bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship between Foot and Knee Angle and Cardiovascular Health
Authors: Oakman Joyann , Perez Avery , Neal Michael , Lenzo Jessica , Cromwell Christina , Aichele Kristin , Bye Naomi , Santaniello Erica , Hill Jessica , Evans Rachel , Wisdo Tia , Chavis Lauren , Thiele Karla , Getty Allyson , Louth Victoria , Feairheller Deborah
Published: June 2021

Joint misalignment and reduced range of motion can lead to discomfort during physical activity, thus creating a barrier to exercise. Lack of physical activity is related to cardiovascular (CV) disease and obesity. Studies show that obese individuals have a larger quadriceps (Q) angle, resulting in misaligned lower extremities. Thus, the connection between CV health status, joint alignment, and range of motion could be used to understand joint pain and reluctance to exercise. We examined associations between joint angles and CV health and fitness in 43 adults (28F, 15M, 25.7 ±10.8 yrs). Joint angle and motion was measured with a goniometer. CV health was measured by: body composition, fasted glucose/cholesterol levels, cardiac stress test, and 24 hour ambulatory blood pressure monitoring. A main finding was that standing Q angle for the left (r= 0.569) and right leg (r= 0.362), and supine Q angle for the right leg (r= 0.418) are all directly related to fat mass (p<0.05, for all). Left supine Q angle was directly related to BMI (r= 0.375), and left standing Q angle was inversely related to VO2max (r= ‐0.307). Ankle dorsiflexion was directly related to VO2max (r= 0.354), and foot inversion was directly related to maximum heart rate (r= 0.450) (p<0.05 for all). In conclusion, CV health seems to have a relationship with Q angle and ankle range of motion. Increased body fat shows an association with knee misalignment, whereas an increased VO2max could be associated with increased range of motion in the ankle.
Effects of Nitrite Infusion on Exercising Skeletal Muscle Vascular Control in Chronic Heart Failure Rats
Authors: Glean A , Ferguson S , Holdsworth C , Hageman K , Poole D , Musch T
Published: June 2021

Chronic heart failure (CHF) compromises nitric oxide (NO) bioavailability and thus impairs skeletal muscle (SkM) vascular control. Reduction of nitrite (NO2‐) to NO likely increases NO bioavailability and may impact exercise‐induced hyperemia particularly in muscles with impaired O2 delivery. We tested the hypothesis that NO2‐ infusion would increase exercising blood flow (BF) and vascular conductance (VC) in CHF rats. CHF was surgically induced in 8 adult male rats via coronary artery ligation. At 21 days post‐surgery, mean arterial pressure (MAP, carotid artery catheter), SkM BF (radiolabelled microspheres), and blood [lactate] were measured during submaximal treadmill exercise (20 m/min, 5% incline) with (CHF+NO2‐) and without (CHF) NO2‐ infusion (5 mg/kg, i.a.). The myocardial infarct size (35 ± 3%) and left‐ventricular end diastolic pressure (18 ± 1 mmHg) indicated moderately‐severe CHF. NO2‐ infusion increased (p < 0.05) total hindlimb SkM VC (CHF: 0.85 ± 0.09, CHF+NO2‐: 0.93 ± 0.09 ml/min/100g/mmHg) without changing MAP (CHF: 123 ± 4, CHF+NO2‐: 120 ± 4 mmHg). Total hindlimb SkM BF (CHF: 102 ± 7, CHF+NO2‐: 109 ± 7 ml/min/100g) was not different with NO2‐; however, BF increased in 6 and VC in 8 out of 28 individual muscles and muscle parts examined (p < 0.05). Blood [lactate] (CHF: 1.6 ± 0.2, CHF+NO2‐: 3.3 ± 0.4 mmol/L) also increased (p < 0.05) with NO2‐ infusion. These data demonstrate that in CHF rats, NO2‐ infusion can increase total VC in exercising SkM and BF in some but not all hindlimb locomotor muscles. Given this scenario, the elevated blood [lactate] with NO2‐ was unexpected and may potentially indicate adverse consequences for exercise tolerance in CHF. NIH HL‐108328
Effects of Long‐term Voluntary Exercise on the Respiratory Muscles in Young Type 2 Diabetic Rats
Authors: Ichinoseki‐Sekine Noriko , Tsuzuki Takamasa , Yoshihara Toshinori , Takamine Yuri , Kobayashi Hiroyuki , Naito Hisashi
Published: June 2021

This study investigated the effects of long‐term voluntary exercise on the respiratory muscles in young type 2 diabetic rats. Twenty‐two Otsuka Long‐Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, and 18 non‐diabetic control Long‐Evans Tokushima Otsuka (LETO) rats were assigned randomly to sedentary or exercise groups subjected to 20 weeks of voluntary wheel running from 5 weeks of age. A strip of diaphragm was used to measure the contractile properties and the rest was frozen and stored for immunohistochemical analysis. The total running distance did not differ between groups. The voluntary exercise significantly reduced the fasting blood glucose and serum triglyceride in OLETF rats. The mean fiber cross‐sectional area (CSA) was significantly greater in OLETF rats at both 5 and 25 weeks of ages. Type IIb fibers comprised 4–8% in OLETF rats, while little or none was expressed in LETO rats. At 25 weeks of age, muscle force production in OLETF rats was significantly lower than in LETO rats at stimulation frequencies of 1 (OLETF: 6.86 ± 0.96, LETO: 8.16 ± 1.25 N/cm2) and 30 Hz (OLETF: 16.35 ± 0.69, LETO: 18.55 ± 1.56 N/cm2). There was a slight, but non‐significant, tendency for voluntary exercise to increase fiber CSA and force production. Our results indicated that voluntary exercise in the young can improve glucose tolerance and hyperlipidemia, but has little effect on respiratory muscle.

