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At least 325 records · Page 18

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DOE OSTI2018

Uncovering transcription factor and microRNA risk regulatory pathways associated with osteoarthritis by network analysis

Osteoarthritis (OA) is the most common form of joint disease. The development of inflammation have been considered to play a key role during the progression of OA. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, deciphering these risk regulatory pathways is critical for elucidating the mechanisms underlying OA. We constructed an OA-specific regulatory network by integrating comprehensive curated transcription and post-transcriptional resource involving transcription factor (TF) and microRNA (miRNA). To deepen our understanding of underlying molecular mechanisms of OA, we developed an integrated systems approach to identify OA-specific risk regulatory pathways. In this study, we identified 89 significantly differentially expressed genes between normal and inflamed areas of OA patients. We found the OA-specific regulatory network was a standard scale-free network with small-world properties. It significant enriched many immune response-related functions including leukocyte differentiation, myeloid differentiation and T cell activation. Finally, 141 risk regulatory pathways were identified based on OA-specific regulatory network, which contains some known regulator of OA. The risk regulatory pathways may provide clues for the etiology of OA and be a potential resource for the discovery of novel OA-associated disease genes.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Fam83h mutation inhibits the mineralization in ameloblasts by activating Wnt/β-catenin signaling pathway

Highlights: • Fam83h mutation altered the expression and subcellular localization of Fam83 h, CK1α and β-catenin. • Fam83h mutation activated the Wnt/β-catenin signaling pathway and inhibited the mineralization in LS8 cells. • The inhibitor of Wnt/β-catenin signaling pathway rescued the inhibited mineralization in LS8 cells with mutant Fam83h. • Fam83h mutation could inhibit the mineralization in ameloblasts by activating Wnt/β-catenin signaling pathway. FAM83H was identified as the major causative gene for autosomal dominant hypocalcified amelogenesis imperfect (ADHCAI). The pathogenic mechanism of FAM83H in ADHCAI remains elusive. The present study aims to investigate the effect of Fam83h mutation on the mineralization of mouse ameloblast cell line LS8 and to explore the possible pathogenesis of ADHCAI. Lentivirus package was performed for the plasmids with mouse Fam83h mutant cDNA (c.1186C > T, M3) and empty vector (Control) and transfected into LS8, which were divided into M3-FLAG and Control groups. Immunoprecipitation, western-blot and immunofluorescence were performed to detect the expression and subcellular localization of Fam83 h, CK1α and β-catenin. ALP activity, ALP staining, expression of the mineralization factors were detected in two groups during mineralization induction. Expression of the mineralization factors was also detected in M3-FLAG and LS8 exposing to pyrvinium pamoate. Compared with the Control, the Fam83h mutation altered the expression and localization of Fam83 h, CK1α and β-catenin in LS8, inhibited the mineralization and down-regulated the expression of mineralization factors in M3-FLAG. Pyrvinium pamoate, an inhibitor of the Wnt/β-catenin signaling pathway, up-regulated expression of mineralization factors in LS8 and rescued the inhibited mineralization in M3-FLAG. The results indicated that the Fam83h mutation could inhibit the mineralization in ameloblasts by activating Wnt/β-catenin signaling pathway.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Vitamin D receptor ligands attenuate the inflammatory profile of IL-1β-stimulated human white preadipocytes via modulating the NF-κB and unfolded protein response pathways

