bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Expression of Neuropilin‐2 in Tumor and Stroma in Oral Dysplasia and Oral Squamous Cell Carcinoma
Authors: Almazyad Asma , Shahrabi‐Farahani Shokoufeh , Gartung Allison , Panigraphy Dipak , Bielenberg Diane R. 
Published: June 2021

The majority of oral malignancies (90%) are squamous cell carcinoma (OSCC), and two‐thirds of OSCC patients present at diagnosis with disseminated disease. OSCC can develop from pre‐cancerous lesions known as oral dysplasia. Early detection of these lesions leads to better management and outcome. We investigated the role of the Neuropilin‐2 (NRP2) cell surface receptor in oral dysplasia and OSCC. NRP2 is regarded as an important mediator of angiogenesis and lymphangiogenesis, but its role in epithelial cells is less understood. NRP2 can bind VEGFA in a complex with VEGFR2 or VEGFC in a complex with VEGFR3 to stimulate the sprouting of blood or lymphatic vessels during development but its role in adult tumor‐associated neovascularization has not been clearly identified. Interestingly, NRP2 also binds Semaphorin‐3F (SEMA3F) in a competitive fashion with VEGFA/C, and SEMA3F is reported to inhibit lymphangiogenesis. Here, we hypothesize that oral dysplasia and OSCC express NRP2 in transformed epithelial cells as well as in tumor‐associated lymphatic endothelium, and that this expression pattern renders them amenable to SEMA3F therapy. Our results indicate that adult human and mice normal tongue do not express NRP2 in the epithelium or in quiescent lymphatic vessels. However, NRP2 is significantly upregulated in moderate or severe oral dysplasia and OSCC in epithelial cells and lesion‐associated lymphatic vessels. Two different human OSCC cell lines injected orthotopically in immunocompromised mice showed high NRP2 expression. Immunocytostaining also confirmed NRP2 protein expression in two different cell lines isolated from 4NQO‐induced OSCC in mice. Additionally, a panel of different human and mice OSCC cell lines showed high expression of NRP2 protein using western blot. Lastly, SEMA3F, in a dose‐dependent manner, inhibited migration of Nrp2‐expressing mouse OSCC cells in vitro. In summary, the upregulation of NRP2 in early stages of cancer progression in OSCC may point to important signaling pathways not previously realized in disease. Targeting NRP2 with neutralizing antibodies or with its inhibitory SEMA3F ligand may a promising new paradigm to treat or prevent progression and metastasis of OSCC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
RAGE targeting ameliorates responses to antenatal SHS exposure
Authors: Hirschi K M , Tsai K YF , Clark C , Hutchinson T , Hall P , Arroyo J A , Reynolds P R 
Published: June 2021

Secondhand tobacco smoke (SHS) exposure during pregnancy is associated with increased health complications to both mother and fetus. Exposure can lead to anomalous organ development, increased blood pressure, and decreased metabolism. Receptors for advanced glycation end‐products (RAGE) are pro‐inflammatory transmembrane receptors increased by SHS. Inhibition of RAGE signaling by semisynthetic glycosaminoglycan ethers (SAGEs) has been shown to reduce inflammation in the adult and improve fetal birthweight. We tested the hypothesis that in vivo inhibition of RAGE by SAGEs during antenatal SHS exposure improves postnatal health of the offspring. Pregnant Balb/C mice were exposed to SHS alone or SHS + SAGEs from embryonic day (E) 14 to E17. RAGE expression and general measures of development were assessed in the offspring at four and twelve weeks of age. Statistical analysis was completed using nonparametric Mann‐Whitney testing. Antenatal SHS resulted in the following at four weeks of age: 1) increased body weight (p =0.0118) which was reduced to basal levels when treated with SAGEs; 2) decreased heart (p=0.0017) and kidney (p=0.0001) weights and improvement with concurrent SAGEs; 3) increased neonatal blood pressure and further increases with SAGEs; 4) increased expression of RAGE in kidney (p=0.0090), heart (p=.044), and lung (p=0.0022) with significant recovery with SAGEs; 5) mild reduction in alveolar surface area via MLI assessment and airspace normalization with SAGE treatment. No significant differences were apparent for any metric at 12 weeks of age. We conclude that inhibition of RAGE protects against fetal health complications following antenatal SHS exposure. Our results further suggest that there is a correlation between RAGE expression and a plausible role for RAGE signaling in key organs following maternal SHS exposure. These studies provide insight into tobacco‐mediated heath compromise and implicate possible avenues worth pursuing further in the alleviation of symptoms of antenatal SHS exposure.Support or Funding InformationThis work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR and JAA) and a BYU Mentoring Environment Grant (JAA and PRR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
IGF1 is Developmentally Regulated in the Neonatal Intestine and Protects Neonatal Mice against Necrotizing Enterocolitis by Preserving the VEGF/VEGFR2 Signaling Pathway in an Animal Model
Authors: Yan Xiaocai , Managlia Elizabeth , De Plaen Isabelle 
Published: June 2021

