bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOC2B enhanced muscle insulin sensitivity by interacting with cytoskeletal proteins
Authors: Zhang Jing 
Published: June 2021

Strategy to enhance skeletal muscle insulin sensitivity is a primary way to substantially reduce the risk of diabetes. Evidences have shown that whole‐body DOC2B over‐expressing mice have enhanced peripheral insulin sensitivity. However, the level of contribution of skeletal muscle specific DOC2B accounting for this enhancement and the underlying mechanism remain unclear. Towards this, we generated a new tetracycline/doxycycline (DOX)‐inducible skeletal muscle specific DOC2B over‐expressing mouse model and demonstrated that the DOC2B enrichment in skeletal muscle is sufficient to enhance peripheral insulin sensitivity as well as whole‐body glucose tolerance. Inaddition, DOC2B overexpressing mice exhibited an increase in insulin‐stimulated GLUT4 accumulation at the plasma membrane and this effect of DOC2B overexpression on promoting insulin stimulated GLUT4 translocation was further confirmed in L6 skeletal muscle cells. Importantly, DOC2B overexpression was sufficient to restore GLUT4 translocation in cells rendered insulin resistant. Proteomic analyses and co‐immunoprecipitation indicate that DOC2B interacts with cytoskeletal proteins. We also found that insulin stimulation phosphorylates DOC2B, which enhances the binding of DOC2B to cytoskeletal proteins to promote GLUT4 translocation and glucose uptake. These results support DOC2B as a potential drug target to restore insulin sensitivity in pre‐diabetic and type 2 diabetic individuals.Support or Funding InformationThis work was supported by grants from the NIH/NIDDK (R01 DK067912; R01 DK102233, to Dr. Debbie Thurmond and the American Heart Association (17POST33661194) to Dr. Jing Zhang. Additional financial support was provided to Dr. Debbie Thurmond.: the Ruth and Robert Lanman Endowment, the George Schaeffer award, and an Excellence award, through the City of Hope.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Elevated PBMC‐derived oxidative stress in healthy young African American women
Authors: Johnson Auburn L. , Vranish Jennifer R. , Kaur Jasdeep , Liu Xian , Blankenship Jeanette K. , Pan Zui , Fadel Paul J. 
Published: June 2021

Several studies have demonstrated that African Americans (AA) exhibit elevations in systemic oxidative stress compared to Caucasian Americans (CA). Peripheral blood mononuclear cells (PBMCs) have been identified as one of the primary contributors to systemic reactive oxygen species (i.e. oxidative stress) and may be an underlying mechanism for the development of hypertension and cardiovascular diseases. Previous work demonstrates that young healthy AA men have elevated PBMC‐derived superoxide production when compared to CA men. However, whether PBMC‐derived superoxide production is also elevated in young healthy AA women remains unknown. This is important because AA women are also more likely to develop hypertension and cardiovascular diseases than women of any other race. Accordingly, this study investigated PBMC‐derived superoxide production in young healthy AA and CA women. We tested the hypothesis that, relative to CA women, AA women would exhibit greater levels of PBMC‐derived oxidative stress. In ten normotensive AA women and ten age‐matched normotensive CA women, resting intracellular superoxide levels were assessed from freshly isolated PBMCs using dihydroethidium fluorescence. Subjects arrived to the lab following an overnight fast. Resting blood pressure was measured following a 10‐minute rest period and a 50‐mL venous blood sample was then drawn. PBMCs were isolated from whole blood using density gradient centrifugation and intracellular superoxide was assessed using dihydroethidium fluorescence. Resting mean arterial pressure was similar between groups (AA 82.9±1.7 vs. CA 79.4±2.4 mmHg; P =0.26) however the resting intracellular superoxide production was elevated in AA women compared to CA (AA 4.1±1.9 vs. CA 2.7±1.0 Relative Fluorescent Units; P=0.025). These preliminary findings suggest that young AA women exhibit greater resting PBMC‐derived superoxide production. Thus, PBMCs may represent a source of elevated oxidative stress in AA women.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Blockade of glutamate receptors abolishes the sensitization of the angiotensin II‐elicited hypertensive response in rats
Authors: Xue Baojian , Beltz Terry G. , Guo Fang , Johnson Alan Kim 
Published: June 2021