This work was supported by grants from the MEXT‐Supported Program for the Strategic Research Foundation at Private Universities (S1101008).
Spironolactone or Eplerenone Treatment Reduce the Exaggerated Pressor Response to Muscle Reflex Activation in Spontaneously Hypertensive Rats
Authors: Downey Ryan , Mizuno Masaki , Brown Philip , Mitchell Jere , Vongpatanasin Wanpen , Smith Scott
Published: June 2021

Exercise is a beneficial treatment for hypertension. However, hypertensive patients frequently exhibit a dangerous, exaggerated rise in mean arterial pressure (MAP) during physical activity. Evidence suggests that the skeletal muscle exercise pressor reflex (EPR) plays a primary role in evoking this potentiated responsiveness, although the mechanisms remain largely undetermined. Studies suggest that mineralcorticoid receptors (MR) can contribute significantly to hypertension. Whether MR activation mediates EPR overactivity is unknown. Changes in MAP in response to EPR activation (via electrically‐induced hindlimb muscle contraction) were assessed in normotensive Wistar‐Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Additional SHR were fed (3 weeks) either normal chow (NC) or a customized diet containing the mineralcorticoid receptor antagonists spironolactone (SPIR, 50 mg/kg/day) or eplerenone (EPL, 100 mg/kg/day). The MAP response to EPR activation was markedly larger in SHR (37±8 mmHg) compared to WKY (9±2 mmHg). Further, the MAP response to EPR activation in SPIR‐treated and EPL‐treated SHR was much less than that elicited in SHR receiving NC (SPIR: 29±6, EPL: 31±5, NC: 42±7 mmHg/kg). These findings provide evidence that i) activation of MR mediates, in part, EPR overactivity in SHR and ii) SPIR and EPL may serve as viable treatments for EPR dysfunction in hypertension. Supported by NIH HL‐113738
Endurance Exercise Confers Neuroprotective Mitochondrial Phenotypes in the Brain of Alzheimer's Disease Mice
Authors: Koo Jung‐hoon , Kang Eun‐Bum , Kwon In‐Su , Jang Yong Chul , Kim Eung‐Joon , Lee Youngil , Cho In‐Ho , Cho Joon‐Yong
Published: June 2021

Endurance exercise (EE) is neuroprotective against Alzheimer's Disease (AD). However, the exact mechanisms remain unclear. Here we report that EE preserves cognitive function, increases mitochondrial biogenesis, and provides neuroprotective mitochondrial phenotypes in the brain of transgenic (NSE/APPsw) AD mice. 9‐month‐old mice were assigned to wild type (WT, n=8), transgenic (Tg, n=8), and transgenic exercise (TgE). TgE group performed treadmill EE for 16 weeks (60 min/day at 15m/min). Amyloid β‐42 (Aβ‐42), a hallmark of AD was significantly reduced at both tissue and mitochondria levels in TgE mice compared with Tg mice. NAD dependent deacetylase sirtuins‐1 (SIRT1) is linked to inducing mitochondrial biogenesis and activating α‐secretase responsible for reducing Aβ production. Intriguingly, we observed that EE increased SIRT1 in parallel with mitochondrial biogenesis factors (PGC‐1α, NRF1, TFAM) and proteins (COX‐I and COX‐IV) in TgE mice. In addition, EE downregulated key components of mitochondria permeability transition pore (cyclophilin D, ANT, and VADC). Conversely, TE upregulated mitochondrial transport proteins (TOM20, TOM40, TIM 23) and a chaperone (mHSP70). Moreover, EE increased levels of SIRT3 known to inactivate cyclophilin D in TgE group compared with Tg. Collectively, the present study suggests that the early start EE prior to initiation of AD provides neuroprotective mitochondrial phenotypes against AD and that these phenotypes may possibly be induced by the posttranslational modification of proteins via exercise‐mediated SIRT1/3 activation.
Acute and Chronic Effects of Sprint Interval Training on Postprandial Lipemia in Women At‐Risk for Metabolic Syndrome
Authors: Freese Eric , Gist Nicholas , Acitelli Rachelle , McConnell Whitni , Beck Catherine , Hausman Dorothy , Murrow Jonathan , Cureton Kirk , Evans Ellen
Published: June 2021

Individuals with the metabolic syndrome (MetS) exhibit elevated postprandial triglycerides (TG). The aims of this investigation were to determine 1) the effectiveness of 6 weeks of sprint interval training (SIT) on postprandial lipemia (PPL) and 2) if the attenuation of PPL following 6‐weeks of SIT is magnified compared to a single session of SIT prior to training in women at‐risk for MetS (n = 45; 30‐65 yrs). Postprandial responses to a high‐fat meal challenge (HFMC) were assessed for 3 h at baseline (B‐HFMC; all participants) without prior exercise, paired with a single session of SIT (four 30‐s all‐out sprints with 4‐min recovery) prior to the intervention (Pre‐HFMC; SIT only), and after the 6‐week SIT intervention without prior exercise (Post‐HFMC; CON) or paired with an acute bout of SIT ~14‐18 h prior to Post‐HFMC (SIT). Responses to the HFMC were assessed by collecting venous blood samples fasted and at 0, 30, 60, 120, and 180 min postprandial. Compared to baseline, an acute bout of SIT before (Pre‐HFMC) and after the 6‐week intervention (Post‐HFMC) significantly attenuated fasted (P<0.05; 16.6% and 12.3%, respectively) and postprandial area under the curve (13.1% and 9.7%, respectively; tAUC) TG responses. There was no difference in fasted or tAUC TG responses between Pre‐HFMC and Post‐HFMC. SIT is an effective mode of exercise to reduce fasting and postprandial TG concentrations in women at‐risk for MetS.
Effect of Low Dose Dopamine on Ventilatory Stability in Healthy Adults
Authors: Veldhoven Lisa , Holbein Walter , Johnson Blair , Limberg Jacqueline , Joyner Michael
Published: June 2021

Background

In models of congestive heart failure, carotid body denervation decreases ventilatory oscillations, thereby increasing ventilatory stability. Low‐dose dopamine can acutely blunt carotid body chemosensitivity assessed by a reduction of the hypoxic ventilatory response (HVR), but whether it affects ventilatory stability was previously unknown. We hypothesized ventilatory oscillations [as assessed by coefficient of variation of tidal volume (%CV Vt) and breathing frequency (%CV Fb)] would be reduced when the carotid chemoreceptors were desensitized by low‐dose dopamine.

