3) treatment. In the present study, we found that adrenal glands in prepubertal mice were sexually dimorphic at the level of the transcriptome. Under T3 treatment, prepubertal females had 1162 genes differentially expressed between the saline and T3 groups, whereas in males of the same age, only 512 genes were T3-responsive. Immunostaining demonstrated that several top sexually dimorphic T3-responsive genes, including Cyp2f2 and Dhcr24, were specifically expressed in the adrenal inner cortex, precisely in an area partially overlapping with the X-zone. Under T3 treatment, a unique cortical layer that surrounds the adrenal X-zone expanded significantly, forming a distinct layer peculiar to females. Our findings identified novel marker genes for the inner adrenal cortex, indicating there are different sub-zones in the zona fasciculata. The results also highlight the sex-specific response to thyroid hormone in the mouse adrenal gland.
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http://dx.doi.org/10.1210/endocr/bqaa126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446775PMC
September 2020

Autophagy Plays Prominent Roles in Amino Acid, Nucleotide, and Carbohydrate Metabolism during Fixed-Carbon Starvation in Maize.

Plant Cell 2020 09 2;32(9):2699-2724. Epub 2020 Jul 2.

Department of Biology, Washington University in St. Louis, St. Louis, Missouri 63130

Autophagic recycling of proteins, lipids, nucleic acids, carbohydrates, and organelles is essential for cellular homeostasis and optimal health, especially under nutrient-limiting conditions. To better understand how this turnover affects plant growth, development, and survival upon nutrient stress, we applied an integrated multiomics approach to study maize () autophagy mutants subjected to fixed-carbon starvation induced by darkness. Broad metabolic alterations were evident in leaves missing the core autophagy component ATG12 under normal growth conditions (e.g., lipids and secondary metabolism), while changes in amino acid-, carbohydrate-, and nucleotide-related metabolites selectively emerged during fixed-carbon starvation. Through combined proteomic and transcriptomic analyses, we identified numerous autophagy-responsive proteins, which revealed processes underpinning the various metabolic changes seen during carbon stress as well as potential autophagic cargo. Strikingly, a strong upregulation of various catabolic processes was observed in the absence of autophagy, including increases in simple carbohydrate levels with a commensurate drop in starch levels, elevated free amino acid levels with a corresponding reduction in intact protein levels, and a strong increase in the abundance of several nitrogen-rich nucleotide catabolites. Altogether, this analysis showed that fixed-carbon starvation in the absence of autophagy adjusts the choice of respiratory substrates, promotes the transition of peroxisomes to glyoxysomes, and enhances the retention of assimilated nitrogen.
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http://dx.doi.org/10.1105/tpc.20.00226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474275PMC
September 2020

Mix Proportion Design of Self-Compacting SFRC with Manufactured Sand Based on the Steel Fiber Aggregate Skeleton Packing Test.

Materials (Basel) 2020 Jun 24;13(12). Epub 2020 Jun 24.

International Joint Research Lab for Eco-building Materials and Engineering of Henan, North China University of Water Resources and Electric Power, Zhengzhou 450045, China.

A scientific and concise mix design method is an impending problem in the engineering application of self-compacting steel-fiber-reinforced concrete (SFRC). This paper focuses on the mix proportion of self-compacting SFRC, which is influenced by the steel fibers, along with its effects on the packing properties of the steel fiber aggregate skeleton. In total, 252 groups of packing tests were carried out for several main factors, including with various maximum particle sizes for the coarse aggregates, manufactured sand ratios ranging from 50% to 62%, and with different types of hooked-end steel fibers and crimped steel fibers, with volume fractions ranging from 0% to 2.0%. The results indicated that the void content and rational sand ratio of the steel fiber aggregate skeleton increased linearly with the fiber factor. These results provided a basis for the calculation of the binder content and rational sand ratio of the self-compacting SFRC. Combined with the absolute volume design method and the calculation formula for the water-to-binder ratio, a systematical procedure was proposed for the mix proportion design of the self-compacting SFRC. Based on the design method, eight groups of mixtures were cast and tested to verify the adaptability and practicability of the workability, air content, density, cubic compressive strength, and splitting tensile strength of the self-compacting SFRC. Meanwhile, the outcomes of this study confirmed the applicability of using manufactured sand as a complete replacement for natural sand for the self-compacting SFRC.
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http://dx.doi.org/10.3390/ma13122833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344632PMC
June 2020

The epitranscriptomic writer ALKBH8 drives tolerance and protects mouse lungs from the environmental pollutant naphthalene.

Epigenetics 2020 10 17;15(10):1121-1138. Epub 2020 Apr 17.

The RNA Institute, University at Albany , Albany, NY, USA.

The epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a transfer RNA (tRNA) methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized translation of selenoproteins. Using deficient ( mice, we have investigated the importance of epitranscriptomic systems in the response to naphthalene, an abundant polycyclic aromatic hydrocarbon and environmental toxicant. We performed basal lung analysis and naphthalene exposure studies using wild type (WT), and mice, the latter of which lack the cytochrome P450 enzymes required for naphthalene bioactivation. Under basal conditions, lungs from mice have increased markers of oxidative stress and decreased thioredoxin reductase protein levels, and have reprogrammed gene expression to differentially regulate stress response transcripts. mice are more sensitive to naphthalene induced death than WT, showing higher susceptibility to lung damage at the cellular and molecular levels. Further, WT mice develop a tolerance to naphthalene after 3 days, defined as resistance to a high challenging dose after repeated exposures, which is absent in mice. We conclude that the epitranscriptomic writer ALKBH8 plays a protective role against naphthalene-induced lung dysfunction and promotes naphthalene tolerance. Our work provides an early example of how epitranscriptomic systems can regulate the response to environmental stress .
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http://dx.doi.org/10.1080/15592294.2020.1750213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518688PMC
October 2020

Hydroxyl and sulfate radical-based oxidation of RhB dye in UV/HO and UV/persulfate systems: Kinetics, mechanisms, and comparison.

Chemosphere 2020 Aug 8;253:126655. Epub 2020 Apr 8.

Department of Environmental Science, School of Geography and Tourism, Shaanxi Normal University, Xi'an, 710119, China. Electronic address:

The degradation kinetics and mechanisms of Rhodamine B (RhB) dye by OH and SO based advanced oxidation processes were investigated. The OH and SO radicals were generated by UV photolysis of hydrogen peroxide and persulfate (i.e., UV/HO and UV/PS), respectively. The effects of initial solution pH, RhB concentration, oxidant dosage, Fe concentration, and water matrices were examined. The results showed that the degradation of RhB followed pseudo-first-order kinetics in both processes, with the UV/HO process exhibiting better performance than that of the UV/PS process. Acidic conditions were favorable to the degradation of RhB in both systems. Increasing the oxidant dosage or decreasing the contaminant concentration could enhance the degradation of RhB. Photo-Fenton-like processes accelerated the performance when Fe was added into both systems. The removal efficiency of RhB was inhibited upon the addition of humic substances. The addition of Cl displayed no significant effect and promoted RhB degradation in UV/HO and UV/PS systems, respectively. The presence of NO promoted RhB degradation, while HPO and CO showed an inhibitory effect on both UV/HO and UV/PS processes. Radical scavenging tests revealed the dominant role of SO radicals in the UV/PS system. Furthermore, the evolution of low molecular weight organic acids and NH during the degradation of RhB in these two processes were compared. Both UV/HO and UV/PS systems led to similar formation trends of NH and some ring-opening products (e.g., formic acid, acetic acid, and oxalic acid), suggesting some analogies in the decay pathways of RhB by OH and SO-induced oxidation processes.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126655DOI Listing
August 2020

β-tricalcium phosphate and octacalcium phosphate composite bioceramic material for bone tissue engineering.

J Biomater Appl 2020 04 6;34(9):1294-1299. Epub 2020 Feb 6.

Key Laboratory of Liquid-Solid Structure Evolution and Processing of Materials, Ministry of Education, School of Materials Science and Engineering, Shandong University, Jinan, China.

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http://dx.doi.org/10.1177/0885328220903989DOI Listing
April 2020

Reticulon proteins modulate autophagy of the endoplasmic reticulum in maize endosperm.

Elife 2020 02 3;9. Epub 2020 Feb 3.

Department of Botany, Laboratory of Cell and Molecular Biology, University of Wisconsin, Madison, United States.

Reticulon (Rtn) proteins shape tubular domains of the endoplasmic reticulum (ER), and in some cases are autophagy receptors for selective ER turnover. We have found that maize Rtn1 and Rtn2 control ER homeostasis and autophagic flux in endosperm aleurone cells, where the ER accumulates lipid droplets and synthesizes storage protein accretions metabolized during germination. Maize Rtn1 and Rtn2 are expressed in the endosperm, localize to the ER, and re-model ER architecture in a dose-dependent manner. Rtn1 and Rtn2 interact with Atg8a using four Atg8-interacting motifs (AIMs) located at the C-terminus, cytoplasmic loop, and within the transmembrane segments. Binding between Rtn2 and Atg8 is elevated upon ER stress. Maize mutants display increased autophagy and up-regulation of an ER stress-responsive chaperone. We propose that maize Rtn1 and Rtn2 act as receptors for autophagy-mediated ER turnover, and thus are critical for ER homeostasis and suppression of ER stress.
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http://dx.doi.org/10.7554/eLife.51918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046470PMC
February 2020

Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model.

Acta Pharm Sin B 2020 Jan 12;10(1):123-135. Epub 2019 Dec 12.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.

