bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alkylated pyridyl amphiphiles display a pro‐apoptotic profile in cancerous cell lines dependent on hydrophobic chain length
Authors: Carrillo‐Alvarado Miguel Angel , Hernandez Evelyn Angel , Pardo Andrew Angel , Varela‐Ramirez Armando Angel , Noveron Juan Angel 
Published: June 2021

Cationic lipids, particularly those with nitrogen containing heterocycles, such as a pyridinium headgroup, display various bactericidal, bacteriostatic and disinfectant activity as reported in various works, all dependent on the length of their respective alkyl chains. Two quaternary alkyl pyridinium amphiphiles, vis. 4‐amino‐1‐decyl (1) and 4‐amino‐1‐dodecyl (2), were evaluated for their cytotoxic activity in a human cervical cancer cell line. These two compounds were assessed for their cytotoxicity and the following CC50's, 15.68 μM and 4.58 μM respectively were established. 1 proves to be a poor candidate as an anti‐cancer therapeutic agent as its cytotoxicity induced necrotic death. At a low concentration, 2 displayed a pro‐apoptotic profile demonstrated by phosphatidylserine externalization suggesting induction via an extrinsic pathway since it did not disrupt mitochondrial polarity. Of both compounds, 2, acts as a cell cycle progression disruptor causing slight S‐phase arrest and a decrease in G2/M phase along with eliciting DNA fragmentation. An explicit difference of two carbons between both 1 and 2 warrants further investigation to elucidate alkyl‐chain length role in anti‐cancer drugs. Furthermore, a series of these cationic amphiphiles with different lengths for their hydrophobic moiety has been synthesized and will be studied on a wider panel of cancer cell lines and have their mechanism of death further elucidated.Support or Funding InformationThe Cytometry, Screening and Imaging Core Facility that was used in this work was supported by the National Institute on Minority Health and Health Disparities (NIMHD) through a Research Centers for Minority Institutions (RCMI) grants 8G12MD007592 and 5G12MD007592, a component of the National Institutes of Health (NIH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Berberine on Insulin, GLP‐1R and DPP4 Gene Expression Levels in Streptozotocin Induced Diabetic Rats
Authors: Kilari Eswar Kumar , Swathi P 
Published: June 2021

Berberine is a quaternary ammonium compound belongs to benzylisoquinoline alkaloids. Traditionally it was used in the treatment of diabetes and associated complications. The aim of the present study was to determine the effect of berberine on antihyperglycemia, in vivo antioxidant, hepatic and lipid biomarkers and gene expressions in streptozotocin induced diabetic rats. Albino Wistar rats were induced for diabetes by streptozotocin and divided into five groups as vehicle control (group I), disease control (group II), standard gliclazide (Group III), group IV, and V received Berberine 50 and 100 mg/kg body weight respectively orally once a day for 15 days in STZ induced diabetic rats. A significant increase in blood glucose, glycosylated hemoglobin (HbA1c), altered Lipid profile (Total cholesterol, triglycerides, HDL, LDL and VLDL) and elevated hepatic serum biomarker levels (AST, ALT, ALP, total & direct bilirubin) in STZ induced diabetic rats. The berberine showed significant reduction of blood glucose and HbA1c and elevation of insulin levels in STZ induced diabetic rats. The Berberine shown to normalize the lipid and hepatic biomarkers during 15 days treatment period in all groups of treatments in a dose dependent manner in STZ induced diabetic rats. Decreased levels of in vivo antioxidant enzymes SOD, CAT, GSH and GPx in both pancreas and ileum, decreased insulin & GLP‐1R and increased hepatic DPP4 mRNA gene expression levels in STZ induced diabetic rats. Treatment with Berberine shown to elevate the pancreatic and intestinal antioxidant enzymes and increased pancreatic insulin & GLP‐1R gene expression in ileum and decreased hepatic DPP4 in STZ induced diabetic rats. The pharmacological activity of the berberine might be due to the antioxidant property and by enhancing the incretin activity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Activation of Notch signalling by soluble Dll4 decreases permeability via a cAMP/PKA‐dependent pathway
Authors: Bates David O. , Boardman Rachel , Pang Vincent , Leach Lopa , Machado Maria J. 
Published: June 2021