Methods

Healthy adults (n=20, 6F/14M, 31±2 years) rested quietly for 5‐min and breath‐by‐breath ventilation was measured during normoxia under 2 IV infusion conditions: 1) saline, 2) an individualized dose of dopamine (1‐4 ug/kg/min) shown to result in a nadir HVR.

Results

Dopamine infusion increased breathing frequency (13±1 to 14±1 breaths/min, p=0.03) with no change in mean tidal volume (740±65 to 700±68 mL, p=0.18). Infusion of dopamine in young healthy adults increased ventilatory oscillations (%CV Vt: saline = 21±2, dopamine = 30±4, p=0.01; %CV Fb: saline = 17±1, dopamine = 21±2, p=0.07). There was no relationship between the decrease in HVR and the increase in ventilatory oscillations (Vt: r=0.15, p=0.54; Fb: r=0.33, p=0.16).

Conclusion

Contrary to our hypothesis, IV dopamine (at an individualized dose that attenuates HVR) significantly increases ventilatory oscillations in healthy subjects. These data suggest the effect of low‐dose dopamine on ventilatory oscillations in healthy adults is in contrast to that seen with carotid body denervation in disease.

Funding: NIH DK090541
The Effects of Perinatal Androgen Deprivation on Locomotor Activity in Male Rats
Authors: Jeong KumHwa , Yn Alicia , Khan Talha , Fickes Dane , Vang Pakou , Yousaf Faeeq , Shah Binita , Taylor George , Gopalan Chaya
Published: June 2021

Testosterone and its metabolites—estrogen and dihydrotestosterone— are involved in the brain sex differentiation during the perinatal period by binding to androgen receptors (AR) or estrogen receptors (ER). However, in the presence of flutamide (FLU), testosterone that is metabolized to estrogen will only bind to ER. Blockade of AR using FLU during the perinatal period could alter the levels of estrogen, which in turn, may modulate the sex differentiation of the brain. This study tested perinatal androgen deprivation on estrogen levels and, in turn, its effects on locomotor activity in male rats.

Long‐Evans rats (N=37) were divided into two groups: Group 1 received FLU (20 mg/kg; SC) during perinatal period (prenatal day 4 ‐ postnatal day 4) & Group 2 served as control. On postnatal day 65, these groups were divided into 3 subgroups (injected 5 days/week x 7 weeks): A. finasteride (20 mg/kg, SC), an α‐reductase inhibitor, B. letrozole (2 mg/kg, SC), an aromatase inhibitor and C. vehicle.

Open Field (OF) Paradigm: Each animal was tested every week in an OF apparatus where the rat was allowed to explore the OF for 6 minutes. The time spent in the center of the field was compared with the time spent in the periphery using Any‐Maze. In addition, serum estrogen levels were measured using ELISA.

Animals receiving FLU not only had high serum estrogen levels but also showed increased locomotor activity by spending significantly more time in the center field. These results suggest that perinatal androgen deprivation results in high levels of estrogen that may contribute to their willingness to explore freely.
Angiotensin II–Dependent Increase in the b=Bone Marrow Sympathetic Drive Initiates the Inflammatory and Endothelial progenitor Cell Imbalance and Precedes Blood Pressure Increase
Authors: Ahmari Niousha , Santisteban Monica , Baekey David , Raizada Mohan , Zubcevic Jasenka
Published: June 2021

Introduction

Dysfunctional brain‐bone marrow (BM) communication is associated with overactive brain RAS, leading to elevated sympathetic drive (SNA) to the BM and increased blood pressure (BP). Here, we hypothesized that angiotensin II (Ang II)‐dependent increase in BM SNA directly initiates the endothelial progenitor (EPC) and inflammatory cell (IC) imbalance, independently of its effects on BP.

Methods

Subpressor dose of Ang II (15 ng/kg/min ICV) was infused in Sprague‐Dawley rats for 3, 7 and 21 days. The in situ decerebrated artificially‐perfused preparation was used to determine femoral BM SNA (fSNA) in control and Ang II rats. Fluorescence‐activated cell sorting (FACS) investigated the levels of EPCs and ICs in blood and BM.

Results

Electrophysiology revealed a 20% increase in the fSNA peak firing as early as 7 days of Ang II infusion. This was associated with elevation in BM IC levels (CD4+:2fold; CD4+.CD25+:4fold; CD3+:2fold; CD3+.CD45+:4fold; CD68+:2fold) and EPCs (CD90+:1.5fold). Femoral BM sympathectomy significantly decreased levels of Ang II‐dependent ICs but not EPCs in the BM. No change was observed in circulating cells at any time point.

Conclusion

These observations demonstrate that Ang II‐dependent increase in BM fSNA directly affects the BM EPC/IC balance, independent of the blood pressure effects. Thus, elevated BM fSNA may initiate early impaired BM activity, but additional prohypertensive signals may be needed for fully blown immune response and development of hypertension‐related pathophysiology. AHA 14SDG18300010.
P2X3 Receptor Antagonism Reduces Peripheral Chemoreceptor Reflex Hypersensitivity and Blood Pressure in the Spontaneously Hypertensive Rat
Authors: Pijacka Wioletta , Ford Anthony , Paton Julian
Published: June 2021

Arterial hypertension is associated with increased peripheral chemoreceptor reflex sensitivity. We have shown that bilateral carotid body (CBR) resection in spontaneously hypertensive (SH) rats reduces arterial pressure (AP). Since ATP is a major participant in CB transduction signalling, and P2X3 receptors are associated with visceral afferent sensitisation, we hypothesized that P2X3 antagonism would reduce chemoreflex hypersensitivity and lower AP in SH rats.