Necrotizing enterocolitis (NEC) is a common gastrointestinal disease affecting premature infants and associated with high morbidity and mortality. Its pathogenesis remains poorly understood. Decreased levels of serum IGF1 has been shown to be associated with a higher incidence of NEC in premature infants. We previously found that neonatal pups are most susceptible to NEC in the first few days of life. Here we hypothesize that IGF‐1 levels are low during the first days of life, and that exogenous IGF1 is protective against NEC via promoting intestinal VEGF/VEGFR2 signaling. To test our hypotheses, we first assessed the developmental expression of IGF1 in the serum and the intestinal tissues in neonatal mice during the first 3 weeks of life, and determined whether exposure to a NEC protocol affects serum and intestinal IGF1 levels. Secondly, we examined whether exogenous IGF1 protects against NEC and affects intestinal VEGF production both in vivo and in vitro. We found that: Serum IGF1 level is low during the first 2 days of life, and gradually increases over 3 weeks. In contrast, IGF1 expression in the intestinal tissue is low at birth, peaks between 3 days and 2 weeks of age, before decreasing to low level by 3 weeks. In pups exposed to a NEC protocol compared to DF controls, serum IGF1concentration was significantly decreased at 12 hours and 24 hours (by 35%, p<0.05; and 59%, p<0.0001 respectively ). Intestinal tissue IGF1 expression decreased as early as 6 hours into NEC, which occurred before the decrease in serum IGF1. Exogenous IGF1 treatment decreased mortality in pups exposed to NEC protocol (41% vs. 68%, p<0.05), decreased the incidence of severe NEC (histological score ≥ 2) (χ2=4.03, p<0.05) and increased intestinal VEGF/VEGFR2 protein expression. Neonatal intestinal endothelial cells treated with IGF1 in vitro had increased VEGF mRNA transcription and protein expression (p<0.05 for both). We conclude that the beneficial effect of IGF1 on experimental NEC may be due to protection of small intestinal microvasculature development through preserving VEGF/VEGFR2 signaling pathway.Support or Funding InformationShireThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Pin1/DAPK1 inhibition on IKK‐mediated cell death in ischemic stroke mice model
Authors: Kang Hyunbon , Hong Yonggeun 
Published: June 2021

Peptidyl prolyl isomerase (Pin1) and Death‐associated protein kinase 1 (DAPK1) have been investigated as a key factor in cell death of cerebral ischemia. But, Pin1 and DAPK1 signaling pathway have not been clearly elucidated in case of ischemia/reperfusion. Cerebral ischemia/reperfusion injury is known to be induced by imbalanced inflammation and oxidative stress. Also, recent articles identified the Ikappa B kinase (IKK), which is a main mediator of inflammation signal‐induced neuronal cell death in ischemic stroke. Here, we examined the close relationship among DAPK1, Pin1 and IKK in ischemia/reperfusion (I/R). To investigate the effect of Pin1/DAPK1/IKK on I/R neuronal cell death, MCAo (Middle cerebral artery occlusion) surgery was performed to experimental animals, and they were injected with either Pin1 inhibitor or DAPK1 inhibitor. The experimental animals were randomly divided into six groups; vehicle‐day1, Pin1 inhibitor‐day1, DAPK1 inhibitor‐day1, vehicle‐day3, Pin1 inhibitor‐day3, DAPK1 inhibitor‐day3. No significant changes were found in the body weight and NDSS scores among groups. However, the inhibition groups exhibited decrease in infarct size and neuronal cell damage after cerebral ischemia/reperfusion. In addition, IKK expression was decreased in inhibition groups. Taken together, regulation of Pin1/DAPK1/IKK interaction would exert neuroprotective effect against I/R injury.Support or Funding InformationNRF‐2013R1A2A2A01067169, NRF‐2017R1A2A2A01067169, KRIBB‐KGM4611714This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Is the Asymmetric Dimethylarginine (ADMA) the Possible Molecule Driving Endothelial Damage in Young Asymptomatic Patients with Cerebral Small Vessel Disease?
Authors: Cifu’ Adriana , Fabris Martina , Janes Francesco , Pessa Maria Elena , Domenis Rossana , Nilo Anna Carmen , Giacomello Roberta , Gigli Gian Luigi , Curcio Francesco 
Published: June 2021

