bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect and mechanism of several polyphenols on inflammation related cancers
Authors: LI Xuejun 
Published: June 2021

Inflammation plays a key role in the development and progression of cancers. Inhibition of inflammation will prevent carcinogenesis. Cancer and inflammation are linked by two pathways. The extrinsic pathway can be activated by inflammation or infection and the activation of the intrinsic pathway can be caused by oncogene activation. The two pathways co‐activate the transcription factors. The neutrophils are important part of the pathways. Previously, we had found that curcumin upregulated α1‐AT in cancer tissue, which is an endogenous inhibitor of neutrophil elastase (NE). Neutrophils and cancer cells are similar in character.Firstly, we used the C57 mouse bearing lung cancer model to observe the effect of EGCG on cancer. EGCG could prolong the survival time of cancer mice, reduce cancer volume. At a lower dose of EGCG showed a significantly reduction on the number of metastases in lung tissue and reduced the MPO activity as well. EGCG reversed the migration of NE‐induced A549 cells, and inhibited the activity of NE in a dose‐dependent manner. Using 2D‐MS, we examined the differential protein profiling of EGCG in mouse cancer tissue and detected 12 differential proteins. Signal pathway enrichment analysis by ToppCluster indicated that the PI3K‐Akt‐mTOR signal pathway had the best network correlation. And the IRS‐1, NE substrate and 14‐3‐3e in the network had higher score than other proteins. EGCG up‐regulated α1‐AT, IRS‐1, inhibited PI3K/Akt. Molecular docking and SPR results revealed that EGCG could dosedependently bind to NE. In addition, we had found that curcumin antagonized α1‐AT mRNA levels and up‐regulates the activity of the α1‐AT promoter, indicating that the expression of α1‐AT is regulated at the transcriptional level. Moreover, molecular docking results showed that curcumin also dose‐dependently bound to NE. Our study shows that EGCG and curcumin may have a certain inhibitory effect on inflammation‐related cancers, and the mechanism is related to their up‐regulation on α1‐AT and their inhibition on NE, the both may be the potential drug target for cancer prevention and treatment.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Nitric Oxide Synthase Inhibitors on Mitochondrial Respiration in Isolated Mouse Brain Mitochondria
Authors: Sperling Jared A. , Sakamuri Siva SVP. , Sure Venkata N. , Dholakia Monica H. , Peterson Nicholas R. , Satou Ryousuke , Katakam Prasad VG. 
Published: June 2021

ObjectiveNitric oxide synthase (NOS) plays an important role in intracellular and intercellular signaling pathways. Experimental studies in mitochondria from various tissues, including the brain, have shown the possibility of the presence of a novel mitochondrial variant of NOS (mtNOS) located within the mitochondrial matrix. We hypothesized that administration of NOS inhibitors significantly affects the mitochondrial respiration in isolated brain mitochondria.MethodsMitochondria were isolated from the mice aged 8–12 weeks old and plated in 24‐well microplates for oxygen consumption rate (OCR) readings in the Seahorse XFe24 Analyzer. Mitochondria were incubated with inhibitors of nNOS (ARL‐17477 and N‐ω‐propyl‐L‐arginine), eNOS (N5‐(1‐iminoethyl)‐L‐ornithine), or a non‐specific NOS inhibitor (L‐NG‐Nitroarginine methyl ester) for 30 minutes prior to the mitochondrial stress test in the XFe24 Analyzer and compared to an untreated control group.ResultsPharmacological inhibition of nNOS in isolated brain mitochondria reduced basal respiration and ATP production. Treatment with nNOS‐specific and non‐specific NOS inhibitors showed reduced basal OCR compared to control mitochondria. Control OCR values of 90.76±1.89 pmol/min were significantly higher than treatment with L‐NAME (74.17±2.12 pmol/min), NPA (77.92±2.83 pmol/min) and ARL (76.60±2.85 pmol/min). eNOS‐specific inhibitor treatment showed no significant change in mitochondrial respiration. ATP production as a bioenergetics parameter represents the portion of basal oxygen consumption that was used to drive ATP synthesis. Isolated mitochondria treated with non‐specific inhibitor L‐NAME and nNOS‐specific ARL‐17477 showed a significant decrease in ATP production. Isolated mitochondria treated with NPA show a slight trend towards decreased ATP production, but the statistical analysis did not show significance. Treatment with NIO demonstrated no significant change in ATP production.ConclusionsPharmacological inhibition of NOS isoforms affects brain mitochondrial respiration. Given the significant effects demonstrated by both nNOS‐specific inhibitors and L‐NAME, it may be postulated that mtNOS may be a new isoform of NOS sharing specific properties of the traditional three isoforms.Support or Funding InformationAmerican Heart Association (PVG: 14SDG20490359 and VNS: 16PRE31450006); National Institute of Health: National Institute of Neurological Disorders and Stroke and National Institute of General Medical Sciences (PVK: R01NS094834); and National Institute of Diabetes and Digestive and Kidney Diseases (RS: DK107694).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Induction of ET‐1‐ and non‐ET‐1‐mediated endothelium‐dependent vasoconstriction in endotoxemic hypotensive shock
Authors: TSENG TZU‐LING , Chen MEI‐FANG , LIU CHIN‐HUNG , Lee Tony JF. 
Published: June 2021

