Neonatal triphenyl phosphate and its metabolite diphenyl phosphate exposure induce sex- and dose-dependent metabolic disruptions in adult mice

2018 ◽  
Vol 237 ◽  
pp. 10-17 ◽  
Author(s):  
Dezhen Wang ◽  
Wentao Zhu ◽  
Li Chen ◽  
Jin Yan ◽  
Miaomiao Teng ◽  
...  
Keyword(s):  
Triphenyl Phosphate ◽  
Adult Mice ◽  
Diphenyl Phosphate ◽  
Dose Dependent

VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature

2006 ◽  
Vol 290 (2) ◽  
pp. H560-H576 ◽  
Author(s):  
Tomomi Kamba ◽  
Betty Y. Y. Tam ◽  
Hiroya Hashizume ◽  
Amy Haskell ◽  
Barbara Sennino ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Kinase Inhibitor ◽  
Normal Function ◽  
Epididymal Adipose Tissue ◽  
Vegf Receptor ◽  
Adult Mice ◽  
Fenestrated Capillaries ◽  
Transmission Electron ◽  
Vegf Inhibition ◽  
Dose Dependent

Unlike during development, blood vessels in the adult are generally thought not to require VEGF for normal function. However, VEGF is a survival factor for many tumor vessels, and there are clues that some normal blood vessels may also depend on VEGF. In this study, we sought to identify which, if any, vascular beds in adult mice depend on VEGF for survival. Mice were treated with a small-molecule VEGF receptor (VEGFR) tyrosine kinase inhibitor or soluble VEGFRs for 1–3 wk. Blood vessels were assessed using immunohistochemistry or scanning or transmission electron microscopy. In a study of 17 normal organs after VEGF inhibition, we found significant capillary regression in pancreatic islets, thyroid, adrenal cortex, pituitary, choroid plexus, small-intestinal villi, and epididymal adipose tissue. The amount of regression was dose dependent and varied from organ to organ, with a maximum of 68% in thyroid, but was less in normal organs than in tumors in RIP-Tag2-transgenic mice or in Lewis lung carcinoma. VEGF-dependent capillaries were fenestrated, expressed high levels of both VEGFR-2 and VEGFR-3, and had normal pericyte coverage. Surviving capillaries in affected organs had fewer fenestrations and less VEGFR expression. All mice appeared healthy, but distinct physiological changes, including more efficient blood glucose handling, accompanied some regimens of VEGF inhibition. Strikingly, most capillaries in the thyroid grew back within 2 wk after cessation of treatment for 1 wk. Our findings of VEGF dependency of normal fenestrated capillaries and rapid regrowth after regression demonstrate the plasticity of the adult microvasculature.

Dose-Dependent Molecular Responses of Labeo rohita to Triphenyl Phosphate

2021 ◽  
Author(s):  
Sathisaran Umamaheswari ◽  
Palanisamy Karthika ◽  
Kanagaraj Suvenitha ◽  
Krishna Kadirvelu ◽  
Mathan Ramesh
Keyword(s):  
Labeo Rohita ◽  
Triphenyl Phosphate ◽  
Molecular Responses ◽  
Dose Dependent

scholarly journals Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

2016 ◽  
Vol 113 (28) ◽  
pp. E4061-E4068 ◽  
Author(s):  
Reitaro Tokumasu ◽  
Kosuke Yamaga ◽  
Yuji Yamazaki ◽  
Hiroyuki Murota ◽  
Koya Suzuki ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Morphological Changes ◽  
Contact Hypersensitivity ◽  
Expression Level ◽  
Barrier Functions ◽  
Knock Out ◽  
Macrophage Recruitment ◽  
Adult Mice ◽  
Dose Dependent

Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1’s effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1’s expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1. Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD.

Developmental Differences Between Newborn and Adult Mice In Response To Romiplostim

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3542-3542 ◽  
Author(s):  
Katherine A Sparger ◽  
Nan Li ◽  
Zhi-Jian Liu ◽  
Haley Ramsey ◽  
Martha Sola-Visner
Keyword(s):  
Conflicts Of Interest ◽  
Fold Increase ◽  
Developmental Differences ◽  
Growth Potential ◽  
Preterm Neonates ◽  
Newborn Mice ◽  
Adult Mice ◽  
Dose Dependent Increase ◽  
Dose Dependent

