bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ubiquitous inactivation of TRPM4 leads to elevated blood pressure in mice
Authors: Mathar Ilka , Vennekens Rudi , Meissner Marcel , Flockerzi Veit , Schweda Frank , Freichel Marc 
Published: June 2021

Recently we showed that transient receptor potential TRPM4 proteins act as Ca2+‐activated nonselective cation channels in mast cells that critically limit the driving force for Ca2+ influx, release of inflammatory mediators and anaphylactic responses. In addition to mast cells we detected TRPM4 proteins in heart, aortic endothelial cells, kidney and adrenal gland from mice. Earley et al suggested that TRPM4 is expressed in vascular smooth muscle cells and it is supposed to act as a mechanosensor regulating vascular myogenic tone.Telemetric blood pressure measurements reveal that mean arterial blood pressure (MAP) is elevated in TRPM4‐/‐ mice by 11mmHg under basal conditions. Blood pressure elevation is observed during the complete circadian period and most notable under resting conditions. Plasma aldosterone levels, renin mRNA expression in the kidney and renin plasma concentrations are not different in TRPM4‐/‐ mice and there are no differences in MAP in response to application of phenylephrine (PE), norepinephrine and L‐NAME. PE induced contraction and acetylcholine induced relaxation of aortic rings is not altered. Currently we analyse the contractility of resistance vessels with respect to smooth muscle‐dependent contraction and endothelium‐dependent relaxation. Inhibition of ganglionic transmission with hexamethonium abolishes the difference in MAP between both genotypes similarly like application of prazosin. Analysis of plasma catecholamine level revealed a significant elevation of epinephrine in TRPM4‐/‐ mice. These results suggest that an increased neurogenic tone contributes to the development of the hypertension.
Identification of the 14‐3‐3/HIP‐55 protein complex as a negative regulator of HPK1 in the Akt signaling
Authors: Li Zijian , Shi Zhi , Park Hae Ryoun , Li Zenggang , Fu Haian 
Published: June 2021

HIP‐55 (hematopoietic progenitor kinase 1 [HPK1]‐interacting protein of 55 kDa) is a multidomain protein that contains an actin‐binding domain at its N terminus and an SH3 domain at its C terminus. It functions in part through controlling the HPK1 function, which appears to be important for organ development and immune response. HIP‐55 de&#64257;ciency caused abnormal structure and function of multiple organs, including the spleen, heart, and lung in both heterozygous and homozygous mice. Here report the identification of a novel HIP‐55 partner protein, 14‐3‐3, with a proteomic approach from lung epithelial cells. We found that the HIP‐55/14‐3‐3 interaction is controlled by Akt. Mutational analysis revealed Ser‐269 and Thr‐191 as critical sites for Akt phosphorylation, which are essential for mediating 14‐3‐3 binding. While HIP‐55WT(wide‐type) decreased the kinase activity of HPK1, mutant HIP‐55 that is defective in Akt phosphorylation and 14‐3‐3 binding failed to inhibit HPK1. This study couples the HIP‐55/HPK1 regulatory axis to an Akt‐mediated signaling pathway and identifies a novel mechanism by which HIP‐55 suppresses HPK1 in an Akt/14‐3‐3‐dependent manner. Our findings reveal a novel Akt‐regulated signaling mechanism that controls HPK1 mediated functions, such as organ development, immune response, and tumorigenesis.This work was supported by Emory Global Health Institute and NIH PO1 CA116676.
Identification of a Novel Regulatory Element Controlling ASK1‐JNK Signaling
Authors: Puckett Mary Clark , Cockrell Lisa M , DeSimone Mia , Vellano Chris , Fu Haian 
Published: June 2021

Jun N‐terminal kinase (JNK) plays a key role in mediating diverse signaling events and controls a number of important cellular processes such as apoptosis, proliferation, metabolism, and DNA repair. Dysregulated activation of JNK signaling has been implicated in numerous disease states, including neurodegenerative diseases, chronic inflammatory disease, ischemia, diabetes, and cancer. Thus, understanding how JNK is regulated may lead to the development of novel therapeutic strategies. Our research focuses on the ASK1 signalosome, an upstream kinase complex that controls JNK activity. Here we report the identification of a novel regulatory element between ASK1 and its associated protein kinase, ASK2. Using protein complex pull‐down assays coupled with mutagenesis, we have conclusively established a ternary protein complex composed of ASK1, ASK2, and 14‐3‐3. The ASK1/ASK2 interaction is essential for 14‐3‐3 association. Through deletion mapping and binding assays, we have identified a critical sequence in ASK2 needed for the ASK1/ASK2 interaction. Expression of this regulatory sequence disrupted the ASK2/ASK1 interaction and inhibited JNK activation in response to stress signals, including hydrogen peroxide. These data established the importance of ASK2 in the ASK1 signalosome for JNK regulation and revealed a regulatory element essential for the control of ASK1‐JNK signaling. The ASK1/ASK2 interface may offer a therapeutic target for manipulating JNK signaling. The identified ASK2 sequence may serve as a basis for the development of novel JNK signaling modulators.The work was supported by NIH P01 CA116676.
Serotonin 5‐HT1A‐like, 5‐HT2, and 5‐HT7 Receptors Modulate Learning and Memory in Drosophila
Authors: Johnson Oralee , Becnel Jaime , Nichols Charles D 
Published: June 2021

