bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect Of ‘Catalytic’ Doses Of Fructose And Its Epimers In Acute Single‐Meal Feeding Trials: A Systematic Review And Meta‐Analysis Of Controlled Trials
Authors: Braunstein Catherine Rose , Noronha Jarvis C , Mejia Sonia Blanco , Kahn Tauseef A , Wolever Thomas MS , Josse Robert G , Kendall Cyril WC , Sievenpiper John L 
Published: November 2023

Objective‘Catalytic’ doses (<10g/meal or 36g/day) of fructose and its epimers (allulose, tagatose, and sorbose) may reduce postprandial glycemic responses to carbohydrate loads in people with and without diabetes by inducing glycogen synthesis. To synthesize the evidence of the effects of fructose and its epimers on acute postprandial carbohydrate metabolism, we conducted a systematic review and meta‐analysis of controlled trials.MethodsWe searched Medline, EMBASE, and the Cochrane Library (through Feb 12 2016). We included controlled, single‐meal feeding trials (≥2 hours) investigating the effect of fructose and its epimers (allulose, tagatose, and sorbose) on the postprandial metabolic responses to carbohydrate control meals compared to the same control meals without the sugars. Two independent reviewers extracted all relevant data and assessed risk of bias of individual trials using the Cochrane Risk of Bias Tool. Outcomes included plasma glucose and insulin incremental area‐under‐the‐curve (iAUC). Data were pooled using the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (95% CI). Heterogeneity was assessed by the Cochran Q statistic and quantified by the I2 statistic.ResultsEligibility criteria were met by 9 controlled feeding trials involving 144 participants in people with and without diabetes. Fructose (5 trial comparisons, MD= −28.65 mmol/L*min [95% CI, −55.36 to −1.93], p=0.04) and allulose (5 trial comparisons, MD= −39.79 mmol/L*min [95% CI, −67.35 to 12.22], p= 0.005) but not tagatose (15 trial comparisons) significantly reduced the postprandial plasma glucose iAUC responses to the carbohydrate control meals. Only allulose significantly reduced the postprandial plasma insulin iAUC to the carbohydrate control meals (MD= −2950.59 pmol/L*min [95% CI, −4844.11 to −1057.06], p=0.002). There was no evidence of heterogeneity in any of the analyses (P>0.1).ConclusionsPooled analyses indicate that small doses of fructose and allulose but not tagatose may improve the postprandial glycemic responses to carbohydrate meals without adversely affecting insulin response. There is a need for long‐term randomized controlled trials to assess whether these acute single‐meal effects lead to sustainable benefits in people with and without diabetes.Protocol registration: clinicaltrials.gov identifier, NCT02776722.Support or Funding InformationThe Tate and Lyle Nutritional Research Fund at the University of Toronto, Canadian Diabetes Association (CDA), Banting & Best Diabetes Centre, and PSI Foundation.
Cyclodextrin‐based nanocarriers for alpha‐tocopheryl phosphate and regulatory activity in THP‐1 monocytes
Authors: Zingg Jean‐Marc , Stamatiou Christina , Daunert Sylvia 
Published: November 2023

The vitamin E derivative, alpha‐tocopheryl phosphate (αTP), occurs in small amounts in plasma and animal tissues. Low amounts of αTP are also present in foods but the bioavailability as an intact molecule is very low, since most of it is hydrolyzed. So far no efficient mechanism of intact cellular αTP uptake and tissue distribution has been identified when compared to vitamin E (alpha‐tocopherol, αT). Since αTP has been reported to be more potent in regulating signal transduction and gene expression than αT (e.g. on atherosclerosis, inflammation), a more efficient system to deliver intact αTP to cells in tissues may be useful. Here we characterize the formation of complexes of αTP with the nanocarrier cyclodextrin (CD). αTP/CD formed soluble complexes in a 1 to 2 ratio and generated a homogenous white colloidal emulsion that stayed in homogenous suspension for weeks. The αTP/CD complex inhibited proliferation of THP‐1 monocytes and CaCo2 colon carcinoma cells slightly stronger than αTP. When compared to CD, the complex of αTP/CD extracted cholesterol from cellular membrane of cultured THP‐1 monocytes and HT29 intestinal epithelial cells with higher efficiency and was associated with delivery of αTP to these cells. The αTP/CD complex induced VEGF promoter activity in THP‐1 and HEK293 cells with slightly higher efficiency than αTP. Interestingly, αTP and αTP/CD also reduced the phagocytosis of fluorescent Staphylococcus aureus bioparticles in THP‐1 monocytes/macrophages. αTP/CD assembled to higher order complexes with three types of modified starches and chitosan. These higher complexes had a comparable activity in the above assays and therefore may be useful as protective vehicles for oral, dermal or ocular delivery or as deposit‐enhancer in mucosa for delivery across epithelia.Support or Funding Information1R21AI124058‐01
Dose‐effect Relationship between Dietary Iron and Hematological Parameters in Rats
Authors: Yokoi Katsuhiko , Konomi Aki 
Published: November 2023

