bluuebunny/crossref_metadata_2025 huggingface dataset:
Crossmodal interactions in perception and learning
Authors: Shams Ladan
Published: June 2021

Humans are generally considered as visual animals. Visual perception, however, can be strongly and radically altered by other modalities. We have found that sound can radically change visual perception, and our neuroimaging studies show that this alteration can occur at short latencies and as early as primary visual cortex. These findings together with a wealth of other recent findings have established that crossmodal interactions are ubiquitous in human perception and can occur at various levels of processing, including very early stages of sensory processing. Therefore, we asked whether crossmodal interactions play a role in perceptual learning. We compared visual training with auditory‐visual training for learning of a low‐level visual task, and discovered that auditory‐visual training accelerates and enhances performance in a visual task even in the absence of sound. Thus, it appears that crossmodal interactions play an important role in perceptual learning, but how are the crossmodal associations acquired themselves? Brain areas mediating multisensory learning, and characteristics of crossmodal associative learning and its relationship with unisensory associative learning will be discussed.
Targets affecting lipid metabolism to treat metabolic diseases
Authors: Rondinone Cristina
Published: June 2021

The excess body fat mass predisposes obese individuals to the development of insulin resistance and metabolic syndrome. The metabolic dysregulation that follows elevated blood lipids and ectopic deposition of fat leads to comorbidities such as type 2 diabetes, coronary heart disease and hypertension. Restoring the exaggerated plasma free fatty acids and triglyceride levels would reduce the accumulation of triglycerides in tissues other than white adipose tissue, such as liver, muscle and the pancreas resulting in decreased hepatic glucose output, increased muscle fatty acid oxidation and improving b‐cell function. Alternatively, regaining metabolic control of lipid synthesis via inhibition of different enzymes would lead to decreased triglyceride levels in the aforementioned tissues, representing an additional approaches to enhance insulin sensitivity in these metabolically active tissues. Thus, different enzymatic regulators of triglyceride synthesis may constitute key drug targets to treat obesity, insulin resistance and other components of metabolic syndrome. Specifically, we will present evidence in support of the critical roles of enzymes (such as diacylglycerol O‐acyltransferase (DGAT) and others) in improving metabolic profiles in animal models of insulin resistance and diabetes.
The role of phospholipid synthesis in lipid‐mediated signaling and regulation in yeast
Authors: Henry Susan Armstrong , Jesch Stephen A. , Nunez Lilia R. , Villa‐Garcia Manuel , Gaspar Maria L. , Aregullin Manuel A. , Lee So Jin , Chang Yu‐Fang
Published: June 2021

Rapid genome‐wide changes in the transcription of hundreds of genes in yeast cells occur in response to changes in lipid metabolism that accompany the provision of inositol, the immediate precursor to phosphatidylinositol (1, 2). Changes in the synthesis and turnover of lipids that accompany these transcriptional responses include decreases in phosphatidic acid and CDP‐diacylglycerol and an increase in the rate of phosphatidylinositol synthesis and phosphatidylcholine turnover (3, 4). These changes in the patterns of synthesis or turnover of these lipids influence several major signaling pathways and transcriptional networks. Moreover, the Protein Kinase C pathway is involved in maintaining lipid homeostasis in cells deprived of inositol when choline is present. A screen of viable gene deletion mutants for phenotypes associated with misregulation of lipid metabolism identified many mutants defective in several major stress response pathways. We will discuss the roles of these signaling pathways in cellular homeostasis under conditions of changing lipid metabolism.

This work is supported by NIH grant GM‐19629.
Increased consumption of legumes improves arterial stiffness in peripheral vascular disease independent of blood pressure, weight and serum cholesterol
Authors: Zahradka Peter , Guzman Randy , Weighell Wendy , Wright Brenda , Baldwin Alanna , Louis Sherif , Rodriguez‐Leyva Delfin , Taylor Carla G.
Published: June 2021

Background

Eating fibre‐rich, low glycemic legumes may benefit cardiovascular health by reducing plasma lipid levels. We therefore undertook a clinical study to address the hypothesis that increased legume consumption would improve arterial stiffness.

Methods

Individuals with peripheral arterial disease were given ½ cup mixed legumes daily for 8 wks.

Results

No changes in glycated hemoglobin, blood pressure, body weight, triglycerides or HDL cholesterol were detected relative to baseline values, but there were significant decreases in total and LDL cholesterol. There was an improvement in ankle‐brachial index (ABI) and a corresponding decrease in arterial stiffness (by pulse wave analysis), but serum markers of endothelial dysfunction or inflammation remained constant. Interestingly, the improvements in ABI and cholesterol were not correlated.

