bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro screening of Glyphae brevis (Tiliaceae) for anticholinesterases and antioxidant potentials as a ethnomedicinal component of memory enhancing agent in Niger Delta Nigeria
Authors: NWIDU LUCKY LEGBOSI , ELMORSY EKRAMY , CARTER WAYNE GRANT 
Published: June 2021

BackgroundThis study investigates the anticholinesterases and antioxidant potential of Glyphae brevis used in ethnomedicine as memory enhancing therapy.MethodsGlyphae brevis crude methanolic leaf extract (GBCMLE), stembark (GBCMSE) and root (GBCMRE), and fractions: ethyl acetate (GB EAF), butanol (GB BUF), aqueous (GB AQF) were investigated for acetylcholinesterase (AChE) inhibitory activity using Ellman's assay and DPPH free radical scavenging activity. The total Phenolic and Flavonoid contents were also examined and expressed in mg Gallic acid (GAE/g) and quercetin (QUER/g) respectively.ResultsThe samples exhibited concentration dependent AChE inhibitions, the leaf: GBCMLE, 52.6%, (IC50 127 μg/mL), GBLEAF, 46.3% (IC50 245 μg/mL), GBL BUF, 24.5% (IC50 425 μg/mL) and GBL AQF, 20.3% (IC50 502 μg/mL); the stem: GBCMSE 68.3% (IC50 19 μg/mL), GBS EAF 172.2% (IC50 172 μg/mL), GBS BUF 65.4% (IC50 21 μg/mL), GBS AQF 85.% (IC50 12 μg/mL); the root: GBCMRE 42.2% (IC50 497 μg/mL), GBR EAF 70.1% (IC50 509 μg/mL), GBR BUF 81.3% (IC50 287 μg/mL) and GBR AQF 60.5% (IC50 521 μg/mL) at a concentration of 200 μg/mL. At this dose, the AChE activities ~20.3 – 52.6%, ~52.2 – 85.6% and ~42.2 – 81.3% for leaf, stem and root respectively of the value observed using eserine 0.02μg/mL. The descending AChE activity is stem > root > leaf.In the DPPH free radicals scavenging assay, highest activity were demonstrated by GBC MLE and GBL EAF, 72.5 ± 3.1 and 65.2 ± 3.2%; for the stem, GBS AQF and GBS BUF, 80.5 ± 3.4 % and 68.3 ± 3.4 %; and the root, GBR BUF and GBR EAF, 78.2 ±3.3% and 67.0 ±3.1% inhibitions of free radicals respectively at 1 mg/mL concentration. The corresponding IC50 were 327, 473, 278, 327, 211 and 473 μg/mL respectively. Similarly, the TPC and TFC are 88.85 and 31.61, 52.36 and 19.45, 75.67 and 27.22, 55.34 and 24.67, 97.0 and 34.33, 51.87 and 19.29 mg Gallic acid GAE/g and quercetin QUER/g respectively. BUF has the highest correlation (r) values, which means that the contents of BUF extracts are the most important for the antioxidant and AChE properties.ConclusionThese results indicate that G. brevis is enriched with phenolic and flavonoid contents that exhibit marked anticholinesterase and antioxidant effects..Support or Funding InformationUniversity of Nottingham Visiting FellowshipThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Perfluorononanoic Acid (PFNA) Suppresses Autophagy and Activates Nrf2 Signaling
Authors: Le Yuan , Cheng Xingguo 
Published: June 2021

