scholarly journals Exosomes derived from plasma: promising immunomodulatory agents for promoting angiogenesis to treat radiation-induced vascular dysfunction

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11147
Author(s):  
Yanxi Li ◽  
Ping Lyu ◽  
Yiting Ze ◽  
Peiran Li ◽  
Xinyi Zeng ◽  
...  
Keyword(s):  
Tissue Regeneration ◽  
Umbilical Vein ◽  
Rat Plasma ◽  
Male Rats ◽  
Sprague Dawley ◽  
Immune Microenvironment ◽  
Vascular Disorders ◽  
Immunomodulatory Agents ◽  
The Impact

Ionizing radiation (IR)-induced vascular disorders slow down tissue regeneration. Exosomes derived from plasma exhibit potential to promote angiogenesis; meanwhile, the immune microenvironment plays a significant role in the process. This study aimed to test the hypothesis that plasma exosomes promote angiogenesis in irradiated tissue by mediating the immune microenvironment. First, we explored the impact of IR on macrophages. We found that cell viability and capacity for promoting angiogenesis were decreased in irradiated macrophages compared to control macrophages. Then, we isolated and characterized rat plasma-derived exosomes (RP-Exos) which were defined as 40–160 nm extracellular vesicles extracted from rat plasma. Afterward, we evaluated the effects of RP-Exos on the behaviors of irradiated macrophages. Our results show that RP-Exos promoted cell proliferation. More importantly, we found that RP-Exos stimulated the immune microenvironment in a manner that improved the angiogenesis-related genes and proteins of irradiated macrophages. The supernatant of macrophage cell cultures was used as conditioned medium to treat human primary umbilical vein endothelial cells, further confirming the pro-angiogenic ability of macrophages receiving RP-Exo intervention. RP-Exos were used in vivo to treat irradiated skin or calvarial defects in irradiated Sprague-Dawley male rats. The results indicated the ability of RP-Exos to enhance angiogenesis and promote tissue regeneration. Our research suggested the potential of plasma exosomes to be used as immunomodulatory agents with angiogenic capacity to treat radiation-associated vascular disorders and facilitate tissue repair.

scholarly journals Stamina-Enhancing Effects of Human Adipose-Derived Stem Cells

2021 ◽  
Vol 30 ◽  
pp. 096368972110354
Author(s):  
Eun-Jung Yoon ◽  
Hye Rim Seong ◽  
Jangbeen Kyung ◽  
Dajeong Kim ◽  
Sangryong Park ◽  
...  
Keyword(s):  
Physical Activity ◽  
Stem Cells ◽  
Locomotor Activity ◽  
Tissue Injury ◽  
Male Rats ◽  
Adipose Derived Stem Cells ◽  
Sprague Dawley ◽  
Serum Triglycerides

Stamina-enhancing effects of human adipose derived stem cells (hADSCs) were investigated in young Sprague-Dawley rats. Ten-day-old male rats were transplanted intravenously (IV) or intracerebroventricularly (ICV) with hADSCs (1 × 106 cells/rat), and physical activity was measured by locomotor activity and rota-rod performance at post-natal day (PND) 14, 20, 30, and 40, as well as a forced swimming test at PND 41. hADSCs injection increased the moving time in locomotor activity, the latency in rota-rod performance, and the maximum swimming time. For the improvement of physical activity, ICV transplantation was superior to IV injection. In biochemical analyses, ICV transplantation of hADSCs markedly reduced serum creatine phosphokinase, lactate dehydrogenase, alanine transaminase, and muscular lipid peroxidation, the markers for muscular and hepatic injuries, despite the reduction in muscular glycogen and serum triglycerides as energy sources. Notably, hADSCs secreted brain-derived neurotrophic factor (BDNF) and nerve growth factor in vitro, and increased the level of BDNF in the brain and muscles in vivo. The results indicate that hADSCs enhance physical activity including stamina not only by attenuating tissue injury, but also by strengthening the muscles via production of BDNF.