We examined the impact of gut inflammation on the expression of cytochrome P450 (P450) and other biotransformation genes in male mice using a dextran sulfate sodium (DSS)-induced colitis model. Several P450 isoforms, including CYP1A, CYP2B, CYP2C, and CYP3A, were down-regulated, accompanied by decreases in microsomal metabolism of diclofenac and nifedipine, in the liver and small intestine. The impact of the colitis on clearance of oral drugs varied for four different drugs tested: a small decrease for nifedipine, a relatively large decrease for lovastatin, but no change for pravastatin, and a large decrease in the absorption of cyclosporine A. To further assess the scope of influence of gut inflammation on gene expression, we performed genome-wide expression analysis using RNA-seq, which showed down-regulation of many CYPs, non-CYP phase-I enzymes, phase-II enzymes and transporters, and up-regulation of many other members of these gene families, in both liver and intestine of adult C57BL/6 mice, by DSS-induced colitis. Overall, our results indicate that gut inflammation suppresses the expression of many P450s and other biotransformation genes in the intestine and liver, and alters the pharmacokinetics for some but not all drugs, potentially affecting therapeutic efficacy or causing adverse effects in a drug-specific fashion.
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http://dx.doi.org/10.1016/j.apsb.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976992PMC
January 2020

Characterization of A Bifunctional Synthetic RNA Aptamer and A Truncated Form for Ability to Inhibit Growth of Non-Small Cell Lung Cancer.

Sci Rep 2019 12 11;9(1):18836. Epub 2019 Dec 11.

Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.

An in vitro-transcribed RNA aptamer (trans-RA16) that targets non-small cell lung cancer (NSCLC) was previously identified through in vivo SELEX. Trans-RA16 can specifically target and inhibit human NCI-H460 cells in vitro and xenograft tumors in vivo. Here, in a follow-up study, we obtained a chemically-synthesized version of this RNA aptamer (syn-RA16) and a truncated form, and compared them to trans-RA16 for abilities to target and inhibit NCI-H460 cells. The syn-RA16, preferred for drug development, was by design to differ from trans-RA16 in the extents of RNA modifications by biotin, which may affect RA16's anti-tumor effects. We observed aptamer binding to NCI-H460 cells with K values of 24.75 ± 2.28 nM and 12.14 ± 1.46 nM for syn-RA16 and trans-RA16, respectively. Similar to trans-RA16, syn-RA16 was capable of inhibiting NCI-H460 cell viability in a dose-dependent manner. IC values were 118.4 nM (n = 4) for syn-RA16 and 105.7 nM (n = 4) for trans-RA16. Further studies using syn-RA16 demonstrated its internalization into NCI-H460 cells and inhibition of NCI-H460 cell growth. Moreover, in vivo imaging demonstrated the gradual accumulation of both syn-RA16 and trans-RA16 at the grafted tumor site, and qRT-PCR showed high retention of syn-RA16 in tumor tissues. In addition, a truncated fragment of trans-RA16 (S3) was identified, which exhibited binding affinity for NCI-H460 cells with a K value of 63.20 ± 0.91 nM and inhibited NCI-H460 cell growth by 39.32 ± 3.25% at 150 nM. These features of the syn-RA16 and S3 aptamers should facilitate the development of a novel diagnostic or treatment approach for NSCLC in clinical settings.
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http://dx.doi.org/10.1038/s41598-019-55280-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906461PMC
December 2019

Proximal Tubular Vacuolization and Hypersensitivity to Drug-Induced Nephrotoxicity in Male Mice With Decreased Expression of the NADPH-Cytochrome P450 Reductase.

Toxicol Sci 2020 02;173(2):362-372

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona.

The effect of variations in the expression of cytochrome P450 reductase (CPR or POR) is determined in mice with decreased POR expression to identify potential vulnerabilities in people with low POR expression. There is an age-dependent appearance of increasing vacuolization in the proximal tubules of the renal cortex in 4- to 9-month-old male (but not female) Cpr-low (CL) mice. These mice have low POR expression in all cells of the body and upregulation of lysosome-associated membrane protein 1 expression in the renal cortex. Vacuolization is also seen in extrahepatic CL and extrarenal CL male mice, but not in mice with tissue-specific Por deletion in liver, intestinal epithelium, or kidney. The occurrence of vacuolization is accompanied by increases in serum blood-urea-nitrogen levels. Male CL mice are hypersensitive to cisplatin- and gentamicin-induced renal toxicity at 3 months of age, before proximal tubular (PT) vacuoles are detectable. At doses that do not cause renal toxicity in wild-type mice, both drugs cause substantial increases in serum blood-urea-nitrogen levels and PT vacuolization in male but not female CL mice. The hypersensitivity to drug-induced renal toxicity is accompanied by increases in circulating drug levels. These novel findings demonstrate deficiency of renal function in mice with globally reduced POR expression and suggest that low POR expression may be a risk factor for drug-induced nephrotoxicity in humans.
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http://dx.doi.org/10.1093/toxsci/kfz225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000068PMC
February 2020

Toxicokinetic Interaction between Hepatic Disposition and Pulmonary Bioactivation of Inhaled Naphthalene Studied Using -Null and CYP2A13/2F1-Humanized Mice with Deficient Hepatic Cytochrome P450 Activity.

