bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioengineered VEGF Therapy Following Angioplasty in Renovascular Disease: More and Better Microvessels
Authors: Guise Erika , Engel Jason , Williams Maxx , Bidwell Gene Lee , Chade Alejandro 
Published: June 2021

Asymmetric dimethylarginine (ADMA) is a pro‐atherogenic marker of endothelial dysfunction and inhibitor of endothelial nitric oxide synthase (eNOS) that may contribute to progression of renal injury. We designed a novel bioengineered fusion of an elastin‐like polypeptide with vascular endothelial growth factor (ELP‐VEGF). We showed that ELP‐VEGF therapy in renovascular disease (RVD) restores renal hemodynamics by improving microvascular (MV) rarefaction in the stenotic kidney. Our preliminary data suggest that co‐adjuvant ELP‐VEGF therapy with renal angioplasty (PTRAs) enhances renal recovery compared to PTRAs alone. We aimed to elucidate underlying mechanisms of renoprotection and test the hypothesis that co‐adjuvant ELP‐VEGF+PTRAs decreases ADMA and thus, its effects on eNOS inhibition, causing augmented renal bioavailability of NO and improvements of MV endothelial function, renal hemodynamics, and reversal of MV rarefaction.RVD was induced by unilateral renal artery stenosis and high cholesterol feeding in 14 pigs. Six weeks later, single‐kidney blood flow (RBF) and filtration (GFR) were quantified in vivo using multi‐detector CT at baseline and during an endothelium‐dependent challenge (with acetylcholine, Ach). Then pigs were randomized to either PTRAs+placebo or PTRAs followed by intra‐renal ELP‐VEGF therapy (RVD+PTRAs+ELP‐VEGF). Pigs were observed for four additional weeks; in vivo CT studies repeated, then pigs were euthanized, and ex vivo renal MV micro‐CT quantification, plasma ADMA concentration, and stenotic kidney eNOS, VEGF, and Flk‐1 expression were measured.Pre‐treatment renal hemodynamics were equally reduced and PTRAs similarly resolved renal artery stenosis in all pigs with RVD. However, PTRAs+ELP‐VEGF led to significantly greater recovery of RBF and GFR and responses to Ach than PTRAs alone. Improvements in renal function were accompanied by decreased plasma ADMA and enhanced stenotic kidney expression of eNOS, VEGF, and its Flk‐1 receptor, and improved MV density and remodeling (Figure).This study extends our previous findings by identifying a potential mechanism of enhanced renal recovery after combined PTRAs+ELP‐VEGF therapy. Reductions in circulating ADMA may have contributed to the improved renal expression of eNOS in tandem with VEGF therapy, resulting in augmented renal bioavailability of NO and ultimately improving functional and structural renal MV rarefaction. Furthermore, decreased ADMA may suggest a slowing down of the atherosclerotic process in the RVD kidney, which may have also helped contribute to the greater improvements in MV density and overall renal function after PTRAs+ELP‐VEGF therapy.Support or Funding InformationR41DK109737, R01HL095638, P01HL51971, P20GM104357, R01HL121527, EIA18490005, IPA34170267, and T32HL105324This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Interleukin‐4 supplementation improves the proinflammatory cell ratios, autoantibodies and blood pressure in response to placental ischemia
Authors: Amaral Lorena , Cottrell Jesse , Harmon Ashlyn , Cornelius Denise , Ibrahim Tarek , Cunningham Mark , Vaka Venkata , Wallukat Gerd , Herse Florian , Dechend Ralf , LaMarca Babbette 
Published: June 2021