Although the study in iron nutrition has a long history, studies on dose‐effect relationship between dietary iron and hematological parameters are still limited. The aim of this study is to clarify this relationship in rats. Fifty‐four three‐week‐old male Wistar rats were equally and randomly divided into nine groups, and fed for five weeks on graded levels of supplemental dietary ferric citrate: 0, 7, 14, 21, 28, 35 (AIN‐93G formulation), 49, 126, and 252 mg iron/kg. Hematological parameters using blood samples after overnight food withdrawal were measured. Data were analyzed by the Williams or Shirley‐Williams multiple comparison test (if significant heterogeneity of variance existed). Values between dietary iron levels 126 mg/kg and 252 mg/kg were tested by Student's t test. P value less than 0.05 was considered significant. Compared with dietary iron level 126 mg/kg where hemoglobin was highest, hemoglobin, hematocrit, MCV, and MCH were significantly lower at dietary iron level 49 mg/kg and less. Compared with dietary iron level 126 mg/kg, red blood cell counts were significantly lower at dietary iron level 7 mg/kg and less. Compared with dietary iron level 126 mg/kg, reticulocyte counts were significantly increased at dietary iron level 14 mg/kg and less. There were no significant differences in all parameters between dietary iron levels 126 mg/ kg and 252 mg/kg. These results suggest that the breakpoint of dietary iron level for hemoglobin and red cell indices is placed between 49 mg/kg and 126 mg/kg.Support or Funding InformationThis work was supported by Grants‐in‐Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI: no. 25350137).
High‐Density Lipoprotein Cholesterol Concentrations and Particle Size Are Modified by Dietary Zinc in Men
Authors: Shenvi Swapna , Chen Kevin , Kim Elijah , Zyba Sarah , King Sarah , Shigenaga Mark , Killilea David , Holland Tai , Sutherland Barbara , Krauss Ronald , King Janet 
Published: November 2023

ObjectiveTo measure biomarkers of lipid metabolism in response to a marginal zinc depletion, repletion, and supplementation in healthy male subjects.MethodsEighteen male subjects between ages of 18–45 consumed a controlled diet (80% carbohydrate, 10% fat, 10% protein) with two levels of dietary zinc. Phase I: Low zinc: 6 mg/day with 1.5 mg of phytate (2 weeks); Phase II: Zinc repletion: 10 mg/day with no phytate (4 weeks). Thereafter, a 25 mg/day zinc supplement was administered with an ad libitum diet for 3 weeks (Phase III). Targeted analysis of lipids and lipoprotein particle size were performed using standard methodology.ResultsPlasma zinc levels remained unchanged during Phases I and II in all subjects; they increased by 17.4 ± 3.8% (mean ± SE) at the end of supplementation (phase III). Apo‐A1 decreased significantly from 119.2 ± 13.2 mg/dL (mean ± SD) to 110.2 ± 13.2 mg/dL (p=0.003) at the end of the low zinc period. Apo‐A1 remained low at the end of phase II, but returned back to baseline after supplementation. A similar pattern was observed in HDL‐c and HDL‐L (large buoyant HDL particles) levels across the three phases. Plasma triglyceride levels increased during the 6‐week high‐carbohydrate diet, but were not modified by shifts in dietary zinc. Based on our previous observation of higher DNA strand breaks in the low zinc metabolic period and literature reports linking cancer to low HDL‐c levels, we performed a correlation analysis of DNA strand breaks and HDL subspecies. Our results show that the percent changes in HDL‐L and DNA strand breaks from phase I to II are negatively correlated (r=−0.45; p=0.05).ConclusionResults from our studies show that low zinc combined with a high carbohydrate diet increased biomarkers of dyslipidemia, but provision of adequate dietary zinc or a zinc supplement for a short period of time mitigated the increase in these biomarkers.Support or Funding InformationHarvest Plus
Acceleration of liver regeneration by betaine supplementation after partial hepatectomy
Authors: Jun Doo Sung , Choi Yeo Jin , Ahn Chul Won , Kim Young Chul 
Published: November 2023