Drug Metab Dispos 2019 12 8;47(12):1469-1478. Epub 2019 Oct 8.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona (N.K., Q.-Y.Z., X.D.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York (N.K., Q.-Y.Z.); Center for Health and the Environment, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, California (J.K., L.V.W.); and College of Nanoscale Science, State University of New York Polytechnic Institute, Albany, New York (X.D.)

Previous studies using -null (lacking all genes of the , , , , and subfamilies), CYP2A13/2F1-humanized, and liver--null (LCN) mice showed that although hepatic cytochrome P450 (P450) enzymes are essential for systemic clearance of inhaled naphthalene (a possible human carcinogen), both hepatic and extrahepatic P450 enzymes may contribute to naphthalene-induced lung toxicity via bioactivation. Herein, we aimed to further understand the toxicokinetics of inhaled naphthalene in order to provide a basis for predicting the effects of variations in rates of xenobiotic disposition on the extent of target tissue bioactivation. We assessed the impact of a hepatic deficit in naphthalene metabolism on the toxicokinetics of inhaled naphthalene using newly generated -null-and-LCN and CYP2A13/2F1-humanized-and-LCN mice. We determined plasma, lung, and liver levels of naphthalene and naphthalene-glutathione conjugate, a biomarker of naphthalene bioactivation, over time after naphthalene inhalation. We found that the loss of hepatic naphthalene metabolism severely decreased naphthalene systemic clearance and caused naphthalene to accumulate in the liver and other tissues. Naphthalene release from tissue, as evidenced by the continued increase in plasma naphthalene levels after termination of active inhalation exposure, was accompanied by prolonged bioactivation of naphthalene in the lung. In addition, transgenic expression of human CYP2A13/2F1 in the respiratory tract caused a reduction in plasma naphthalene levels (by 40%, relative to -null-and-LCN mice) and corresponding decreases in naphthalene-glutathione levels in the lung in mice with hepatic P450 deficiency, despite the increase in local naphthalene-bioactivating P450 activity. Thus, the bioavailability of naphthalene in the target tissue has a significant effect on the extent of naphthalene bioactivation in the lung. SIGNIFICANCE STATEMENT: In this study, we report several novel findings related to the toxicokinetics of inhaled naphthalene, the ability of which to cause lung carcinogenesis in humans is a current topic for risk assessment. We show the accumulation of naphthalene in the liver and lung in mice with compromised hepatic cytochrome P450 (P450) activity; the ability of tissue-stored naphthalene to redistribute to the circulation after termination of active inhalation exposure, prolonging exposure of target tissues to naphthalene; and the ability of non-CYP2ABFGS enzymes of the lung to bioactivate naphthalene. These results suggest potentially large effects of deficiencies in hepatic P450 activity on naphthalene tissue burden and bioactivation in human lungs.
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http://dx.doi.org/10.1124/dmd.119.088930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042723PMC
December 2019

Flexural Fatigue Performance of Steel Fiber Reinforced Expanded-Shales Lightweight Concrete Superposed Beams with Initial Static-Load Cracks.

Materials (Basel) 2019 Oct 6;12(19). Epub 2019 Oct 6.

School of Civil Engineering and Communications, North China University of Water Resources and Electric Power, Zhengzhou 450045, China.

Concerning the structural applications of steel fiber reinforced expanded-shales lightweight concrete (SFRELC), the present study focuses on the flexural fatigue performance of SFRELC superposed beams with initial static-load cracks. Nine SFRELC superposed beams were fabricated with the SFRELC depth varying from 50% to 70% of the whole sectional depth, and the volume fraction of steel fiber ranged from 0.8% to 1.6%. The fatigue load exerted on the beams was a constant amplitude sinusoid with a frequency of 10 Hz and a fatigue characteristic value of 0.10; the upper limit was taken as the load corresponded to the maximum crack width of 0.20 mm at the barycenter of the longitudinal rebars. The results showed that with the increase of SFRELC depth and the volume fraction of steel fiber, the fatigue life of the test beams was prolonged with three altered failure modes due to the crush of conventional concrete in the compression zone and/or the fracture of the tensile rebar; the failure pattern could be more ductile by the prevention of fatigue fracture by the longitudinal tensile rebar when the volume fraction of steel fiber was 1.6% and the reduction of crack growth and concrete strain in the compression zone; the fatigue life of test beams was sensitive to the upper-limit of the fatigue load, a short fatigue life appeared from the higher stress level and larger stress amplitude of the longitudinal rebar due to the higher upper-limit of the fatigue load. The methods for predicting the stress level, the stress amplitude of the longitudinal tensile rebar, and the degenerated flexural stiffness of SFRELC superposed beams with fatigue life are proposed. With the optimal composites of the SFRELC depth ratio and the volume fraction of steel fiber, the controllable failure of reinforced SFRELC superposed beams could be a good prospect with the trend curves of fatigue flexural stiffness.
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http://dx.doi.org/10.3390/ma12193261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804112PMC
October 2019

Chitosan/Dextran Hydrogel Constructs Containing Strontium-Doped Hydroxyapatite with Enhanced Osteogenic Potential in Rat Cranium.