Serotonin is a neurotransmitter involved in many behaviors in mammals including regulation of mood, appetite, sleep, memory, aggression, and sexual behavior. In the fly, serotonin has also been demonstrated to be involved in many of these same complex behaviors. The effects of serotonin are primarily mediated through interactions with G‐protein coupled receptors to initiate multiple signal transduction pathways. Drosophila expresses orthologs of four mammalian 5‐HT receptor subtypes: 5‐HT1ADro, 5‐HT1BDro, 5‐HT2Dro, and 5‐HT7Dro. Here, we present data demonstrating involvement of all three serotonin receptor families in olfactory learning and memory in the fly.We probed the involvement of the 5‐HT1A‐like, 5‐HT2, and 5‐HT7 receptors in short‐term memory in the fly. The 5‐HT1A receptor agonist U92106A and the 5‐HT1A receptor antagonist WAY100635 reduced performance indices in a dose‐dependent manner. The 5‐HT2 receptor agonist DOI, and the 5‐HT2 receptor antagonist ketanserin also abated performance indices in a dose‐dependent manner (IC50 value for DOI = 0.21 mM). A putative 5‐HT7 receptor antagonist SB 269970, also diminished performance levels. Since both agonists and antagonists for a given receptor inhibit performance, a homeostasis likely exists at each receptor, and perturbation of homeostasis disrupts this behavior.Research support: NIMH grants 5R21MH078454‐02 and 3R21MH078454‐01A1S1
An Elevated Fibrinogen Increases Matrix Metalloproteinases Activity in Cardiac Microvascular Endothelial Cells
Authors: Patibandla Phani Kumar , Tyagi Neetu , Tyagi Suresh C. , Dean William L. , Roberts Andrew M. , Lominadze David 
Published: June 2021

Cardiovascular diseases such as hypertension, diabetes, and stroke are accompanied by increased blood fibrinogen (Fg) content. Increased levels of Fg is considered to be a high cardiovascular risk factor. We previously showed that elevated concentration Fg causes arteriolar constriction through release of endothelin‐1 (AJP, 2005; 288: H1257‐H1264) and increases endothelial cell (EC) layer permeability through formation of filamentous actin (Mol. Cell. Biochem, 2008; 307: 13‐22). To further investigate the mechanisms of Fg effects on microvascular permeability, we tested the hypothesis that Fg may be involved in vascular remodeling by activating matrix metaloproteinases (MMPs). Rat cardiac microvascular endothelial cell (RMVEC) cultures were treated with one of the following for 24 h: Fg (2 or 4 mg/ml), Fg (4 mg/ml) with MMP inhibitor GM6001 (1 μM), or medium (control). Activation of MMPs in the subendothelial matrix after addition of MMP substrate was assessed by measuring fluorescence intensity of the medium using a fluorometer. Activation of MMP9 was determined by an MMP9‐specific ELISA kit. Fg caused a dose‐dependent increase in activation of MMPs in the medium (97 ± 6 and 137 ± 12 fluorescence intensity units, FIU with 2 and 4 mg/ml Fg respectively, vs. 82 ± 6 FIU for control, mean±SE). Formation of active MMP9 was increased by 4 mg/ml of Fg (0.054 ± 0.001 ng/ml vs. 0.034 ± 0.004 ng/ml for control). Activation of MMPs by this dose of Fg was inhibited by GM6001, a nonspecific MMP inhibitor. These data suggest that an increased level of Fg induces activation of MMPs, and thus, may be a mechanism for the Fg‐induced increased EC layer permeability seen earlier.Supported by NIH grant # HL080394 to DL.
heparin inhibits injury‐induced femoral artery remodeling in mouse Via CD44
Authors: Zhao Gaofeng , Kolliputi Narasaiah , Zhao Hang , Beagle John , Yu Lunyin , Syrkina Olga , Leu Shawwei , Hicham Mrabat , Hales Charles 
Published: June 2021

