bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the Toll‐like receptor adaptor protein, TIRAP in regulation of gene expression of hepatic drug metabolizing enzymes
Authors: Ghose Romi , Guo Tao 
Published: June 2021

BackgroundAltered expression of drug metabolizing enzymes (DMEs) in inflammation can affect the metabolism and toxicity of drugs. We have recently shown that the Toll‐like receptor (TLR) 2 ligand, lipoteichoic acid (LTA) can regulate the gene expression of drug metabolizing enzymes (DMEs). However, the role of the TLR2 adaptor protein, TIRAP in regulating hepatic DME genes is not known. We hypothesize that TIRAP mediates TLR2‐dependent regulation of hepatic DME gene expression.MethodsTIRAP+/+ and TIRAP−/− mice were i.p. injected with LTA, (6mg/kg) or saline. Livers were harvested and RNA and proteins were analyzed by real‐time PCR and western blotting, respectively.ResultsCyp2b10, Cyp2a4 and Sultn were significantly reduced by LTA in TIRAP+/+ mice (~70‐80% reduction), but not in TIRAP−/− mice. Gene expression of the DMEs is regulated by members of the nuclear receptor superfamily (PXR, CAR and RXRα). RNA levels of PXR and CAR was significantly reduced by LTA treatment in TIRAP+/+, but not in TIRAP−/− mice. Interestingly, RNA levels of the pro‐inflammatory cytokines, IL‐1β, IL6 and TNFα were induced by LTA in both the TIRAP+/+ and TIRAP−/− mice.ConclusionsTIRAP is involved in regulating hepatic DME gene expression by LTA, but is not involved in regulating LTA‐mediated induction of pro‐inflammatory cytokines in the liver.
A novel designer natriuretic peptide integrating human C‐type natriuretic peptide, atrial natriuretic peptide, and B‐type natriuretic peptide
Authors: Lee Candace Y.W. , Burnett John C. 
Published: June 2021

BackgroundThe 17‐amino‐acid (AA) ring of C‐type natriuretic peptide (CNP) is essential for activation of NP receptor (NPR)‐B and the 2nd messenger cGMP. CNP induces minimal hypotension as NPR‐B is more abundantly found in veins vs arteries, but possesses limited renal properties. We designed a novel peptide fusing the CNP ring with AAs from ANP and BNP to test our hypothesis that this unique peptide, CAB‐NP, would exert enhanced renal actions without inducing excessive hypotension.MethodsCAB‐NP was synthesized (SLRRSSCFGLKLDRIGSMSGLGCKVLRRH) and infused (21 pmol/kg/min iv) in 5 anesthetized dogs. GFR was assessed by inulin clearance. Mean±SE, P<.05*, <.01 †, BL vs 30 min infusion.ResultsCAB‐NP increased plasma cGMP (3.5±0.6 to 10.9±1 † pmol/mL), urinary cGMP excretion (980±96 to 4587±825* pmol/min), net renal cGMP generation (823±88 to 4091±824* pmol/min), urine flow (0.2±.03 to 1.2±.4* mL/min) and Na+ excretion (19±7 to 191±55* †Eq/min). Proximal (85±3 to 68±1 † %) and distal (98±1 to 91±2 † %) FRNa were reduced; GFR was preserved (46±4 to 45±3 mL/min). MAP mildly decreased (121±4 to 111±5* mmHg). PCWP (6±1 to 4±1 † mmHg) and RAP (3±1 to 2±1* mmHg) were reduced. Plasma renin activity (11±1 to 2±0.3 † ng/mL/hr) and aldosterone (15±4 to 7±2* ng/dL) were suppressed.ConclusionsCAB‐NP exerts favorable in vivo actions without excessively lowering BP. The therapeutic potential of CAB‐NP warrants further studies.Supported by the NIH, HFSA, and ASCPT.
Survey of "Off‐ Label" Drug Use in Pediatric Department of a Teaching Hospital ‐ A Prospective Study
Authors: Patel Kamlesh Prahladbhai , Panchal Dhaval J. , Patel Varsha J. , Bhavsar Rekha H. 
Published: June 2021