Highlights: • IL-1β enhances the inflammatory profile of preadipocytes by post-translationally modifying relA of the NF-κB pathway. • Vitamin D ligands inhibit expression of pro-inflammatory factors in IL-1β-stimulated preadipocytes by decreasing phosphorylation or increasing methylation of relA. • Vitamin D ligands reduce secretion of proinflammatory factors from IL-1β-stimulated preadipocytes by increasing eIF-2α phosphorylation in the UPR pathway. Metaflammation in adipose tissue, which is characterized by increased local gene expression and secretion of pro-inflammatory factors, may contribute to the increased risk of metabolic complications in obesity. It has been suggested that IL-1β might induce metaflammation in adipose tissue via modulating the NF-κB signaling pathway. In our study, the mRNA and secretion levels of major pro-inflammatory factors including IL (interleukin)-1β, IL-6, IL-8, MCP (monocyte chemoattractant protein)-1 and RANTES (regulated on activation, normal T cell expressed and secreted) were measured as indicators of the inflammatory profile. We herein showed that IL-1β could induce adipose tissue metaflammation by enhancing the inflammatory profile of preadipocytes. Moreover, IL-1β could enhance pro-inflammatory gene expression by increasing the phosphorylation or decreasing the methylation of relA (NF-κB p65) of the NF-κB signaling pathway. VDR (vitamin D receptor) ligands have been shown to have anti-inflammatory properties in adipocytes. Likewise, our study demonstrated that the inflammatory profile of IL-1β-stimulated preadipocytes is significantly attenuated by VDR ligands 1α,25(OH){sub 2}D{sub 3}, ZK159222 and ZK191785. Importantly, we showed that ZK159222 and ZK191785 could inhibit pro-inflammatory gene expression by decreasing the phosphorylation or increasing the methylation of relA. Furthermore, pro-inflammatory secretion could be reduced by 1α,25(OH){sub 2}D{sub 3}, ZK159222 and ZK191785 via increasing the phosphorylation of eIF (eukaryotic translation initiation factor)-2α of the UPR (unfolded protein response) pathway. These observations suggest that the VDR ligands may be considered potential anti-inflammatory treatments for obesity associated metabolic complications.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Alternative pathway linked by hydrogen bonds connects heme-Fe of cytochrome c with subunit II-CuA of cytochrome a

Highlights: • Hydrogen bond, rather than carbon-carbon σ-bond, as the bridging element for electron transfer in proteins gained experimental evidence. • An alternative pathway linked by hydrogen bonds, is identified from heme-Fe of cytochrome c to subunit II-CuA of cytochrome a. • Such hydrogen bond-linked pathways occur in proteins and may be considered for intramolecular and intermolecular electron transfer. The bridging element for electron transfer in proteins is the hydrogen bond according to the new experimental perspective in preference to carbon-carbon σ-bond presently used. The purpose of this study is to identify an alternative pathway linked by hydrogen bonds suitable for electron transfer from heme-Fe of cytochrome c to subunit II-CuA of cytochrome a. A pathway consisting of 15 delocalized electron systems including peptide bonds, 5 polar groups of side chains of amino acid residues and 8 water molecules, linked by 27 hydrogen bonds, exists between the two metal electron centers of heme-Fe of cytochrome c, cytochrome c and of subunit II-CuA of cytochrome a. Pathways built of delocalized π-electron systems, polar groups and water molecules linked by hydrogen bonds may be considered for intramolecular and intermolecular electron transfer in proteins.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Calcium sensing receptor activates the NLRP3 inflammasome via a chaperone-assisted degradative pathway involving Hsp70 and LC3-II

Highlights: • CaSR activates the NLRP3-inflammasome via proteasome and lysosome. • CaSR signals via Gα{sub q} and Gβγ to activate the NLRP3 inflammasome. • CaSR stimulates Hsp70 expression leading to chaperone-assisted protein degradation. • CaSR promotes IL-1β processing via proteasome and lysosome-dependent pathways. • CaSR generates homeostasis-altering molecular processes. Calcium sensing receptor (CaSR) activates the NLRP3 inflammasome with consequences on homeostatic responses. However, little is known about how this process is orchestrated. Since proteolysis of critical regulators of NLRP3 inflammasome contribute to its activation, we aimed to understand how CaSR stimulates proteolytic pathways to activate the NLRP3 inflammasome. We found that proteasome and lysosome-dependent mechanisms are activated by CaSR to promote the degradation of important regulators of NLRP inflammasome. The pathway involves Gαq/PLC/PKC and Gβγ/PI3K signaling cascades and IRAK1 ubiquitination. In addition, CaSR stimulates Hsp70 expression activating a chaperone-assisted protein degradation that dictates the fate of ASC, NLRP3 (NOD-like receptor family protein 3), IRAK1 and TRAF6 proteins, turning on the NLRP3 inflammasome. In response to CaSR signaling, these proteins are degraded through the combination of CUPS (chaperone-assisted ubiquitin proteasome pathway) and CAEMI (chaperone-assisted endosomal microautophagy) systems being integrated by autophagosomes (chaperone-assisted macroautophagy, CAMA), as indicated by LC3-II, a classical marker for autophagy, that is induced in the process. Furthermore, CaSR triggers the proteolytic cleavage of pro-IL-1β (IL-1β, 31 kDa) into mature IL-1β (IL-1β, 17 kDa), via the proteasome. Taken together, our results indicate that CaSR promotes NLRP3 inflammasome activation and proteolytic maturation of IL-1β by inducing CUPS and CAEMI, chaperone-assisted degradation pathways. Overall, these results support the inclusion of CaSR as an activator of homeostasis-altering molecular processes.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Clotrimazole inhibits the Wnt/β-catenin pathway by activating two eIF2α kinases: The heme-regulated translational inhibitor and the double-stranded RNA-induced protein kinase