Cerebral small vessel disease (CSVD), detected as white matter hyperintensities (WMH) on brain MRI, could be a distinct pathological entity within cerebrovascular diseases. CSVD has a high prevalence in aging population and in stroke patients. In the last years, the increasing use of MRI has led to more incidental finding also in young people without classical vascular risk factor. Our intent was to investigate different pathways implicated in endothelial dysfunction such as inflammation, autoimmunity, coagulation, nitric oxide pathway, in a well selected, homogeneous population of patients with WMH, without significant vascular risk factors or neurological diseases. We selected 35 consecutive patients with evidence of CSVD features at brain MRI and 35 controls age‐sex matched. We evaluated markers for thrombophilia (antithrombin III, protein C, protein S, fibrinogen, plasminogen activator inhibitor – 1, tissue plasminogen activator, von Willebrand factor, homocysteine, C‐reactive protein) and autoimmunity (ANA, ENA, anti‐phospholipids antibodies, lupus anticoagulant) using diagnostic assays. In addition, we evaluated several markers of endothelial activation and inflammation. Interleukin 6, interleukin 10, E‐selectin, P‐selectin and asymmetrical dimethylarginine (ADMA) were assayed by ELISA. Platelet Activating Factor‐Acetyl Hydrolase and nitric oxide were measured with a colorimetric assay, while vascular cell adhesion molecule‐1 and intercellular adhesion molecule‐1 were assayed by Luminex® assay. Statistical analyses were conducted with SPSS 20 (SPSS Inc., Chicago USA). We did not find any significant difference between patients and controls, except for ADMA. Indeed, patients displayed significantly higher levels of ADMA (71.97 ± 36.49 vs 44.46 ± 29.94, p=0.002) than controls. ADMA levels showed positive correlation with the total Fazekas score (r = 0,304; p = 0,01). ROC curve analysis showed a moderate accuracy in discriminating patients and controls (AUC = 0,70; CI 0,57–0,82; p = 0,004): a cut‐off of 46 ng/ml is associated with 80% sensitivity but limited (54%) specificity. In this very large biomarker study, ADMA results the only endothelial marker significantly associated to WMH. This reinforces the hypothesis of the key role of endothelial dysfunction and nitric oxide pathway in CSVD. Further studies should explore the cause‐effect relationship between ADMA pathway and CSVD in selected groups of subjects.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anchor targeting ligands, inorganic nanocomposites, and loads drug in nanobubbles for renal cell carcinoma immune/chemotherapy
Authors: Chan Ming‐Hsien , Liu Ru‐Shi , Hsiao Michael 
Published: June 2021

BackgroundNanobubble (NB) possess two regions for loading therapeutic agents, namely, the perfluoropentane core and the external surface. Drug release is controlled when encapsulated inside the NB because the drugs are only delivered when an NB is activated by an external stimulus. For instance, ultrasound‐induced cavitation of NBs causes the formation of 150–300 nm holes in the cell membrane, thereby facilitating drug or gene uptake. NBs are ideal vehicles for delivering a wide range of molecules because they are versatile, easily modified for specific targeting of various acoustically active organs, and exhibit low toxicity.DesignThe aim was to synthesize a stable nanosystem which, enhances ultrasound imaging, has optimal luminescence efficiency and stimulates a conducive, synergistic immune/chemotherapy effect. The theranostic agent chosen was, an upconversion nanoparticles (UCNP) associated‐PD1 (UCNP‐PD1) encapsulated inside a folic acid‐nanobubble (Fa‐NB). The cavity of NB can be loaded with the drug, doxorubicin (DOX). Encapsulation of the system within the Fa‐NB provided stability and active targeting to the tumor cell line. Renal cell carcinomas (RCCs) show a high level of folate receptors. When fa‐NB accumulates around RCCs, we can apply ultrasonic energy to release the UCNP‐PD1 from the NB, and bind with the PD‐L1 on the cancer cells and can be tracked by the fluorescence of UCNP.ResultsThis encompasses, a Fa‐NB which selectively targets the folic acid receptor found on RCCs. Embedded inside the Fa‐NB is a hybrid nanoconjugate; composed of, UCNPs conjugated to PD1 and loaded with DOX. The aim was to create a nanoscale reagent which implements a selective, immunotherapy and chemotherapy to organs found deep below the body's surface.ConclusionsA novelly nanotheranostic hybrid system was assembled for immune/chemotherapeutic anticancer treatment. An effective multistep synthesis required the sequential characterization of each individual counterpart, to determine the optimal conditions for the synthesis of the nanocomposite.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Interactions of Aldolase A with ATPase Inhibitory Factor 1 Reprogram Energy Metabolism to Maintain Cancer Stemness
Authors: Chang Yu‐Chan , Hsiao Michael 
Published: June 2021