Conclusions

These data indicate that a legume‐rich diet can elicit major improvements in arterial function in the absence of changes in either body mass or blood pressure. Furthermore, the lack of correlation with serum cholesterol levels suggests improved vascular function was not a consequence of the high fibre and low glycemic index properties of the legumes. Finally, the absence of changes in circulating markers of endothelial dysfunction suggests the positive effects on arterial stiffness are mediated by another mechanism.

Funding from Pulse Canada.
The Healthy Eating Index scores of low‐income women in early postpartum and its association with lipid profiles
Authors: Shah Bijal Sanghani , Cahill Jodi , Lu Hongxing , Freeland‐Graves Jeanne H
Published: June 2021

The Healthy Eating Index (HEI) is a composite tool that assesses the degree to which individuals conform to the recommendations of the 2005 Dietary Guidelines. Previous versions of this index have shown to influence lipid levels. The objective was to evaluate the diet quality of triethnic, overweight/obese women in early postpartum (n=131) using the HEI‐2005 and its ability to reflect serum lipids, a cardiovascular risk factor. Dietary data were collected via a 24‐hour recall and 3 day food intake records. Anthropometrics and serum lipids also were measured. Less than 40% had adequate intakes of fruits, total vegetables, whole grains, low‐fat milk and meat and oil. Additionally, more than 60% exceeded the guidelines for sodium, saturated fats and discreationary calories. Those in the highest tertile of HEI scores had lower BMI (35.4 vs. 32.5), body fat % (41.6 vs. 42.5), LDL (135.1 vs. 118.4) and triglycerides (148.8 vs.129.2) and greater HDL (51.9 vs.56.2) (P for trend<0.01) than those in lowest. Early postpartum women had minimal compliance to dietary guidelines. Moreover, HEI scores were reflective of anthropometrics and lipid profiles. Interventions that focus on improving lipid profile might benefit from inclusion of dietary modification component that improves HEI scores.

Grant Funding Source

TX Coordinating Board # UTA00‐377
Non‐genomic effects of retinoic acid in stem cell biology
Authors: Wei Li‐Na
Published: June 2021

Retinoic acid (RA) has been known as an inducer for embryonic stem cell differentiation. This is mediated through its binding to its nuclear receptors which act as transcription factors to regulate gene expression for cell differentiation. Recent studies provide more conclusive evidence for novel non‐genomic activities of RA. Particularly in stem cells, RA can rapidly trigger intricate cytosolic events that ultimately regulate homeostatsis of Oct4, a critical gate keeper for healthy stem cell proliferation. This occurs via a signaling pathway initiated from RA‐stimulated complex formation of extracellular‐signal‐regulated kinase 2 (ERK2) with its upstream kinase, mitogen‐activated protein kinase kinase (MEK), which triggers specific SUMOylation of an orphan receptor TR2 that is a transcription factor of Oct4. The parallel effects of RA, one mediated through its nuclear receptors to augment genomic programming for cell differentiation and the second mediated through various cytosolic kinases to regulate stem cell proliferation, will be discussed.
Dual‐localization of ZnT2 to mitochondria and exocytotic vesicles redistributes zinc pools in mammary cells
Authors: Seo Young Ah , Kelleher Shannon L
Published: June 2021

ZnT2 plays a major role in mammary gland zinc (Zn) secretion; however, the mechanisms through which ZnT2 exports Zn from the mammary gland are not understood. ZnT2‐attenuation significantly reduced 65Zn export in cultured mammary epithelial cells (HC11) illustrating its role in Zn export in mammary gland. Expression of a ZnT2‐HA fusion protein increased vesicular Zn pools (quantified by FluorZin‐3 fluorescence) by ~35%, likely through increased Zn accumulation in the endoplasmic reticulum and exocytotic vesicles (co‐localized with calnexin and VAMP8 by confocal microscopy, respectively). Interestingly, endogenous ZnT2 was detected in mitochondria (co‐localized with COX IV by confocal microscopy) which was verified by immunoblotting proteins from isolated mitochondria that were rigorously digested with proteinase K. ZnT2‐attenuation significantly reduced mitochondrial ZnT2 abundance and Zn uptake. Importantly, expression of a ZnT2‐HA fusion protein was detected in mitochondria which expanded mitochondrial Zn pools (~23%) as quantified by RhodZin‐3 fluorescence (mitochondria‐specific Zn fluorophore). Taken together, our data indicate that ZnT2 is a dual‐localized protein which resides in mitochondria and intracellular vesicles. We propose that alterations in the sub‐cellular localization of ZnT2 modulates intracellular Zn pools in response to changes in cellular Zn requirements.