scholarly journals Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xin-Yang Wang ◽  
Xin-Yu Li ◽  
Cheng-Hua Wu ◽  
Yu Hao ◽  
Pan-Han Fu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Cytokines ◽  
Tissue Regeneration ◽  
Umbilical Vein ◽  
Endothelial Glycocalyx ◽  
Lipid Mediator ◽  
Protective Effects ◽  
Pulmonary Vascular Permeability

Abstract Background Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. Methods PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. Results In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. Conclusion PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.

scholarly journals Bone Regeneration Capacity of Newly Developed Uncalcined/Unsintered Hydroxyapatite and Poly-l-lactide-co-glycolide Sheet in Maxillofacial Surgery: An In Vivo Study

Nanomaterials ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 22
Author(s):  
Huy Xuan Ngo ◽  
Quang Ngoc Dong ◽  
Yunpeng Bai ◽  
Jingjing Sha ◽  
Shinji Ishizuka ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Reconstructive Surgery ◽  
Early Stage ◽  
Maxillofacial Surgery ◽  
Male Rats ◽  
Regeneration Ability ◽  
Sprague Dawley ◽  
Micro Computed Tomography ◽  
Rat Mandible

Uncalcined/unsintered hydroxyapatite and poly-l-lactide-co-glycolide (u-HA/PLLA/PGA) is a new bioresorbable nanomaterial with superior characteristics compared with current bioresorbable materials, including appropriate mechanical properties, outstanding bioactive/osteoconductive features, and remarkably shorter resorption time. Nevertheless, the bone regeneration characteristics of this nanomaterial have not been evaluated in maxillofacial reconstructive surgery. In this study, we used a rat mandible model to assess the bone regeneration ability of u-HA/PLLA/PGA material, compared with uncalcined/unsintered hydroxyapatite and poly-l-lactide acid (u-HA/PLLA) material, which has demonstrated excellent bone regenerative ability. A 4-mm-diameter defect was created at the mandibular angle area in 28 Sprague Dawley male rats. The rats were divided into three groups: u-HA/PLLA/PGA (u-HA/PLLA/PGA graft + defect), u-HA/PLLA (u-HA/PLLA graft + defect), and sham control (defect alone). At 1, 3, 8, and 16 weeks after surgeries, the rats were sacrificed and assessed by micro-computed tomography, histological analysis with hematoxylin and eosin staining, and immunohistochemical analyses. The results confirmed that the accelerated bone bioactive/regenerative osteoconduction of u-HA/PLLA/PGA was comparable with that of u-HA/PLLA in the rat mandible model. Furthermore, this new regenerative nanomaterial was able to more rapidly induce bone formation in the early stage and had great potential for further clinical applications in maxillofacial reconstructive surgery.

scholarly journals Metabolomic and transcriptomic analysis reveals endogenous substrates and metabolic adaptation in rats lacking Abcg2 and Abcb1a transporters

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0253852
Author(s):  
Samit Ganguly ◽  
David Finkelstein ◽  
Timothy I. Shaw ◽  
Ryan D. Michalek ◽  
Kimberly M. Zorn ◽  
...  
Keyword(s):  
Uric Acid ◽  
Rat Plasma ◽  
Drug Clearance ◽  
Transcriptomic Analysis ◽  
Metabolic Adaptation ◽  
Sprague Dawley ◽  
Knock Out ◽  
Primary Driver ◽  
Endogenous Substrates ◽  
The Impact

Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. The systemic impact of Bcrp and Pgp ablation on metabolic homeostasis of endogenous substrates is incompletely understood. We performed untargeted metabolomics of cerebrospinal fluid (CSF) and plasma, transcriptomics of brain, liver and kidney from male Sprague Dawley rats (WT) and Bcrp/Pgp double knock-out (dKO) rats, and integrated metabolomic/transcriptomic analysis to identify putative substrates and perturbations in canonical metabolic pathways. A predictive Bayesian machine learning model was used to predict in silico those metabolites with greater substrate-like features for either transporters. The CSF and plasma levels of 169 metabolites, nutrients, signaling molecules, antioxidants and lipids were significantly altered in dKO rats, compared to WT rats. These metabolite changes suggested alterations in histidine, branched chain amino acid, purine and pyrimidine metabolism in the dKO rats. Levels of methylated and sulfated metabolites and some primary bile acids were increased in dKO CSF or plasma. Elevated uric acid levels appeared to be a primary driver of changes in purine and pyrimidine biosynthesis. Alterations in Bcrp/Pgp dKO CSF levels of antioxidants, precursors of neurotransmitters, and uric acid suggests the transporters may contribute to the regulation of a healthy central nervous system in rats. Microbiome-generated metabolites were found to be elevated in dKO rat plasma and CSF. The altered dKO metabolome appeared to cause compensatory transcriptional change in urate biosynthesis and response to lipopolysaccharide in brain, oxidation-reduction processes and response to oxidative stress and porphyrin biosynthesis in kidney, and circadian rhythm genes in liver. These findings present insight into endogenous functions of Bcrp and Pgp, the impact that transporter substrates, inhibitors or polymorphisms may have on metabolism, how transporter inhibition could rewire drug sensitivity indirectly through metabolic changes, and identify functional Bcrp biomarkers.

scholarly journals Bone Regeneration Potential of Uncalcined and Unsintered Hydroxyapatite/Poly l-lactide Bioactive/Osteoconductive Sheet Used for Maxillofacial Reconstructive Surgery: An In Vivo Study

Materials ◽  
2019 ◽  
Vol 12 (18) ◽  
pp. 2931 ◽  
Author(s):  
Quang Ngoc Dong ◽  
Takahiro Kanno ◽  
Yunpeng Bai ◽  
Jingjing Sha ◽  
Katsumi Hideshima
Keyword(s):  
Bone Regeneration ◽  
Maxillofacial Surgery ◽  
Male Rats ◽  
Regeneration Ability ◽  
Sprague Dawley ◽  
Control Groups ◽  
Critical Size Defect ◽  
Hematoxylin And Eosin ◽  
Regenerative Ability

Uncalcined and unsintered hydroxyapatite/poly l-lactide (u-HA/PLLA) material has osteoconductive characteristics and is available for use as a maxillofacial osteosynthetic reconstruction device. However, its bone regeneration ability in the maxillofacial region has not been fully investigated. This study is the first to assess the bone regenerative potential of osteoconductive u-HA/PLLA material when it is used for repairing maxillofacial bone defects. A total of 21 Sprague-Dawley male rats were divided into three groups—the u-HA/PLLA, PLLA, or sham control groups. A critical size defect of 4 mm was created in the mandible of each rat. Then, the defect was covered with either a u-HA/PLLA or PLLA sheet on the buccal side. The rats in each group were sacrificed at 2, 4, or 8 weeks. The rats’ mandibles were sampled for histological analysis with hematoxylin and eosin staining, histomorphometry, and immunohistochemistry with Runx2 and osteocalcin (OCN) antibody. The amount of newly formed bone in the u-HA/PLLA group was significantly higher than that of the PLLA group. The expression of Runx2 and OCN in the u-HA/PLLA group was also significantly higher. These results demonstrate that the u-HA/PLLA material has excellent bone regenerative ability and confirm its applicability as a reconstructive device in maxillofacial surgery.

scholarly journals Metabolic and cardiac signaling effects of inhaled hydrogen sulfide and low oxygen in male rats

2012 ◽  
Vol 112 (10) ◽  
pp. 1659-1669 ◽  
Author(s):  
Asaf Stein ◽  
Zhengkuan Mao ◽  
Joanna P. Morrison ◽  
Michelle V. Fanucchi ◽  
Edward M. Postlethwait ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Tissue Injury ◽  
Biological Effects ◽  
Male Rats ◽  
Sprague Dawley ◽  
Low Oxygen ◽  
Creatine Kinase Mb ◽  
Gsk 3Β