Angiotensin (ANG) II‐elicited hypertension is associated with neuroplasticity of glutamate receptors (GluRs) in the brain nuclei involved in blood pressure regulation including the lamina terminalis (LT) and hypothalamic paraventricular nucleus (PVN). Using the Induction‐Delay‐Expression (IND‐DEL‐EXP) experimental paradigm, our previous studies demonstrated that administration of a subpressor dose of angiotensin (ANG) II (10 ng/kg/min) during IND sensitizes subsequent ANG II (120 ng/kg/min)‐elicited hypertension during EXP. This subpressor dose of ANG II also induced increased phosphorylation of the GluN1 subunit in LT structures. The present study investigated whether the blockade of GluRs during IND abolishes sensitization of subsequent ANG II‐elicited hypertension. We found in the rat that the sensitized ANG II hypertensive response produced by a subpressor of dose ANG II given during IND was blocked by co‐administration of either MK‐801 (sc) or of (2R)‐amino‐5‐phosphonovaleric acid (a.k.a. AP5, icv). Moreover, ANG II‐induced upregulation of mRNA expression of several renin‐angiotensin system (RAS) and proinflammatory components in the LT and PVN was also attenuated. These results indicate that central nervous system (CNS) neuroplasticity associated with hypertension response sensitization requires NMDA‐R activation. Furthermore, the inhibitory effect of NMDA‐R blockade on hypertension response sensitization is associated with reducing upregulation of prohypertensive components of the brain RAS and of inflammatory mediators in the CNS.Support or Funding Informationthe National Institutes of Health grants HL‐14388, HL‐84207 and HL‐98207.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evidence that Zinc Deficiency Impairs Gut Epithelial Barrier and intestinal Immunity
Authors: Sarkar Paramita , Saha Tultul , Aoun Joydeep , Chakraborty Subhra Hoque , Chakrabarti Manoj K. , Dutta Shanta K. , Hoque Kazi Mirajul 
Published: June 2021

There is growing interest in dietary factors, in particular micronutrients, from the perspective of disease pathogenesis and potential for treatment. Diarrheal disease in infant results in abnormally low concentrations of serum zinc. Zinc has been tested for its ability to treat and prevent diarrheal diseases in many large field trials over a period of over 4 decades and has generally been found effective. The mechanism by which zinc deficiency causes diarrhea is not known. The present study investigated the impact of zinc deficiency on the host, particularly of intestinal tight junction (TJ) integrity and proteins that are involved in intestinal absorption and secretion along with the pathogenesis of enteric infection. We have used human colonic T84 cells to study barrier function and Shigella to test susceptibility of intestinal infection due to zinc deficiency. T84 grown onto transwell inserts in zinc deficient media showed a low transepithelial electrical resistance (TEER) compare to zinc sufficient media (1014 ± 165 Ω.cm2 vs 3663 ± 293 Ω.cm2) in confluent T84 monolayers. We furthermore analysed the correlation between TEER and paracellular ionic conductance. We found that zinc deficiency altered paracellular ionic conductance. Bacterial transmigration studies showed a significant increase in apico‐basolateral transmigration of Shigella (6.58 ± 0.13 vs 7.98 ± 0.23 log10 CFU/ml) which peaked at 6hrs post infection. Transmission electron microscopy data showed widened TJ complex due to few membrane fusion proteins and distorted TJ morphology, whereas the desmosomes were still intact. Electrophysiological studies with Ussing chamber and qPCR quantification demonstrated reduced cAMP dependent electrogenic Cl− secretion (34.5 ± 1.25 μA/cm2 vs 17.75 ± 2.3 μA/cm2) along with reduced expression of CFTR in zinc deficient cells, resulting dehydrated lumen thus aiding in bacterial colonization. Our results suggest that zinc deficiency caused (1) perturbed barrier function and integrity (2) altered Cl− secretion leading to susceptibility of infection. We conclude that adequate zinc is required to maintain intestinal barrier health to avoid risk against intestinal infection.Support or Funding InformationGovt of India National Funding AgencyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Na+ transporters, electrolyte excretion and renal injury in female and male C57Bl/6 and IL17A−/− mice during AngII hypertension
Authors: McFarlin Brandon E. , McDonough Jillian C. , Ralph Donna Lee , Veiras Luciana C. , Madhur Meena S. , McDonough Alicia A. 
Published: June 2021