Grant Funding Source

NIH
High maternal folate intake by Sprague Dawley rats results in higher weight gain and lower plasma folate in male offspring
Authors: Huot Pedro S. P. , Ly Anna , Reza‐López Sandra , Cho Daniel , Duan Jiuhua , Kim Young‐In , Szeto Ignatius M.Y. , Anderson G. Harvey
Published: June 2021

High multivitamin intake during pregnancy leads to increased weight gain, food intake, and hyperinsulinemia in rat offspring (Szeto et al. Am J Physiol 2008; 295: R575‐82). The objective of this study was to investigate the role of maternal folate intake on offspring body weight (BW) and hypothalamic gene expression. Pregnant Sprague Dawley rats (n=10/group) were randomized to the AIN‐93G diet containing either the recommended (RF) or 2.5‐fold the folate content (HF) during pregnancy and lactation. All offspring were weaned to the RF diet. BW was measured from 1 wk post‐weaning (pw) to 25 wk pw. Plasma and liver folate levels were measured and hypothalamic gene expression of leptin receptor (LR) and POMC were determined by real‐time RT‐PCR. Males from HF dams were 6% heavier compared with those from RF dams (p<0.0001). Males from HF dams had 27% lower plasma folate compared to males from RF dams (p=0.01), while there were no differences in liver folate levels. Males from HF dams had 39% lower POMC mRNA compared to males from RF dams (p<0.05). No differences in LR mRNA levels were detected. In conclusion, a moderate increase in maternal folate intake resulted in higher BW, which may be related to lower hypothalamic POMC expression, and lower plasma folate concentrations in the male offspring.

Grant Funding Source

CIHR‐INMD (OOP‐77980), Ontario Graduate Scholarship
The effect of a high multivitamin diet during the first gestation on the dams and their offspring from the first and second pregnancy
Authors: Reza‐Lopez Sandra , Szeto Ignatius M. , Huot Pedro S.P. , Ma David W.L. , Anderson G. Harvey
Published: June 2021

High multivitamin intake during pregnancy of the Wistar rat results in increased body weight, food intake and characteristics of the metabolic syndrome in the offspring (Szeto IM et al. Am J Physiol Regul Integr Comp Physiol 2008; 295: R575‐82). The objective of the study was to investigate the effect of a high multivitamin diet during pregnancy on body weight (BW) and glucose tolerance of the dams and their offspring after both the first and second pregnancy. Wistar rats (n=19) received the AIN‐93G diet with either the required (RV) or 10‐fold amount of multivitamins (HV) during the first pregnancy. After delivery all dams received only the RV diet and were mated again at 12 wk post‐weaning (PW). The offspring from both pregnancies were weaned to the RV diet and followed for 15 wk PW. BW and oral glucose tolerance were measured in the dams and offspring. Dams given the HV diet during the first pregnancy gained more weight at 12 and 20 wk after the first and second litters, respectively. First litter females, but not males, from the HV dams gained less BW than those from RV dams (239±7 vs 271±12g, p=0.03). Second litter males, but not females, from dams given the HV diet during the first pregnancy gained more BW (592±14 vs 539±18g, p=0.04) and had 7% higher glucose response at 4 wk PW. In conclusion, the effects of a high vitamin diet during the first pregnancy persist after the second pregnancy.

Grant Funding Source

CIHR‐INMD‐OOP‐77980 and CONACyT to S. Reza
Maternal exposure to diets containing high fructose and saturated fats, low B vitamins, or their combination programs growth, adiposity, and insulin sensitivity in adult offspring
Authors: Chen Chung‐Yen Oliver , Crott Jimmy , Liu Zhenhua , Smith Donald
Published: June 2021