SH and Wistar rats were implanted with telemeters to record AP. Doses of a P2X3 receptor antagonist (AF‐219) were administered as an i.v. bolus: 0.5 (n=4), 1 (n=4), 2 (n=5), 4 (n=5) and 8 mg/kg (n=4), and changes in both basal AP and chemoreflex sensitivity assessed. The chemoreflex was stimulated with sodium cyanide (NaCN; 120 μg/kg i.v.).

At all doses, AF‐219 diminished NaCN evoked AP responses (P=0.084) in SH rats. In SH rats, basal AP was reduced by AF‐219 (P<0.05): ‐8±3 mmHg, 0.5mg/kg; ‐16±1 mmHg, 1mg/kg: ‐18±3 mmHg, 2mg/kg; ‐13±1 mmHg, 4mg/kg; ‐13±2 mmHg, 8mg/kg. In normotensive Wistars, AF‐219 did not reduce AP vs. baseline (‐4±2 mmHg, 1 mg/kg; P>0.05). Injections of vehicle had no effect in either rat strain (n=4). In SH rats, CBR blunted the 1 mg/kg AF‐219 induced fall in AP vs. non‐CBR rats. However, the fall versus baseline in AP in SH‐CBR rats remained significant (‐8±1 mmHg,P<0.01).

P2X3 receptor antagonism depresses chemoreflex hypersensitivity and lowers AP in SH rats to a level observed after selective CBR. P2X3 receptor antagonism may provide a novel way to attenuate CB tonicity in SH rats and as such become a novel target for controlling hypertension.

Supported by: British Heart Foundation and the NIH
Role of the peripheral chemoreceptor reflex on cardiovascular and sympathetic responses to obstructive sleep apnea in rats
Authors: Miki Kenju , Yoshimoto Misa , Kajihara Chisato , Mizukami Yuri
Published: June 2021

The potential contribution of peripheral chemoreceptors to the responses of systemic arterial pressure, heart rate, and sympathetic nerve activity (SNA) to obstructive sleep apnea was studied. Male Wistar rats had a tracheal balloon inserted to allow induction of apnea, with electrodes for measurement of renal SNA (RSNA) and lumbar SNA (LSNA), and a catheter for measurement of systemic arterial pressure. Electroencephalogram, electromyogram, and electrocardiogram records were also obtained. The tracheal balloon was inflated for 40 seconds during non‐rapid eye movement sleep. Systemic arterial pressure, RSNA, and LSNA increased after onset of tracheal balloon inflation while heart rate decreased. Bilateral carotid body section significantly attenuated the magnitude of the decrease in heart rate observed in intact rats, but had only minor effects on the responses of systemic arterial pressure, RSNA, and LSNA to obstructive sleep apnea. These data suggest that peripheral chemoreceptors may play a critical role in bradycardia in response to obstructive sleep apnea, and a minor role in the increases in systemic arterial pressure, RSNA, and LSNA in conscious rats. JSPS Grant.
The Rev1‐Pol ζ Mutasome
Authors: Burgers Peter , Makarova Alena , Binz Sara
Published: June 2021

Rev1 and DNA polymerase ζ (Pol ζ) play key roles in DNA translesion synthesis (TLS) and are largely responsible for both spontaneous and damage‐induced mutagenesis in eukaryotic cells. Pol ζ is a 4‐subunit complex (Rev7‐Rev3‐Pol31‐Pol32). The Pol31 and Pol32 subunits of Pol δ bind the Rev3 catalytic subunit of Pol ζ, and those subunits are required for PCNA‐dependent TLS by Pol ζ.

The catalytic activity of Rev1 is largely dispensable for mutagenesis, however the interactions of Rev1 with mono‐ubiquitinated PCNA and with Pol ζ are essential. This suggests that Rev1 may act as a scaffold for TLS. We have identified a conserved regulatory motif (M1) in Rev1 that, when mutated results in a large stimulation of Pol ζ replication activity. Stimulation requires the interaction domains between Rev1 and Pol ζ, and is absolutely dependent on the presence of PCNA. However, the catalytic activity of Rev1 is not required. We hypothesize that the M1 motif participates in a negative regulation of Pol ζ‐mediated TLS that is relieved upon Rev1 modification during DNA damage response, which then leads to the initiation of mutagenesis.
Entrepreneurial Drug Hunter: A Trek for Breakthrough Medicines at the Academic‐Industrial Interface
Authors: Sawyer Tomi
Published: June 2021

This presentation will focus on my career at the academic‐industrial interface that began with a plunge into the biomedical sciences from undergraduate studies at Minnesota State University Moorhead and graduate studies at the University of Arizona. Over the my 33 years in pharmaceutical and biotechnology industry, I have had the opportunity to drive both drug discovery and innovative technologies to advance the development of novel medicines. I will share some fascinating episodes and words of wisdom that reflect upon my trek as an entrepreneurial drug hunter which I hope will be inspirational to those attending this special session.
The Role of Metallothioneins in the Differential Pro‐oxidant Effects of (‐)‐Epigallocatechin‐3‐gallate (EGCG) in Oral Cells
Authors: Tao Ling , Sun Mingyao , Khoo Weslie , Park Jong‐Yung , Lee Soo‐Yeon , Kelleher Shannon , Lambert Joshua
Published: June 2021

