bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of hydrogen sulfide on carbohydrate metabolism and blood pressure in obese type‐2 diabetic rats
Authors: Kashfi Khosrow , Gheibi Sevda , Jeddi Sajad , Ghasemi Asghar 
Published: June 2021

AimDiabetes is associated with altered endogenous hydrogen sulfide levels, which plays an important role in regulating glucose homeostasis. Here we report on the long‐term effects of sodium hydrosulfide (NaSH) administration on carbohydrate metabolism in obese type 2 diabetic rats.MethodType‐2 diabetes was established using high fat‐low dose streptozotocin. Rats were treated for 9 weeks with intraperitoneal injections of NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg) or vehicle. Serum fasting glucose was measured weekly for one month and then at the end of the study. Fasting serum insulin was measured before and after the treatment. At the end of the study, glucose tolerance, pyruvate tolerance, and insulin secretion were determined and blood pressure was measured.ResultsIn diabetic rats, NaSH at 1.6–5.6 mg/kg increased serum glucose and decreased serum insulin; NaSH at 0.28 and 0.56 mg/kg had no effect on these parameters. High doses of NaSH in diabetic rats decreased glucose and pyruvate tolerance as well as insulin secretion; 0.28 mg/kg had no effect, 0.56 mg/kg improved glucose tolerance but not pyruvate tolerance and insulin secretion. Diabetic rats had higher BP than controls; all doses of NaSH decreased blood pressure in these cohorts. In controls, NaSH (5.6 mg/kg) decreased insulin secretion as well as glucose and pyruvate tolerance, while increased serum glucose. NaSH at 1.6–5.6 mg/kg decreased blood pressure in controls.ConclusionIn diabetic rats high doses of NaSH increased serum glucose level, decreased serum insulin and impaired glucose and pyruvate tolerance, a low dose decreased serum glucose during glucose tolerance. NaSH decreased blood pressure at all doses.Support or Funding InformationKK: Supported in part by the National Institutes of Health [R24DA018055; R01GM123508]. SG, SJ, AG: Supported in part by Shahid Beheshti University of Medical Sciences[grant No. 1396/D/93065], Tehran, Iran.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Generic Recombinant Factor VIIa is Comparable to the Branded Novoseven in In‐Vitro and Pharmacokinetic Studies in Primates
Authors: Sadeghi Nasir , Kouta Ahmed , Duff Rick , Iqbal Omer , Abro Schuharazad , Hoppensteadt Debra , Jeske Walter , Mehrotra Siddharth , Walenga Jeanine , Iacobelli Massimo , Fareed Jawed 
Published: June 2021

BackgroundRecombinant factor VIIa (NovoSeven®, NovoNordisk, Bagsvaerd, Denmark) is used in the management of bleeding in patients with hemophilia. A generic version of NovoSeven® is also developed for the same indication (AryoSeven™, AryoGen, Tehran, Iran). The purpose of this study was to compare several batches of generic of rFVIIa, namely AryoSeven™, with multiple commercially available batches of branded NovoSeven® to determine biosimilarity.MethodsFour commercially available random lots of Novoseven® were obtained through US and European sources and compared to 5 clinical batches of AryoSeven™. These drugs were profiled in vitro using surface enhanced laser desorption ionization (SELDI) mass spectrometry, gel electrophoresis (GE), immunoblotting studies, and procoagulant activity as measured by a clot based method. Thrombin generation studies were carried out using NHP supplemented with 0–1.0 ug/ml rFVIIa. The pharmacokinetic profiles of one representative batch each of the NovoSeven® and AryoSeven™ were studied in primates after a 50 ug/kg bolus IV.ResultsThe molecular weight profile of all rFVIIa preparations were comparable. The GE and immunoblotting studies of the two groups of agents showed a comparable profile. The two FVIIa products produced comparable procoagulant effects in the PT and aPTT assays. In the plasma prepared from rFVIIa‐supplemented whole blood, the products produced comparable effect on the PT and aPTT assays. In platelet rich plasma (PRP) and platelet poor plasma (PPP) AryoSeven™ and NovoSeven® at concentrations from 0.125 to 1 μg/ml did not produce any measurable change in either the PT or aPTT assay. The degree of reversal of anticoagulation in samples collected from patients treated with oral anticoagulants was similar in terms of relative correction of the plasma INR with both FVIIa preparations over the concentration range of 0.03 to 1 μg/ml. In the thrombin generation studies NovoSeven® and AryoSeven™ produced similar effects. In the primate pharmacokinetic studies at a dose of 50 ug/kg, both groups exhibited similar pharmacokinetic profiles in terms of biologic half‐life, Cmax, volume of distribution and other parameters.ConclusionsThese studies demonstrated bioavailability between the branded and generic products. The pharmacokinetic profile of the NovoSeven® and AryoSeven™ as studied in primates by measuring the factor VIIa level for up to 4 hours post‐administration were also found to be comparable. These results support the hypothesis that NovoSeven® and AryoSeven™ are biosimilar. Further clinical validation studies are warranted.Support or Funding InformationNone.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluation of the Reproductive Toxicity of L‐Histidine Methyl Ester Hydrochloride of Amphotericin‐B In Vivo
Authors: Jaimes Paola , Reyes‐Esparza Jorge , Blake Ivan Ortega , Rodriguez‐Fragoso Lourdes 
Published: June 2021