Objective: To detect extent of off label drug use in pediatric outpatients and to correlate different variables of patients.Method: The data of 400 patients were collected prospectively in a proforma during one year study period. Anatomical Therapeutic Chemical (ATC) Classification was used for the prescribed drugs. The drugs were ascribed off label status in different categories using standard references. The data were analyzed with Epi Info 2002 software. The χ2 test was used and value of p<0.05 was considered statistically significant.Result: Out of total 1744 drug prescriptions, 39.73% were prescribed in off label manner and 63% patients received at least one or more off label drug prescription. Use in child of inappropriate age, administration in sub therapeutic doses and in high doses were responsible for off label use of drugs. Antiemetics, antianemics, nasal preparations, vitamins and drugs for obstructive airway disease were commonly prescribed in off label manner. Infectious diseases, neonates and infants were the risk factors for being prescribed a drug in off label manner.ConclusionOff label use of drugs is highly prevalent in pediatric practice. Greater emphasis on pediatric prescribing in Pharmacology curriculum, continuous medical education programmes for practitioners and availability of updated National Formulary may help in improvement.Research support ‐ none.
Oxidative stress mediates homocysteine proatherosclerotic effects on human endothelial cells through a MAP kinase pathway
Authors: Alkhoury Kenan , Parkin Susan Mary , Graham Anne Margaret 
Published: June 2021

Homocysteine (Hcy) is implicated in inducing cellular oxidative stress (OXS) which mediates endothelial cell (EC) damage via unknown mechanisms. We have previously shown Hcy induces activation of MAPK JNK and increases EC:leukocyte interactions. However, the JNK activator has yet to be identified. OXS is known to cause activation of the JNK MAP kinase pathway. Objective: to study the effects of antioxidants on Hcy EC damage.Human umbilical vein EC (HUVEC) were cultured for 5‐9 days in medium containing 1mM DL‐Hcy alone, with 5mM N‐acetylcysteine (NAC) or 100µM vitamin C. and JNK kinase assays conducted on cell lysates Reactive oxygen species (ROS) generated in HUVEC were also detected after treatment, by confocal microscopy. Confluent cells after treatment were subjected to flowing neutrophils (1x106 cells/ml) at 1.1dynes and tethered, rolled, fixed and transmigrated neutrophils on HUVEC counted.DL‐Hcy caused activation of JNK (1.5fold) and increased ROS accumulation. NAC reversed these effects. Furthermore, DL‐Hcy significantly increased HUVEC:neutrophil interactions. However, the presence of either NAC or Vitamin C reversed these Hcy mediated effects. These results show that OXS mediates Hcy effects through a MAPK kinase dependent pathway. Antioxidants block Hcy stimulated JNK activation, so preventing HUVEC: neutrophil interactions under flow conditions.Funding: HR UK, ORSAS
Lymphatic pacemaking
Authors: Imtiaz Mohammad Shariq , von der Weid Pierre‐Yves , Crowe Melissa , van Helden Dirk 
Published: June 2021

Lymphatic vessels display rhythmic constriction‐dilation cycle which is known as vasomotion. The rhythmic constrictions propel fluid through the lymphatic chambers which are connected by valves. Our previous study has shown that lymphatic smooth muscle pacemaking occurs through a mechanism that involves Ca2+ release from intracellular Ca2+ stores through inositol 1,4,5‐trisphosphate (IP3) receptor, and depolarization through L‐type Ca2+ channels. The aims of this study were to extend our study on single lymphatic chambers to understand lymph propulsion in chains of valve connected lymphatic chambers.Our study shows that phase locking of Ca2+ oscillations can occur across many lymphatic chambers and result in phase waves which manifest as slowly propagating waves of contractions within and across chambers. Our study also indicates that electrical coupling between chambers across valves is relatively poor. Numerical simulations indicate that chambers could partially interact through mechanical coupling between chambers.
Development of an interactive, FLASH‐animated model for teaching regulation of glomerular filtration
Authors: Gookin Jody , Lit Ari , Bonin Alex , Groch Chris 
Published: June 2021