The Notch ligand Delta like ligand 4 (Dll4), which is upregulated by VEGF during angiogenesis, is a key regulator of vessel morphogenesis, maturation and function. It has been widely described as a regulator of tip and stalk cell selection during sprouting angiogenesis. Inhibition of Dll4 results in hyper‐sprouting, non‐functional and poorly perfused vessels, which suggests a role for Dll4 in the formation of mature, reactive, functional vessels, that have low permeability and are able to restrict fluid and solute exchange across vessel walls. We therefore tested the hypothesis that Dll4 plays a role in controlling transvascular fluid exchange. Using a recombinant protein expressing only the extracellular portion of Dll4 (soluble Dll4: sDll4), we were able to induce Notch signalling in endothelial cells (EC), resulting in an increased expression of VE‐Cadherin at intercellular junctions. sDll4 decreased permeability of FITC labelled albumin across EC monolayers and this effect was abrogated by co‐culture with DAPT. One of the known molecular effectors responsible for strengthening EC‐EC contacts is the cyclic AMP dependent protein kinase PKA, so we tested the effect of modulation of PKA on sDll4‐mediated reduction of permeability. Inhibition of PKA reversed the sDll4‐mediated reduction in permeability and reduced Hey‐1 expression. We showed that sDll4 caused a significant decrease in the hydraulic conductivity of rat mesenteric microvessels in vivo. This reduction was abolished upon co‐perfusion with the PKA inhibitor H89 dihydrochloride. These results indicate that Dll4 signalling, through Notch activation, acts upon intercellular adherens junctions through a cAMP/PKA pathway, to regulate endothelial barrier function.Support or Funding InformationSupported the British Heart FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sodium Chloride Cotransporter Upregulation in Settings of Zinc Deficiency Offers New Insight into Blood Pressure Dysregulation in Chronic Diseases
Authors: Mistry Monisha , Mallick Rickta , Mistry Abinish , Cheryian Aswathy M. , Ellis Carla L. , Ko Ben , Hoover Robert S. , Williams Clintoria R. 
Published: June 2021

BackgroundZn2+ deficiency is a common comorbidity with numerous chronic diseases including type II diabetes and chronic kidney disease. Experimental data show that Zn2+ deficiency exacerbates hypertension in these settings. Moreover, Zn2+ deficiency alone is sufficient to alter blood pressure. However, the mechanisms involved are unknown.ObjectiveThe renal distal convoluted tubule sodium chloride cotransporter (NCC) plays a critical role in blood pressure regulation and hypertension. The objective of this study was to determine if NCC plays a role in Zn2+ deficiency‐induced hypertension.Experimental DesignTo this end, WT mice were pair‐fed a diet with 50 ppm Zn2+ (Zn2+ adequate [ZnA]) or a diet with 1 ppm Zn2+ (Zn2+ deficient [ZnD]) for 6 weeks. A subset of mice was administered 50 mg/kg hydrochlorothiazide, a NCC inhibitor. To reduce intracellular Zn2+ levels in vitro, WT mouse distal convoluted tubular (mDCT‐15) cells were cultured in 1 nM N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethylenediamine (TPEN)‐ or vehicle (DMSO)‐containing medium for 24 hours. To replete intracellular Zn2+, TPEN‐exposed cells were then cultured in 1 nM Zn2+‐supplemented medium for 24 hours. Select cell monolayers were treated with 100 nM diphenyliodonium (DPI), a general NADPH oxidase inhibitor, prior to TPEN treatment. In mice, systolic blood pressure was monitored by tail cuff plethysmography. NCC protein expression was examined in vivo and in vitro via western blot and immunohistochemistry. NCC activation was assessed by cellular localization (via biotinylation and immunofluorescence) and Na+ uptake activity (via thiazide‐sensitive assays).ResultsIn ZnD mice, increased blood pressure is accompanied with enhanced NCC protein expression compared to mice receiving a ZnA‐diet. However, NCC inhibition by hydrochlorothiazide treatment reverses blood pressure increases. In the in vitro model of Zn2+ deficiency, Zn2+ chelation with TPEN stimulates NCC protein expression compared to vehicle‐treated cells. Furthermore, TPEN promotes NCC surface localization and Na+ uptake activity. Notably, restoration of intracellular Zn2+ levels by supplementation reverses TPEN effects on NCC. Additionally, NADPH oxidase inhibition with DPI treatment prevents TPEN‐induced NCC upregulation.ConclusionsOur findings indicate that NCC is a Zn2+‐sensitive transporter and is upregulated in settings of Zn2+ deficiency via a NADPH oxidase‐mediated mechanism.SignificanceNCC represents a novel mechanism by which Zn2+ deficiency alters blood pressure and contributes to hypertension in chronic disease settings.Support or Funding InformationCR. Williams (AHA‐SDG), JL. Gooch (VA‐MERIT), RS. Hoover (VA‐MERIT and NIH‐R01)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Adverse Cardiac Effects Due to Cardiac Specific Disruption of the Nuclear Receptor Corepressor 1 (NCOR1)
Authors: Zhang Jie , Vatner Dorothy E. , Vatner Stephen F. 
Published: June 2021