Highlights: • A zebrafish phenotypic screening repositioned antifungal azoles to Wnt inhibitors. • Clotrimazole reduces β-catenin levels in a proteasome-independent manner. • Clotrimazole inhibits Wnt/β-catenin signaling by activating eIF2α kinases. The Wnt/β-catenin signaling pathway controls cell proliferation and differentiation, and therefore, when this pathway is excessively activated, it causes tumorigenesis. Our chemical suppressor screening in zebrafish embryos identified antifungal azoles including clotrimazole, miconazole, and itraconazole, as Wnt/β-catenin signaling inhibitors. Here we show the mechanism underlying the Wnt/β-catenin pathway inhibition by antifungal azoles. Clotrimazole reduced β-catenin revels in a proteasome-independent fashion. By gene knockdown of two translational regulators, heme-regulated translational inhibitor and double-stranded RNA-induced protein kinase, we show that they mediate the clotrimazole-induced inhibition of the Wnt/β-catenin pathway. Thus, clotrimazole inhibits the Wnt/β-catenin pathway by decreasing β-catenin protein levels through translational regulation. Antifungal azoles represent genuine candidate compounds for anticancer drugs or chemopreventive agents that reduce adenomatous polyps.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

FFAR1-and FFAR4-dependent activation of Hippo pathway mediates DHA-induced apoptosis of androgen-independent prostate cancer cells

Highlights: • DHA induces cell growth inhibition and apoptosis of human prostate cancer cells. • DHA promotes YAP phosphorylation in androgen-independent prostate cancer cell lines. • DHA induces cell growth inhibition and apoptosis of PC3 cells via YAP. • DHA promotes YAP phosphorylation via FFAR1/4-dependent activation of the Hippo pathway. Evidence indicates that diets enriched in Docosahexaenoic acid (DHA), a 22:6 n-3 polyunsaturated fatty acid, reduces the risk of prostate cancer, but the biochemical mechanisms are unclear. The Hippo pathway has been well established as a tumor suppressor pathway and is involved in many diverse biologic processes including cell growth, cell death, and organ size control in organisms. Here we showed that DHA induces cell growth inhibition and apoptosis of human androgen-independent prostate cancer cells dependent on the Hippo pathway. DHA inactivates YAP by promoting phosphorylation in androgen-independent prostate cancer cell lines, accompanied by increased YAP cytoplasm translocation. We also observed that DHA-induced YAP phosphorylation was reversed by both the LATS1 and MST1 siRNAs. Further experiments showed that the mechanism of DHA-induced YAP phosphorylation associated with FFAR1 and FFAR4. Down-regulation of FFAR1 and FFAR4 resulted in reduced YAP phosphorylation and reversed DHA-induced YAP phosphorylation. In addition, DHA-induced YAP phosphorylation was abolished by dominant negative Gαs and PKA inhibitor H-89. Overall, these findings define a mechanism by which FFAR1-and FFAR4-dependent activation of Hippo pathway mediates DHA-induced apoptosis of androgen-independent prostate cancer cells, thus providing a promising therapeutic target for prostate cancer.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Low-temperature oxidation pathways are critical to thermal incineration of PFAS-laden materials

With growing desire to destroy per- and poly-fluoroalkyl substances (PFAS) now known to be detrimental to human health, a sound understanding of fluorocarbon combustion chemistry is important to efficient thermal destruction within incinerators. While most fluorocarbon combustion models and the sets of reactions contained within them were originally developed for the high temperatures encountered in flame suppression applications, they have often been used to assess PFAS destruction in incinerators, which emphasize a lower range of temperatures. We present results that demonstrate that low-temperature fluorocarbon oxidation pathways—not yet known to play a role in fluorocarbon combustion—impact key incinerator performance metrics, including: PFAS surrogate mole fractions, products of incomplete destruction, and waste destruction efficiencies. The results further point to the utility of NO as a potential additive. The present results show the influence of these pathways for CF 3 O 2 , for which some data are available, but analogous pathways would also occur for other fluoroalkylperoxy radicals, for which little is known. Furthermore, the results demonstrate the need for future work to identify and characterize low-temperature pathways more generally, consider such pathways in kinetic model development, and experimentally probe intermediate temperature conditions to better understand, design, and control thermal destruction technologies for improved PFAS management.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2021