ACS Biomater Sci Eng 2019 Sep 27;5(9):4574-4586. Epub 2019 Aug 27.

Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People's Republic of China.

It is an effective way in bone tissue engineering to promote the mechanical and osteogenic capability of hydrogels by encapsulating mineral particles into polymer matrix. In this work, we reported novel kinds of nanocomposite scaffolds based on hydroxypropyl chitosan/aldehyde dextran hydrogel (CDH) and strontium-nanohydroxyapatite (Sr-nHA) nanoparticles. The molar ratios of Sr/(Sr + Ca) at 0% (nHA), 50% (Sr50nHA), and 100% (Sr100nHA) were fabricated and subsequently incorporated into CDH. The characterization of Sr-nHA/CDH constructs and CDH alone was studied by Fourier transform infrared analysis, X-ray powder diffraction detection, and scanning electron microscopy. The physical properties of hydrogels were further detected by swelling studies, degradation behavior, rheological measurements, mechanical testing, and ion-release behavior. Cell biocompatibility on the scaffolds was determined , and bone formation was examined by a rat calvarium defect model. The results showed that either nHA or Sr-nHA nanoparticles incorporation into CDH would significantly improve the rheological and mechanical properties ( < 0.05). The Sr released from the Sr100nHA/CDH was in the range of optimal concentration for pro-osteogenesis. The addition of Sr-nHA significantly enhanced the cell proliferation and osteogenic differentiation of osteoblasts ( < 0.05). The Sr100nHA/CDH exerted the highest promotion on the polarization of macrophages toward the M2 phenotype. The new bone formation of Sr100nHA/CDH was 2.5-fold and 2-fold higher than that of CDH at 4 and 8 weeks, respectively ( < 0.05). HE staining, Masson's trichrome staining, and immunofluorescence staining of OCN results also confirmed that Sr100nHA/CDH had superior bone regeneration compared to other hydrogels . In conclusion, this novel gelling hydrogel based on injectable and load-bearing 100% Sr-substituted nHA in CDH is expected to have wide orthopedic, dental, and craniofacial applications to enhance bone regeneration.
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http://dx.doi.org/10.1021/acsbiomaterials.9b00584DOI Listing
September 2019

Behavior of Rectangular-Sectional Steel Tubular Columns Filled with High-Strength Steel Fiber Reinforced Concrete Under Axial Compression.

Materials (Basel) 2019 Aug 24;12(17). Epub 2019 Aug 24.

International Joint Research Lab for Eco-building Materials and Engineering of Henan, North China University of Water Resources and Electric Power, Zhengzhou 450045, China.

This paper studies the effect of high-strength steel fiber reinforced concrete (SFRC) on the axial compression behavior of rectangular-sectional SFRC-filled steel tube columns. The purpose is to improve the integrated bearing capacity of these composite columns. Nine rectangular-sectional SFRC-filled steel tube columns and one normal concrete-filled steel tube column were designed and tested under axial loading to failure. The compressive strength of concrete, the volume fraction of steel fiber, the type of internal longitudinal stiffener and the spacing of circular holes in perfobond rib were considered as the main parameters. The failure modes, axial load-deformation curves, energy dissipation capacity, axial bearing capacity, and ductility index are presented. The results identified that steel fiber delayed the local buckling of steel tube and increased the ductility and energy dissipation capacity of the columns when the volume fraction of steel fiber was not less than 0.8%. The longitudinal internal stiffening ribs and their type changed the failure modes of the local buckling of steel tube, and perfobond ribs increased the ductility and energy dissipation capacity to some degree. The compressive strength of SFRC failed to change the failure modes, but had a significant impact on the energy dissipation capacity, bearing capacity, and ductility. The predictive formulas for the bearing capacity and ductility index of rectangular-sectional SFRC-filled steel tube columns are proposed to be used in engineering practice.
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http://dx.doi.org/10.3390/ma12172716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747621PMC
August 2019

Role of mouse cytochrome P450 enzymes of the CYP2ABFGS subfamilies in the induction of lung inflammation by cigarette smoke exposure.

Toxicol Sci 2019 Aug 6. Epub 2019 Aug 6.

College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY.

Background: Many constituents of tobacco smoke (TS) require bioactivation to exert toxic effects; however, few studies have examined the role of bioactivation enzymes in the adverse effects of TS exposure. This knowledge gap is a major source of uncertainty for risk assessment and chemoprevention efforts.

Objectives: Our aim is to test the hypothesis that cytochrome P450 (P450) enzyme mediated bioactivation is essential to the development of TS exposure-induced lung toxicity, by determining the contributions of P450 enzymes in the mouse Cyp2abfgs gene subfamilies to environmental tobacco smoke (ETS)-induced lung inflammation.

Methods: Adult female wildtype (WT) and Cyp2abfgs-null mice (both on C57BL/6J background) were exposed to filtered air or ETS, intermittently, for 1 or 2 weeks. Lung inflammation was assessed by quantification of inflammatory cells, cytokines, chemokines, proteins in bronchoalveolar lavage fluid (BALF), and histopathological analysis. Glutathione (GSH) conjugates of two ETS constituents, naphthalene (NA) and 3-methylindole (3MI), were measured in mice exposed to ETS for four hours.