Abstract Thrombocytopenia affects 20-35% of infants admitted to Neonatal Intensive Care Units. The incidence of thrombocytopenia is inversely proportional to gestational age, and approaches 70% among the most preterm neonates (birth weight <1,000 grams). Preterm infants also have the highest incidence of bleeding of any age group, with 25-31% developing intracranial hemorrhage. Currently, platelet (plt) transfusions are the only therapeutic option for thrombocytopenic neonates. In the last 5 years, two thrombopoietin (TPO) mimetics, romiplostim (ROM) and eltrombopag, received FDA approval for the treatment of adults with ITP. Based on the severity and duration of thrombocytopenia, 10% of thrombocytopenic neonates could benefit from TPO-mimetic therapy. Our prior in vitro studies demonstrated that human neonatal megakaryocyte (MK) progenitors are significantly more sensitive to TPO than adult progenitors (Pastos et al., Blood, 2006; Liu et al., Blood, 2011). This study was designed to compare the in vivo responses of newborn vs. adult mice to ROM. Based on prior observations, we hypothesized that newborn pups would be more sensitive to TPO-mimetics than adult mice. As a first step, healthy adult C57BL/6 mice were given a single subcutaneous (SC) injection of 0.1% BSA (control) or ROM at a dose of 10, 30, 100, or 300 ng/g body weight. Newborn mice on post-natal day 1 (P1) received a single SC injection of either 0.1% BSA or ROM at a dose of 30 or 300 ng/g. Plt count and immature plt fraction (IPF) were measured on the day of injection and every other day for 14 days. The baseline plt count in adult mice was 1,184±204 x103/µL. Adult mice treated with ROM (n=3-4 per group) exhibited a dose-dependent increase in plt count and IPF, which peaked on day 5 in those receiving lower ROM doses (10 and 30 ng/g), and on day 7 in those receiving higher ROM doses (100 and 300 ng/g). On day 7, adult mice treated with ROM 300 ng/g had a 4.2-fold increase in plt count compared to BSA controls (6,733±511 vs. 1,600±216 x103/µL, respectively; p<0.0001). Newborn mice (P1) had significantly lower baseline plt counts (624±130 x103/µL; p<0.0001) compared to adults, and similarly responded to ROM injection with a dose-dependent increase in plt count that peaked on day 5. However, plt counts on post-natal day 5 (P5) were 1,020±198 x103/µL for newborn mice treated with ROM 30 ng/g and 1,355±137 x103/µL for newborn mice treated with ROM 300 ng/g (n=17 per group), representing less than a 2-fold increase over BSA treated pups (701±119 x103/µL). To evaluate the effect of ROM on megakaryopoiesis, a subset of adult and newborn mice treated with 0.1% BSA or ROM 300 ng/g (n=3-4 per group) were euthanized on day 5 after injection. Liver, spleen, and bone marrow (BM) MKs were immunohistochemically stained for von Willebrand factor and quantified as described (Hu Z et al., Neonatology, 2010). Overall, ROM-treated adult mice had significantly increased numbers of MKs compared to controls in BM (2.3-fold increase; p=0.0002) and spleen (3.9-fold increase; p=0.006). ROM-treated newborn mice exhibited non-significant increases in MK numbers in BM (2.2-fold increase; p=0.19), spleen (1.6-fold increase; p=0.35), and liver (1.4-fold increase; p=0.31). Because newborn C57BL/6 mice transition from fetal liver to adult BM hematopoiesis during the first 10 to 14 days of life and the BM is not well formed until P10, we injected newborn mice at P5 (instead of P1) and evaluated the response to ROM. Similar to the younger group, P5 mice treated with ROM 300 ng/g reached peak platelet counts at P11, but the plt count was only 1.4-fold higher than BSA control animals (1,340±440 vs. 927±151 x103/µL, respectively; p=0.19). In conclusion, this study indicated that newborn mice are less responsive to ROM than adult mice. This was a surprising finding, given that human neonatal MK progenitors have been consistently shown to be more sensitive to TPO than adult MK progenitors. The reasons underlying the modest in vivo response of neonates are unclear, but might be related to the transition in hematopoietic sites that occurs during this period in murine development (corresponding to the second trimester of human gestation), high baseline thrombopoietic demands associated with rapid growth, potential pharmacokinetic factors, or developmental differences in the splenic or BM microenvironments of newborn and adult mice. Disclosures: No relevant conflicts of interest to declare.