Low concentrations of inhaled hydrogen sulfide (H2S) induce hypometabolism in mice. Biological effects of H2S in in vitro systems are augmented by lowering O2 tension. Based on this, we hypothesized that reduced O2 tension would increase H2S-mediated hypometabolism in vivo. To test this, male Sprague-Dawley rats were exposed to 80 ppm H2S at 21% O2 or 10.5% O2 for 6 h followed by 1 h recovery at room air. Rats exposed to H2S in 10.5% O2 had significantly decreased body temperature and respiration compared with preexposure levels. Heart rate was decreased by H2S administered under both O2 levels and did not return to preexposure levels after 1 h recovery. Inhaled H2S caused epithelial exfoliation in the lungs and increased plasma creatine kinase-MB activity. The effect of inhaled H2S on prosurvival signaling was also measured in heart and liver. H2S in 21% O2 increased Akt-PSer473 and GSK-3β-PSer9 in the heart whereas phosphorylation was decreased by H2S in 10.5% O2, indicating O2 dependence in regulating cardiac signaling pathways. Inhaled H2S and low O2 had no effect on liver Akt. In summary, we found that lower O2 was needed for H2S-dependent hypometabolism in rats compared with previous findings in mice. This highlights the possibility of species differences in physiological responses to H2S. Inhaled H2S exposure also caused tissue injury to the lung and heart, which raises concerns about the therapeutic safety of inhaled H2S. In conclusion, these findings demonstrate the importance of O2 in influencing physiological and signaling effects of H2S in mammalian systems.

scholarly journals Therapeutic Effects of Water Soluble Danshen Extracts on Atherosclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Yoon Hee Cho ◽  
Cheol Ryong Ku ◽  
Zhen-Yu Hong ◽  
Ji Hoe Heo ◽  
Eun Hee Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Platelet Aggregation ◽  
Ex Vivo ◽  
Umbilical Vein ◽  
Water Soluble ◽  
Therapeutic Effects ◽  
Sprague Dawley ◽  
Tail Vein ◽  
Vein Thrombosis

Danshen is a traditional Chinese medicine with many beneficial effects on cardiovascular diseases. The aim of this study was to evaluate the mechanisms responsible for the antiatherogenic effect of water soluble Danshen extracts (DEs). Rat vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) were treated with DE. To evaluate the effects of DEin vivo, carotid balloon injury and tail vein thrombosis were induced in Sprague-Dawley (SD) rats and iliac artery stent was induced in New Zealand white rabbits. The inhibitory action of DE on platelet aggregation was confirmed with an impedance aggregometer. DE inhibited the production of reactive oxygen species, and the migration and proliferation of platelet-derived growth factor-BB stimulated VSMCs. Furthermore, DE prevented inflammation and apoptosis in HUVECs. Both effects of DE were reconfirmed in both rat models. DE treatment attenuated platelet aggregation in bothin vivoandex vivoconditions. Pretreatment with DE prevented tail vein thrombosis, which is normally induced byκ-carrageenan injection. Lastly, DE-treated rabbits showed decreased in-stent restenosis of stented iliac arteries. These results suggest that water soluble DE modulates key atherogenic events in VSMCs, endothelial cells, and platelets in bothin vitroandin vivoconditions.