Results: Persistent macrophagic and neutrophilic lung inflammation was observed in ETS-exposed WT mice; the extent of which was significantly reduced in ETS-exposed Cyp2abfgs-null mice. Levels of proinflammatory cytokines and chemokines, along with the total protein concentration, were increased in cell-free BALF from ETS-exposed WT mice, but not Cyp2abfgs-null mice. Additionally, GSH-conjugates of NA and 3MI were detected in the lungs of WT, but not Cyp2abfgs-null, mice following ETS exposure.

Conclusions: These results provide the first in vivo evidence that the mouse Cyp2abfgs gene cluster plays an important role in ETS-induced lung inflammation.
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http://dx.doi.org/10.1093/toxsci/kfz171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813748PMC
August 2019

The endoscopically assisted transcrestal sinus floor elevation with platelet-rich fibrin at an immediate implantation of periapical lesion site: A case report.

Medicine (Baltimore) 2019 Jul;98(27):e16251

School and Hospital of Stomatology, Jilin University, Department of Dental Implantology, Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun, Jilin Province, China.

Rationale: The traditional maxillary sinus floor elevation has serious postoperative complications and long healing periods, for patients with insufficient residual bone height (RBH). The endoscopic technique improves the blind nature of the sinus floor elevation procedure. Platelet-rich fibrin (PRF) can promote tissue healing and prevent perforation.

Patient Concern: A 25-year-old female with residual roots in the maxillary right second molar visited our hospital for dental implants.

Diagnose: CBCT results showed a low-density shadow at the root tip, and the height of the periapical distance from the maxillary sinus floor was less than 1 mm.

Intervention: Patient was immediately subjected to implant after root extraction. Two-step sinus floor elevation was performed under endoscopy. A 12 mm-long implant was installed.

Outcomes: At 10 months after surgery, the hard and soft tissues were stable, and a full-ceramic crown was placed.

Lessons: Immediate implant and endoscope-guided sinus floor elevation through a transcrestal approach by using PRF as the only grafting material is viable in periapical infected sites with a RBH of less than 1 mm.
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http://dx.doi.org/10.1097/MD.0000000000016251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635277PMC
July 2019

Safety and efficacy of ex vivo expanded CD34 stem cells in murine and primate models.

Stem Cell Res Ther 2019 06 13;10(1):173. Epub 2019 Jun 13.

Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215126, China.

Background: Hematopoietic stem cell (HSC) transplantation has been widely applied to the treatment of malignant blood diseases. However, limited number of functional HSCs hinders successful transplantation. The purpose of our current study is to develop a new and cost-efficient medium formulation that could greatly enhance the expansion of HSCs while retaining their long-term repopulation and hematopoietic properties for effective clinical transplantation.

Methods: Enriched human CD34 cells and mobilized nonhuman primate peripheral blood CD34 cells were expanded with a new, cost-efficient expansion medium formulation, named hematopoietic expansion medium (HEM), consisting of various cytokines and nutritional supplements. The long-term repopulation potential and hematologic-lineage differentiation ability of expanded human cells were studied in the non-obese diabetic/severe combined immunodeficiency mouse model. Furthermore, the efficacy and safety studies were performed by autologous transplantation of expanded primate cells in the nonhuman primate model.

Results: HEM could effectively expand human CD34 cells by up to 129 fold within 9 days. Expanded HSCs retained long-term repopulation potential and hematologic-lineage differentiation ability, as indicated by (1) maintenance (over unexpanded HSCs) of immunophenotypes of CD38CD90CD45RACD49f in CD34 cells after expansion; (2) significant presence of multiple human hematopoietic lineages in mouse peripheral blood and bone marrow following primary transplantation; (3) enrichment (over unexpanded HSCs) in SCID-repopulating cell frequency measured by limiting dilution analysis; and (4) preservation of both myeloid and lymphoid potential among human leukocytes from mouse bone marrow in week 24 after primary transplantation or secondary transplantation. Moreover, the results of autologous transplantation in nonhuman primates demonstrated that HEM-expanded CD34 cells could enhance hematological recovery after myelo-suppression. All primates transplanted with the expanded autologous CD34 cells survived for over 18 months without any noticeable abnormalities.

Conclusions: Together, these findings demonstrate promising potential for the utility of HEM to improve expansion of HSCs for clinical application.
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http://dx.doi.org/10.1186/s13287-019-1275-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567473PMC
June 2019

Contributions of Hepatic and Intestinal Metabolism to the Disposition of Niclosamide, a Repurposed Drug with Poor Bioavailability.

Drug Metab Dispos 2019 07 30;47(7):756-763. Epub 2019 Apr 30.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona (X.F., X.D., Q.-Y.Z.); and Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (H.L.)