The tea catechin, (‐)‐Epigallocatechin‐3‐gallate (EGCG), has been shown to exert cancer preventive effects. We and others have found that EGCG induces oxidative stress in oral cancer cells but causes antioxidant responses in normal cells. Here, we examined the role of antioxidant protein metallothionein (MT) in the differential pro‐oxidant effects of EGCG. qPCR analysis showed that EGCG significantly down‐regulated several MT isoforms (MT1E, F, G, X and MT2A) in oral cancer cells (SCC‐25), but up‐regulated several MTs in normal gingival fibroblasts (HGF‐1), particularly MT1G (209‐fold) and MT1X (3.5‐fold). We have previously reported that EGCG suppressed sirtuin 3 (SIRT3), a mitochondrial redox regulator, in cancer cells resulting in oxidative stress and apoptosis. Here, we unexpectedly found that siRNA‐mediated knock‐down of SIRT3 in cancer cells significantly up‐regulated MT1G, MT1X and metal regulated transcription factor 1 (MTF1), reduced oxidative stress, and enhanced cell growth. By contrast, knocking down MTF1 in cancer cells suppressed the mRNA expression of MT1G, MT1X and SIRT3, and increased cell susceptibility to EGCG‐induced growth inhibition. These results suggest MT is a potential target underlying EGCG's selective cytotoxicity, and demonstrate a cross‐talk between MT and SIRT3 signaling which may be mediated by MTF1. (Supported by AICR grant and Penn State University)
Activity‐Guided Isolation of a Sirtuin2 Inhibiting Compound from Coffee: Structural and Activity Confirmation of Javamide‐II (N‐caffeoyltryptophan) and its Cellular Effects on Histone H3, Alpha‐Tubulin and p53 Implicated in Human Diseases.
Authors: Park Jae
Published: June 2021

Coffee is one of most consumed drinks worldwide with potential health effects on several chronic diseases including neuronal diseases. Interestingly, recent studies suggest that the inhibition of sirtuin2 may be beneficial in restoring cognition in Alzheimer's disease. Therefore, in this paper, potential sirtuin2 inhibitors were screened using several coffee samples. For this study, a HPLC method was developed and coffee samples were fractionated by the HPLC method. Then, the fractions were screened using a sirtuin2 inhibition assay. The screening led to the isolation of a potent sirtuin2 inhibitory compound from the fraction with the highest inhibition activity. Using HPLC and NMR spectroscopic techniques, the chemical structure of the compound was determined as Javamide‐II (N‐caffeoyltryptophan). Javamide‐II was a potent sirtuin2 inhibitor inhibiting the enzymes by 39% at the concentration of 1 microM (P < 0.05). To confirm that Javamide‐IIis the compound able to inhibit sirtuin2, the amide was chemically synthesized and its capability of inhibiting sirtuin2 was evaluated. Both isolated and synthesized N‐caffeoyltryptophan exhibited very similar pattern of sirtuin2 inhibition with identical IC50 and Ki values, suggesting that Javamide‐II may be the compound able to inhibit sirtuin2. In this paper, we also report potential effects of Javamide‐II and its analogues on histone H3, alpha‐tubulin and p53 in cellular levels, suggesting that Javamide‐II and analogues found in coffee are potent sirtuin2 inhibitors with potential uses on several human diseases.
The bioactivity of flavonoids is likely the result of cumulative low exposure to a variety of structurally similar phenolic metabolites
Authors: Kay Colin , de Gesso Jessica , Warner Emily , Amin Hiren , de Ferrars Rachel , Edwards Michael , Zang Qing , O'Hagan David , O'Connell Maria
Published: June 2021

Activities of 21 flavonoid metabolites were investigated relative to their unmetabolized structures, utilizing 20 assays of vascular reactivity, inflammation and cellular adhesion, in endothelial (HUVEC), smooth muscle (AVSMC) and monocyte (THP‐1) cells, at physiologically relevant concentrations (0.1‐10µM). Unmetabolized flavonoids were generally less active than their phenolic metabolites. In vascular screens no metabolites altered expression of endothelin‐1 or nitric oxide, 3 metabolites induced eNOS, 2metabolites reduced angiotensin‐II induced superoxide, no metabolites induced NOX or p47phox, 1 metabolite upregulated p22phox and 3 metabolites induced HO‐1. In vascular inflammation and adhesion screens in HUVEC, 10, 9 and 6 metabolites reduced IL‐6 following CD40L, oxLDL or TNF‐α stimulation, respectively. 10 and 6 metabolites reduced sVCAM‐1 following CD40L or TNF‐α stimulation, respectively. 2 metabolites attenuated IL‐1β‐stimulated phosphorylation of NF‐κB p65, 1 metabolite induced Nrf2. In monocyte activity assays, 5 metabolites reduced LPS‐induced TNF‐α, 1 metabolite induced IL1B, no metabolites were active on HO‐1, tissue factor, NFkB or nfKB. The evidence suggests that bioactivity of flavonoids in vivo results from low exposure to a variety of structurally similar metabolites modifying inflammation and cellular adhesion pathways.

Support: UK Biotechnology and Biological Sciences Research Council (BB/I006028/1, BB/H004963/1).
Adherence to Dietary Guidelines and Successful Aging
Authors: Gopinath Bamini , Flood Victoria , Kifley Annette , Russell Joanna , Mitchell Paul
Published: June 2021

Increases in life expectancy make it important to remain disease‐free and fully‐functional for as long as possible. We aimed to prospectively examine the relationship between overall diet quality (reflecting adherence to dietary guidelines) and successful aging in a population‐based cohort of older adults. We used 10‐year follow‐up data from 2519 adults, aged 49+ years and free of cancer, coronary artery disease and stroke at the baseline examination. Dietary data were collected using a semi‐quantitative food‐frequency questionnaire. Total diet scores (TDS) were allocated for intake of selected food groups and nutrients for each participant as described in the national dietary guidelines. Higher scores indicated closer adherence to dietary guidelines. Successful aging was defined as the absence of: disability, depressive symptoms, cognitive impairment, respiratory symptoms and chronic diseases (cancer, coronary artery disease and stroke). After 10 years, 842 participants had died and 281 participants qualified as successfully aging. After multivariable‐adjustment, each unit increase in TDS at baseline was associated with a 10% increased odds of successful aging 10 years later, odds ratio, OR, 1.10 (95% confidence intervals, CI, 1.03‐1.18). Participants in the highest (high adherence to dietary guidelines) versus lowest quartile of TDS at baseline had 2‐fold higher odds of aging successfully after 10 years, OR 2.41 (95% CI 1.40‐4.17). In summary, greater compliance with published dietary guidelines was associated with an increased likelihood of good functional status and absence of chronic diseases in older age.
New Strategies for Cellular‐Scale Imaging of Bone and Cartilage
Authors: Williams Rebecca
Published: June 2021