A Framework for Patient-Centered Pathways of Care for Radiopharmaceutical Therapy: An ASTRO Consensus Document

Radiopharmaceutical therapy (RPT) is an area of projected growth and importance with several agents in clinical use, new agents in late-phase clinical trials, and many others under testing and development. This article proposes a framework for developing pathways of care that can be broadly applied to all RPTs, representing the current status of RPT. It suggests foundational elements for many pathways of care for patients with cancer and concludes with areas in active development and the future horizon for RPT treatment centers. Developing a framework for patient-centered pathways of care is a critical step in establishing RPT as standard therapy for patients with a diverse spectrum of cancers. This expected increase in RPT treatment options will affect a much larger population of patients with complex cancer. It will also require enhanced coordination and collaboration among appropriately qualified personnel with diverse expertise in image acquisition, image interpretation, quantitative imaging, dosimetry calculation, radiation quality assurance and safety as well as oncology care and RPT-induced sequelae and response assessment. The essential role of this evolving RPT care team within multidisciplinary oncology care is a cornerstone of this framework for a patient-centered pathway of care for RPT. Given the status of current RPT practice and the horizon for future applications, this patient-centered pathway of care guidance is timely and should help inform future clinical RPT practice paradigms. A task force was recruited from the Theranostic Working Group of the American Society for Radiation Oncology (ASTRO) in May 2019 with equal representation from the nuclear medicine community. The task force expanded on a framework that was originally conceived by the Working Group for patient-centered care. This framework was developed to incorporate the strengths of both radiation oncologists and nuclear medicine physicians. The manuscript was then developed by the task force and posted on the ASTRO website for a 6-week public comment period ending in July 2020. Comments were adjudicated, and the draft was sent to external organizations for potential endorsement. This document was sent to the ASTRO Board of Directors in October 2020 for approval.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2021

Bacterial effectors mimicking ubiquitin-proteasome pathway tweak plant immunity

Plant pathogenic Gram-negative bacteria evade the host plant immune system by secreting Type III (T3E) and Type IV effector (T4E) proteins into the plant cytoplasm. Mostly T3Es are secreted into the plant cells to establish pathogenicity by affecting the vital plant process viz. metabolic pathways, signal transduction and hormonal regulation. Ubiquitin-26S proteasome system (UPS) exists as one of the important pathways in plants to control plant immunity and various cellular processes by employing several enzymes and enzyme components. Pathogenic and non-pathogenic bacteria are found to secrete effectors into plants with structural and/or functional similarity to UPS pathway components like ubiquitin E3 ligases, F-box domains, cysteine proteases, inhibitor of host UPS or its components, etc. The bacterial effectors mimic UPS components and target plant resistance proteins for degradation by proteasomes, thereby taking control over the host cellular activities as a strategy to exert virulence. Thus, the bacterial effectors circumvent plant cellular pathways leading to infection and disease development. Finally, this review highlights known bacterial T3E and T4E proteins that function and interfere with the ubiquitination pathway to regulate the immune system of plants.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Developmental defects in zebrafish for classification of EGF pathway inhibitors

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems. - Highlights: • We analyze the functions of Egf signaling on zebrafish development. • Genetic blocking of Egf expression causes cartilage, myelin and circulatory defects. • Chemical inhibition of Egf receptor function causes similar defects. • Developmental defects can reveal the specificity of Egf pathway inhibitors.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

TNF/TNFR{sub 1} pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes

Background and purpose: Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR{sub 1} pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes. Experimental approach: Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR{sub 1}, TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR{sub 1} was suppressed with its siRNA. The protein levels of TNFα, TNFR{sub 1} and caspase-12 were assayed using Western blotting. Key results: The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR{sub 1} and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR{sub 1}, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR{sub 1}–siRNA interference. Conclusions and implications: Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR{sub 1} pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage. - Highlights: • Chondrocyte apoptosis is induced by ofloxacin in a time- and concentration-dependent manners. • TNF/TNFR{sub 1} pathway is involved in ofloxacin-induced apoptosis of chondrocytes in the early stage. • Endoplasmic reticulum stress is involved in ofloxacin-induced apoptosis of chondrocytes in the early stage.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Attenuation of Aβ{sub 25–35}-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ{sub 25–35}-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ{sub 25–35} (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ{sub 25–35} treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ{sub 25–35} treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ{sub 25–35}-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ{sub 25–35}-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens or gypenosides. - Highlights: • GP-17 showed protection against Aβ{sub 25–35}-induced neurotoxicity. • The neuroprotective effects of GP-17 are dependent on estrogen receptors. • GP-17 activates Nrf2/ARE/HO-1 pathways. • GP-17 activates PI3K/Akt/GSK-3β pathways.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells

Paclitaxel, etoposide, vincristine and doxorubicin are examples of natural products being used as chemotherapeutics but with adverse side effects that limit their therapeutic window. Natural products derived from plants and having low toxicity, such as quercetin, resveratrol, epigallocatechin gallate and piceatannol, have been shown to inhibit tumor cell growth both in vitro and in pre-clinical models of cancer, but their mechanisms of action have not been fully elucidated, thus restricting their use as prototypes for developing synthetic analogs with improved anti-cancer properties. We and others have demonstrated that one of the earliest and consistent events upon exposure of tumor cells to these less toxic natural products is a rise in cytoplasmic calcium, activating several pro-apoptotic pathways. We describe here a G protein/inositol 1,4,5-trisphosphate pathway (InsP3) in MDA-MB-231 human breast cancer cells that mediates between these less toxic natural products and the release of calcium from the endoplasmic reticulum. Further, we demonstrate that this elevation of intracellular calcium modulates p53 activity and the subsequent transcription of several pro-apoptotic genes encoding PIG8, CD95, PIDD, TP53INP, RRM2B, Noxa, p21 and PUMA. We conclude from our findings that less toxic natural products likely bind to a G protein coupled receptor that activates a G protein-mediated and calcium-dependent pathway resulting selectively in tumor cell death. - Highlights: • Natural products having low toxicity increase cytoplasmic calcium in cancer cells. • A G-protein/IP{sub 3} pathway mediates the release of calcium from the ER. • The elevation of intracellular calcium modulates p53 activity. • p53 and other Ca{sup 2+}-dependent pro-apoptotic pathways inhibit cancer cell growth.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

The regulation of cellular apoptosis by the ROS-triggered PERK/EIF2α/chop pathway plays a vital role in bisphenol A-induced male reproductive toxicity

Bisphenol A (2,2-bis(4-hydroxyphenyl)propane, BPA) is ubiquitous in the environment, wildlife, and humans. Evidence from past studies suggests that BPA is associated with decreased semen quality. However, the molecular basis for the adverse effect of BPA on male reproductive toxicity remains unclear. We evaluated the effect of BPA on mouse spermatocytes GC-2 cells and adult mice, and we explored the potential mechanism of its action. The results showed that BPA inhibited cell proliferation and increased the apoptosis rate. The testes from BPA-treated mice showed fewer spermatogenic cells and sperm in the seminiferous tubules. In addition, BPA caused reactive oxygen species (ROS) accumulation. Previous study has verified that mitochondrion was the organelle affected by the BPA-triggered ROS accumulation. We found that BPA induced damage to the endoplasmic reticulum (ER) in addition to mitochondria, and most ER stress-related proteins were activated in cellular and animal models. Knocking down of the PERK/EIF2α/chop pathway, one of the ER stress pathways, partially recovered the BPA-induced cell apoptosis. In addition, an ROS scavenger attenuated the expression of the PERK/EIF2α/chop pathway-related proteins. Taken together, these data suggested that the ROS regulated PERK/EIF2α/chop pathway played a vital role in BPA-induced male reproductive toxicity. - Highlights: • BPA exposure caused the damage of the endoplasmic reticulum. • BPA exposure activated ER stress related proteins in male reproductive system. • ROS regulated PERK/EIF2α/chop pathway played a vital role in BPA-induced toxicity.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

The evolution of the GAL actose utilization pathway in budding yeasts

The Leloir galactose utilization or GAL pathway of budding yeasts, including that of the baker’s yeast Saccharomyces cerevisiae and the opportunistic human pathogen Candida albicans, breaks down the sugar galactose for energy and biomass production. Here, the GAL pathway has long served as a model system for understanding how eukaryotic metabolic pathways, including their modes of regulation, evolve. More recently, the physical linkage of the structural genes GAL1, GAL7, and GAL10 in diverse budding yeast genomes has been used as a model for understanding the evolution of gene clustering. In this review, we summarize exciting recent work on three different aspects of this iconic pathway’s evolution: gene cluster organization, GAL gene regulation, and the population genetics of the GAL pathway.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