Niclosamide, an antiparasitic, has been repositioned as a potential therapeutic drug for systemic diseases based on its antiviral, anticancer, and anti-infection properties. However, low bioavailability limits its in vivo efficacy. Our aim was to determine whether metabolic disposition by microsomal P450 enzymes in liver and intestine influences niclosamide's bioavailability in vivo, by comparing niclosamide metabolism in wild-type, liver-Cpr-null (LCN), and intestinal epithelium-Cpr-null (IECN) mice. In vitro stability of niclosamide in microsomal incubations was greater in the intestine than in liver in the presence of NADPH, but it was much greater in liver than in intestine in the presence of UDPGA. NADPH-dependent niclosamide metabolism and hydroxy-niclosamide formation were inhibited in hepatic microsomes of LCN mice, but not IECN mice, compared with wild-type mice. In intestinal microsomal reactions, hydroxy-niclosamide formation was not detected, but rates of niclosamide-glucuronide formation were ∼10-fold greater than in liver, in wild-type, LCN, and IECN mice. Apparent Km and values for microsomal niclosamide-glucuronide formation showed large differences between the two tissues, with the intestine having higher Km (0.47 M) and higher (15.8) than the liver (0.09 M and 0.75, respectively). In vivo studies in LCN mice confirmed the essential role of hepatic P450 in hydroxy-niclosamide formation; however, pharmacokinetic profiles of oral niclosamide were only minimally changed in LCN mice, compared with wild-type mice, and the changes seem to reflect the compensatory increase in hepatic UDP-glucuronosyltransferase activity. SIGNIFICANCE STATEMENT: These results suggest that efforts to increase the bioavailability of niclosamide by blocking its metabolism by P450 enzymes will unlikely be fruitful. In contrast, inhibition of niclosamide glucuronidation in both liver and intestine may prove effective for increasing niclosamide's bioavailability, thereby making it practical to repurpose this drug for treating systemic diseases.
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http://dx.doi.org/10.1124/dmd.119.086678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592404PMC
July 2019

Metabolism and Lung Toxicity of Inhaled Naphthalene: Effects of Postnatal Age and Sex.

Toxicol Sci 2019 08;170(2):536-548

Center for Health and the Environment, University of California Davis, Davis, California 95616.

Human exposure to naphthalene (NA), an acute lung toxicant and possible human carcinogen, is primarily through inhalation. Acute lung toxicity and carcinogenesis are thought to be related because the target sites for both are similar. To understand susceptibility of the developing lung to cytotoxicity of inhaled NA, we exposed neonatal (7 days), juvenile (3 weeks), and adult mice to 5 or 10 ppm NA vapor for 4 h. We measured vacuolated airway epithelium morphometrically, quantified NA and NA-glutathione levels in plasma and lung, and quantified gene expression in microdissected airways. NA inhalation caused airway epithelial cytotoxicity at all ages, in both sexes. Contrary to a previous study that showed the greatest airway epithelial cytotoxicity in neonatal mice following intraperitoneal NA injection, we observed the most extensive airway epithelial toxicity in older, juvenile, animals exposed to NA by inhalation. Juvenile female animals were the most susceptible. Furthermore, NA inhalation in juvenile animals resulted in damage to conducting airway Club cells that was greater in proximal versus distal airways. We also found NA tissue burden and metabolism differed by age. Gene expression pathway analysis was consistent with the premise that female juvenile mice are more predisposed to damage; DNA damage and cancer pathways were upregulated. Our data demonstrate special susceptibility of young, juvenile mice to NA inhalation-induced cytotoxicity, highlight the importance of route of exposure and airway location in toxicity of chemicals in the developing lung, and provide metabolic and molecular insights for further identification of mechanisms underlying age and sex differences in NA toxicity.
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http://dx.doi.org/10.1093/toxsci/kfz100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657577PMC
August 2019

Novel ultrafine-grained β-type Ti-28Nb-2Zr-8Sn alloy for biomedical applications.

J Biomed Mater Res A 2019 08 9;107(8):1628-1639. Epub 2019 Apr 9.

Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun 130021, China.

Titanium alloys are widely accepted as orthopedic or dental implant materials in the medical field. It is important to evaluate the biocompatibility of an implant material prior to use. A new β-type ultrafine-grained Ti-28Nb-2Zr-8Sn (TNZS) alloy with low Young's modulus of 31.6 GPa was fabricated. This study aims to evaluate the biocompatibility of TNZS alloy. In this study, we examined the microstructure, chemical composition and surface wettability of the TNZS alloy. The mouse embryonic osteoblast MC3T3-E1 cells and human umbilical vein endothelial cells (HUVECs) were cultured to study the cytocompatibility of TNZS alloy. Also, we evaluated the proinflammatory response of TNZS alloy in vitro and in vivo. The results show that the TNZS did not cause cytotoxicity, genotoxicity to MC3T3-E1 cells and HUVECs. Whereas, the TNZS alloy could significantly promote the cell proliferation, cell spreading and cell adhesion of MC3T3-E1 cells and HUVECs, as well as facilitate the osteogenic differentiation of MC3T3-E1 cells. Moreover, the TNZS alloy did not induce any remarkable proinflammatory response in vitro and in vivo. Thus, the novel TNZS alloy with an elasticity closer to that of human bone is biologically safe and could be a potential candidate for biomedical implant application. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1628-1639, 2019.
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http://dx.doi.org/10.1002/jbm.a.36679DOI Listing
August 2019

Statistical Analysis and Preliminary Study on the Mix Proportion Design of Self-Compacting Steel Fiber Reinforced Concrete.