Confocal microscopy can be used to obtain detailed, 3D‐resolved images of cells inside bone and cartilage. However the high scattering coefficients of dense connective tissues often necessitate tissue sectioning for resolving cellular scale detail inside. Multiphoton microscopy enables clearer imaging and greater depth penetration into these tissues and the related technique of second harmonic generation enables acquisition of collagen images at the single‐fibril level in 3D and in some cases in vivo. New improvements in clearing technologies and optical methods such as light sheet microscopy continue to advance the depth in to which dense tissues can be imaged using highly‐specific fluorescent probes. Concurrently, improvements in X‐ray computed tomography, the standard method for 3D medical assessment of bone morphology and lesions, have led to resolutions rivaling those obtained with optical microscopy, in some cases with specifically targeted electron dense contrast agents. Different techniques excel for different specific questions to be addressed within this diverse and powerful imaging landscape.
Improving Infant and Young Child Feeding in Ethiopia through Community Based Grain Banks Using Local Foods
Authors: Roche Marion , Sako Binta , Osendarp Saskia , Adish Abdulaziz , Tolossa Azeb
Published: June 2021

Background

Inadequate infant and young child feeding practices contribute to the concerning malnutrition situation in Ethiopia. To improve availability, accessibility and quality of complementary foods, development partners in Ethiopia supported women's groups to produce complementary food by processing local grains and legumes at community grain banks. Flour was sold in the semi‐urban communities and a subsidized barter system was created in the rural areas.

Objective

To assess the acceptability, perceived impact, feasibility and sustainability for local grain bank interventions to improve infant and young child nutrition, in four regions of Ethiopia.

Methods

A total of 51 key informant interviews and 33 focus group discussions (n=237) were conducted based on a purposive sampling framework of project stakeholders.

Results

The grain bank flour was valued for its quality and diverse locally grown ingredients. Mothers were motivated to give the flour because of perceived benefits to their child's health; while the community grain bank was credited as labor saving for women. The grain bank flour offered improved dietary diversity; however, further micronutrient interventions including dietary modification or fortification are needed to improve diet adequacy. The greatest risks to sustainability were dependence on external resources to subsidize the barter model and reliance on volunteer work from women's groups in the rural context.

Conclusions

Integrated agricultural and health interventions leveraging local crops can appeal to diverse stakeholders and may offer an acceptable approach to improving infant and young child feeding.

Funding: UNICEF & Micronutrient Initiative
Early Supplementation of Phospholipids and Gangliosides Affects Brain and Cognitive Development in Neonatal Piglets
Authors: Radlowski Emily , Liu Hongnan , Conrad Matthew , Li Yao , Dilger Ryan , Johnson Rodney
Published: June 2021

As human breast milk is a rich source of phospholipids (PHOS) and gangliosides (GLS), and breastfed infants have improved learning compared to formula fed, the importance of dietary PHOS and GLS for brain development is of interest. Herein, we sought to determine the effects of these lipids on brain and cognitive development. Male and female piglets were artificially reared and fed formula containing 0% (control), 0.8%, or 2.5% LACPRODAN® (PL‐20, Arla Foods Ingredients, DK), a PHOS/GLS supplement, from postnatal day (PD) 2 to PD28. Beginning PD14, performance in a spatial T‐maze task was assessed. At PD28, brain MRI data were acquired and piglet hippocampal tissue was obtained for metabolic profiling. Diet affected maze performance with piglets receiving 0.8% and 2.5% PL‐20 making fewer errors than 0% (80% vs 75% correct on average) (P<0.05) and taking less time to make a choice (3 seconds vs 5 seconds per trial) (P<0.01). Mean brain weight was 5% higher for piglets receiving 0.8% and 2.5% PL‐20 (P<0.05) compared to 0%; and voxel‐based morphometry revealed multiple brain areas with greater volumes and more gray and white matter in piglets receiving 0.8% and 2.5% PL‐20 compared to 0%. Metabolic profiling of hippocampal tissue revealed that multiple phosphatidylcholine metabolites were altered by diet. In summary, dietary PHOS and GLS improved spatial learning and affected brain growth and composition. (Supported by Arla Foods Ingredients and R01 HD069899).
Mild Zinc Deficiency Augments Increased TNF‐α Expression But Not Decreased Muscle Protein Synthesis after Acute Sepsis
Authors: Crowell Kristen , Navaratnarajah Maithili , Kelleher Shannon , Soybel David , Lang Charles
Published: June 2021

Moderate Zinc (Zn) imbalances are common among the elderly and individuals with chronic inflammatory conditions such as obesity, diabetes and rheumatoid arthritis. Here we developed a mouse model to study the influence of such imbalance on innate immune and metabolic responses to polymicrobial sepsis. We hypothesize that pre‐existing, mild Zn deficiency amplifies the systemic inflammatory responses, thereby exacerbating the decrease in muscle protein synthesis observed in sepsis. In this study, adult male mice were fed a Zn adequate (ZA) or Zn deficient (ZD) diet (30 or 7 ppm Zn, respectively) over 4 weeks, and then were subjected to cecal ligation and puncture (CLP) and sacrificed 24 h later (n = 8‐11 mice/group). Acute mortality did not differ between either diet. Sepsis increased TNF‐α mRNA in muscle of ZA mice and further increased TNF‐α in ZD mice. The mRNA content of key Zn transporters ZnT2, Zip7 and Zip14 was increased in septic animals, although this increase did not differ with ZD. In both septic groups, the in vivo rate of skeletal muscle protein synthesis was similarly decreased as was the phosphorylation of 4E‐BP1, suggesting a down‐regulation of the mTOR pathway. The muscle‐specific E3 ubiquitin ligases atrogin‐1 and MuRF1 increased after sepsis, and ZD did not alter this increase. While mild Zn deficiency amplified the expression of some pro‐inflammatory cytokines, it did not further modulate protein synthesis, protein degradation, or the expression of Zn transporters in muscle during the acute phase of the septic response. Whether mild Zn deficiency negatively impacts convalescence during the recovery phase of sepsis remains to be assessed. (Supported by F32GM112401 and GM38032)
High dietary selenium intake alters tissue lipid and protein profiles and metabolisms of growing pigs
Authors: Lei Xingen , Zhao Zeping , Barcus Matthew
Published: June 2021