Disruption of the nuclear receptor corepressor 1 (NCOR1) knockout (KO), a transcriptional coregulatory, has been shown to exert only beneficial effects on disease processes, particularly in skeletal muscle, e.g., it improves exercise endurance, insulin sensitivity and reduces inflammation. The goal of this investigation was to determine if the cardiac specific NCOR1 KO also protects the heart against the stress of chronic pressure overload, induced by chronic thoracic aortic constriction. Baseline cardiac function, as reflected by left ventricular (LV) ejection fraction (EF), assessed echocardiographically, was similar in NCOR1 KO mice (62±2%) and their wild type (WT) littermates (68±1%). Surprisingly, after one week of pressure overload, induced by thoracic aortic banding, cardiac function deteriorated significantly more in NCOR1 KO than in their WT controls. LV EF was significantly less (31±7.4%), p<0.01, in NCOR1 KO than WT (59±3.1%) with higher LV end diastolic diameter (4.0±0.3 mm), compared to WT (3.4±0.2 mm). Survival rate was lower (60%) in NCOR1 KO with 1 week of pressure overload than WT, which all survived. At autopsy, lung/body weight, an index of heart failure, was also greater, p<0.01, in NCOR1 KO mice (10±0.7) vs. WT (6.5±0.4); confirmed by similar results for lung/tibial length. Histological analysis demonstrated greater fibrosis, reflecting greater cell death in NCOR1 KO compared with WT controls. Thus, the salutary features of other NCOR1 KOs could not be recapitulated in the heart with the stress of chronic pressure overload, where the cardiac specific NCOR1 KO actually fared worse with exacerbation of heart failure and mortality.Support or Funding InformationN/AThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Loss of biliverdin reductase‐A (BVRA) promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells
Authors: Adeosun Samuel O. , Gordon Daren M. , Weeks Mary‐Frances , Moore Kyle H. , Hall John E. , Hinds Terry D. , Stec David E. 
Published: June 2021

Obesity and increased lipid availability have been implicated in the development and progression of chronic kidney disease. The proximal tubule cells of the kidney are the major site of lipid accumulation in the kidney, and thus are a major target for the toxic effect of excessive lipid accumulation –lipotoxicity. The aim of the current study was to test the hypothesis that the loss of biliverdin reductase‐A (BVRA) increases the susceptibility of mouse proximal tubule cells to excess lipid accumulation and lipotoxicity. We used CRISPR‐Cas9 technology to generate a BVRA knock out (BVRA‐KO) cell line from wildtype (WT) immortalized mouse MCT proximal tubule cells. We exposed the cells for 24 hrs to 400 μM Palmitic acid (PA) and then measured lipid accumulation and markers of lipotoxicity. Lipid accumulation was 83% (p=0.0033) and 54% higher (p=0.0002) in BVRA‐KO versus WT cells at baseline and following PA treatment respectively. This suggests that both de novo lipogenesis and fatty acid uptake were higher in BVRA‐KO versus WT cells. CD36, which play a major role in fatty acid uptake, was upregulated 7.8 folds in BVRA‐KO vs. WT cells (p=0.002). In addition, NGAL1 expression, Annexin‐v FITC staining, and LDH release were all significantly higher in BVRA‐KO cells vs. WT cells, demonstrating that BVRA‐KO cells are more sensitive to PA‐induced lipotoxicity than WT cells. Phosphorylation of AKT and BAD, which play important roles in cell survival and inhibition of apoptosis, were significantly reduced by PA, only in BVRA‐KO cells (52% and 39% reduction; p=0.0019 and 0.0061 respectively). These data demonstrate the protective role of BVRA in proximal tubule cells against saturated fatty acid‐induced lipotoxicity and suggest that activating BVRA may play a protective role in obesity‐induced kidney injury.Support or Funding InformationThis work was supported by grants from the National Heart, Lung and Blood Institute K01HL‐125445 (T.D.H.), PO1HL‐051971 (D.E.S.), HL088421 (J.E.H.), and 1T32HL105324 (S.O.A) and the National Institute of General Medical Sciences P20GM‐104357 (J.E.H.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MicroRNA‐21 Antagonism Attenuates Inflammation and Endothelial‐Mesenchymal Transition in Aged Kidney Ischemia Reperfusion Injury
Authors: Pushpakumar Sathnur , Weber Gregory , Majumder Suravi , Sen Utpal 
Published: June 2021