Teaching renal physiology in a manner that promotes an integrated concept of dynamic function is a challenge. The glomerular filtration rate (GFR) is largely controlled by changes in vascular resistance of the afferent and efferent arterioles. The aim of this teaching project was to develop an interactive model capable of animating 1) the effect of afferent and efferent arteriolar resistance on GFR and 2) the autoregulatory mechanisms by which the kidney controls GFR in response to changes in systemic blood pressure.In the program, afferent and efferent arteriolar resistance are controlled by moving a slider to either constrict or relax positions. For each position the effect on renal blood flow, glomerular hydrostatic pressure, GFR, filtration fraction, and tubular flow are animated and categorically summarized. A "show notes" feature provides a written explanation of the observed physiology. Systemic blood pressure is controlled by moving a slider to the 180, 80 or <60 mmHg positions. Each intervention results in animation of an uncompensated response, followed by increasing levels of autoregulatory responses which are selected by the student.Use of this model may translate into improved problem‐solving skills compared to students receiving traditional instruction in glomerular physiology.Funded by a Teaching Innovation Grant from North Carolina State University College of Veterinary Medicine.
Human internal mammary and radial arteries express different level of endothelial nitric oxide synthase (eNOS)
Authors: FAN Li , GROVE Kevin L , WEI Wei , FURNARY Anthony , YANG Qin , HE Guo‐Wei 
Published: June 2021

The internal mammary artery (IMA) has better long‐term patency rate than the radial artery (RA) after coronary artery bypass grafting surgery with unknown mechanisms. We investigated endothelial nitric oxide synthase (eNOS) in these arteries taken from redundant parts during surgery. Cumulative concentration‐relaxation curves for acetylcholine (ACh, ‐9 ~ ‐4.5 log M) against U46619 were established in IMA and RA rings pretreated with/without eNOS inhibitor Nω‐nitro‐L‐arginine (L‐NNA, 300 μM). Expression levels of eNOS in the whole tissue, as well as in the endothelial cells (EC) and smooth muscle cells (SMC) of human IMA and RA were quantified with quantitative real‐time PCR (qRT‐PCR). Immunohistochemistry (IHC) technique was also adopted to determine the localization of eNOS. Without L‐NNA, ACh‐induced relaxation was similar between IMA and RA rings (Rmax: 48.5 ± 5.2% vs 55.9 ± 6.0%, n = 8, 9). L‐NNA pretreatment significantly inhibited Rmax in IMA (14.7 ± 3.0%, p < 0.001) and in RA (15.2 ± 3.2%, p < 0.01). eNOS mRNA expression level in integrated tissues was similar in IMA and RA, but significantly higher in EC of IMA than in RA (1.03 ± 0.19 vs 0.53 ± 0.09, p < 0.05, n = 7). In addition, IHC showed that eNOS immunoreactivity was higher in EC of IMA than that in RA. Thus, the EC of IMA has higher eNOS expression than that in RA. This may be the cause of better long‐term patency of IMA.Supported by St. Vincent Medical Foundation.
Extracellular Superoxide Dismutase Activity is Reduced with Aging in Humans: Relation to Impaired Vascular Endothelial Function and Exercise Capacity
Authors: LaRocca Thomas J. , Seals Douglas R. , Walker Ashley E. , Eskurza Iratxe , Pierce Gary L. 
Published: June 2021