Effective managements of refractory hypotension to vasoconstrictors in severe sepsis are limited. A new strategy to ameliorate endotoxemic hypotension by inducing endothelium‐dependent constriction of endotoxemic large arteries was examined. In lipopolysaccharide (LPS)‐induced endotoxemic rats, oroxylin‐A (OroA, 15 mg/kg, iv) administered 6 hours after LPS‐challenge promptly reversed/normalized diminished mean arterial pressure and heart rate. OroA (1–10 μM), which did not constrict isolated normal arteries, repeatedly induced exclusive endothelium‐dependent sustained‐constriction without tachyphylaxis of isolated endotoxemic aortic and tail arteries. OroA‐induced constriction of mesenteric arteries with intact‐endothelium (EC+) was blocked by endothelin‐1 (ET‐1)‐receptor antagonists which, did not affect that of tail or aortic arteries, suggesting ET‐1‐mediated and non‐ET‐1‐substance(s)‐mediated vasoconstrictions, respectively. In parallel, repeated applications of ET‐1 to mesenteric arteries lead to significant tachyphylaxis, OroA, however, induced repeated constriction of tail arteries without tachyphylaxis, Moreover, OroA significantly decreased LPS‐induced expression of ET‐1 mRNA and proteins in tail arteries, while OroA increased those in the mesenteric arteries, suggesting the heterogeneities of the endothelial cells. OroA‐induced ET‐1‐mediated and non‐ET‐1‐substance(s)‐mediated constrictions of all isolated arteries (EC+) were blocked exclusively by ROCK inhibitors. OroA reversed LPS‐induced suppression of RhoA‐activities and enhanced ROCK‐phosphorylation only in arteries with endothelium. Activated muscle ROCK‐activities in mesenteric arteries (EC+) but not those in tail or aortic arteries (EC+) were blocked by ET‐1‐receptor antagonists. Moreover, OroA‐post‐treatment suppressed, via inhibiting NF‐κB, inducible‐NOS expression and circulating NO. LPS induces region‐dependent expression of endothelial ET‐1‐ and/or non‐ET‐1‐vasoconstrictors. Both ET‐1 and non‐ET‐1 were released specifically by OroA‐activated muscle RhoA/ROCK‐pathway, causing prompt‐and‐sustained vasoconstriction that partly is due to OroA‐induced decrease of circulating NO. Simultaneous preservation of endothelial functions, induction of endothelium‐dependent constriction of large arteries, and suppression of systemic inflammation, as shown by OroA, offer new strategies for acute management of endotoxemic‐hypotensive shock.Support or Funding Informationsupported by MOST & Tzu Chi FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Sphingosine‐1‐Phosphate on Endothelial Barrier Function Following Hypoxic Injury and Hemorrhagic Shock
Authors: Alves Natascha Guimaraes , Yuan Sarah , Breslin Jerome William 
Published: June 2021