Perfluorinated compounds (PFCs), a group of persistent environmental pollutants, are frequently detected in human blood. Epidemiological and animal studies show that there are positive associations between higher blood levels of PFCs and greater risk of liver disorders, thyroid disorders, reproductive toxicity, and immunotoxicity. Nuclear factor erythroid 2‐related factor (Nrf) 2, a transcription factor that can be activated by oxidative stress, electrophiles, and accumulated p62 protein after autophagy repression, plays important anti‐inflammatory, anti‐oxidative and cytoprotective roles. We previously reported that PFCs increased the expressions of several Nrf2 target genes in mouse liver. However, the underlying mechanism by which PFCs activate Nrf2 signaling remains largely unknown. The present study was designed to determine whether PFNA activates Nrf2 signaling; and if so, the underlying mechanism. PFNA increased mRNA expressions of Nrf2‐target genes, including Heme oxygenase (Ho/HO) 1 and NAD(P)H: quinone oxidoreductase (Nqo/NQO) 1, as well as nuclear levels of Nrf2/NRF2 protein in both mouse liver and cultured human Hep3B hepatoma cells. To our surprise, PFNA did not produce apparent oxidative stress in both mouse liver and cultured human Hep3B hepatoma cells. We next determined the impact of PFNA on autophagy progression. In both mouse liver and cultured human Hep3B hepatoma cells, PFNA decreased the conversion of microtubule‐associated protein 1 light chain 3 beta (LC3B)‐I into LC3B‐II, and increased cytosolic levels of p62 protein, indicating that PFNA repressed autophagic flux. In addition, PFNA decreased nuclear levels of transcription factor EB (TFEB) protein, an upstream signaling molecule of autophagy. Morphologically, PFNA caused liver injury in both wide‐type and Nrf2‐null mouse liver, evidenced by hepatocyte necrosis and hemorrhage. In consistency with histology study, PFNA (0.1mmole/kg) increased serum AST and ALT levels in both wide‐type mice and Nrf2‐null mice. In addition, PFNA produced clear inflammation foci in Nrf2‐null mouse liver, but not in wide‐type mouse liver. Furthermore, PFNA induced mRNA expressions of pro‐inflammatory cytokines, including IL‐1β, IL‐6, and TNF‐α only in Nrf2‐null mouse liver, but not in wide‐type mouse liver. In conclusion, PFNA activates Nrf2 signaling, primarily mediated by accumulated p62 protein after autophagy repression, which significantly attenuated PFNA‐induced inflammation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Phenobarbital Increased Hepatic Toxicity of Acetaminophen due to Cytochrome P450 Induction in Young and Adult Mice
Authors: Shao Xueyan , Wang Pei , Bao Yifan , Chen Liming , Zhong Xiao‐bo 
Published: June 2021

Cytochrome P450 (P450) enzymes, phase I drug metabolizing enzymes, are responsible for the metabolism of a variety of substances, including endogenous compounds, xenobiotics and drugs. The expression of P450s could be altered by factors including drug treatment, which may lead to decreased drug therapeutic efficacy or increased toxicity. Phenobarbital is a known inducer of P450s and commonly utilized to treat seizures in children and adults. Although acetaminophen serves as the most commonly used drug for pain and fever in children and adults, an overdose of acetaminophen could lead to severe liver damage. The aim of our study was to examine the short‐term effect of phenobarbital administration on the hepatic toxicity of acetaminophen and the correlation of this effect with the alterations in P450s expression in young and adult mice. Mice were pre‐treated with saline or phenobarbital at the age of Day 10 or Day 59. 24 hours later, saline, 200 mg/kg, or 400 mg/kg acetaminophen was administered to mice. Real‐time polymerase chain reaction (RT‐PCR) was used to detect mRNA expression of P450s. Moreover, liver toxicity was evaluated based on plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Phenobarbital pre‐treatment enhanced ALT and AST levels in response to acetaminophen treatment in young and adult mice. For young mice with phenobarbital pre‐treatment, CYP1A2, CYP2B10 and CYP2C29 mRNA levels were significantly increased in male mice and the mRNA expression of CYP2B10, CYP2C29, CYP2E1 and CYP3A11 showed significant enhancement in female mice. As for adult mice with phenobarbital pre‐treatment, the mRNA expression of CYP2B10, CYP2C29 and CYP3A11 were found to go up in male and female mice, while only male mice showed a significant increase in CYP1A2 mRNA expression. In summary, our data indicate that phenobarbital pre‐treatment elevated hepatic toxicity of acetaminophen as a result of P450s induction in both young and adult mice. Therefore, much attention should be paid to the enhanced hepatic toxicity of acetaminophen when combined with phenobarbital in clinical setting.Support or Funding InformationThis study was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01GM‐118367] (to X.‐b.Z.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
In vitro Transporter Screens to Investigate Uremic Solute‐Drugs Interaction
Authors: Chang Shih‐Yu , Chapron Alenka , Imaoka Tomoki Imaoka , Yeung Catherine K 
Published: June 2021