Modulation of in vivo 3-deoxyglucosone levels

2003 ◽  
Vol 31 (6) ◽  
pp. 1433-1437 ◽  
Author(s):  
T.R. Brown ◽  
B. Su ◽  
K.A. Brown ◽  
M.A. Schwartz ◽  
A.M. Tobia ◽  
...  
Keyword(s):  
Fold Increase ◽  
Rat Plasma ◽  
Diabetic Rat ◽  
Kidney Tubules ◽  
Sprague Dawley ◽  
Birth Rates ◽  
Fischer 344 ◽  
Sprague Dawley Rats ◽  
Eker Rat

Fructoselysine 3-phosphate is synthesized in vivo by the recently discovered fructoseamine-3-kinase (F3K) from fructoselysine and ATP and decomposes to lysine, Pi and 3-deoxyglucosone (3DG). This pathway appears to dominate 3DG production in vivo, making it possible to modulate 3DG levels by stimulating or inhibiting the reaction. Present inhibitors are non-reacting substrate analogues with relatively high Ki values and can inhibit F3K sufficiently in vivo to reduce 3DG in diabetic rat plasma by approx. 50%. Stimulation of the F3K pathway by feeding glycated casein causes an increase of 10–20-fold in plasma levels of 3DG and 3-fold in kidney tubules. Consequences of this increase were studied in two systems: the Eker rat, a model of susceptible kidney tubules; and birth rates in two rat strains. In both cases substantial pathological effects were observed. In the Eker rats, an approx. 3-fold increase in kidney lesions was observed (P<0.00001). In both Fischer 344 and Sprague–Dawley rats, birth rates were reduced by 56% (P<0.0001) and 12% (P<0.015) respectively. These results suggest that inhibition of F3K is a promising new therapeutic target for diabetic complications, as well as other 3DG-dependent pathologies.

scholarly journals Oestradiol decreases rat apolipoprotein AI transcription via promoter site B

2000 ◽  
Vol 25 (2) ◽  
pp. 207-219 ◽  
Author(s):  
AH Taylor ◽  
AE Fox-Robichaud ◽  
C Egan ◽  
J Dionne ◽  
DE Lawless ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Target Genes ◽  
Inhibitory Effect ◽  
Male Rats ◽  
Sprague Dawley ◽  
Male Adult ◽  
Nuclear Extracts ◽  
Major Mode ◽  
Apo Ai

Oestrogens protect against ischaemic heart disease in the post-menopausal female by increasing serum concentrations of apolipoprotein (apo) AI and the abundance of high-density lipoprotein particles. In men and experimental male animals, the administration of oestrogen has variable effects on apo AI expression. As the major mode of oestrogen action on target genes involves regulating promoter activity and hence transcription, oestrogen is expected to alter transcription of the apo AI gene. To test this hypothesis, the effect of 17beta-oestradiol (E(2)), on rat apo AI promoter activity in male hepatoma HuH-7 cells, was tested by co-transfecting a reporter template, pAI.474.CAT containing-474 to-7 of the rat apo AI promoter and an oestrogen receptor (ER) expression vector, pCMV-ER. Transfected cells exposed to E(2) showed a dose-dependent decrease in chloramphenicol acetyltransferase (CAT)-activity, with a maximum 91+/-1.5% reduction at 1 microM E(2). Deletional analysis of the promoter localized the inhibitory effect of ER and E(2) to site B (-170 to-144) with an adjacent 5' contiguous motif, site S (-186 to-171) acting as an amplifier. HuH-7 cell nuclear extracts showed binding activities with both sites S and B, but recombinant human ER did not. Furthermore, nuclear extracts from E(2)-treated HuH-7 cells showed weaker binding activity to site B, but not to site S. In summary, the inhibitory effect of ER and E(2) on rat apo AI gene activity is mediated by a promoter element, site B. This inhibitory effect arises from a mechanism that does not involve direct ER binding to the B-element. The conclusion that E(2) inhibits apo AI transcription was confirmed in vivo. Treatment of male adult Sprague-Dawley rats with up to 200 microg E(2) for 7 days decreased apo AI protein and hepatic mRNA by 72+/-21% and 68+/-1.4% respectively. Results of 'run-on' transcription of the apo AI gene in isolated hepatic nuclei showed a 55% decrease in hormone-treated male rats. These findings suggest that E(2) exerts primarily an inhibitory effect within male hepatic nuclei.

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