Systemic mycosis has increased in recent years. The drug that is used for the treatment of these mycoses is amphotericin‐B, which is a highly toxic drug generating hepatotoxicity and nephrotoxicity. These adverse effects are very serious, which causes an abandonment of the treatment, there are some alternatives such as new lipid formulations of amphotericin‐B. Unfortunately these types of medications are not available for all people because of their high cost. Recently this group has found that derivative AmB (A21) has similar pharmacological effects of AmB but not induce nephotoxicity and hepatotoxicity. However we unknown if it induces other side effects than AmB. Therefore, the aim of this work was to evaluate the effect of a derivative of AmB (A21) on the structure and function of the male and female reproductive system of Wistar ratsDerivative A21 was given intraperitoneally at a dose of 2 mg/Kg daily to female and male rats for a period of 45 days, 120 days and a third group received during 120 days and 65 days without treatment with the analog A21 in order to study the reversion of the injury.. Samples were collected after sacrificed and tissues were fixed with formalin 4% then were cut to histology which were stained with hematoxylin‐eosin. Blood was obtained by cardiac puncture and seric hormone levels were measured. Testosterone levels for male rats and progesterone for female rats, levels were measured by an Enzyme‐linked Immunosorbent Assay (ELISA).The analog A21 did not cause structural and functional damage in male and female reproductive system from rats when were treated for a period of 45 days, since the morphology was integrated and hormone levels were normal compared with their respective control. The analog A21 caused structural and functional damage when was given during 120 days. Testosterone levels was increased (3‐fold) and were observed several alterations in the structure of testis. While in female rats in this period of treatment did not generate structural and functional damage. When rats were treated during 120 days, suspended the treatment and sacrificed 65 days without treatment, the structures of the male reproductive system was reestablished and the levels of testosterone reduced. Female Wistar rats dis not show any functional and structural damage.Derivative A21 is able to induce structural and functional damage in male reproductive system after 120 days of treatment, however, this effect is reverted after 65 days after stopping the treatment. Derivative did not show any alteration in female reproductive system. Therefore, derivative could be used as treatment for mycosis with the advantage that the side effects produced are reversible.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Stromal Vascular Fraction Vasculogenesis, Vessel Incorporation, and Integration with Intact Angiogenic Microvascular Networks in an Ex Vivo Cultured Tissue Model
Authors: Hodges Nicholas A , Shang Hulan , Guevara Rocio R , Porvasnik Stacy L , Schmidt Christine , Katz Adam J. , Murfee Walter L 
Published: June 2021