Experimental AngII hypertension is reported to be blunted in female (F) vs. male (M) mice and in mice lacking the inflammatory cytokine IL17A (time point dependent). This study aimed to determine how sex impacts renal Na+ transporters, Na+ and K+ excretion, and markers of renal injury during AngII hypertension (A) in both C57Bl/6 (WT) and IL17A−/− (IL17−/−) mice.11–16 wk old F and M mice were infused with AngII (490 ng/kg/min) or sham treated for 3 wk (n=6/group). Rate of excretion of a saline load (10% b.wt. subcutaneous) was slowed in all AngII infused groups, indicating Na+ reabsorption activation. Blood pressure (BP), by tail cuff, increased similarly across groups (in Δ mmHg): WTMA: 40 ± 1.6, WTFA: 37 ± 10, IL17−/−MA: 37 ± 3.8, IL17−/−FA: 46.4 ± 4.7. Thus, no blunting of hypertension was detected at 3 wk time point by tail cuff in F or in IL17−/−.In both M and F WT and IL17−/−, AngII provoked activation (‐phosphorylation) of NKCC2 and NCC, and activation of ENaC (more ‐cleaved (Cl), less full length (FL)). These distal anti‐natriuretic responses were balanced by natriuretic responses including: decreased abundance of proximal NHE3, NaPi2, and decreased medullary thick ascending limb NHE3, NKCC2 and NaK‐ATPase (see Figure). We previously proposed that increased ‐NCCp is a secondary compensation, driven by AngII activation of ENaC, to minimize K+ secretion (PMID27600183). Providing further support for this idea, urinary Na/K ratio (UNa/K), collected overnight (during fasting +water), was significantly reduced by AngII (WTM: from 0.71 ± 0.1 at baseline to 0.41 ± 0.9 with AngII, WTF: 0.80 ± 0.1 to 0.28 ±0.05, IL17−/−M: 0.99 ±0.13 to 0.41 ± 0.041, IL17−/−F: 1.05 ± 0.07 to 0.46 ± 0.46). UNa/K fell due to decreased o/n UNa as o/n UK was unaltered by AngII. Urine volume (V), unaltered by AngII treatment, was 2‐fold higher in M vs. F of both genotypes, and 2‐fold higher in IL17−/− vs. WT within each sex.During AngII, the injury marker U albumin increased across groups. Renal cortical angiotensinogen was lower in IL17−/− vs. WT (by 50% in F and 25% in M). KIM1 also tended to be lower in IL17−/− vs. WT in both sexes during AngII.From these results, we propose: AngII stimulation of ENaC drives UK secretion which activates NCCp (more in WT than IL17−/− males), thus reducing UNa to limit K secretion and lowering UNa/K which may contribute to BP elevation. IL17−/− mice exhibit higher UV and lower intrarenal angiotensinogen and KIM1 which suggests less tissue injury.Support or Funding InformationAHA GIA (15GRNT23160003) and an NIH NIDDK R01 (DK083785) to A.A. McDonough, NIH NHLBI K08 award (HL121671), Gilead Cardiovascular Scholars Grant, and NIH DP2 award (HL137166) to M.S. MadhurThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MicroRNA‐146a Deficiency Promotes Atherosclerosis by Dysregulating Cholesterol Homeostasis in Macrophages
Authors: Chen Li‐Jing , Huang Yi‐Hsuan , Shih Ting‐Ying , Chien Shu , Chiu Jeng‐Jiann 
Published: June 2021

Atherosclerosis is a chronic inflammatory disease that results from imbalance of high‐density lipoprotein (HDL) cholesterol metabolism and a maladaptive immune response driven by the accumulation of cholesterol‐laden macrophages in the artery wall. MicroRNA‐146a (miR‐146a) serves as anti‐inflammatory function in a variety of cell types, but the underlying mechanisms of miR‐146a in atherosclerosis still remain unclear. In the present study, we assessed the impact of the genetic deficiency of miR‐146a in a mouse model of atherosclerosis and determined the miR‐146a‐mediated balance of cholesterol metabolism in macrophages. In comparison with miR‐146a+/+ApoE−/− mice fed with high‐cholesterol diet for 10 weeks, miR‐146a−/−ApoE−/− mice showed an increase number and area of atherosclerotic plaques, lipid content, pro‐inflammatory cytokines and abundant macrophages accumulated in the plaques. In addition, miR‐146a−/−ApoE−/− mice also showed decrease in HDL levels. Bone marrow chimera experiments indicated a major effect of miR‐146a deficiency on lesional macrophages. Bone marrow derived‐macrophages (BMDMs) were isolated from miR‐146a−/−ApoE−/− and miR‐146a+/+ApoE−/− mice to stimulated with oxidized low‐density lipoprotein (oxLDL). In comparison with BMDMs of miR‐146a+/+ApoE−/−, BMDMs of miR‐146a−/−ApoE−/− showed a significant oxLDL uptake and reduction in cholesterol efflux capacity. The expression of cholesterol transporters, including the ATP‐binding cassette sub‐family A1 (ABCA1) and sub‐family G1 (ABCG1) were significantly decreased in BMDMs of miR‐146a−/−ApoE−/−. By using the global gene expression analysis and argonaute‐2 immunoprecipitation, we demonstrated that toll‐like receptor 4 (TLR4) is directly targeted by miR‐146a. Overexpression of miR‐146a and silence of TLR4 not only increased the expression of ABCA1 and ABCG1, but also increased the cholesterol efflux capacity and reduced the oxidized LDL uptake. These data demonstrated that miR‐146a is involved in regulation of ABCA1 and ABCG1 by targeting TLR4, and that maintains the balance of HDL cholesterol metabolism to protect against the atherosclerosis. MiR‐146a is a potential target in treatment of atherosclerotic vascular disease.Support or Funding InformationMOST 104‐2321‐B‐400‐020‐MY3 (to L.‐J. C.) and MOST 104‐2321‐B‐400‐017 (to J.‐J. C.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Improvement in Glucose Tolerance in Mice Fed a High‐fat Diet with a Low Omega‐6:Omega‐3 Ratio is Associated with Changes in Gut Microbiota
Authors: de Almeida‐Suhett Camila Pinheiro , Crott Jimmy , Graham Alice , Deuster Patricia 
Published: June 2021