Early exposure to unfavorable nutrition programs risk of adult‐onset diseases. In this rat study, we investigate morphological, metabolic and endocrinal phenotypes of offspring born to dams consuming isocaloric diets containing 30% fructose, 9.9% coconut fat and 0.5% cholesterol (F+SFA), mild deficiencies of four B vitamins (VBD), or their combination (F+SFA+VBD) for 4 wk before conception and during gestation and nursing. After weaning, all offspring were rehabilitated with the control diet (C) containing 30% glucose, 11% corn oil, and optimal vitamins for 12 wk. The VBD and F+SFA+VBD diets caused intrauterine growth retardation. The VBD offspring underwent a period of catch‐up growth and had the largest body weight (BW) at age of 15 wk. However, the F+SFA+VBD male adult offspring were stunted. The F+SFA and F+SFA+VBD led to at least 44% smaller BW‐adjusted retroperitoneal fat depots in male offspring. Further, the F+SFA male offspring had 64% larger fasted plasma insulin and the VBD male offspring had 2.6‐fold larger plasma testosterone than the C. Our results illustrate that nutrition in early life may have great impacts on growth trajectory, adiposity, and hormonal status in adulthood in a sex dependent manner. However, mechanistic mechanisms underlying this nutrient programming remain to be investigated. The study was sponsored by the USDA ARS under Cooperative Agreement.
Diet and intestinal sulfate reducing bacteria populations distinguish native Africans from Caucasian and African Americans
Authors: Nava Gerardo M. , Ou Junhai , O'Keefe Stephen J. , Gaskins H. Rex
Published: June 2021

Americans of African (AAs) descent have the highest incidence and mortality from sporadic colorectal cancer (CRC) in the USA (65:100,000 vs. 50:100,000 in Caucasian Americans (CAs). In contrast, native Africans (NAs) are rarely diagnosed with the disease (<1:100,000). Reduced susceptibility to CRC in NAs is associated with low consumption of animal protein and greater microbial production of colonic methane compared to AAs and CAs. The present study examined in stool samples from these three groups the extent to which populations of sulfate reducing bacteria (SRB) vary. These bacteria contribute to an alternate pathway for colonic hydrogen disposal and in the process generate the potent genotoxin hydrogen sulfide. Molecular ecological analysis using a nested PCR‐based approach and principal component analysis revealed that Desulfovibrio spp. (major genus of colonic SRB) 16S rRNA gene profiles cluster in NAs (n = 19) compared to those of AAs (n = 18) and CAs (n = 17). This observation is consistent with the hypothesis that interactions among genetic background, diet and microbial mechanisms of hydrogen disposal may influence susceptibility to sporadic colorectal cancer.

Grant Funding Source

National Institutes of Health
Chemoprotective fish oil/pectin diets temporally alter gene expression profiles in exfoliated colonocytes
Authors: Cho Youngmi , Turner Nancy D. , Taddeo Stella S. , Davidson Laurie A. , Wang Naisyin , Vannucci Marina , Carroll Raymond J. , Chapkin Robert S. , Lupton Joanne R.
Published: June 2021

We have demonstrated that fish oil/pectin (FP) diets are protective against colon cancer compared to corn oil/cellulose (CC) in part by upregulating apoptosis at the promotion stage of carcinogenesis and suppressing peroxisome proliferator‐activated receptor δ(PPARδ) expression at the tumor stage. To elucidate the underlying mechanisms whereby FP diets induce apoptosis and suppress PPAR signals, we analyzed the temporal gene expression profiles from exfoliated rat colonocytes. Rats consumed diets containing either FP or CC and were injected with azoxymethane (2x, 15 mg/kg BW, sc). Fecal material was collected at 7, 14, and 28 wk in the same rats and was used for poly A+ RNA extraction. Gene expression signatures were determined using GE Codelink arrays. GO analysis identified 10 genes upregulated by FP at the promotion stage of carcinogenesis involved in apoptosis (p=0.006). KEGG pathway analysis indicated that FP suppressed seven genes in the PPAR signaling pathway at the tumor stage (p=0.056). We conclude that the effects of chemotherapeutic diets on epithelial cell gene expression can be monitored noninvasively throughout the tumorigenic process.

Grant Funding Source

Funded by NSBRI NASA NCC 9‐58 and NIH (CA59034, CA57030).
Associations of specialty herbal supplements with lung and colorectal cancer risk
Authors: Satia Jessie A , Littman Alyson , Slatore Christopher , Galanko Joseph , White Emily
Published: June 2021

Aim

Millions of Americans use dietary supplements with little knowledge about their benefits or risks. We examined associations of various specialty herbal supplements with lung and colorectal cancer (CRC) risk.