Aging is associated with impaired exercise capacity and vascular endothelium‐dependent dilation (EDD), the latter mediated by oxidative stress and reduced nitric oxide (NO ?) bioavailability. The antioxidant enzyme extracellular superoxide dismutase (EC‐SOD) binds to the endothelial wall via a heparin binding domain and protects NO ? from inactivation by superoxide (O2 ?−). However, the effects of aging on EC‐SOD and its relation to EDD and exercise capacity are unknown. Two groups of healthy non‐obese adults were studied: young sedentary (YS: n = 7; age 22 ± 2 yr; 2M) and older sedentary (OS: n = 12; 62 ± 2 yr; 6M). EDD (brachial artery flow‐mediated dilation) was lower (P < 0.05) in OS (5.4 ± 0.7 Δ%) vs. YS (7.4 ± 0.9 Δ%). EC‐SOD activity, measured by the release of EC‐SOD into plasma following intravenous heparin bolus (5000U), also was lower (P < 0.01) in OS vs. YS (AUC15min: 5.4 ± 1.4 vs. 14.0 ± 1.7 U/mL/min). EC‐SOD activity was inversely related to age (r = ‐0.61, P < 0.01) and positively related to EDD (r = 0.64, P < 0.01) and exercise capacity (maximal oxygen consumption, r = 0.50, P < 0.05). EC‐SOD activity was inversely related to plasma oxidized low‐density lipoprotein (r = ‐0.44, P < 0.05), a circulating marker of oxidative stress, but not to any other anthropometric or metabolic risk factor. These results provide the first evidence that EC‐SOD activity is reduced with aging in healthy humans and may contribute to oxidative stress‐associated vascular endothelial dysfunction and impaired exercise capacity.NIH AG000279, AG013038, AG022241, AG006537, RR00051
Activation of Vinculin Induced by Cholinergic Stimulation Regulates Tension Development in Tracheal Smooth Muscle (TSM)
Authors: Huang Youliang , Craig Susan W. , Gunst Susan J. 
Published: June 2021

The adhesion protein vinculin functions in focal adhesions to link actin filaments to membrane adhesion junctions by binding to the integrin‐binding protein talin at its head domain (Vh) and to actin filaments at its tail domain (Vt). In the inactive (closed) state, Vh and Vt bind to each other, masking the binding sites for actin and talin; in the active (open) state, vinculin binding sites for talin and actin are exposed. We hypothesized that the contractile activation of TSM might regulate conformation of vinculin and thereby contribute to the regulation of tension development. Stimulation of TSM tissues with acetylcholine (ACh) increased the co‐immunoprecipitation of vinculin and talin from tissue extracts, and increased vinculin phosphorylation at tyr 1065, an indicator of vinculin activation. Recombinant Vh (EGFP‐Vh) expressed in TSM tissues competed with endogenous vinculin for binding to talin and inhibited vinculin tyr 1065 phosphorylation. Expression of EGFP‐Vh depressed TSM contraction to ACh by 60% and inhibited ACh‐induced actin polymerization. EGFP‐Vh did not affect myosin light chain phosphorylation. We conclude that vinculin is activated in TSM by ACh, and that vinculin regulates tension by promoting connections between actin filaments and talin‐integrin adhesion complexes and by facilitating the initiation of actin polymerization.Support: AHA 0820074Z, HL 29289, HL 074099
Hyperthyroid rats display increased adrenergic ‐mediated contraction in cavernosal tissue
Authors: Carneiro Zidonia Nunes Noetzold , Carrillo ‐Sepulveda Maria Alicia , Carneiro Fernando Silva , Giachini Fernanda Regina , Lima Victor Vitorino , Webb R Clinton , Tostes Rita C 
Published: June 2021