BackgroundPrevious studies have indicated heparin which has both anti‐coagulant and anti‐proliferative properties, may be used as a possible therapeutic agent for the treatment of post‐angioplasty restenosis. CD44 is the receptor of hyaluronan and plays essential roles in many aspects including SMC proliferation, inflammation and injury repair. This study investigates the effects of heparin on injury‐induced femoral artery remodeling and the expression of CD44 , to illuminate the molecular mechanism by which heparin blocks injury‐induced femoral artery stenosis.HypothesisHeparin decreases injury‐induced femoral artery remodeling through the CD44 signal pathway,MethodsThe injury‐induced artery remodeling model was prepared in wild‐type and CD44 knock‐out mice by inserting a straight spring wire into the femoral artery via arterioctomy in a small muscular branch. Then mice were treated with heparin by subcutaneous injection at a dose of 20mg/kg once a day. 4 weeks later, we sacrificed the mice for assessment of histology of the injured femoral artery and for the expression of CD44.ResultsIn wild‐type mice, heparin significantly decreased femoral artery remodeling, and western blot showed heparin could markedly promote CD44 expression in the injured arteries. In contrast with wild‐type mice, CD44 deficient mice demonstrated considerable greater arterial remodeling, which when treated with heparin, no longer showed any significant reduction in vascular remodeling.ConclusionHeparin can decrease injury‐induced femoral artery remodeling, at least partially, by upregulating the expression of CD44.
Decreased arterial distensibility in patients with systemic lupus erythematosus
Authors: Lanphere Kathryn Rosie , Sharrar Janeen M , Sibbitt Wilber L , Roldan Carlos R , Greene Ernest R 
Published: June 2021

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease that is atherogenic. Arterial distensibility (AD) is a risk factor and an independent predictor of cardiovascular morbidity and mortality. Importantly, AD can be easily determined noninvasively with hand held, portable, low power, and relatively inexpensive equipment. Operator training is required, but minimal. Nevertheless, an association between SLE and AD has not been reported. Accordingly, we tested the hypothesis that patients with SLE would have a significantly (p<0.05) decreased AD when compared to healthy controls. We used noninvasive, high spatial resolution, 10 MHz, image‐guided, M‐mode sonography to measure maximal systolic and minimal diastolic diameters and diastolic intima‐media thickness (IMT) at 3 sites in the right common carotid artery of 17 SLE patients and 51 healthy age and gender matched controls. In the one blinded observer, the 95% confidence levels for accuracy and precision for noninvasive tonometric blood pressures and sonographic diameters were ~5mmHg and ~0.15mm, respectively. The calculated values for AD were determined by standard arterial mechanical models and algorithms. Results are given as X/SD with *= p<0.05 versus controls:These preliminary data suggest that AD is significantly (p<0.05) decreased in young patients with SLE. Thus, arterial distensibility may be an efficient and inexpensive marker of clinically important atherosclerosis in young patients with systemic lupus eyrthematosus.(Funded, in part, by NIHRO1HL077422)
Inhibitors of aldose reductase and sorbitol dehydrogenase mitigate hyperglycemia‐induced arteriolar dysfunction
Authors: Veres Zoltan , Koller Akos 
Published: June 2021

Hyperglycemia by activating the polyol pathway elicits increases in intracellular sorbitol and fructose concentrations. Previously we showed that in isolated arterioles administration of sorbitol (10−7 M) elicited oxidative stress, which interferes with nitric oxide (NO) bioavailability and thus dilations. We hypothesized that an elevated level of fructose also contributes to the development of hyperglycemia‐induced dysfunction of microvessels. In isolated rat gracilis muscle arterioles (~150 μm at 80mmHg), high glucose treatment (25 mM for 30 min) reduced flow dependent dilation (max: 39 ±2 vs. 15 ±1 %), which was significantly reversed by an aldose reductase inhibitor, zopolrestat (max: 27±2 %) and partially by a sorbitol dehydrogenase inhibitor (SDI), CP‐470,711 (max: 23±3 %). Also, SDI ‐ in part ‐ restored dilations to flow in the presence of elevated sorbitol. Incubation of arterioles with fructose (10−4 M) reduced flow dependent dilations (max: 39±2 vs. 12±2 %), which were not further affected by inhibition of NO synthase by L‐NAME, but were partially reversed by SOD/CAT and PGH2/TXA2 receptor blocker SQ‐29548. Thus, we suggest that hyperglycemia ‐ by elevating intracellular sorbitol and fructose levels ‐ induces oxidative stress, which interferes with NO‐mediated dilations and promotes PGH2/TXA2 release. Thus the polyol pathway may contribute to the development of microvascular dysfunction in diabetes mellitus.(Grants: Hungarian SRF/OTKA T48376, K71591; HSC/ETT 364/2006 and AHA F. Aff. 0855910D, USA)
Historical Note: Yackzan of Vanderbilt, an unacknowledged investigator in the discovery of ergothioneine in biological tissues
Authors: Tipton Charles M. 
Published: June 2021