Preeclampsia (PE), new onset hypertension, is associated with chronic inflammation, autoantibodies to the AT1 receptor (AT1‐AA) and placental ischemia. Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Evidence indicates a shift towards proinflammatory NK cell, CD4+TH1 vs CD4+TH2 profile exist in PE and in response to placental ischemia in pregnant rats (RUPP). Therefore, we hypothesized that decreasing cytolytic NK and CD4+ TH1 cells and increasing CD4+TH2 cells would improve blood pressure during pregnancy. To do so we infused IL‐4, an anti‐inflammatory cytokine strongly associated with the proliferation of TH2 cells, in to normal pregnant (NP) and RUPP rats. Interleukin‐4, 600 ng/day, was administered via a mini‐osmotic pump on day 14 of gestation, carotid catheters were inserted on gestation day 18, and blood pressure (MAP), AT1‐AA, NK cells, TH2 and B cells were measured on GD 19. MAP in NP rats (n=10) was 96 ± 2, 101 ± 2 in NP+IL‐4 rats (n=14), 130 ± 4 in RUPP rats (n=6), and 108 ± 2 mmHg in RUPP+IL‐4 rats (n=15), p< 0.05. Circulating TH2 cells were 17 ± 3 in NP rats (n=3), 9.0 ± 2.0 in RUPP rats (n=5), but improved to 13 ± 3 % gated in RUPP+IL‐4 rats (n=9). Total placental NK cells were 0.7±0.1 in NP rats (n=4), 0.7±0.3 in NP+IL‐4 rats (n=7), 5.0 ±2 in RUPP rats (n=3) which significantly decreased to 1.6±4 in RUPP±IL‐4 rats (n=7), p<0.05. Placental cytolytic NK cells were 6±2 % in RUPP rats but reduced significantly to 2±0.8 in RUPP+IL‐4 rats. Importantly, circulating B cells were 2.5±0.3 in NP rats (n=3), which increased to 7.5±2 in RUPP rats (n=4) and reduced to 1.4±0.5 in RUPP+IL‐4 rats (n=3). Similarly, AT1‐AA were 0.3±0.4 in NP rats (n=8), 18±0.3 in RUPP rats (n=9), and were blunted to 4±1 bpm in RUPP+IL‐4 rats (n=14), p<0.05. This study illustrates the importance of a balanced CD4+ TH1/TH2, B and NK cell profile during pregnancy and that this can be achieved by administration of IL‐4, which ultimately improved hypertension in response to placental ischemia during pregnancy.Support or Funding InformationNIH grants R01HD067541‐06, T32HL105324This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
H1/H2 Histamine Receptor Blockade Alters the Glutathione Redox Status in Skeletal Muscle Following a Bout of Prolonged Exercise
Authors: Turnbull Patrick C , Wallace Helen Elizabeth , Davidson Laura R , Samson Erin M , Graham Amy PR , Bell Mackenzie CW , Brebner Karen , Perry Christopher GR , Kane Daniel A 
Published: June 2021

The effects of an acute bout of prolonged exercise on muscle include increases in oxidative metabolism and altered cellular redox environment. Histamine mediates many acute exercise responses, including sustained vasodilation and associated delivery of substrates to muscle. Previously, we demonstrated that H1 and H2 histamine receptor blockade with oral antihistamines resulted in a diminished capacity for mitochondrial H2O2 emission in skeletal muscle following an acute bout of prolonged exercise. Here, we tested the hypothesis that along with diminishing mitochondrial H2O2 emission, H1 and H2 histamine receptor blockade would attenuate exercise‐induced changes in skeletal muscle glutathione redox status. Adult male Wistar rats (83 ± 5.5 days old; 440.04 ± 40.70 g) were assigned to one of four groups (n = 12/group): exercise, in the form of one hour of continuous treadmill running at 20 cm/sec (Group 1); mass‐specific oral gavage with H1 antagonist fexofenadine (7.11 mg/kg) and H2 antagonist ranitidine (3.95 mg/kg) one hour prior to the same exercise protocol (Group 2); a group receiving oral H1 and H2 antagonists, but not exercised (Group 3); and a control group, which received neither antihistamines nor exercise (Group 4). An hour post‐exercise, total, reduced (GSH) and oxidized glutathione (GSSG) were assessed in red gastrocnemius (mixed fiber types) and soleus (oxidative) skeletal muscles. Redox status was expressed as GSH/GSSG. While no changes were observed in total glutathione for any treatment in either muscle, in soleus, antihistamine treatment, but not exercise decreased GSH/GSSG (main effect; p < 0.05). In red gastrocnemius, exercise, but not antihistamine treatment decreased GSH/GSSH (main effect; p < 0.05). These observations trend with those of a blunted capacity for mitochondrial H2O2 emission in skeletal muscle with antihistamine treatment and suggest an altered redox response to exercise following H1/H2 histamine receptor blockade in soleus. Given the widespread and routine use of antihistamines, further research into the effects of these antagonists on redox status in muscle is warranted.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada, Nova Scotia Health Research Foundation, Canada Foundation for Innovation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
INTEGRATIVE QUANTUM ELECTROMAGNETIC ENERGY HOMEOSTASIS SYSTEM
Authors: Holets Hilary 
Published: June 2021