Renal tubule secretion via transporter proteins plays a critical role in the renal clearance of drugs and endogenous compounds. We hypothesize that competition between accumulating uremic solutes and drugs for proximal tubule transport results in unpredictable drug exposure in people with kidney disease. The goal of this study was to characterize the potential of prominent uremic solutes, including hippuric acid (HA), indoxyl sulfate (IS), p‐cresol sulfate (pCS) and trimethylamine N‐oxide (TMAO), to inhibit renal tubule transport. We used penciclovir (PEN), oseltamivir carboxylate (OST) and tenofovir (TEN) in our study as model transporter substrates. We conducted systemic screens of transporter inhibition using in vitro assays, including uptake (overexpressed cell lines) and efflux (in‐side out vesicle membranes) transporters, to investigate whether uremic solutes and model drugs are potential inhibitors/substrates of renal uptake and efflux transporters involved in tubular secretion (OAT1/2/3, MRP2/4, MATE1/2K, P‐gp, BCRP). This systematic study of uremic solute ‐ drug interaction demonstrated that some uremic solutes and drugs (PEN and TEN) might compete and inhibit uptake transporters via OATs and efflux via MRPs transporters. A clearer understanding of the interactions between drugs and uremic solutes may lead to personalized approaches for the selection and dosing of medications in people with kidney disease.Support or Funding Information5 R01 GM 121354‐02 UREMIA TRANSPORTThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hepatic GSTZ1 Expression in Pregnant Ewes and Their Offspring: Influence of Treatment with Dichloroacetate
Authors: James Margaret O , Luzi Michelle , Miller Megan L , Faux Laura Rowland , Joseph Serene , Stacpoole Peter W , Keller‐Wood Maureen 
Published: June 2021

Dichloroacetate (DCA) is an investigational drug that can stimulate mitochondrial energy metabolism by inhibiting pyruvate dehydrogenase kinase. We hypothesize that DCA could be used in high‐risk pregnancy to reduce perinatal mitochondrial deficiency and resulting cardiac dysfunction in at‐risk fetuses and are testing this postulate in a pregnant sheep model. DCA is metabolized by the enzyme glutathione transferase zeta1 (GSTZ1) to glyoxylate. GSTZ1 is not expressed in human fetal liver, but expression rises after birth. Furthermore, DCA inactivates GSTZ1, resulting in altered pharmacokinetics with repeated dosing. The objectives of this research were (1) to investigate the relative expression of GSTZ1 in maternal and fetal sheep liver from untreated controls close to full term (140 days gestation) and (2) to determine if treatment of sheep with DCA resulted in reduced expression of GSTZ1. We administered DCA intravenously to either the ewe or the fetus at daily divided doses of 25 mg/kg for three to five days prior to sacrifice 24 h after the last dose. We used samples of maternal and fetal liver to prepare cytosol and mitochondria and employed a custom‐made polyclonal antibody to rat GSTZ1 to measure expression relative to a single rat hepatic cytosol standard by Western blot. The sheep liver samples exhibited good cross‐reactivity to the rat antibody. Surprisingly, expression of GSTZ1 in the full‐term fetal liver cytosol fractions from controls was similar to that in the control maternal liver. Treatment with DCA resulted in reduced expression in both maternal and fetal liver cytosol fractions to less than 10% of the control values. In control fetuses, mitochondrial expression of GSTZ1 was 17.6 ± 7.6% of the cytosolic expression. In the DCA‐treated group, mitochondrial expression decreased and levels were undetectable in one‐half of the fetal sheep. These studies demonstrate that (1) GSTZ1 expression in liver cytosol and mitochondria in the late fetal period varies with animal species and (2) repeated treatment with DCA results in reduced GSTZ1 expression, which is likely to alter DCA pharmacokinetics.Support or Funding InformationSupported in part by the US Public Health Service, grant R21HD91599This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Angiotensin II Inhibits DDAH1‐nNOS Signaling through AT1R and μOR Dimerization in the Central Nervous System to Modulate Central Control of Blood Pressure
Authors: Cheng Pei‐Wen , Sun Gwo‐Ching , Tseng Ching‐Jiunn 
Published: June 2021