In 1909, Tanret in France, extracted ergothioneine (ET) from the ergot of rye. Its empirical formula is C9 H15 O2 N3 ; regarded as a betaine, and recognized as the only naturally occurring thiolimidazole amino acid. Within its structure is the sulfhydryl group which is the main effector of antioxidation. Its biological importance is its role as an antioxidant; but, to have physiological significance, a transporter (ONCT1) is needed to enter the plasma cell. In 1950, it was known that ET was present in blood but unknown whether it was present in biological tissues. Kamal Yackzan, a graduate student in the laboratory of Dr. Oscar Touster at Vanderbilt University, investigated this subject by (a)altering concentrations and ratios of existing reagents of prevailing methods and (b) using paper chromatographic analytical techniques and found quantifiable concentrations were found in liver, kidney, cardiac and spleenic tissues. In 1951, these results were recorded in an obscure publication of the University (1). Three years later while using column chromatography, Melville confirmed Yackzan's tissue findings and that the liver and kidney had the highest concentrations with the heart and the spleen having the lowest values (JBC. 206: 221, 1954). In the decades that have followed,ET has received research and commercial interest as a strong antioxidant with therapeutic value for select health disorders and diseases.___________________________________________________1. Yackzan, K. Paper chromatographic analysis for ergothioneine in tissue. In: Bulletin of Vanderbilt University Abstracts of Theses. Nashville, 1951, p. 56.
Exercise attenuates doxorubicin‐induced skeletal muscle damage
Authors: Smuder Ashley J , Min Kisuk , Kavazis Andreas N 
Published: June 2021

Doxorubicin (DOX) is an antitumor agent used in cancer treatment. However, DOX induces myocyte oxidative damage via increased free radical generation. In this regard, exercise presents a possible intervention for DOX toxicity through the induction of cytoprotective proteins. Therefore, we tested the hypothesis that DOX‐induced skeletal muscle damage could be attenuated by endurance exercise training. Sprague‐Dawley rats were randomly assigned to one of the following groups: sedentary, exercise, DOX, or exercise with DOX. Following the treatment protocol, soleus muscle was removed for subsequent analysis. Exercise prevented DOX induced increases in muscle lipid peroxidation. In addition, exercise training was sufficient in preventing muscle DOX induced HSP72 reduction. Furthermore, muscle levels of catalase, CuZn, and Mn‐superoxide dismutase increased with DOX suggesting antioxidant upregulation may act to combat increased oxidant production. Moreover, DOX resulted in increased muscle levels of ubiquitin‐protein conjugates as well as caspase‐3 and calpain I activity, all of which were attenuated with exercise training. These results suggest that DOX promotes skeletal muscle oxidative damage and protease activation. Importantly, exercise training appears to counteract the deleterious side effects of DOX.Supported by an AHA grant awarded to ANK.
Subcontracture depolarization alters doublet potentiation
Authors: Barnes William Stephen 
Published: June 2021

Doublet potentiation occurs when a brief, high‐frequency burst of pulses is added to a subtetanic train of pulses. The purpose of this investigation was to determine the effect of subcontracture K+‐induced depolarization on doublet potentiation. Sartorii muscles (60‐70 mg) from R. pipiens were excised and mounted in water‐jacketed (20°C) chambers containing oxygenated (100%) Ringer's solution (R; pH 7.2) containing 2.5 mM KCl (R+KCl2.5). Muscles were exposed to an 800 ms train (20 Hz) of supramaximal square‐wave pulses (.2 ms) via field stimulation. An additional pulse was inserted between the 9th and 10th pulses (ISI = 10 ms). Peak tensions (PT, g) for contractions (PTA‐E) between the eighth and twelveth pulses were determined. Tension‐time integrals (TTI, g·s) were calculated. This protocol was then repeated with the [KCl] of R increased incrementally up to 15 mM/L.Subcontracture depolarization lessens the effect of transient high‐frequency paired stimulation and may mitigate its potential as a motor control strategy.
Dynamics structures of mechanosensory cilia
Authors: Lo Shao , Przybylski Eric S , AbouAlaiwi Wissam A , Takahashi Maki , Nauli Surya M 
Published: June 2021