Ischemia‐reperfusion (IR) is one of the most common causes of acute kidney injury (AKI) in the aging population. MicroRNAs (miRs) are endogenous non‐coding RNA which have the ability to target the expression of multiple genes involved in the inflammatory and repair processes, thus influencing the course of disease. Although elevation of miR‐21 following renal IR has been observed in several studies involving young animals including humans, its role in the aged kidney remains unknown. The purpose of this study was to determine whether miR‐21 contributes directly to persistent inflammation in the aged kidney following IR injury and whether its inhibition attenuates inflammation to promote repair. Because profibrotic cues originating from inflammatory cells are known to favor endothelial‐mesenchymal transition (endoMT) by activation of myofibroblasts, we also investigated whether miR‐21 inhibition reduces endoMT. Wild type (WT, C57BL/6J) mice aged 12–14 wk and 75–78 wk were used in this study. After treatment without or with Locked Nucleic Acid Anti‐miR‐21 (20 mg/kg b.w.), mice underwent bilateral renal ischemia (27 min.) followed by reperfusion for 7 days. Aged mice exhibited severe renal IR injury and anti‐miR‐21 treatment improved glomerular filtration rate, renal blood flow and decreased renal resistive index. Anti‐miR‐21 treated mice demonstrated predominance of M2 macrophages associated with increased expression of arginase‐1 and IL‐4 and reduction of inflammatory cytokines. Further, anti‐miR‐21 reduced TGF‐β, matrix metalloproteinase‐9 and collagen expression in the aged kidney. Double labeling for endothelial marker, Tie2, and fibroblast markers, FSP‐1/α‐SMA showed significant reduction in their coexpression suggesting reduction in endoMT. Our findings suggest that miR‐21 inhibition reduces macrophage mediated inflammation and endoMT to promote reparative process following IR injury in the aged kidney.Support or Funding InformationAHA grant to SP: 15SDG25840013NIH grant to US: DK104653This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Twist2 is a Novel Pro‐Fibrotic Mediator in the Aging Kidney
Authors: Parrish Alan R. , Grunz‐Borgmann Elizabeth 
Published: June 2021

Twist2 (also known as Dermo‐1) is a basic helix‐loop‐helix transcription factor that binds E‐boxes (CAnnTG) to regulate gene expression. We identified Twist2 as pro‐fibrogenic in a study testing the effects of a soy protein diet on renal dysfunction in aging Fischer 344 rats; the soy diet decreased Twist 2 expression and markedly attenuated fibrosis and loss of renal function. Furthermore Twist2, but not Twist1, expression is significantly increased in aging rats and Twist2 overexpression was inhibited by lifelong caloric restriction, which prevents renal fibrosis and dysfunction. Twist2 expression is also increased in several other models of renal fibrosis, including the mouse unilateral ureteral obstruction (UUO) model of fibrosis, and Zucker obese rats. Twist2 is predominantly expressed in the distal tubular epithelium of both mice and rats. In an effort to delineate the mechanism of Twist2 overexpression, we have shown that hypoxia increases Twist2 in mouse distal convoluted tubule cells (DCT209 cells). In addition, RNAseq analysis of a cell line constitutively overexpressing Twist2 (DCT209‐Twist2) identified overexpression of CCL2, a pro‐fibrotic mediator that has been shown to recruit fibrocytes and promote extracellular matrix production in fibroblasts, and osteopontin. Based on these data, we hypothesize that hypoxia induces Twist2 which leads to fibrosis and renal dysfunction.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 REGULATION OF SKELETAL MUSCLE FUNCTION BY MUSCLE GP130 SIGNALING
Authors: VanderVeen Brandon , Fix Dennis , Counts Brittany , Hardee Justin , Carson James 
Published: June 2021