IntroductionDisturbances in thyroid function lead to sexual dysfunction in humans. However, the mechanisms by which hyperthyroidism causes erectile dysfunction (ED) are unknown. Whereas nitric oxide (NO) is the mediator of erection, sympathetic activation causes detumescence.ObjectiveWe hypothesized that hyperthyroidism increases sympathetic‐mediated contractility in cavernosal tissue.Methods and ResultsWistar male rats were submitted to experimental hyperthyroidism (70ug/Kg T3 for 14 days). Thyroid hormone T3 plasmatic levels were increased in hyperthyroid animals (Hyper) (Control: 0.43±0.08 vs Hyper: 1.45±0.64, ng/mL). After euthanasia, penises were excised and dissected. Cavernosal strips were mounted in a myograph and stretched to a resting force of 3.0 mN. Cavernosal contractility to phenylephrine (PE) (Control: 1.72±0.2 vs Hyper: 3.06±0.2, mN) and sympathetic‐nerve stimulation (Control: 0.9±0.4 vs Hyper: 2.03±0.3, mN) were increased in Hyper rats. Cavernosal responses to nonadrenergic‐noncholinergic‐mediated relaxation and endothelium‐independent relaxation were not altered.ConclusionOur results suggest that increased sympathetic‐ mediated responses contribute to ED in hyperthyroidism.
Chloroquine and resveratrol stimulate ATM‐independent phosphorylation of AMPK and AKT
Authors: Spears Larry D. , Hobbs Supriya B. , Zhang Zhihong , Ralston Lyle , Liang Cheryl A. , Royer Nathaniel K. , Fisher Jonathan S. 
Published: June 2021

It was hypothesized that ataxia telangiectasia mutated (ATM) activators would increase phosphorylation of the AMP‐activated kinase (AMPK) and AKT. To test this hypothesis, C2C12 cells were lentivirally transduced with short hairpin RNA (shRNA) against ATM, which decreased expression of ATM by ~80%. A control C212 cell line was produced by lentiviral transduction with green fluorescent protein (GFP), and non‐transduced C2C12 cells (wild‐type) were also used controls. Myotubes were incubated with or without 500 μM chloroquine, an ATM activator, for one hour. AMPK phosphorylation and AKT‐T308 phosphorylation were stimulated by chloroquine in all cell lines (i.e. wild‐type, cells expressing GFP, and cells expressing shRNA against ATM). In wildtype C2C12 cells, one hour of incubation with 150 μM resveratrol, another ATM activator, increased phosphorylation of AMPK even in the presence of KU55933, a specific inhibitor of ATM. Thus, chloroquine and ATM both cause AMPK and AKT phosphorylation in an ATM‐independent fashion.This work was supported by NIH DK080437 and by NICHD/NCMRR through a Pilot Project subcontract from the National Skeletal Muscle Research Center.
Serotonergic cell transplant and cervical spinal cord injury
Authors: Dougherty Brendan J. , White Todd E. , O'Steen Barbara E. , Reier Paul J. , Fuller David D. 
Published: June 2021

Phrenic motor recovery following cervical hemisection (HS) positively correlates with recovery of serotonergic input to ipsilateral phrenic motoneurons (PhrMNs). In preliminary studies, we are testing the hypothesis that respiratory motor recovery following HS can be enhanced by intraspinal grafting of embryonic (E14) brainstem tissue containing serotonergic (5‐HT) neurons or their precursors. E14 dorsal raphe nucleus tissue was placed into an acute C4HS cavity in adult male rats. At 8 weeks post‐surgery histological analysis showed that donor tissue filled the cavity and robust 5‐HT immunostaining was seen in the ipsilateral spinal cord rostral and caudal to the graft. Ventilation was assessed in conscious rats with plethysmography. Normoxic breathing patterns were similar between control (C4HS only) and transplant animals. However, during hypoxic challenge (10% O2) graft rats had increased frequency and minute ventilation (both p=0.01) compared to controls. Although additional control experiments are needed to determine if graft effects are specific to DRN tissue (vs. a non‐specific effect of embryonic tissue), these preliminary findings suggest that neurotransplantation may be a viable strategy for promoting respiratory motor recovery by enhancing serotonergic innervation of PhMNs.Funding: NIH 1R01HD052682‐01A1 (DDF), NIH RO1 NS054025 (PJR), NIH T32 HD043730 (BJD)
Skin‐surface cooling increases left‐ventricular preload but not contractility in older humans
Authors: Gao Zhaohui , Wilson Thad E. , Hess Kari L. , Monahan Kevin D. 
Published: June 2021