Cancer cells utilize glycolysis for the production of ATP and metabolic reprogramming (Warburg effect), as opposed to differentiated bulk tumor cells relying on glycolysis. Cancer Stem cells (CSCs) showed a distinct metabolic phenotype that, depending on the cancer type, could be highly glycolytic or rely on an OXPHOS‐dependent pathway. Aldolase A (ALDOA) has been regarded as one of the key enzymes involved in glycolysis. Overexpression of ALDOA correlated with cancer proliferation and metastasis, and formed a positive feedback loop with HIF‐1alpha during tumorigenesis. Through mass spectrometry‐based ALDOA interactive proteomic database analysis, we have discovered that ALDOA binds directly to ATPase inhibitory factor 1 (IF1). ATPIF1 is a physiological inhibitor of H+‐ATP synthase that is highly overexpressed in the mitochondria of cancer cells. Overexpression of IF1 results in the inhibition of ATP synthesis by the enzyme and a switch to increased aerobic glycolysis and increased ROS‐mediated signaling related to several features of the oncogenic phenotype. We further identified ATPIF1 could be degraded after binding to ALDOA and this function could be rescued by the addition of proteasome inhibitor. In addition, ATP5 family members were found to be upregulated with or without ALDOA enzymatic activity to maintain cancer stemness phenotypes in various types of cancer cells. The additions of IFA could significantly reverse the ALDOA‐induced cancer stemness in a dose‐dependent manner. Moreover, we observed the inverse RNA and protein expression correlations of ALDOA and ATPIF1 predict significant poor prognosis in many clinical cohorts including gliomas, lung and colon cancers. In conclusions, our results provided evidences that ALDOA binding ATPIF1 induce its degradation to modulate energy reprogramming controls and maintain cancer stemness in human cancer cells. This niche may allow new target‐drug development by aiming at the inhibition of ALDOA/IF1 protein binding to suppress cancer stemness.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Localization of the CYP4A Enzymes that Produce 20‐HETE and the 20‐HETE Receptor in the Brain
Authors: Gonzalez‐Fernandez Ezekiel , Xu Rui , He Xiaochen , Wang Shaoxun , Fan Letao , Coolen Lique , Fan Fan , Roman Richard 
Published: June 2021

20‐HETE is an arachidonic acid metabolite that is catalyzed by cytochrome P450 (CYP) enzymes of the 4A and 4F families. 20‐HETE is a potent vasoconstrictor that plays an important role in the regulation of cerebral vascular function. Numerous human studies have found that inactivating mutations in the enzymes that produce 20‐HETE are associated with hypertension, stroke, and dementia. Our group previously reported that the Dahl salt‐sensitive (SS) rat also has decreased 20‐HETE levels and exhibits impaired autoregulation of cerebral blood flow and loss of cognitive function following the development of hypertension. A G‐protein coupled receptor (GPR 75) was recently identified as an effector for 20‐HETE, however, little is known about the sites where 20‐HETE is produced in the brain and where its receptors are located. In this study, we used immunohistochemistry (IHC) to identify neuroanatomical structures and landmarks that express CYP4A enzymes and the GPR 75 receptor in SS and control rats. We found that CYP4A enzymes are expressed in hippocampal and hypothalamic neurons, pial and penetrating arterioles in control rats. GPR 75 is expressed in the vascular smooth muscle cells of pial and penetrating arterioles and possibly pericytes at branch points of cerebral arterioles/capillaries. We also found that GPR 75 levels are higher and CYP4A levels are lower in SS vs. control by RT‐PCR, Western Blot and IHC. These findings are consistent with 20‐HETE's emerging role in the regulation of cerebral vascular diseases and dementia.Support or Funding InformationThis study was supported by grants DK104184 (Roman), HL138685 (Roman), AG050049 (Fan), P20GM104357 (Fan and Roman) from the National Institutes of Health, 16GRNT31200036 (Fan) from American Heart Association and the MD/Ph.D. program/Conway Scholarship (Gonzalez‐Fernandez).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Immunomodulation of Mature Dendritic Cells in Parkinson's Disease: A Novel Role of Intracellular Toll Like Receptors
Authors: Paterniti Irene , Campolo Michela , Cordaro Marika , Casili Giovanna , Lanza Marika , Filippone Alessia , Esposito Emanuela , Cuzzocrea Salvatore 
Published: June 2021