Photonic energy measured and applied by individual healing frequencies to each individual's homeostasis system is a modern approach to determining food allergies and health imbalances. Throughout time and especially the last few decades there has been an uprise of food sensitivities, extending past the general peanut, lactose intolerance, and infant honey allergies. Gluten intolerance for instance is more than a health trend. While the standard blood test has been used by physicians to determine allergy sensitivities, it does not help with determining how to measure the energy of foods categorized by macronutrient, nor the energy frequency of that food prior to, nor its immediate and long‐term effects on the body's energy prior to and post‐consumption of that particular food. Modern companies' products such as Dexafit's Biomarker Analysis and Habit's personalized nutrition package promise they are more accurate than the archaic blood test by accounting for individuals' DNA and its effect on how foods are metabolized; however, there have been no significant testimonials for disease or allergy reversal. This thesis deals with measuring different foods' effects on the body's homeostatic system, thereby allowing quantitative evidence and overall awareness of what foods individuals are allergic or sensitive to, further causing infection or disease. With this quantitative approach it is possible to then take the poisonous or toxic energy levels of foods and determine proper healing frequency for safe consumption, allowing for homeostasis to either return, be maintained, or further improved to the most optimal level for that particular individual. All of this is to represent how food sources either maintain, improve, or disrupt our body's homeostasis. The methods are specifically analyzing vegan and raw food diets compared to other well‐known lifestyles such as the keto diet to assess proper amounts of macronutrients required for individuals as well as from which nutrient sources. These experiments disclose data such as disease causation, mental illness, weight gain, and others pressed upon our systems. Once data is derived and applied, the body can ultimately heal itself. Photonic energy is the future for determining how we can bring our bodies back to their ideal state by proper mind, body, and soul alignment, eliminating instability and sickness.Support or Funding InformationThe University of Washington and other institutes are providing laboratory assistance in the following research conducted.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ultrasound Contrast Microbubble Targeted Cardiac‐specific Copper Delivery Improves Myocardial Recovery from Ischemic Injury
Authors: Feng Qipu , Fan Suzhen , Kang Y. James 
Published: June 2021

Previous studies demonstrated that ischemic insult causes a decrease in myocardial copper concentrations but an increase in serum copper concentrations. In addition, copper supplementation to the ischemic heart improves the structural and functional recovery of this organ. However, the high level of serum copper is not available for the copper‐depleted ischemic heart. The present study was undertaken to develop an ultrasound contrast microbubble targeted cardiac‐specific copper delivery procedure. Copper‐albumin microbubbles (Cu‐MB) were produced. Copper sulfate solution was mixed with human albumin solution through a series of reactions to reach an optimal proportion to form a saturated copper‐albumin complex as the membrane of microbubble (MB). The copper‐albumin complex was then subjected to gas‐filling and sonication to generate copper‐albumin microbubbles (Cu‐MB). The quality and the stability of the Cu‐MB were tested and proved to be applicable in vivo. Mice were then used to test the efficacy of the ultrasound‐targeted and Cu‐MB‐mediated cardiac‐specific copper delivery. The mice were subjected to permanent ligation of left anterior descending (LAD) coronary artery to induce myocardial ischemic injury. Four weeks after the LAD ligation, Cu‐MB was infused to mice via tail vein injection, and ultrasound treatment was applied to target the ultrasound probe at the position where infarcted myocardium was identified. Copper concentration in the blood was significantly increased after Cu‐MB infusion. The hearts were harvested 3 min after the Cu‐MB and ultrasound treatment and were found to contain significantly higher concentrations of copper than that in control or those mice subjected to Cu‐MB infusion without ultrasound treatment. Importantly, this Cu‐MB and ultrasound treatment significantly improved the myocardial structural and functional recovery from ischemic injury. This study thus demonstrates that the ultrasound Cu‐MB targeted cardiac‐specific copper delivery system is effective and the treatment with this procedure leads to improved myocardial recovery from ischemic injury in the mouse model.Support or Funding InformationScientific research funds of West China Hospital of Sichuan UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impact of Melatonin on Vascular Health in Humans
Authors: Jeong Jinhee , Tucker Matthew A , Rodriguez‐Miguelez Paula , Looney Jacob , Thomas Jeffery , Blackburn Marsha , Derella Casandra , Harshfield Gregory A , Harris Ryan A 
Published: June 2021