Chronic consumption of a high‐fat diet (HFD) contributes to excessive weight gain and development of metabolic alterations, such as glucose intolerance. It also leads to changes in the gut microbiota, which recent findings suggest are associated with impaired glucose metabolism1. Although supplementing with omega‐3 polyunsaturated fatty acids (PUFAs) has been previously shown to affect glucose tolerance and the gut microbiota, the effect of increasing the amount of omega‐3 and lowering the ratio of omega‐6 to omega‐3 (O‐6:O‐3) PUFAs in a HFD has not been determined. Additionally, the association between improvement in glucose tolerance and changes in the gut microbiota in response to omega‐3 PUFAS needs to be investigated. In the present study, a HFD was modified to adjust the O‐6:O‐3 ratio to 1:1 by increasing the amount of omega‐3 PUFAs. Changes in glucose metabolism, gut microbiota and the association between these two outcomes were then investigated.Objectives(1) Determine the impact of reducing the dietary ratio of O‐6:O‐3 in HFDs on glucose tolerance. (2) Investigate the association between changes in the gut microbiome and glucose metabolism.MethodsC57BL/6J male mice were fed for 18 weeks either (a) standard chow (SD − 18% fat; (b) HFD (60% fat–10:1 O‐6:O‐3) or (c) omega‐3 enriched HFD diet (O3 −60% fat–1:1 O‐6:O‐3). After 16 weeks, they underwent glucose tolerance testing. Fecal samples were collected for microbiome analysis by 16S rRNA sequencing.ResultsSD mice gained less weight (13.1±0.4 g) when compared to HFD (26.0±1.1 g) and O3 mice (24.5±0.8 g). The area under the glucose tolerance curve (AUCglu) was lower in SD (44,106±1,081 mg/dL/hr) and O3 mice (45,542±2,873 mg/dL/hr) compared to HFD mice (66,193±1,947 mg/dL/hr; p<0.0001). The ratio of Firmicutes:Bacteroidetes in O3 mice (19.6±3.1) was lower than in HFD (36.6±5.3; p<0.0) and higher than in SD mice (2.3±0.5; p<0.01). Relative abundance of Firmicutes positively correlated with AUCglu (R=0.55; R2=0.316; p<0.0001). Relative abundance of Bacteroidetes negatively correlated with AUCglu (R=−0.51; R2=0.26; p<0.0001). The ratio of Firmicutes:Bacteroidetes positively correlated with AUCglu (R=0.59; R2=0.35; p<0.0001).DiscussionReducing the ratio of O‐6:O‐3 in a HFD from 10:1 to 1:1 prevented development of glucose intolerance regardless of excessive weight gain, and reduced the ratio of Firmicutes:Bacteroidetes in the gut microbiota. Additionally, correlation analyses show a strong association between changes in the microbiome and improvement in the glucose metabolism. Further analyses are needed to identify which specific family/genus in each phylum are driving this relationship.Support or Funding InformationCenter Alliance for Nutrition and Dietary Supplement ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
AMP‐activated protein kinase in muscle is essential in ketone body utilization
Authors: Bedarida Tatiana , Han Young‐Min , Wu Yue , Liu Zhaoyu , Song Ping , Zou Ming‐Hui 
Published: June 2021