A synthetic mechano-growth factor E peptide promotes rat tenocyte migration by lessening cell stiffness and increasing F-actin formation via the FAK-ERK1/2 signaling pathway

Tendon injuries are common in sports and are frequent reasons for orthopedic consultations. The management of damaged tendons is one of the most challenging problems in orthopedics. Mechano-growth factor (MGF), a recently discovered growth repair factor, plays positive roles in tissue repair through the improvement of cell proliferation and migration and the protection of cells against injury-induced apoptosis. However, it remains unclear whether MGF has the potential to accelerate tendon repair. We used a scratch wound assay in this study to demonstrate that MGF-C25E (a synthetic mechano-growth factor E peptide) promotes the migration of rat tenocytes and that this promotion is accompanied by an elevation in the expression of the following signaling molecules: focal adhesion kinase (FAK) and extracellular signal regulated kinase1/2 (ERK1/2). Inhibitors of the FAK and ERK1/2 pathways inhibited the MGF-C25E-induced tenocyte migration, indicating that MGF-C25E promotes tenocyte migration through the FAK-ERK1/2 signaling pathway. The analysis of the mechanical properties showed that the Young's modulus of tenocytes was decreased through treatment of MGF-C25E, and an obvious formation of pseudopodia and F-actin was observed in MGF-C25E-treated tenocytes. The inhibition of the FAK or ERK1/2 signals restored the decrease in Young's modulus and inhibited the formation of pseudopodia and F-actin. Overall, our study demonstrated that MGF-C25E promotes rat tenocyte migration by lessening cell stiffness and increasing pseudopodia formation via the FAK-ERK1/2 signaling pathway. - Highlights: • Mechano-growth factor E peptide (MGF-C25E) promotes migration of rat tenocytes. • MGF-C25E activates the FAK-ERK1/2 pathway in rat tenocytes. • MGF-C25E induces the actin remodeling and the formation of pseudopodia, and decreases the stiffness in rat tenocytes. • MGF-C25E promotes tenocyte migration via altering stiffness and forming pseudopodia by the activation of the FAK-ERK1/2 pathway.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Involvement of IGF-1 and MEOX2 in PI3K/Akt1/2 and ERK1/2 pathways mediated proliferation and differentiation of perivascular adipocytes

Perivascular adipocyte (PVAC) proliferation and differentiation were closely involved in cardiovascular disease. We aimed to investigate whether phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways enhance PVAC functions activated by insulin-like growth factor 1(IGF-1) and suppressed by mesenchyme homeobox 2 (MEOX2). In this study, PVACs from primary culture were cultured and induced to differentiate. Cell viability assays demonstrated that IGF-1 promoted PVAC proliferation and differentiation. However MEOX2 counteracted these IGF-1-mediated actions. Flow Cytometry revealed that IGF-1 increased S phase cells and decreased apoptosis; however, MEOX2 decreased S phase cells, increased G0–G1 phase cells, and promoted apoptosis. During PVAC proliferation and differentiation, IGF-1 activated PI3K/Akt1/2 and ERK1/2 signaling pathways, upregulated the expression of these signaling proteins and FAS, and increased PVAC lipid content. In contrast, MEOX2 constrained the phosphorylation of ERK1/2 and Akt1/2 protein, down-regulated these signaling molecules and FAS, and decreased PVAC lipid content. Instead, MEOX2 knockdown enhanced the ERK1/2 and Akt1/2 phosphorylation, augmented the expression of these signaling molecules and FAS, and increased PVAC lipid content. Our findings suggested that PI3K/Akt1/2 and ERK1/2 activation mediated by IGF-1 is essential for PVAC proliferation and differentiation, and MEOX2 is a promising therapeutic gene to intervene in the signaling pathways and inhibit PVAC functions. - Highlights: • IGF-1 activated PI3K/Akt2 and ERK1/2 pathways to mediate PVAC proliferation and differentiation. • The expression of ERK1, ERK 2, PI3K, Akt1 and Akt2 showed different change trends between PVAC proliferation and differentiation. • MEOX2 effectively expressed in PVAC, increased early and late cellular apoptosis, and inhibited its proliferation. • MEOX2 depressed PVAC differentiation and FAS expression, and decreased lipid content in PVAC. • MEOX2 repressed the effects of IGF-1 on PVAC by restraining the activation of PI3K/Akt1/2 and ERK1/2 signaling pathways.

60 APPLIED LIFE SCIENCES↗