Melatonin, a circadian hormone released from the pineal gland, has recently been recognized to be involved in the pathophysiology of cardiovascular disease. Due to systemic localization of its receptors, melatonin is thought to play an important role in the regulation of vascular function. Data from animal models provide evidence that melatonin is protective against endothelial damage and the subsequent development of atherosclerosis. However, the effects of melatonin on vascular function in humans have yet to be determined.PurposeThe present study tested the hypotheses that, in humans 1) endogenous melatonin production is associated with vascular health and 2) supplemental melatonin improves vascular health.MethodsUpon arrival to the lab, 12 apparently healthy adult men (28±3 y) provided an overnight urine sample to measure 6‐sulfatoxymelatonin, the urine metabolite of melatonin. Subsequently, vascular endothelial function (flow‐mediated dilation; FMD) was assessed. In a follow‐up experiment, a comprehensive assessment of vascular health including brachial arterial blood pressure, FMD, and arterial stiffness (carotid‐femoral pulse wave velocity; PWV) was assessed in 4 individuals (31±6 y) at baseline and 1 hour following a single oral dose of melatonin (5 mg).ResultsFMD (%) was positively associated with total overnight melatonin production (ng; r=0.592, p=0.042) and melatonin excretion rate (ng/hour; r=0.539, p=0.071). Compared with baseline, PWV significantly decreased (5.9±1.3 to 5.7±1.3 m/s, p=0.003) and FMD increased (7.5±2.2 to 8.1±1.8 %, p=0.173) 1 hour following ingestion of supplemental melatonin. Supplemental melatonin did not change blood pressure (114±6 to 114±9 mm Hg, p=0.927).ConclusionThese novel data in humans demonstrate that higher endogenous melatonin production is associated with greater vascular endothelial function. In addition, a single dose of supplemental melatonin is capable of reducing arterial stiffness and improving endothelial function. Together, these findings suggest that melatonin may serve a beneficial role in regulating vascular function in humans. Achieving adequate overnight melatonin production may represent an important therapeutic strategy for the maintenance of optimal vascular health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Bacterial modification of bile acids alters host physiology
Authors: Devlin Sloan 
Published: June 2021

The human gut microbiome is known to play a crucial role in human energy harvest and homeostasis and has been implicated in the pathophysiology of obesity and metabolic syndromes. Defining the roles of specific microbial activities and metabolites on host phenotypes has proven challenging, however, due to the complexity of the microbiome‐host ecosystem. This lack of mechanistic understanding regarding the functions of microbial species has limited the effectiveness of both dietary and therapeutic approaches to improving host physiology. Using both genetic and chemical tools that target gut bacteria, we now report that we can selectively modulate the in vivo levels of a class of metabolites called bile acids, and that this controlled alteration of the bile acid pool exerts distinct effects on host physiology.Bile acids are steroidal metabolites that play crucial roles in host metabolism by acting both as detergents that aid in digestion and as ligands for host receptors, including nuclear hormone receptors and GPCRs. In the colon, bacteria chemically modify host‐produced primary bile acids, generating a group of approximately 50 metabolites called secondary bile acids. While imbalances in this bile acid pool have been correlated with metabolic disorders, it is unclear which bile acids exert beneficial or harmful effects on host metabolism. Here, we report that we can control the in vivo pool of bile acids in mice by inhibiting the keystone enzyme of bacterial bile acid metabolism, bile salt hydrolases (BSH). Germ‐free mice monocolonized with a BSH‐deleted strain displayed altered metabolism, including reduced weight gain and reduced respiratory exchange ratios, as well as transcriptional changes in metabolic, circadian rhythm, and immune pathways in the gut and liver. We also determined that the metabolic differences observed were not due to differential detergent abilities of the bile acid pools but rather to bile acid‐mediated signaling. These results indicate that the deletion of a single bacterial gene can profoundly alter host metabolism. In ongoing work, we have developed a small molecule pan‐inhibitor of BSH. We are currently using this inhibitor as a chemical tool to probe the effects of bacterial bile acid modifications on host metabolism in fully colonized animals.Support or Funding InformationR35 GM128618, NIH/NIGMS; 5P30DK034854‐33, NIH/NIDDK (Harvard Digestive Diseases Center); Center for Microbiome Informatics and Therapeutics at MIT Innovation Award; Karin Grunebaum Cancer Research Foundation Faculty Research Fellowship; Quadrangle Fund for Advancing and Seeding Translational Research (Q‐FASTR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells
Authors: Liu David 
Published: June 2021