BackgroundNon‐motile primary cilia have been proposed to be mechanosensory organelles in chondrocytes, cholangiocytes, osteocytes, renal epithelial, pancreatic epithelial, endocardial, and vascular endothelial cells. We report here the dynamic structure of the biophysical property of cilia.Methods and ResultsUsing formvar as a flexible substrate, we record ciliary behavior for a period of time with a high resolution differential interference contrast microscopy. Under static conditions in the absence of fluid flow, we can observe that each well‐developed cilium contains a bulb in the middle of the ciliary shaft. In a less‐developed cilium, the bulb is less likely to be present. However, bending of cilium by mechanical fluid flow could induce the appearance of the bulb or bulbs within one cilium. Furthermore, fluid flow tends to dynamically move the bulb to the tip of the cilium.ConclusionWe propose that the dynamics of ciliary bulb is mechanically regulated. Ciliary bulb may therefore have sensory function within mechano‐ciliary structure.
Sinoaortic denervation prevents training‐induced plasticity in the central oxytocinergic (OT) system
Authors: Michelini Lisete C. , Cavalleri Marina T. , Ceroni Alexandre 
Published: June 2021

Aerobic training (T) increase both ascending noradrenergic innervation to OT preautonomic neurons (Am J Physiol 2007;292:R1717) and OTmRNA expression within the hypothalamic paraventricular nucleus (PVN) (Hypertension 2005;46:1004), thus facilitating the slow down of the heart. We sought now to identify whether baroreceptor inputs affects T‐induced plasticity. WKY and SHR submitted to sinoaortic denervation (SAD) or SHAM surgery were trained (55% VO2 max, 5‐times/week, 1h/day) or kept sedentary (S) for 3 month. After pressure and heart rate (HR) measurement at rest, rats were anesthetized and perfused transcardiacally (0.01M PBS). Brains were removed, frozen and sliced to isolate dorsal brainstem (DBS, comprising the solitary‐vagal complex) and hypothalamic (directed to PVN) areas; tissue samples were processed for Real Time PCR. GAPDH was used as reporter gene. T‐induced pressure fall (‐8% in the SHR) and resting bradycardia (‐9% in both groups) were absent after SAD. SAD also completely blocked T‐induced OT mRNA expression in the PVN (4.3‐fold and 20% increases in SHAM WKYT and SHRT, respectively). Hypertension and SAD did not affect OT receptor expression within the DBS. In the chronic absence of baroreceptor inputs, the lack of plasticity on PVN OTergic neurons and HR response indicate that baroreceptor signaling plays a decisive role to drive beneficial T‐induced adjustments.SupportFAPESP, CNPq.
A Selective Inhibitory Effect of the Posterior Cerebellar Vermis on 10‐Hz Sympathetic Nerve Discharge
Authors: Barman Susan M , Gebber Gerard L 
Published: June 2021

We compared the changes in inferior cardiac sympathetic nerve discharge (SND) and mean arterial pressure (MAP) produced by aspiration of portions of lobule IX and in some cases lobule X of the posterior cerebellar vermis with those produced by chemical inactivation (muscimol microinjection) or electrical stimulation of the same regions. The experiments were performed on 13 baroreceptor‐denervated and vagotomized cats anesthetized with urethane. Autospectral analysis was used to decompose SND into its frequency components. Special attention was paid to the question of whether the experimental procedures differentially affected the rhythmic and aperiodic components of SND. Aspiration or chemical inactivation with muscimol of lobule IX produced an approximately three‐fold increase in the 10‐Hz rhythmic component of SND (P = 0.05). In contrast, wideband SND at lower frequencies (= 6 Hz) was either slightly reduced or unaffected. Total power (0‐ to 20‐Hz band) was unchanged. Despite this, there was a statistically significant increase in MAP. High frequency (50‐Hz) electrical stimulation of depressor sites in lobule IX of the posterior vermis selectively and significantly reduced 10‐Hz power in SND. The lower frequency components of SND were unchanged. These results demonstrate for the first time a role of cerebellar cortical neurons of the posterior vermis in regulating the frequency composition of naturally occurring SND. The functional implications of these findings are discussed.(Supported by NIH HL33266.)