Skin‐surface cooling acutely increases arterial blood pressure, left‐ventricular (LV) afterload, and myocardial oxygen demand. To determine whether skin surface cooling increases LV preload and contractility more in older than in young adults, we measured indices of LV preload and myocardial contractility using standard and tissue‐Doppler imaging (TDI) echocardiography in 6 young (23 ?1 yrs; mean ?SE) and 6 older (65 ?3 yrs) adults during normothermia (35° C water perfused through a tube‐lined suit) and skin‐surface cooling (15‐18° C water perfused for 20 min). Cooling increased LV end‐diastolic volume (EDV, from 98±1 to 108±1 ml, P<0.001) and LV internal diameter in diastole (IDd, from 4.61±0.03 to 4.77±0.03 cm, P<0.01) in older, but not young adults (EDV=101±1 and 99±1 ml, IDd=4.67±0.03 and 4.62±0.03 cm, for normothermia and cooling, respectively). In contrast LV ejection fraction and TDI myocardial functional indices (myocardial acceleration during contraction and peak velocities during systole and diastole) were unchanged by cooling in both young and older adults. These data indicate that skin surface cooling acutely increases LV preload, without influencing LV contractility in older, but not young adults. Increases in LV preload and afterload likely contribute to greater increases in myocardial oxygen demand during cold exposures in older than in young adults.Support: NIH AG24420 and M01 RR10732
Administration of 17‐ β estradiol in the medial preoptic area prevents reduction of body temperature during cold exposure in ovariectomized rats
Authors: Uchida Yuki , Tohi Madoka , Tokizawa Ken , Nagashima Kei 
Published: June 2021

BACKGROUNDWe reported that ovariectomized rats could not maintain body temperature (Tcore) well in the cold; however, local administration of 17‐β estradiol (E2) in the medial preoptic area (MPO) restored the cold intolerance. The E2 administration had no effect on UCP1 mRNA level in the interscapular brown adipose tissues, suggesting less influence on metabolic heat production.PURPOSETo test the hypothesis that the local E2 administration in the MPO affects heat dissipation, the tail surface temperature was assessed by thermography.METHODSAfter ovariectomy for 9‐wk old rats, a stainless steel canula was placed in the MPO for local administration of E2 or cholesterol. A rat was placed at 10 or 25°C for 2h, 48 h after the administration E2 or cholesterol. Tcore and tail temperature (Ttail) were measured by telemetry and thermography.RESULTSBoth the groups showed decrease in Ttail at 10°C; however the reduction was greater in the estrogen group than in the cholesterol group.CONCLUTIONWithout estrogen in the MPO, heat dissipation from the tail in ovariectomized rats may not be fully suppressed in the cold, resulting in reduction of Tcore.
Effects of ganoderma lucidum spores on the change of hyaluronic acid content and glutamine synthetase activity in epilepsy rats
Authors: Wang Shu‐Qiu , Kang Yu‐Ming , Zhang Shi‐Ling , Wang Xian‐Gang , Qin Wen‐Bo , Zhao Xiao‐Lian , Liu Lei , Wang Fang‐Fang , Zhao Lu , Zhang Ting 
Published: June 2021

To investigate the effects of ganoderma lucidum spores on the mossy fiber sprouting (MFS), the hyaluronic acid (HA) content, the expression of glial fibrillary acidic protein (GFAP) and the activity of glutamine synthetase (GS) in hippocampus of rats with epilepsy induced by pentylenetetrazol (PTZ), and to further study the pathogenesis of epilepsy and the anti‐epilepsy mechanism of ganoderma lucidum spores. Thirty‐six male SD rats were randomly divided into control group, PTZ epilepsy group and ganoderma lucidum spores (GLS) group. The results showed that MFS, HA content and GFAP‐positive cells in rats of PTZ model group were significantly higher than those in control group and GLS group. The Timm scores were significantly higher in PTZ model group than those of control group and GLS group at the CA3 region, also Timm scores in GLS group were higher than control group. In PTZ model group, the astrocytes activation phenomenon in hippocampus was more obvious than GLS group, while the activity of GS was much lower than control group and GLS group.Conclusionganoderma lucidum spores can reduce MFS and the content of HA in hippocampus, and enhance the function of astrocytes, and then reduce the seizures.