We previously demonstrated that high dietary Se intake induced mild hyperinsulinemia and up‐regulated lipogenesis and protein synthesis signaling. The present study was conducted to reveal impacts of the high Se intake on tissue lipid and protein profiles and metabolic regulations. A total of 12 weanling pigs were divided into 2 groups (n = 6/group), and fed a corn‐soybean meal basal diet supplemented with Se (as Se enriched yeast) at normal (0.3 mg/kg) or high (3.0 mg/kg) concentration for 11 wk. While the high Se diet elevated (P < 0.05) total triglycerides and cholesterol concentrations in both liver and adipose tissues and non‐esterified fatty acid concentrations in the liver, it showed little effect on any of these measures in the muscle. The high Se diet enhanced (P < 0.05) myristic acid, margaric acid, and eicosapentaenoic acid concentrations, but decreased (P < 0.05) arachidonic acid concentrations in the liver. Concentrations of total protein in the liver and muscle as well as of 3 amino acids (Asp GLu, and Ala) were elevated (P < 0.05) by the high Se diet. Meanwhile, hepatic phosphoenolpyruvate carboxykinaseactivity and total and phosphorylated AMP‐activated protein kinase were up‐regulated (P < 0.05) by the high Se diet, although such effects were less in the muscle. In conclusion, high dietary Se intake seemed to exert differential impacts on the overall energy metabolism and biosynthesis of lipids and proteins in the liver, muscle, and adipose tissue of growing pigs. (NIH DK 53018).
Defect in Stress Erythropoiesis during Selenium Deficiency
Authors: Liao Chang , Paulson Robert , Prabhu K Sandeep
Published: June 2021

Redox homeostasis occupies a pivotal role during stress erythropoiesis, but the key players and mechanisms are not well understood. We hypothesized that selenium (Se), well recognized for its redox properties, regulates stress erythroid progenitors, in part through stabilizing hemoglobin and efficient erythrocyte replenishment. Here we report preliminary findings in a classical model of phenyl hydrazine (PHZ)‐induced hemolytic anemia in mice fed diets deficient in Se (<0.01 ppm; Se‐D) or adequate in Se (0.08 ppm; Se‐A). Se‐D mice displayed poor survivability upon PHZ treatment with severe hemolysis and low hematocrit; while mice on Se‐A diet recovered from PHZ treatment within 10 days. In response to anemia, erythropoiesis occurs in the murine spleen. Se‐A mice rapidly expanded stress erythroid progenitors (BFU‐E; Burst forming unit‐ erythroid) during the first 3 days of recovery. In contrast Se‐D mice were unable to expand progenitors. In addition,qPCR analysis of the spleen showed that Se‐D mice failed to upregulate α‐hemoglobin stabilizing protein (AHSP), supporting defects in hemoglobin formation. Interestingly, Hsp70 was greatly upregulated in Se‐D mice, suggesting a compensatory mechanism of α‐hemoglobin chaperoning. These studies suggest that Se plays an important role in protection from hemolytic anemia by affecting expansion of erythroid progenitors in addition to enhancing the formation of stable hemoglobin molecules. Supported by grants from the National Institutes of Health to KSP and RFP
A Comparison of the Healthfulness of Prepackaged Children's Foods from Participants and Non‐Participants of the Canadian Voluntary Code on Marketing to Children
Authors: Murray Chelsea , L'Abbé Mary
Published: June 2021

This study's purpose was to determine whether children's food and beverage products from companies participating in the Canadian voluntary code on marketing to children (CAI), which does not cover product packaging, were healthier than children's products from non‐participating companies. All products marketed to children (n=415) were identified in a database of Canadian food products (n=10,488). The Ofcom nutrient profiling method was used to calculate a summary score of the healthfulness of each children's product based on its content of specific nutrients. These scores, ranging from 1 to 100 (where 1 is least healthy), were compared between children's products from CAI participants (n=164) and non‐participants (n=251). The Ofcom model provides a cutoff score for products to be classified as “healthier”; the proportion of products meeting this “healthier” cutoff was compared between products from CAI participants and non‐participants. The median healthfulness score of children's products from CAI participants was 43 (interquartile range 37‐66); this score was not significantly different compared to children's products from non‐participants, which scored 54 (interquartile range 38‐64). However, a significantly lower proportion of children's products from CAI participants were considered “healthier”, 14% of products, compared to 23% from non‐participants; p = .02. These results indicate that voluntary codes, such as the CAI, in which companies commit to reduce the marketing of unhealthy foods and beverages to children, should also apply to all components of their marketing, including product packaging.

Supported by McHenry Chair grant (ML); and OGS, CIHR Master's, and CIHR PICDP graduate scholarships (CM)
Dietary Fiber and Added Fiber
Authors: Gordon Dennis
Published: June 2021

The challenges to achieve more dietary fiber (DF) in foods and beverages, and achieving recommended intakes, can be traced to IOM recommendation to have two categories or definitions of DF. Objective: Recommend and justify the use of “Added Fiber” (AF) in foods and beverages.

Methods

Document current non‐reported use of AF in foods.

Results

Quantitate and contrast current total DF intakes (endogenous DF and AF) in meeting recommended Adequate Intakes (AI).