Our lab has previously demonstrated that S1P reduces hemorrhagic shock and resuscitation (HSR)‐induced microvascular hyperpermeability. HSR can cause poor perfusion and hypoxia in the gut, leading to endothelial apoptosis and injury to the endothelial surface layer (glycocalyx). In the current study our objective was to investigate the extent to which S1P can prevent apoptotic signaling, shedding of the (glycocalyx), and elevated microvascular permeability in response to HSR in vivo or hypoxia in a cultured endothelial cell model. For our in vivo studies, we used a rat model of HSR, in which S1P was administered in the intravenous resuscitation fluid. The mesenteric microvasculature was dissected and protein was extracted for the assessment of pro‐apoptotic proteins by western blot. We also performed immunofluorescence of the mesenteric microvasculature to evaluate paracellular junction protein interaction. As an indicator of glycocalyx health, we used an intravenous injection of FITC‐labeled lectin and measured the amount of lectin bound to the microvascular endothelium. For the in vitro studies, we placed cultured primary endothelial cells in a low‐oxygen environment and applied S1P during the hypoxic challenge. We tested whether S1P has the potential to protect barrier function of endothelial cells grown on Transwell membranes (0.4 μm pores) from hypoxia‐induced hyperpermeability by determining permeability to FITC‐albumin. We have found that HSR causes an increase in pro‐apoptotic protein BAK in vivo, but S1P fails to blunt this increase. However, S1P seems to decrease levels of cytosolic cytochrome c compared to HSR‐treated rats. Furthermore, we found that the amount of lectin bound to the mesenteric microvasculature is higher in HSR animals treated with S1P compared to HSR only. In our in vitro studies, we found that S1P prevents hypoxia‐induced permeability in different types of endothelial cells, characterized by a decrease in endothelial permeability. Taken together, our results suggest that S1P has the potential to protect microvascular barrier dysfunction caused by HSR by preventing glycocalyx shedding. However, how S1P reduces the activation of apoptotic cascade following HSR remains elusive.Support or Funding InformationSupported by NIH grants R01HL098215 and R01GM120774.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Selective disruption of IGF‐1 signaling in astrocytes impairs neurovascular coupling in mice: implications for cerebromicrovascular aging
Authors: Tarantini Stefano , Fulop Gabor A. , Yabluchanskiy Andriy , Kiss Tamas , Sonntag William E. , Csiszar Anna , Ungvari Zoltan 
Published: June 2021

Insulin‐like growth factor 1 (IGF‐1) exerts multifaceted protective effects on the cerebral microcirculation and age‐related reduction of circulating IGF‐1 levels is known to promote cognitive decline. Astrocyte‐mediated neurovascular coupling (NVC), which adjusts cerebral blood flow to increased energy requirements of activated neurons, plays a critical role in the maintenance of normal neuronal function. Although previous studies demonstrate that circulating IGF‐1 deficiency significantly impairs NVC, the role of astrocyte‐specific effects of IGF‐1 in regulation of NVC is not completely understood. On the basis of previous findings we hypothesized that disruption of IGF‐1 signaling specifically in astrocytes impairs NVC responses mediated by epoxyeicosatrienoic acids (EETs). To test this hypothesis, we assessed changes in local cerebral blood flow elicited by contralateral whisker stimulation in mice with astrocyte‐specific knock‐down of IGF‐1 receptor 1 (Igfr1f/fGfap‐Cre), and respective controls using laser speckle contrast imaging. We found that NVC responses were significantly impaired in Igfr1f/fGfap‐Cre mice (4±1%) as compared to that in control mice (10±1%). In control mice NVC responses were significantly decreased by pharmacological inhibition of EETs synthesis (MS‐PPOH) (4±1%). In contrast, NVC responses in Igfr1f/fGfap‐Cre were unaffected by MS‐PPOH. Collectively, our findings support the concept that normal astrocyte function is essential for the adequate NVC responses and provide evidence that decreased IGF‐1 input to astrocytes results in impaired EET mediation of NVC responses, which may contribute to cognitive decline associated with age‐related IGF‐1 deficiency.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on AgingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of Cerebral Vascular Dysfunction on Alzheimer‐Like Cognitive Deficits in Diabetic T2DN rats
Authors: Fan Fan , Wang Shaoxun , He Xiaochen , Travis Olivia , Do Nga , Amaral Lorena , Cornelius Denise , LaMarca Birdie 
Published: June 2021