AimsG protein‐coupled receptors (GPCRs) play an important role in drug therapy, and represent one of the largest families of drug targets. Blockade of angiotensin II type 1 receptor (AT1R) signaling has been shown to alleviate hypertension and improve outcomes in patients with heart failure. GPCRs formations or desensitization and trafficking can lead to pathophysiological processes. The aim of the present study was to investigate that may Ang II through induce AT1R and μOR dimerization in the NTS leads to the progress of hypertension.MethodFormation of heterodimers was assessed with proximity ligation assays. Microinjections of μOR or α2A‐AR agonists into the NTS and measured changes in BP of WKY rats. Real‐time PCR and immunoblotting analyses were used to quantify RNA and protein expression levels.ResultThe levels of μOR and α2A‐AR heterodimer were increased and the extracellular signal–regulated kinases 1/2T202/Y204, ribosomal protein S6 kinaseT359/S363, nNOSS1416 phosphorylation; DDAH1expression were abolished in the NTS of adult spontaneously hypertensive rats (SHRs), however, the overexpressed endomorphins‐2 in the NTS of SHR when compared with young SHR. Microinjection of μOR agonist into NTS induced persist presser effect of WKY rats, decreased NO production and DDAH1. Immunoblotting analysis showed that μOR agonist significantly reduced the DDAH1 activity and decreased the expression of nNOS phosphorylation. Additionally, Ang II inhibitors (losartan) significantly decreased the BP and abolished AT1R‐induced both formation of AT1R and μOR heterodimers and α2A‐AR and μOR heterodimers. Besides, also has the same founding, losartan significantly enhanced nNOSS1416 phosphorylation and DDAH1 expression. In summary, these results represent a novel finding that Ang‐II induces endomorphins‐2 and abolished DDAH1 through enhancing the formation of AT1R and μOR heterodimers formation in the NTS to progress hypertension.Support or Funding InformationThis work was supported by funding from the Ministry of Science and Technology (MOST106‐2314‐B‐037‐022‐MY2, MOST107‐2320‐B‐075B‐001) and Kaohsiung Veterans General Hospital (VGHKS107‐175) (to P.‐W. C). The authors declare that they have no competing interests.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The role of Sirt3‐AMPK in mediating oxidative stress‐induced hypertension in the brain stem nuclei of rats
Authors: Ho Chiu‐Yi , Cheng Pei‐Wen , Chen Hsin‐Hung , Tseng Ching‐Jiunn 
Published: June 2021

Essential hypertension is the most common cardiovascular disease and is a major risk factor for stroke and heart disease. It is known the nucleus tractus solitarii (NTS) located on the dorsal medulla play an important role in regulating cardiovascular responses. More recently, metabolic syndrome‐induced phosphorylated AMPK defect has been demonstrated to underline the initiation of superoxide elevation. In recent years, fructose induces a decrease in SOD2 activity, which leads to a large increase in superoxide and a decrease in the pathway of Akt‐nNOS. Studies have found that stimulation with abnormal diet factor can promote the reduction of Sirt3 and increase the content of superoxide. Therefore, we hypothesize that the SOD2 activity in the NTS was inhibited via Sirt3‐AMPK dysfunction induced superoxide expression and hypertension. During this study, the rats were fed 10% fructose with or without natural compound 3H‐1,2‐Dithiole‐3‐thione (D3T) for 4 weeks with the D3T treatment beginning at week 2. The systolic blood pressure and serum fasting high‐density lipoprotein decreased significantly in the D3T‐treated group compared fructose‐fed group after feeding D3T for 2 weeks. The protein levels of Sirt3, and AMPKT172 showed a significant increase in the D3T‐treated group compared fructose group after feeding D3T for 2 weeks by immunoblotting analyses. However, the acetylation of SOD2 were significantly decreased in the D3T‐fed group compared the fructose‐fed groups. Superoxide anion expression levels in the NTS were clearly eliminated in the D3T‐fed group compared the fructose‐fed groups. Collectively, fructose induced Sirt3 and AMPK defect and acetylation of SOD2 in the NTS of fructose‐fed rats, while treatment of D3T in the fructose‐fed rat reversed the effect. This study suggest that fructose‐induced hypertension may through Sirt3‐AMPK to mediate the acetylation of SOD2 and causes superoxide generation in the central nervous system. Our findings suggested a better understanding of complex cardiovascular neural pathways and may provide a new link between hypertension and neuronal superoxide that could be targeted for the treatment of cardiometabolic diseases.Support or Funding InformationThis work was supported by funding from the Ministry of Science and Technology (MOST‐107‐2320‐B‐075B‐002).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Type 2 Diabetic Human Coronary Vascular Smooth Muscle Cells Are Less stiff and Less Adhesive to Fibronectin
Authors: Trask Aaron J. , McCallinhart Patricia E. 
Published: June 2021