Angiogenesis, the growth of new vessels from pre‐existing vessels, is vital to wound healing in the cases of myocardial infarction and peripheral arterial disease. Adipose‐derived stromal vascular fraction (SVF), consisting of endothelial cells, endothelial progenitor cells, pericytes, smooth muscle cells, fibroblasts and immune cells, can be transplanted to assist in wound healing as seen in various clinical trials. However, the spatiotemporal incorporation of the SVF within living tissues remains largely unknown. As such, understanding where and how SVF cells contribute to microvascular growth and remodeling will help guide their therapeutic use. The objective of this study was to evaluate the impact of SVF cells and their fate during microvascular growth utilizing a novel tissue culture model that enables time‐lapse observation of cell dynamics across intact networks. SVF was isolated from adipose of an adult male Wistar rat, labeled with DiI, and seeded onto mesentery tissues harvested from the same rat before culturing in MEM + 10% fetal bovine serum and 1% PenStrep for 3 days. Tissues were then labeled for lectin to identify vessels. Alternatively, SVF was isolated from adipose harvested from adult male or female SD‐EGFP rats, seeded onto lectin labeled mesentery from adult male Wistar rats, placed under the same culture conditions, and imaged every 24 hours. Vascularized area was increased in SVF treated versus control tissues (SVF = 84.5±1.3%; Control = 56.5%; p < 0.001; n = 4 tissues per group). The SVF related microvasculature was characterized by asterisk‐shaped clusters. GFP tracking of SVF revealed vessel segment formation via vasculogenesis containing endothelial cells and pericytes in previously avascular areas. In pre‐vascularized regions, SVF cells contributed to new vessel growth and integration with and along native vessels. SVF cells were observed both in apparent endothelial cell and wrapping pericyte locations. Interestingly, examples of new vessel segments derived from SVF cells were observed along LYVE‐1 positive lymphatic vessels. These results suggest that SVF transplantation increases vascular area through vasculogenesis and contributes to angiogenesis of pre‐existing vasculature. The results also support the use of the rat mesentery culture model as a novel tool for elucidating SVF cell transplant dynamics in an intact tissue environment.Support or Funding InformationFunded by NIH R01AG049821This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anti‐angiogenesis Triggers VEGF‐enriched Exosomes Release from Endothelial Cells
Authors: Zeng Ye , Fu Bingmei M 
Published: June 2021

Although anti‐angiogenic therapies (AATs) have some effects against multiple malignancies, they are limited by subsequent tumor vasculogenesis and progression. To investigate the mechanisms by which tumor vasculogenesis and progression following AATs, we transfected microRNA (miR)‐9 into human umbilical vein endothelial cells (HUVECs) to mimic the tumor‐associated endothelial cells in hepatocellular carcinoma and simulated the AATs in vitro and in vivo. We found that administration of the angiogenesis inhibitor vandetanib completely abolished miR‐9‐induced angiogenesis and promoted autophagy in HUVECs, but induced the release of vascular endothelial growth factor (VEGF)‐enriched exosomes. These VEGF‐enriched exosomes significantly promoted the formation of endothelial vessels and vasculogenic mimicry in hepatocellular carcinoma and its progression in mice. Anti‐autophagic therapy is proposed to improve the efficacy of AATs. However, similar effects by AATs were observed with the application of anti‐autophagy by 3‐methyladenine. Our results revealed that tumor vasculogenesis and progression after AATs and anti‐autophagic therapies were due to the cross‐talk between endothelial cells and tumor cells via VEGF‐enriched exosomes. These findings provide a critical insight into a new interpretation of why AATs have not achieved expected outcomes. They also suggest that control of exosome release or alteration of exosome cargo composition to inhibit tumor vasculogenesis may augment the anti‐angiogenic and anti‐autophagic therapies for tumors.Support or Funding InformationSupported by National Natural Science Foundation of China (Grant no.11402153).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Amyloid‐β Peptide‐mediated Disruption of Ca2+ dynamics in Contractile Pericytes
Authors: Gonzales Albert L. , Nelson Mark 
Published: June 2021