Diabetes mellitus is the leading risk factor for cerebrovascular disease and vascular cognitive impairment. However, the underlying mechanisms remain to be determined. The present study examines whether cerebrovascular function is impaired in diabetic T2DN rat, and whether it induces inflammation and neurodegeneration that contribute to the development of Alzheimer‐like cognitive deficits. We found that cerebral blood flow rose by 137 ± 15% and 36 ± 5%, respectively, in T2DN and SD rats when MAP was increased from 100 to 180 mmHg. Levels of infiltrated T cells (CD3+CD4+) and macrophages (CD68+) were significantly higher in the brains of T2DN (506.6 ± 26.2 and 60.5 ± 13.0 cells/g, respectively) than SD rats (45.6 ± 18.5 and 13.0 ± 1.38 cells/g, respectively). Levels of IL‐1 β and IL‐2, and the expression of Amyloid β 42 (Aβ) and p‐tau (S416) was significantly higher in the brains of T2DN vs. SD rats. The T2DN rats exhibited neurodegeneration in the hippocampus and cortex. Elderly T2DN rats exhibited learning and short and long term memory disabilities. Latency of escape were longer in an eight‐arm water maze test in T2DN rats (2‐hour: T2DN 96 ± 12 vs. SD 13 ± 3 seconds; 24‐hour: T2DN 105 ± 15 vs. SD 8 ± 2 seconds), and they spent less time in the target arm 48 hours after removal of target platform (T2DN 3.4 ± 2.6 vs. SD 45.0 ± 1.7%). These results indicate that diabetes is associated with cerebral vascular dysfunction that induces inflammation and neurodegeneration and may all contribute to Alzheimer‐like cognitive deficits in T2DN rats.Support or Funding InformationThis study was supported by grants AG050049 (FF), P20GM104357 ( FF ) from the National Institutes of Health; 16GRNT31200036 (FF) from the American Heart Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Obesity in aging exacerbates neuroinflammation and alters eicosanoid profiles in the mouse hippocampus: potential role in impaired synaptic plasticity and cognitive decline
Authors: Kiss Tamas , Valcarcel‐Ares Marta Noa , Yabluchanskiy Andriy , Tarantini Stefano , Deak Ferenc , Ungvari Zoltan , Csiszar Anna 
Published: June 2021

There is strong evidence that obesity has deleterious effects on cognitive function of older adults. Previous preclinical studies demonstrate that obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood brain barrier disruption, promoting neuroinflammation and oxidative stress. To test the hypothesis that synergistic effects of obesity and aging on inflammatory processes exert deleterious effects on hippocampal function, young and aged C57BL/6 mice were rendered obese by chronic feeding of a high fat diet followed by measurement of long‐term potentiation (LTP) in acute hippocampal slices, assessment of changes in hippocampal expression of genes relevant for synaptic function and determination of synaptic spine density. Because there is increasing evidence that altered production of lipid mediators modulate LTP, neuroinflammation and neurovascular coupling responses, the effects of obesity on hippocampal levels of relevant eicosanoid mediators were also assessed. We found that aging exacerbates obesity‐induced microglia activation, which is associated with deficits in hippocampal‐dependent learning and memory tests, impaired LTP, decreased synaptic density and dysregulation of genes involved in regulation of synaptic plasticity. Obesity in aging also resulted in an altered hippocampal eicosanoid profile, including decreases in vasodilator and pro‐LTP epoxy‐eicosatrienoic acids (EETs). Collectively, our results taken together with previous findings suggest that obesity in aging promotes hippocampal inflammation, which in turn may contribute to synaptic dysfunction and cognitive impairment.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on AgingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Partial loss of Ca2+‐Activated K+ channel (KCa) in Rat Cerebral Arterial Muscle in Insulin‐dependent diabetes mellitus
Authors: Gebremedhin Debebe , Harder David Rae 
Published: June 2021