Adrenomedullin is a potent stimulator of osteoblastic activity in vitro and in vivo

1997 ◽  
Vol 273 (6) ◽  
pp. E1113-E1120 ◽  
Author(s):  
Jillian Cornish ◽  
Karen E. Callon ◽  
David H. Coy ◽  
Ning-Yi Jiang ◽  
Liqun Xiao ◽  
...  
Keyword(s):  
Thymidine Incorporation ◽  
Cell Number ◽  
Osteoblastic Activity ◽  
Adult Mice ◽  
Fetal Rat ◽  
Neonatal Mouse Calvaria ◽  
Dose Dependent Increase ◽  
Dose Dependent

Adrenomedullin is a 52-amino acid vasodilator peptide produced in many tissues, including bone. It has 20% sequence identity with amylin, a regulator of osteoblast growth, and circulates in picomolar concentrations. The present study assesses whether adrenomedullin also acts on osteoblasts. At concentrations of 10−12 M and greater, adrenomedullin produced a dose-dependent increase in cell number and [3H]thymidine incorporation in cultures of fetal rat osteoblasts. This effect was also seen with adrenomedullin-(15—52), -(22—52), and -(27—52), but adrenomedullin-(40—52) was inactive. These effects were lost in the presence of amylin blockers, suggesting they were mediated by the amylin receptor. Adrenomedullin also increased [3H]thymidine incorporation into cultured neonatal mouse calvaria but, unlike amylin, did not reduce bone resorption in this model. Adrenomedullin stimulated phenylalanine incorporation into both isolated osteoblasts and calvaria. When injected daily for 5 days over the calvariae of adult mice, it increased indexes of bone formation two- to threefold ( P < 0.0001) and increased mineralized bone area by 14% ( P = 0.004). It is concluded that adrenomedullin regulates osteoblast function and that it increases bone mass in vivo. The potential of this family of peptides in the therapy of osteoporosis should be further evaluated.

Thrombopoietin promotes mixed lineage and megakaryocytic colony-forming cell growth but inhibits primitive and definitive erythropoiesis in cells isolated from early murine yolk sacs

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1329-1335 ◽  
Author(s):  
Xiaodong Xie ◽  
Rebecca J. Chan ◽  
Scott A. Johnson ◽  
Mark Starr ◽  
Jennifer McCarthy ◽  
...  
Keyword(s):  
Growth Factors ◽  
Yolk Sac ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Growth Factors ◽  
Adult Mice ◽  
Mrna Transcripts ◽  
Definitive Erythropoiesis ◽  
Dose Dependent Increase ◽  
Dose Dependent

The role of thrombopoietin (Tpo) in promoting hematopoiesis has been extensively studied in late fetal, neonatal, and adult mice. However, the effects of Tpo on early yolk sac hematopoiesis have been largely unexplored. We examined whole embryos or the cells isolated from embryo proper and yolk sacs and identified both Tpo and c-mpl (Tpo receptor) mRNA transcripts in tissues as early as embryonic day 6.5 (E6.5). Presomite whole embryos and somite-staged yolk sac and embryo proper cells were plated in methylcellulose cultures and treated with selected hematopoietic growth factors in the presence or absence of Tpo. Tpo alone failed to promote colony-forming unit (CFU) formation. However, in the presence of other growth factors, Tpo caused a substantial dose-dependent reduction in primitive and definitive erythroid CFU growth in cultures containing E7.5 and E8.0 whole embryos and E8.25 to 9.5 yolk sac–derived cells. Meanwhile, Tpo treatment resulted in a substantial dose-dependent increase in CFU-mixed lineage (CFU-Mix) and CFU-megakaryocyte (CFU-Meg) formation in cultures containing cells from similar staged tissues. Addition of Tpo to cultures of sorted E9.5 yolk sac c-Kit+CD34+ hematopoietic progenitors also inhibited erythroid CFU growth but augmented CFU-Mix and CFU-Meg activity. Effects of Tpo on CFU growth were blocked in the presence of a monoclonal antibody with Tpo-neutralizing activity but not with control antibody. Thus, under certain growth factor conditions, Tpo directly inhibits early yolk sac erythroid CFU growth but facilitates megakaryocyte and mixed lineage colony formation.

scholarly journals The rapamycin analog Everolimus reversibly impairs male germ cell differentiation and fertility in the mouse†