Parkinson's disease (PD) is a devastating clinical disorders that is characterized by progressive and selective neuronal injury and cell death. Recent studies have provided accumulating evidence for a significant role of the immune system and neuroinflammation in PD pathogenesis. In particular, neuroinflammation associated to PD is the prerequisite for the maturation of dendritic cells (DC) and their migration to the respective sites in the brain. It has become clear that Toll‐like receptors (TLRs), a major family of pattern recognition receptors could mediate innate and adaptive immune response, providing an important mechanism by which microglia are able to sense both pathogen‐ and host derived ligands within the CNS.The aim of our study was to evaluate the role of TLR 7,8 and 9 in DC maturation that trigger to adaptive autoimmune response related to PD.We performed an in vivomodel of PD, by MPTP, in single KO mice for TLR7−, TLR8− and TLR9−; and in double KO mice for TLR 7/8−/−and TLR7/9−/−. All animals was compared with WT animals used as a control group.Animals were sacrificed after 8 days and their midbrains were harvested, sectioned and processed in order to evaluate: the principal markers of PD with particular attention to TH, DAT and α‐synuclein aggregate; astrocytes and microglia activation through GFAP and IBA‐1; pro‐inflammatory cytokine's expression such as INF‐γ and TNF‐α like major product of activated microglia and astrocytes. Moreover to evaluate the formation of neuromelanin pigments in the midbrain we made the Masson‐Fontana staining.The result obtained demonstrated that the genetic absence of TLR 7,8 and 9 modified PD pathway increasing significantly the immunoreactivity for TH and DAT compared to PD groups where we found an evident reduction of these markers.Therefore, TLRs could be considered as a possible target to develop new therapies for neurodegenerative disorders.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
N‐Palmitoylethanolamine‐oxazoline (PEA‐OXA): a new therapeutic strategy to reduce neuroinflammation and oxidative stress associated to vascular dementia
Authors: Cuzzocrea Salvatore , Impellizzeri Daniela , Siracusa Rosalba , Cordaro Marika , Crupi Rosalia , Peritore Alessio Filippo , Gugliandolo Enrico , D'Amico Ramona , Di Paola Rosanna 
Published: June 2021

Recent studies revealed that pharmacological modulation of NAE‐hydrolyzing acid amidase (NAAA) can be achieved with PEA oxazoline (PEA‐OXA). Hence, the aim of the present work was to thoroughly evaluate the anti‐inflammatory and neuroprotective effects of PEA‐OXA in an experimental model of vascular dementia (VaD) induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, animals were orally administered with 10 mg/kg of PEA‐OXA daily for 15 days. Brain tissues were handled for histological, immunohistochemical, western blot, and immunofluorescence analysis. PEA‐OXA treatment evidently reduced the histological alterations and neuronal death induced by VaD and additionally improved behavioral deficits. Further, PEA‐OXA decreased GFAP and Iba‐1, markers of astrocytes, and microglia activation, as well as MAP‐2, a marker of neuron development. Moreover, PEA‐OXA reduced oxidative stress, modulated Nrf2‐mediated antioxidant response, and inhibited the apoptotic process.Some drugs may demonstrate their healing potential by regulating neuroinflammation, rather than by their habitually attributed actions only. Palmitoylethanolamide (PEA) is a prototype ALIAmide, well‐known for its analgesic, anti‐inflammatory, and neuroprotective properties. The inhibition of PEA degradation by targeting NAAA, its catabolic enzyme, is a different approach for treating neuroinflammation. This research offers new insight into the mechanism of PEAOXA‐induced neuroprotection. Thus, the modulation of intracellular NAAA by PEA‐OXA could offer a novel means of controlling neuroinflammatory conditions associated with VaDSupport or Funding Informationno fundingsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.