Point mutations represent the majority of known human genetic variants associated with disease but are difficult to correct cleanly and efficiently using standard nuclease‐based genome editing methods. In this lecture I will describe the development, application, and evolution of base editing, a new approach to genome editing that directly converts a target base pair to another base pair in living cells without requiring DNA backbone cleavage or donor DNA templates. Through a combination of protein engineering and protein evolution, we recently developed two classes of base editors (BE4 and ABE) that together enable all four types of transition mutations (C to T, T to C, A to G, and G to A) to be efficiently and cleanly installed or corrected at target positions in genomic DNA. The four transition mutations collectively account for most known human pathogenic point mutations. Base editing has been widely used by many laboratories around the world in a wide range of organisms including bacteria, fungi, plants, fish, frogs, insects, mammals, and even human embryos. We have recently expanded the scope of base editing by enhancing its efficiency, product purity, targeting scope, and DNA specificity. By optimizing base editor expression, we developed “max” versions of cytosine and adenine base editors with greatly increase editing efficiency in mammalian cells. We also show that base editing can function in vivo in post‐mitotic somatic cells that do not support homology‐directed repair. To improve the targeting scope of base editing, we used our phage‐assisted continuous evolution (PACE) system to rapidly evolve Cas9 and base editor variants with both broadened PAM compatibility and higher DNA specificity. Finally, we integrated several of these developments to address cell and animal models of human genetic disease. Base editing can be used to correct pathogenic point mutations, introduce disease‐suppressing mutations, and create new models of genetic diseases.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anticancer effects of Qizhen Capsule in human colorectal cancer cells in vitro and in vivo
Authors: Guo Dandan , Guo Chenjie , Wang Yujie , Wu Kaikai , Fang Liu , Guo Cuiling , Wang Xingya 
Published: June 2021

Qizhen capsule is a new type of anti‐cancer traditional Chinese medicine preparation. As an adjuvant therapy for cancer, it has been widely used in clinical practice with remarkable therapeutic effects in clinic. According to the current research reports, Qizhen capsule is mainly used for the treatment of lung, gastric and breast cancer. However, whether Qizhen capsule has an inhibitory effect on colorectal cancer has not been reported, and the specific molecular mechanism of its anti‐tumor activity has not been well studied. In this study, the effect of Qizhen capsule water extracts on the proliferation and apoptosis of human colon cancer HCT116 cells was studied in vitro and in vivo. MTT assay revealed that Qizhen capsule at 0.3 to 0.7 mg/ml significantly inhibited proliferation of HCT116 cells in a dose‐and time‐dependent manner. Furthermore, Qizhen capsule water extracts induced apoptosis in HCT116 cells that determined by flow cytometric, which is associated with deregulation of the expression of key genes and proteins (Bcl‐2, Bax, PARP, caspase‐3 and caspase‐9) that regulate apoptosis. Moreover, oral administration of 4.5 g/kg and combination treatment of 1.5 g/kg Qizhen capsule and 5‐Fu significantly inhibited HCT116 xenograft tumor growth in nude mice by reducing HIF‐1α, Bcl‐2, NF‐κB and c‐FOS at mRNA levels, and up‐regulating PARP, FoxO3a and NAG‐1 at protein levels, which was further confirmed by suppressed Ki‐67, caspase‐3, Bcl‐2 and PCNA staining in tumor samples as determined by immunochemistry. Taken together, our study suggests that Qizhen capsule could inhibit the development of colorectal cancer by inhibiting cell proliferation, inducing cell apoptosis, and suppressing tumor growth. These results also suggest that Qizhen capsule may be a promising anticancer drug for the prevention and treatment of colorectal cancer.Support or Funding InformationNational Natural Science Foundation of China (Grant No. 81473397).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.