2020 ◽  
Vol 103 (5) ◽  
pp. 1132-1143
Author(s):  
Oleksandr Kirsanov ◽  
Randall H Renegar ◽  
Jonathan T Busada ◽  
Nicholas D Serra ◽  
Ellen V Harrington ◽  
...  
Keyword(s):  
Body Weight ◽  
Negative Impact ◽  
Transplant Rejection ◽  
Recovery Period ◽  
Mammalian Target Of Rapamycin ◽  
Organ Transplant ◽  
Testis Weight ◽  
Adult Mice ◽  
Germ Cell Differentiation ◽  
Dose Dependent

Abstract Sirolimus, also known as rapamycin, and its closely related rapamycin analog (rapalog) Everolimus inhibit “mammalian target of rapamycin complex 1” (mTORC1), whose activity is required for spermatogenesis. Everolimus is Food and Drug Administration approved for treating human patients to slow growth of aggressive cancers and preventing organ transplant rejection. Here, we test the hypothesis that rapalog inhibition of mTORC1 activity has a negative, but reversible, impact upon spermatogenesis. Juvenile (P20) or adult (P&gt;60) mice received daily injections of sirolimus or Everolimus for 30 days, and tissues were examined at completion of treatment or following a recovery period. Rapalog treatments reduced body and testis weights, testis weight/body weight ratios, cauda epididymal sperm counts, and seminal vesicle weights in animals of both ages. Following rapalog treatment, numbers of differentiating spermatogonia were reduced, with concomitant increases in the ratio of undifferentiated spermatogonia to total number of remaining germ cells. To determine if even low doses of Everolimus can inhibit spermatogenesis, an additional group of adult mice received a dose of Everolimus ∼6-fold lower than a human clinical dose used to treat cancer. In these animals, only testis weights, testis weight/body weight ratios, and tubule diameters were reduced. Return to control values following a recovery period was variable for each of the measured parameters and was duration and dose dependent. Together, these data indicate rapalogs exerted a dose-dependent restriction on overall growth of juvenile and adult mice and negative impact upon spermatogenesis that were largely reversed; following treatment cessation, males from all treatment groups were able to sire offspring.

scholarly journals Unique and Highly Selective Anticytomegalovirus Activities of Artemisinin-Derived Dimer Diphenyl Phosphate Stem from Combination of Dimer Unit and a Diphenyl Phosphate Moiety

2013 ◽  
Vol 57 (9) ◽  
pp. 4208-4214 ◽  
Author(s):  
Ran He ◽  
Michael Forman ◽  
Bryan T. Mott ◽  
Rajkumar Venkatadri ◽  
Gary H. Posner ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Structural Similarity ◽  
Selective Inhibitor ◽  
Selectivity Index ◽  
Triphenyl Phosphate ◽  
Reversible Inhibitors ◽  
Artemisinin Derivatives ◽  
Chemical Structures ◽  
Phosphate Compound ◽  
Diphenyl Phosphate

ABSTRACTWe report that the artemisinin-derived dimer diphenyl phosphate (DPP; dimer 838) is the most selective inhibitor of human cytomegalovirus (CMV) replication among a series of artemisinin-derived monomers and dimers. Dimer 838 was also unique in being an irreversible CMV inhibitor. The peroxide unit within artemisinins' chemical structures is critical to their activities, and its absence results in loss of anti-CMV activities. Surprisingly, the deoxy dimer of 838 retained modest anti-CMV activity, suggesting that the DPP moiety of dimer 838 contributes to its anti-CMV activities. DPP alone did not inhibit CMV replication, but triphenyl phosphate (TPP) had modest CMV inhibition, although its selectivity index was low. Artemisinin DPP derivatives dimer 838 and monomer diphenyl phosphate (compound 558) showed stronger CMV inhibition and a higher selectivity index than their analogs lacking the DPP unit. An add-on and removal assay revealed that removing DPP derivatives (compounds 558 and 838) but not the non-DPP backbones (artesunate and compound 606) at 24 h postinfection (hpi) already resulted in dominant CMV inhibition. CMV inhibition was fully irreversible with 838 and partially irreversible with 558, while non-DPP artemisinins were reversible inhibitors. While all artemisinin derivatives and TPP reduced the expression of the CMV immediate early 2 (IE2), UL44, and pp65 proteins at or after 48 hpi, only TPP inhibited the expression of both IE1 and IE2. Combination of a non-DPP dimer (compound 606) with TPP was synergistic in CMV inhibition, while ganciclovir and TPP were additive. Although TPP shared structural similarity with monomer DPP (compound 558) and dimer DPP (compound 838), its pattern of CMV inhibition was significantly different from the patterns of the artemisinins. These findings demonstrate that the DPP group contributes to the unique activities of compound 838.

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