In living donor liver transplantation (LDLT), stimulation of hepatic regeneration can have tremendous therapeutic relevance for both recipients and donors, however, very few substances have been found capable of stimulating liver regeneration. In this study we examined the effect of betaine, a methyl donor utilized for remethylation of homocysteine to methionine, on liver recovery in rats subjected to two‐thirds partial hepatectomy (PHx). Betaine (1 %) provided either from 2 wk before PHx or after PHx enhanced the growth of liver significantly, reaching a normal liver weight in 7 days after the surgery. Protein expression of cyclin D1 and proliferating cell nuclear antigen (PCNA) was also stimulated by betaine intake. The surgical treatment induced a significant change in hepatic levels of sulfur‐containing amino acids and polyamines. Methionine, S‐adenosylmethionine (SAM), S‐adenosylhomocysteine (SAH), cysteine and taurine were elevated rapidly in the remnant livers after PHx, which was intensified by betaine intake. A drastic increase in hepatic putrescine was noted from 6 h after PHx, while spermidine unchanged and spermine decreased slightly. Betaine administration elevated putrescine and spermidine significantly, but not spermine in the liver. It is suggested that an alteration in the metabolomics of sulfur‐containing substances critically influences the early phase of liver regeneration, probably via modulation of polyamine metabolism. The enhancement of liver recovery by betaine may be attributed to the increase in spermidine levels resulting from an elevation of the SAM availability. This finding raises the possibility that betaine may be effective in promoting the regeneration of liver tissue after damage or transplantation, and therefore, warrants further studies to examine its clinical significance.Support or Funding InformationSupported by National Research Foundation (NRF) grants (No. 2014‐R1A2A1A11052967 and No. 2009‐0083533) funded by the Ministry of Education, Science and Technology (MEST), Korea.
Evidence for agonist‐specific mechanisms of cannabinoid tolerance.
Authors: Nealon Caitlin , LaFleur Rebecca , Morgan Daniel 
Published: November 2023

The focus of this study was to investigate whether G protein‐coupled receptor kinase (GRK)‐ and βarrestin2‐mediated receptor desensitization is required for antinociceptive tolerance to WIN55,212‐2, a synthetic, high potency cannabinoid agonist. We used S426A/S430A mutant mice expressing a desensitization‐resistant form of cannabinoid receptor 1 (CB1) to investigate the essential role of this mechanism in tolerance to WIN55,212‐2. We have previously shown that antinociceptive tolerance to Δ9‐THC is mediated in part by this mechanism, while tolerance to CP55,940, another high potency, synthetic cannabinoid, is only very modestly affected by blockade of this pathway. Antinociceptive tolerance to repeated daily administration of WIN55,212‐2 and CP55,940 was assessed in wild‐type and S426A/S430A mice using the hot plate, tail flick, and formalin tests. We found that antinociceptive tolerance to WIN55,212‐2 was profoundly delayed in the desensitization‐resistant mice compared to wild‐type counterparts. Interestingly, this difference was not observed in tolerance to the hypothermic or cataleptic effects of WIN55,212‐2. We found that antinociceptive tolerance to CP55,940 was slower to develop in wild‐type mice than in mice administered WIN55,212‐2. However, antinociceptive tolerance to CP55,940 was only modestly delayed in desensitization‐resistant mice compared to wild‐type counterparts. These findings suggest that GRK‐ and βarrestin2‐mediated desensitization of CB1 may be the predominant mechanism responsible for antinociceptive tolerance to WIN55,212‐2. This finding suggests the possibility of agonist‐specific mechanisms of tolerance for different cannabinoid agonists.Support or Funding InformationThis research was supported by NIH grant DA036385 and a grant from the Pennsylvania Department of Health using Tobacco CURE funds.
Macrophage COX‐2/mPGES‐1/PGE2 mediates inflammatory pain in peripheral tissues
Authors: Chen Lihong , Yang Guangrui , Grosser Tilo 
Published: November 2023