Previous data from our laboratory has demonstrated that type 2 diabetic (T2DM) coronary resistance microvessels (CRMs) undergo inward hypertrophic remodeling associated with reduced stiffness and reduced coronary blood flow in both mice and pig models. Further analysis revealed that the reduced stiffness was in part due to increased tissue elastin expression and decreased vascular smooth muscle cell (VSMC) stiffness in mice. The goal of the present study was to test the hypothesis that T2DM coronary VSMCs from humans are less stiff than normal. De‐identified, low‐passage normal and T2DM human coronary VSMCs were purchased from Lonza and ATCC for all experiments (n=4–5 per group). Using an atomic force microscope with probes coated with fibronectin (FN), a nano‐indentation protocol was used to measure cellular stiffness and adhesion to FN. Elastic modulus, a measurement of cellular stiffness, was reduced in T2DM human coronary VSMCs compared to normal (Normal: 3.60 ± 0.32 kPa vs. T2DM: 2.75 ± 0.22 kPa, p<0.05). Additionally, T2DM human coronary VSMCs were less adhesive to fibronectin compared to normal human coronary VSMCs (Normal: 58.3 ± 7.7 vs. T2DM: 43.5 ± 4.9 pN, p=0.17). Immunoblot analysis showed that T2DM human coronary VSMC expressed reduced vinculin (Normal: 1.0 ± 0.17 vs. T2DM: 0.31 ± 0.11, p<0.05) and increased cofilin (Normal: 1.0 ± 0.16 vs. T2DM: 1.8 ± 0.35, p=0.052) compared to normal human coronary VSMCs; this expression profile favors a less stiff cell phenotype given that vinculin deficient mice exhibit reduced cytoskeletal stiffness and that increased cofilin binding to F‐actin reduces stiffness. These data show that reductions in stiffness and adhesion to the ECM of diabetic CRM VSMCs may be due to underlying alterations in the cytoskeletal arrangement. Collectively, reduced stiffness in T2DM human coronary VSMCs may drive whole tissue microvascular mechanical properties to account for reduced CRM stiffness. These findings will inform future studies on the mechanisms of stiffness in the diabetic coronary circulation.Support or Funding InformationNIH R00 HL116769, NIH R21 EB026518, and Nationwide Children's Hospital to AJTThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Estrogen Receptor‐α Counterbalances the Endotoxic Inflammatory Response and Associated Arterial Baroreflex Dysfunction in Ovariectomized Rats
Authors: El‐Lakany Mohammed A , Fouda Mohamed A , El‐Gowelli Hanan M , El‐Mas Mahmoud M 
Published: June 2021

Evidence from clinical and experimental studies suggests that the female population is tolerant to inflammatory and cardiovascular anomalies of endotoxemia. In this study we investigated the possibilities that female rats are also protected against the arterial baroreceptor depressant effect of endotoxemia and that this interaction is modulated by gonadal hormones. The effect of i.v. lipopolysaccharides (LPS, 10 mg/kg) on baroreflex chronotropic activity were assessed in conscious sham‐operated (SO) female rats as well as in ovariectomized (OVX) rats supplemented with or without gonadal hormones. Baroreflex curves relating changes in chronotropic responses to increases or decreases in blood pressure evoked by i.v. doses (1–16 μg/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed and slopes of the curves were taken as measures of baroreflex sensitivity (BRSPE, BRSSNP). While LPS had no effect on baroreflex activity tested by PE in SO rats, it caused downward shifts in baroreflex curves generated by SNP and significant reductions (by ~ 25%) in slopes of the curves (BRSSNP). Compared with SO rats, significantly greater reductions in BRSSNP were caused by LPS in OVX rats (~ 50%), inferring a restraining influence for gonadal hormones on LPS‐BRSSNP interaction. The BRSSNP depressant effect of LPS in OVX rats was largely eliminated after supplementation with PPT (estrogen receptor‐α agonist), in contrast to no effect for DPN (estrogen receptor‐β agonist), estrogen, or medroxyprogesterone. Immunohistochemical studies revealed that PPT was more effective than estrogen or DPN in attenuating the LPS‐evoked increases in myocardial expressions of NF‐κB and iNOS in OVX rats. Further, the three estrogenic drugs caused comparable increases in myocardial HSP70 expression in the same rat model. None of these molecular entities was improved by medroxyprogesterone. These findings preferentially implicate antiinflammatory pathways of estrogen receptor‐α in the alleviation of baroreflex dysfunction induced by endotoxemia in female rats.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.