Materials (Basel) 2019 Feb 20;12(4). Epub 2019 Feb 20.

International Joint Research Lab for Eco-building Materials and Engineering of Henan, North China University of Water Resources and Electric Power, Zhengzhou 450045, China.

With the sustainable development of green construction materials in civil engineering, self-compacting steel fiber reinforced concrete (SC-SFRC) has attracted widespread attention due to its superior self-compacting performance and excellent hardened properties. In this paper, 301 groups of test data from published literatures were collected to quantify the characteristics of the mix proportion of SC-SFRC. The type, aspect ratio and volume fraction of steel fiber commonly used in SC-SFRC are discussed and the effects of steel fiber on the workability and mechanical properties of SC-SFRC are statistically studied. The relationship of cubic compressive strength and water-to-binder ratio and that of the splitting tensile strengths between SC-SFRC and referenced self-compacting concrete (SCC) are also evaluated. Based on these analyses, the reasonable ranges of material components in the mix proportion design of SC-SFRC are determined. The results showed that with several adjusted parameters, the calculation model of the water-to-binder ratio for the mix proportion design of ordinary concrete is suitable for SC-SFRC. The calculation model of tensile strength is suggested for SC-SFRC with various types of steel fiber.
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http://dx.doi.org/10.3390/ma12040637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416611PMC
February 2019

Naphthalene genotoxicity: DNA adducts in primate and mouse airway explants.

Toxicol Lett 2019 May 24;305:103-109. Epub 2019 Jan 24.

Center for Health and the Environment, University of California Davis, Davis, CA 95616, USA; Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA. Electronic address:

Naphthalene (NA) is a ubiquitous environmental pollutant and possible human carcinogen that forms tumors in rodents with tissue/regional and species selectivity. This study seeks to determine whether NA is able to directly adduct DNA in an ex vivo culture system. Metabolically active lung tissue was isolated and incubated in explant culture with carbon-14 labeled NA (0, 25, 250 μM) or 1,2-naphthoquinone (NQ), followed by AMS analyses of metabolite binding to DNA. Despite relatively low metabolic bioactivation in the primate airway, dose-dependent NA-DNA adduct formation was detected. More airway adducts were detected in female mice (4.7-fold) and primates (2.1-fold) than in males of the same species. Few adducts were detected in rat airway or nasal epithelium. NQ, which is a metabolic product of NA, proved to be even more potent, with levels of adduct formation 70-80-fold higher than seen when tissues were incubated with the parent compound NA. This is the first study to demonstrate NA-DNA adduct formation at a site of carcinogenesis, the mouse lung. Adducts were also detected in non-human primate lung and with a NQ metabolite of NA. Taken together, this suggests that NA may contribute to in vivo carcinogenesis through a genotoxic mechanism.
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http://dx.doi.org/10.1016/j.toxlet.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459408PMC
May 2019

Naphthalene DNA Adduct Formation and Tolerance in the Lung.

Nucl Instrum Methods Phys Res B 2019 Jan 13;438:119-123. Epub 2018 Jul 13.

Center for Health and the Environment, University of California, Davis, CA USA.

Naphthalene (NA) is a respiratory toxicant and possible human carcinogen. NA is a ubiquitous combustion product and significant component of jet fuel. The National Toxicology Program found that NA forms tumors in two species, in rats (nose) and mice (lung). However, it has been argued that NA does not pose a cancer risk to humans because NA is bioactivated by cytochrome P450 monooxygenase enzymes that have very high efficiency in the lung tissue of rodents but low efficiency in the lung tissue of humans. It is thought that NA carcinogenesis in rodents is related to repeated cycles of lung epithelial injury and repair, an indirect mechanism. Repeated exposure to NA leads to development of tolerance, with the emergence of cells more resistant to NA insult. We tested the hypothesis that tolerance involves reduced susceptibility to the formation of NA-DNA adducts. NA-DNA adduct formation in tolerant mice was examined in individual, metabolically-active mouse airways exposed to 250 μΜ C-NA. dosing was used since it had been done previously and the act of creating a radioactive aerosol of a potential carcinogen posed too many safety and regulatory obstacles. Following extensive rinsing to remove unbound C-NA, DNA was extracted and C-NA-DNA adducts were quantified by AMS. The tolerant mice appeared to have slightly lower NA-DNA adduct levels than non-tolerant controls, but intra-group variations were large and the difference was statistically insignificant. It appears the tolerance may be more related to other mechanisms, such as NA-protein interactions in the airway, than DNA-adduct formation.
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http://dx.doi.org/10.1016/j.nimb.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322674PMC
January 2019