Alzheimer's diseases and Cerebral amyloid angiopathy are diseases centered on the accumulation of toxic amyloid‐β‐containing plaques leading to the slow and progressive deterioration of the brain. Recent work has linked cardiovascular pathologies with these forms neurodegeneration, whereby vascular dysfunction potentiates the inability to efficiently clear toxic amyloid‐β from ageing brains. Our recent work describes how brain capillaries, the point of nutrient delivery and waste removal between circulating blood and surrounding neurons, and contractile pericytes act in concert to detect and respond to neural activity, increasing blood flow to meet local demand (functional hyperemia). Capillary pericytes closest to the terminal arteriole possess multiple vessel‐wrapping projections and are capable of exerting subcellular Ca2+‐dependent contraction. We tested the hypothesis that amyloid‐β peptides form Ca2+‐permeable pores within the plasma membrane of pericytes, leading to membrane permeabilization and pericyte Ca2+ dysregulation. Using transgenic mice expressing genetically encoded Ca2+ biosensors in contractile pericytes and smooth muscle cells, we found that free amyloid‐β oligomers (1–40) selectively increased the frequency of Ca2+ events in pericytes but not on neighboring arteriole smooth muscle cells. In addition, administration of amyloid‐β oligomers prevented the membrane depolarization‐induced contraction of pericytes by 60 mM KCl. These data suggest amyloid‐β peptide‐mediated increases in Ca2+ event frequency “short‐circuits” pericyte Ca2+ signaling, leading to Ca2+ overload and disruption of pericyte‐mediated control of junctional blood flow.Support or Funding InformationTotman Medical Research Trust, Foundation Leducq, Horizon 2020, NIH R01HL131181, R01HL121706, R37DK053832, and K01HL138215.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Macrophage Insulin‐Like Growth Factor 1 Downregulated Matrix Metalloproteinases and Promoted Features of a Stable Atherosclerotic Plaque
Authors: Snarski Patricia , Danchuk Svitlana , Sukhanov Sergiy , Yoshida Tadashi , Higashi Yusuke , Shai Shaw Yung , Chandrasekar Bysani , Delafontaine Patrice 
Published: June 2021

We have shown that insulin‐like growth factor I (IGF‐1) reduced atherosclerosis in Apoe‐null mice. We also reported that deficiency for macrophage (MF)‐specific IGF‐1 receptor (IGF1R) upregulated matrix metalloproteinases (MMPs), decreased MMP inhibitor RECK (reversion inducing cysteine rich protein with kazal motifs) and promoted atherogenesis. To study whether increase in MF IGF‐1 will suppress MMPs and decrease atherosclerosis, we generated Apoe‐null mice with IGF‐1 overexpression driven by MF‐specific promoter (scavenger receptor A) called SRA mice and we also performed experiments with cultured THP‐1 macrophages. THP‐1 MFs were incubated with IGF‐1 (0, 20, 100ng/mL) for 48 hrs. IGF‐1 (20 ng/ml) decreased expression of MMP8 (34+/−13% decrease, P<0.05) and MMP14 protein (35+/−17% decrease, P<0.05) as quantified by ELISA. To demonstrate that IGF‐1 effect on MMPs was mediated via IGF1R‐dependent mechanism, we used Picropodophyllin (PPP), a specific IGF1R inhibitor. MF pre‐treatment with PPP (1 ug/ml, 2hrs) completely abolished IGF‐1‐induced MMP8 downregulation in MF. We generated two mouse lines overexpressing IGF‐1 in MF: SRA12 and SRA17. IGF‐1 level was increased in peritoneal MF isolated from SRA12 (21±4% increase) and from SRA17 mice (52±9% increase) compared to control Apoe‐null mice (both are P<0.05). SRA12 and SRA17 mice were fed with a high fat diet for 12 weeks. MF‐specific IGF‐1 overexpression significantly decreased atherosclerotic burden (SRA12, 23±3% decrease, n=20, and SRA17, 28±6% decrease, n=16, vs. control, n=29, en face analysis) and increased plaque collagen levels (11.1±6%, SRA12 and 66.5±11%, n=11, SRA17, Trichrome staining). Atherosclerotic plaques in both SRA12 and SRA17 mice had reduced necrotic cores suggesting elevated plaque stability. Of note, the increased levels of plaque collagen in SRA17 mice correlated with a significant decrease of MMP1, MMP2, MMP8, MMP12, MMP13, and MMP14 protein levels in peritoneal MF (immunoblotting, 30–72% decrease vs. control). Protein level of RECK was increased in both SRA12 and SRA17 peritoneal MF. In summary, we show that IGF‐1 reduced MMPs in vitro and MF IGF‐1 decreased MMPs, upregulated collagen and suppressed atherosclerotic burden in vivo. Thus, we identified the novel MMP‐ (and collagen) dependent mechanism potentially mediating MF IGF‐1 atheroprotective effect.Support or Funding InformationNIH/NHLNI 2R01HL070241‐13A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Adipose Specific Loss of PCPE2 Promotes Microvascular Endothelial Dysfunction and Decreased Angiogenic Potential
Authors: Brand Lukas , Hader Shelby N , Sorci‐Thomas Mary , Beyer Andreas M 
Published: June 2021