Cerebral arteries depolarize and constrict upon pressurization. This is one of the intrinsic mechanisms underlying autoregulation of cerebral blood flow (CBF). The Ca2+‐activated K+ channel (KCa) channel in arterial muscle is an important target through which cerebral arterial response to changes in endogenous or environmental stimulatory factors are sensed. The level of open state probability (NPo) of KCa channels determines the degree of myogenic tone and cytosolic Ca2+ concentration. In the present study we report impaired pressure‐dependent constriction of cerebral arteries and diminished density and NPo of KCa channel currents associated with reduced expression of KCa channel α‐ and β‐subunit proteins in cerebral arteries of genetically insulin‐dependent diabetic rats. In this study we also found that the expression of the CYP 4A ω‐hydroxylase protein and the production of 20‐HETE was significantly increased in the type 1 diabetic cerebral arteries compared to that in the non‐diabetic cerebral arteries. The observed changes in KCa channel function and expression of CYP 4A ω‐hydroxylase and production level of 20‐HETE could represent an important pathologic mechanisms that could underlie abnormalities in cerebral arterial reactivity in insulin‐dependent diabetes mellitus. It is concluded that the diminished KCa channel function, increased production of 20‐HETE and altered pressure‐dependent cerebral arterial constriction in insulin‐dependent diabetes mellitus may lead to impaired autoregulation of CBF that could contribute to increased risk of stroke in this disease condition.Support or Funding InformationNIH RO1 HL0338833This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Prefrontal and muscle oxygenation responses to supraventricular tachycardia
Authors: Ishii Kei , Machino Takeshi , Yamagami Fumi , Nogami Akihiko , Aonuma Kazutaka , Tsurushima Hideo , Hatori Yasuhiro , Gwak Jongseong , Takahashi Naoki , Komine Hidehiko , Kitazaki Satoshi , Akamatsu Motoyuki 
Published: June 2021

Supraventricular tachycardia (SVT) causes hypotension and cerebral hypoperfusion leading to syncope at times. The cerebral and peripheral vascular systems probably operate to maintain cerebral oxygenation against SVT‐induced hypoperfusion. However, time courses of cerebral and peripheral oxygenation responses to SVT has not been fully understood. The aim of this study was to examine the time course and relationship between cerebral and peripheral oxygenation responses and SVT‐induced hypotension. Prefrontal and forearm tissue oxygen index (TOI) and normalized tissue hemoglobin index (nTHI) were collected by near‐infrared spectroscopy (NIRS) during electrophysiological study (EPS) in 14 patients (55 ± 4 years old, 9 men) with SVT. AP decreased during 2–20 s of SVT. The prefrontal TOI and nTHI began to decrease (P < 0.05) transiently at 6 s of SVT and then returned to the baseline level from 14 s. The initial decrease of prefrontal TOI appears to occur when hypotension was over approximately 20 mmHg. In contrast, the forearm TOI and nTHI decreased continuously from 11 s (P < 0.05). The AP and prefrontal NIRS responses suggest that SVT‐induced great hypotension (>20 mmHg) caused the transient reduction of cerebral oxygenation and blood volume, which may be followed by a recovering process owing to cerebral vasodilatation. The continuous reductions of forearm TOI and nTHI during SVT suggest restriction of muscle blood flow by vasoconstriction, which may contribute to redistribution of the blood to the brain.Support or Funding InformationThis research is supported by Automotive and Medical Concert Consortium (AMECC).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.