Nonsteroidal anti‐inflammatory drugs (NSAIDs) alleviate inflammatory pain by inhibiting prostanoid formation, but are associated with serious cardiovascular and gastrointestinal adverse effects. Identification of the dominant tissue sources of prostanoid formation may lead to more targeted therapeutic approaches. We studied the contribution of macrophage derived prostanoid formation to inflammatory pain in mice. Selective deletion of COX‐2 in macrophages (Mac‐COX‐2‐KO) by crossing LysMCre mice with COX‐2flox/flox mice resulted in complete suppression of lipopolysaccharide‐induced prostaglandin (PG) E2, prostacyclin and thromboxane in peritoneal macrophages. Mac‐COX‐2‐KO mice exhibited normal mechanical and heat sensitivity at baseline, as well as normal formalin induced chemical pain, while both mechanical and thermal hyperalgesia were significantly reduced in complete Freund's adjuvant (CFA) evoked hind paw inflammation. Inflammatory cell infiltration and concentrations of PGE2, IL‐1β and TNFα were significantly reduced in Mac‐COX‐2‐KO paw tissues following CFA induction. This was reflected by a reduction in paw swelling. Mechanical and thermal pain hypersensitivity were also reduced in the zymosan‐evoked monoarticular arthritis and collagen II antibody‐induced polyarthritis. We identified PGE2 as the major prostanoid which underlies the effect of macrophage COX‐2 on hyperalgesia using macrophage mPGES‐1 deficient mice obtained by crossing mPGES‐1flox/flox with LysMCre mice (Mac‐mPGES‐1‐KO). These mice fully recapitulated the phenotypes observed with Mac‐COX‐2‐KO. Pretreatment of Mac‐mPGES‐1‐KO mice with celecoxib at a biochemically‐validated COX‐2 selective concentration (100mg/kg/day) failed to reduce CFA‐induced inflammation and hyperalgesia beyond deletion of mPGES‐1 in macrophages, further demonstrating the importance of macrophage‐derived PGE2. This also indicates that central COX‐2 plays only a minor role in this setting. Our results demonstrated that the macrophage COX‐2‐mPGES‐1‐PGE2 biosynthetic pathway might be the dominant source of prostanoids in inflammatory pain hypersensitivity in peripheral tissues and may afford a more targeted approach to NSAID therapy.Support or Funding InformationAmerican Heart Association Scientist Development Grant: 15SDG22780013
Study of Daily Genistein Ingestion on Spatial Memory and Olfaction in Triple Transgenic Alzheimer's Mice
Authors: LeBlanc Hayley Rachel , Williamson Alyson Caye , Wrenn Craige Charles 
Published: November 2023

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by the accumulation of beta amyloid plaques and the formation of neurofibrillary tau tangles. These plaques and tangles lead to the learning and memory deficits characteristic of AD. Estrogen and estrogen‐like compounds have been shown to slow the development of plaques and tangles. Though estrogen receptors are found in the male hippocampus, it is unclear how estrogen affects learning and memory in the male hippocampus. Male triple‐transgenic (3×Tg‐AD) mice mimic the pathology and learning and memory deficits of AD in humans. To examine the potential effects on the male hippocampus, 3×Tg‐AD mice were either fed a dose of 4–5 mg/kg of genistein, a phytoestrogen found in soy or a placebo and tested behaviorally in the Morris Water Maze and Olfactory Habituation‐Dishabituation tasks. The 3×Tg‐AD mice had significantly longer swim paths to find a hidden platform as well as a lack of selective search in the platform location when the platform was removed. There was no significant difference between the 3×Tg‐AD and wild type mice during the olfactory task of habituation‐dishabituation. As the pathology of the AD develops in the 3×Tg‐AD mice, the mice will be retested to examine the differences in learning and memory. Presently, the 3×Tg‐AD were impaired in successfully learning the location of a hidden platform but were not impaired in their olfactory abilities.Support or Funding InformationRonald Troyer Research Fellowship, Drake UniversityHarris Research Endowment, Drake UniversityDrake Undergraduate Science Collaborative Institute, Drake University
Stroke protection via stimulation of fatty acid oxidation increases astrocyte spare respiratory capacity
Authors: Sifuentes Mikaela , Lechleiter James 
Published: November 2023