Procollagen C‐endopeptidase enhancer 2 (PCPE2) is an extracellular matrix protein which regulates the oligomerization of the high and low‐density lipoprotein (HDL/LDL) receptors that enable cellular uptake of HDL/LDL from the extracellular matrix under healthy conditions. To evaluate Effect of adipose PCPE2 floxed mice were crossed with mice expressing adipose specific cre recombinase. We hypothesized elevated lipid levels induced by PCPE2 KO mice vascular function and angiogenic potential.In Adipose specific PCPE2 KO we found that due to the inability of lipoprotein lipids in HDL to be taken up by the adipocytes, the concentration of HDL in the plasma compartment significantly increased. Using this model vascular function was evaluated using pressure mayo graph setup. Endothelial function was determined by dose response curves to ACH or increasing levels of shear stress. Smooth muscle function was tested by response to Papaverine. Angiogenic potential was evaluated by embedding sections of brown adipose tissue in Matrigel and vascular growth measured by sprout formation. Statistical significance was established using a student t‐test P<0.05 vs. CTRL.Adipose specific PCPE2 KO resulted in elevated plasma lipid levels as elevated by insert numbers. Homozygous loss of Ad‐PCPE2 resulted in decreased endothelial function compared to control mice. Interestingly heterozygote deletion of Ad‐PCPE2 deletion trended toward increase in endothelial mediated dilation (Fig. 1A and B). Smooth muscle function was not affected by either genotype (Fig. 1C). Angiogenic Potential was significantly decreased in both heterozygote Ad‐PCPE2 KO mice compared to CTRLs (% growth Mean, SEM, N: CTRL 3.05±1.31, 6; Het 1.07±0.59*, 4)In conclusion, our data suggest that ad‐PCPE2 loss of function elevated plasma lipid levels that promote endothelial dysfunction as assessed by decreased vasodilator capacity and angiogenic potential.Support or Funding InformationFunded by MST HL127649 and HL138907; AMB R01‐HL133029‐02This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reduced expression of inflammation regulatory proteins, ETS‐1 and TNIP‐1, may cause lupus in humans
Authors: Econome Jason , Malkiel Susan , Diamond Betty 
Published: June 2021

Systemic Lupus Erythematosus is a painfully crippling autoimmune disorder whereby its victims suffer from chronic inflammation, and an increased susceptibility to kidney failure if left untreated. The illness can in part be triggered by a number of known environmental factors including ultraviolet light but its genetic roots remain unclear. Identifying the causal risk alleles would greatly aide in earlier detection and the administration of effective immunotherapies as well as a longer life for the lupus sufferer. Suspected risk alleles for genes, ETS‐1 and TNIP‐1, normally associated with regulating inflammation, were tested for allelic expression imbalance. Leukocytes were isolated from middle age females, of Asian descent who were heterozygous for either suspected gene. After cells were isolated from differential centrifugation, total RNA was collected, cDNA synthesized, and a Taqman quantitative PCR assay performed in order to detect reduced levels of expression for either gene. Neither B cells nor T cells showed Ct values (Ct ≥ 1 or 2x difference in mRNA) outside the standard deviation range in comparison to negative controls. Adjustments to the current procedure to enrich for a larger, more stable population of total RNA, leading to more reliable qPCR results, are needed to corroborate a role for these two risk alleles in the cause of this devastating disease.Support or Funding InformationThis research was funded by the American Physiology Society and hosted by Dr. S. Malkiel and Dr. B. Diamond at The Feinstein Institute, Manhasset, NY.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.