Conclusions

Report disparity, and recommend how, AF can help meet AI, with advantages, disadvantages and risks. Dietary fiber remains a nutrient of great interest to the consumer and the health community. This interest is attributed to the consumer's strong belief in DF benefits and quest to find and consume more foods with DF, and the IOM's recommended AI levels at approximately twice current intakes.. The average DF intake is 16 g/day, and AI recommendations are 38 and 25 g/day for men and women, respectively. The IOM defined “Dietary Fiber” as that endogenous in foods and “Added Fiber” is that extracted and or modified and added to foods. While of academic and taxonomical interest, two DF definitions, and specifically use of the term “Added Fiber” are limiting and possibly discriminating to the science of DF, the consumer and food labeling. The FDA in proposing changes to the food label has decided there will be only one term on food labels, “Dietary Fiber”. For “Added Fiber” to be included in this term, is must have demonstrated beneficial physiological effects for human health. While increased whole grain (WG) consumption is recommended, most WG foods as presently available and consumed are not a good source of DF. (No support)
Canned Fruit and Vegetable Intake is Associated with Greater Total Fruit and Vegetable Consumption, Better Diet Quality, Increased Nutrient and Same Sodium and Added Sugar Intake in Adults: NHANES 2001‐2010
Authors: Freedman Marjorie , Fulgoni Victor
Published: June 2021

The association of canned fruit and vegetable (CF+CV) consumption with nutrient intake, dietary quality, and physiological parameters was examined in adults 19+ years (N=24,807) using NHANES (2001‐2010). CF+CV consumers (n=2,746) were defined as those who ate any amount of CF+CV during the first 24‐hr diet recall. The National Cancer Institute (NCI) method was used to estimate the distribution of usual dietary intakes of foods and nutrients. Regression analyses were conducted to assess differences in consumers and non‐consumers. The Healthy Eating Index‐2010 (HEI) was used to assess diet quality. Adults who consumed CF+CV, as compared to non‐consumers, had higher Healthy Eating Index‐2010 (HEI) scores (49.0 ± 0.35 v 47.4 ± 0.28). Adults who ate CF+CV consumed more total fruit (2.5±0.06 v 2.1±0.03), whole fruit (2.6 ± 0.05 v 2.0 ± 0.03) and total vegetables (3.5±0.04 v 3.0±0.02). CF+CV consumers ate significantly more fiber (17.2±0.2 v 16.0±0.15 g/d) and potassium (2,841.9±23.3 v 2,712.9 ±13.7 mg/d) and significantly less total fat (79.7±0.69 v 82.4±0.26 g/d) and saturated fat (26.0±0.25 v 27.2±0.11 g/d). Sodium and added sugar intake was not different between groups. All physiological parameters (body weight, BMI, waist circumference and blood pressure) were comparable. Since canned fruits and vegetables make important dietary contributions without affecting sodium and added sugar intake, their consumption should be recommended as part of a healthful diet.
Leucine Guides Meal Distribution of Dietary Protein for Muscle Protein Synthesis and Mass
Authors: Layman Donald , Norton Layne
Published: June 2021

Efficiency of indispensable amino acid (IAA) utilization for muscle protein synthesis (MPS) decreases in adults. Potential causes include reduced blood flow, membrane transports & sensitivity to anabolic signals including growth factors (insulin) and amino acids (Leu). The objective was to determine if meal distribution of dietary Leu within complete meals impacts MPS and ultimately muscle mass. Adult rats (350 g) consumed 3 meals/d of complete diet for 11 wk to test the importance of meal protein distribution and Leu content on MPS, muscle mass and body composition. Expt. 1, rats received identical macronutrient diets with whey protein either in a balanced (BD) or unbalanced distribution (UD). BD provided 16% En as protein at each meal and UB had 8% at 7:00 and 13:00h and 27% at 18:00h. BD had greater MPS and translation factor (4E‐BP1 & S6K) activation at 7:00h and greater muscle mass after 11 wk. Expt. 2, rats received identical 16% diets that differed in source of protein and Leu content [wheat (Leu: 6.8% w/w), soy (8.0%), egg (8.8%) & whey (10.9%)]. After 7:00h meal, MPS was determined and whey > egg > soy = wheat and after 11 wk muscle mass was whey = egg > soy > wheat. In summary, long‐term changes in muscle mass indicate that meal distribution of protein and the associated Leu content can impact the efficiency of utilization. Research supported in part by the American Egg Board.
Determination of the Tolerable Upper Intake Level of Leucine in Healthy Elderly (70‐75y)
Authors: Rasmussen Betina , Turki Abrar , Madden Kenneth , Elango Rajavel
Published: June 2021

Leucine, a branched‐chain amino acid, has been shown to stimulate muscle protein synthesis, and thus it has been proposed to prevent age related muscle atrophy (sarcopenia). Therefore, leucine supplementation may have potential benefits in elderly populations. The UL (tolerable upper intake level) for leucine intake in young men has been recently determined to be 500 mg/kg/day, and increases in ammonia concentrations were seen at intake levels above 500/mg/kg/day. The objective of the current study was to determine the UL for leucine in healthy elderly men, as this is currently unknown. Five healthy elderly men (70 – 76 yrs) received graded stepwise increases in leucine intakes ranging from 50 ‐ 650 mg/kg/day, provided on eight separate study days. The UL of leucine was identified by measurements of plasma and urinary biochemical variables, including blood ammonia, glucose and insulin concentrations. Further, the participants received an oral primed‐continuous protocol of 1‐13C‐leucine on all study days to measure changes in leucine oxidation. None of the participants reported any adverse physical symptoms on study days. Leucine oxidation appears to plateau with increasing leucine intakes. Blood ammonia concentrations above normal values (35 µmol/L) were observed at leucine intake of 350mg/kg/day and above. Plasma glucose stayed within normal ranges. These preliminary results suggest that the UL for leucine in healthy elderly men may be lower than the current UL of 500 mg/kg/d for healthy young men.

(Supported by ICAAS)