Stroke is a growing threat among the aging population in the United States, yet few treatments exist for afflicted patients. Research in our lab identified the stimulation of astrocyte mitochondrial metabolism as a protective strategy against stroke. Thyroid hormone has been observed to reduce stroke lesion size, a treatment that we hypothesize is mediated by stimulating fatty acid oxidation (FAO) via the mitochondrial trifunctional protein (MTP). We observe that treatment with the active form of thyroid hormone (T3) protects the mouse brain from stroke in a mechanism requiring astrocyte metabolism and the presence of brain MTP. T3 stimulates an increase in maximal respiration and spare respiratory capacity in a dose‐dependent manner, which is blocked by inhibition of FAO. We also report that T3 increases astrocyte viability and reduces the formation of starvation‐induced lipid droplet formation, suggesting that T3 directly increases astrocyte resistance to conditions of nutrient‐deprivation, such as that observed in stroke. Altogether, our data indicate that thyroid hormone protects the brain against stroke by increasing astrocyte survival in a FAO‐dependent mechanism.Support or Funding InformationResearch supported by National Institutes of Health R01AG007218 and the American Heart Association Predoctoral Fellowship 16PRE27670002
Enhanced Mitochondrial Biogenesis for the Treatment of Spinal Cord Injury
Authors: Scholpa Natalie E , Narang Aarti , Wang Wenxue , Corum Daniel , Tomlinson Stephen , Schnellmann Rick G 
Published: November 2023

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. It has been suggested that pharmacological interruption of this secondary injury could improve neuron survival, allowing for enhanced functional recovery. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, directly reducing the ability of mitochondria to maintain homeostasis, leading to loss of ATP‐dependent cellular functions, calcium overload, excitotoxicity and oxidative stress, further exacerbating injury. While therapeutics targeting restoration of single facets of mitochondrial function have proven ineffective post‐SCI, pharmacologically stimulating mitochondria biogenesis (MB) is a previously unexplored strategy. This study examined the effects of formoterol, an FDA‐approved β2‐adrenergic receptor agonist, and LY344864 (LY), a selective 5‐HT1F receptor agonist, on spinal cord MB and functional recovery following SCI in mice. Female C57BL/6 mice were subjected to moderate SCI using a force‐controlled pneumatic impactor‐induced contusion model (80 Kdyn), and administered daily formoterol or LY (i.p) beginning 1 h post‐SCI. Both treatments induced MB in the injury and peri‐injury sites post‐SCI, as evidenced by increased mitochondrial DNA content and nuclear‐encoded mitochondrial genes, as well as 2–3‐fold increases in various mitochondrial‐encoded genes. Drug‐treated mice also exhibited less histological damage than vehicle‐treated mice at 72 h post‐SCI, namely decreased loss of white matter and structural preservation of the central canal and anterior median fissure. The Basso‐Mouse Scale (BMS) was used to assess locomotor capability, where a BMS score of 0 indicates no movement of the hind limbs (observed 24 h following SCI) and a score of 9 indicates normal function (sham controls). Importantly, five days post‐SCI, LY‐treated mice demonstrated improved motor function compared to vehicle‐treated mice (BMS = 1 v 0.2). Following seven days of administration, the locomotor capability of both LY‐ and formoterol‐treated mice were greater than that of the vehicle group (BMS = 1.8 v 1.2 v 0.5). Fifteen days post‐injury, both formoterol‐ and LY‐treated mice exhibited the same overall improvement in motor function, with BMS scores twice that of vehicle‐treated mice (BMS = 4 v 2). We suggest that MB is a good drug target for the treatment of SCI and that LY‐ and formoterol‐induced MB as a therapeutic avenue for the treatment of SCI.Support or Funding InformationSouth Carolina Spinal Cord Injury Research Fund