BackgroundStarvation leads to a series of metabolic adaptations that enables continuous production and delivery of nutrients to critical organs, tissues and cells. Under conditions of nutrient withdrawal, ketone bodies provide an alternative source of energy for highly oxidative tissues. Although the AMP‐activated protein kinase (AMPK) is best known as a sensor of cellular energy status, its implication in ketone regulation remains unclear.ObjectiveThe aim of this study was to evaluate the effects of AMPKα2 on ketone body utilization, and to elucidate the underlying mechanisms.MethodsGlobal AMPKα2 knockout mice (AMPKα2−/−), muscle‐specific AMPKα2 knockout mice, and their age‐matched wild type (WT) littermates were subjected to either 3‐day fasting or received an intra‐peritoneal injection of β‐hydroxybutyrate salt (1.5 mg/kg body weight) to assess the β‐hydroxybutyrate consumption.ResultsFasting blood and urine ketone levels were significantly elevated in AMPKα2−/− mice when compared to their littermate WT mice. After an intra‐peritoneal bolus of β‐hydroxybutyrate, the main circulating ketone body, AMPKα2−/− mice presented a lower clearance of β‐hydroxybutyrate compared to their littermate WT mice. Further, fasting induced hyperketosis without any change in body weight or glycaemia in muscle‐specific AMPKα2 knockout mice. Consistently, these mice displayed impaired ketone utilization after β‐hydroxybutyrate injection. Furthermore, AMPKα2 deficiency in muscle significantly decreased locomotor activity, with a quicker switch from utilizing carbohydrate to fat as the predominant energy source compared to their littermate WT mice. Mechanistically, AMPKα2 deficiency in muscle presented a 50% reduced activity of succinyl‐CoA:3‐oxoacid CoA transferase compared to their littermate WT mice.ConclusionTaken together, these findings establish AMPKα2 in muscle as an essential mediator of ketolysis in fasting, through the regulation of the rate‐limiting ketolytic enzyme.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Testosterone Supplementation Does Not Affect Skeletal Muscle Growth When Administered Alone in Either Sex and Requires an Additional Anabolic Stimulus to Exert Its Effects in Female Mice
Authors: Davidyan Arik , Baar Keith , Bodine Sue C. 
Published: June 2021

Testosterone (T), the main androgenic hormone, is thought to positively affect skeletal muscle mass and function. The anabolic effects of T have been attributed to its effects on satellite cell proliferation and differentiation as well as its activation of pathways downstream of the IGF‐1 receptor and AKT. The role of T activity in skeletal muscle health and growth however remains equivocal, with some studies showing T to have great importance in muscle hypertrophy, while others suggest a limited role or no significant effect. Considering the increased use of chemical castration as a treatment for prostate cancer, and the growing use of testosterone in the elderly population, there is a growing need to establish T's role on skeletal muscle in relation to sex and age. Therefore, the aim of this project is to delineate molecular pathways that are affected by T as well as the phenotypic outcome of T treatment in skeletal muscle.The effects of supra‐physiological levels of T, in the form of subcutaneously implanted slow‐release T pellets, on muscle mass and strength were determined in 5‐month‐old male and female C57Bl6 mice. Mice were subjected to 3‐weeks of treatment and analyzed for muscle mass, plantar‐flexor strength, protein synthesis and degradation, and mTORC activity. Under free living conditions, T supplementation has no effect on mass of the TA, gastrocnemius, or quadriceps muscles in either sex; nor did it result in a gain in ankle extensor torque. In addition, T supplementation resulted in no significant changes in proteasome activity or whole muscle protein synthesis.To determine whether T has a greater effect on skeletal muscle mass when combined with increased load, we utilized the functional overload (FO) model, removing both the gastrocnemius and soleus muscles, in both sexes. Female mice that underwent FO and were supplemented with T for two weeks showed 94.6% ± 12.2% greater hypertrophy in the plantaris muscle compared to those that were not supplemented. However, in male mice T supplementation in addition to FO failed to significantly increase the plantaris mass when compared to those that only underwent FO. Fiber cross sectional area analysis of the investigated muscles compliments these phenotypic results. Together these data suggest that an additional and concurrent stimulus may be required for T to exert an anabolic effect in skeletal muscle of female mice. Additionally, T supplementation to male mice does not provide a beneficial effect when administered alone or together with increased load.Support or Funding InformationUC Davis Clinical and Translational Science CenterThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.