Chronic inflammation is integral to the pathology of several chronic diseases and has been linked to muscle wasting, weakness, and fatigue resulting in reduced life quality and survival. Interleukin‐6 (IL‐6) signaling through the membrane gp130 receptor has been implicated as a regulator of skeletal muscle mass in both atrophic and hypertrophic conditions through the regulation of STAT3, MAPK, and AKT signaling. Additionally, elevated plasma IL‐6 and associative increases in IL‐6/gp130 signaling have been demonstrated to contribute to disrupted metabolic homeostasis and increased perceived fatigue during chronic disease; however, the regulation of skeletal muscle function by IL‐6/gp130 signaling has not been well described. The purpose of this study was to determine the regulation of skeletal muscle strength and fatigability by gp130 signaling. To test the role of muscle gp130 signaling on muscle strength and fatigability, male gp130 floxed (WT) mice were bred with Cre‐expressing mice driven by myosin light chain to obtain a skeletal muscle specific gp130 knockout (gp130 KO). Both WT and gp130 KO mice were electroporated with an IL‐6 plasmid into the quad to increase circulating IL‐6 for 2 weeks. Littermate controls were electroporated with an empty vector. The functional properties of the Tibialis Anterior (TA) were assessed in situ. Neither gp130 nor elevated plasma IL‐6 (>40pg/mL) had an effect on body or muscle weight. IL‐6 overexpression increased (215%) spleen weight regardless of genotype. While specific force (kN/m2) was reduced (9.8%) in gp130 KO compared to WT, elevated plasma IL‐6 had no effect on TA maximal force across all groups. Muscle fatigability was not different between WT and gp130 KO. Interestingly, elevated plasma IL‐6 increased (15.2%) muscle fatigability in the WT, but had no effect on muscle fatigability in the gp130 KO. Together these results demonstrate that increased levels of IL‐6 accelerates skeletal muscle fatigability through muscle gp130 signaling independent of changes in body weight or skeletal muscle mass.Support or Funding InformationThis work was supported by National Institute of Health (NIH) #NCI‐R01CA121249 (JAC)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Soleus and gastrocnemius tenotomy causes fiber type specific muscle atrophy in mouse tibialis anterior
Authors: Bott Kirsten N. , Watson Colton J.F. , Leveille Cameron F. , MacNeil Adam J. , Peters Sandra J. , LeBlanc Paul J. , Fajardo Val Andrew 
Published: June 2021

Examining the molecular mechanisms regulating muscle mass is critical in determining potential therapeutic strategies for preventing muscle loss in a variety of conditions. We have previously utilized a simultaneous muscle overload/unload model, whereby tenotomy of soleus and gastrocnemius tendons mechanically overloads plantaris leading to hypertrophy while unloading soleus leading to atrophy after two weeks. In this model, the foot of the tenotomized leg appears to be held in dorsiflexion, likely due to the loss of soleus and gastrocnemius muscle function, which synergistically act towards plantar flexion. Previous research has shown that dorsiflexion immobilization results in significant muscle atrophy of tibialis anterior (TA) due to an increase in inflammation and polyubiquitylation. Therefore, the present study examined whether TA muscles from the tenotimized leg would also display significant muscle atrophy, and whether increased inflammation and polyubiquitylation would contribute to the muscle loss. We also examined glycogen synthase kinase 3 (GSK3) activation, given this enzyme's role in promoting polyubiquitylation and muscle atrophy. Ten male C57BL/6N mice (28.1 ± 0.8g) were subjected to soleus and gastrocnemius tenotomy (TN) in one leg, while the other leg was subjected to a sham surgery to serve as an internal control (CON). Two‐weeks post‐surgery the mice were euthanized and the TA muscles were collected. On average, TA muscles in the TN leg were smaller compared to the CON leg (CON, 60.0 +/− 2.0 mg vs TNY 52.8 +/− 2.2 mg, p<0.01), suggesting muscle atrophy was occurring in the TN leg. Using immunofluorescent fiber typing, it was found that this was due to a selective reduction in myofiber cross‐sectional area of type IIB (CON 4091± 275 μm2 vs. TN 3599± 193 μm2, p<0.01) and type IIX‐IIB (CON 3281± 243 μm2 vs. TN 2933± 262 μm2, p<0.05), without any significant reductions in total number of myofibers or fiber type distribution. H&E staining showed some centralized nuclei with no signs of mononuclear cell infiltration in the TN TA. Correspondingly, no significant changes in mRNA expression of IL‐6 and TNFa inflammatory cytokines were observed in TN TA. However, we did observe a 1.9‐fold (p<0.05) increase in polyubiquitylated proteins and higher GSK3 activation as revealed by a 30% reduction in phosphorylated GSK3 (relative to total GSK3; p<0.05) in the TN TA compared to CON. In conclusion, TA muscle undergoes a selective atrophy of fast‐glycolytic fibers in response to soleus and gastrocnemius TN, and this may be due to GSK3 activation and polyubiquitylation. Future studies should investigate whether GSK3 represents a viable therapeutic target in this model.Support or Funding InformationNSERCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.