Methods

Eligible men and women, 50‐76 y, in the VITAL (VITamins And Lifestyle) cohort Study (n=77,126) completed a 24‐page baseline questionnaire. Duration (years) and frequency (days/week) of use over the previous 10 years was collected on 20 specialty herbal supplements. Dose was not assessed due to lack of accurate potency information. Supplement exposure was categorized as "no use" or "any use" over the previous 10 years. Hazard ratios (HR) were estimated from Cox regression models, with control for covariates. Incident lung (n=665) and CRC cancers (n=428) were obtained from the SEER cancer registry.

Results

Any use of glucosamine and chondroitin over the previous 10 years was associated with significantly lower lung cancer risk: HR: 0.74 (95% CI: 0.58, 0.94) and HR: 0.72 (95% CI: 0.54, 0.96), respectively. There were statistically significantly inverse associations of fish oil, glucosamine, chondroitin, MSM, and St. John's Wort (HR: 0.35, 95% CI: 0.14, 0.85) with CRC risk; garlic pills were associated with a significant 35% elevated risk.

Conclusions

Glucosamine and chondroitin were associated with reduced risk for both cancers, whereas use of garlic pills correlated with higher CRC risk. Given the popularity of herbal supplements, studies examining their effects on risk for cancer and other diseases are urgently needed.
Protein anabolism is resistant to insulin action in lung cancer cachexia
Authors: Winter Aaron , Marliss Errol B. , Baracos Vickie E. , Chevalier Stéphanie
Published: June 2021

Cachexia is frequently observed in advanced non‐small cell lung cancer (NSCLC) and compromises functional status, response to treatment and survival. Inherent muscle loss could be due to a defective protein response to the main anabolic hormone, insulin. We assessed insulin resistance of whole body protein and glucose metabolism using the hyperinsulinemic, euglycemic, isoaminoacidemic clamp with 13C‐leucine and 3H‐glucose tracers, in 5 men with NSCLC (stage III‐IV) and 8 healthy weight‐stable men matched for age (67 ± 2 vs. 69 ± 1 yrs). In NSCLC, recent weight loss was 6.3 ± 0.9% and BMI (20.8 ± 1.3 vs. 25.1 ± 0.9 kg/m2), body fat and fat‐free mass (FFM) were lower. Postabsorptive plasma glucose and insulin did not differ, but branched‐chain amino acid (BCAA) concentrations were lower. During hyperinsulinemia, glucose infusion rates did not differ between groups (4.4 ± 0.4 vs. 5.5 ± 0.7 mg/kg.min), indicating no further resistance beyond that conferred by aging. In contrast, AA infusion rates were markedly lower in NSCLC: 31.1 ± 2.5 vs. 39.9 ± 1.8 mg/min, adjusted for FFM and postabsorptive BCAAs (p=0.039). This could be due to impaired suppression of protein breakdown or stimulation of synthesis by insulin, or both, which will be determined from kinetic analyses. These preliminary results are consistent with a blunted protein anabolism and may help define optimal approaches to prevent muscle loss in cancer cachexia. (CIHR)
Long‐term leucine induced stimulation of muscle protein synthesis is amino acid dependent
Authors: Wilson Fiona A , Suryawan Agus , Gazzaneo Maria C , Orellana Renán A , Nguyen Hanh V , Davis Teresa A
Published: June 2021

Infusing leucine for 1 h increases skeletal muscle protein synthesis in the neonate, but this is not sustained for 2 h unless the corresponding fall in amino acids is prevented. This study aimed to determine whether a continuous leucine infusion can stimulate protein synthesis for a prolonged period when baseline amino acid concentrations are maintained. Overnight fasted neonatal pigs (n = 18) were infused for 24 h with saline, leucine (400 µmol · kg−1 · h −1),or leucine with replacement amino acids. Leucine stimulated muscle protein synthesis only when other amino acids were maintained at fasting. Leucine had no effect on the phosphorylation of protein kinase B, AMP‐activated protein kinase, tuberous sclerosis complex 2, or eukaryotic elongation factor 2, the association of mTOR with raptor, G‐protein ßsubunit‐like protein, or rictor, or the phosphorylation of raptor or proline‐rich Akt Substrate of 40 kDa. Phosphorylation of mTOR, eukaryotic initiation factor (eIF) 4E binding protein (4EBP1) and ribosomal protein S6 kinase, and eIF4E▸eIF4G association were increased and eIF2 phosphorylation was reduced by leucine, in the absence and presence of replacement amino acids. Thus, prolonged infusion of leucine activates mTOR and its downstream targets in skeletal muscle; however, protein synthesis stimulation is dependent upon amino acid availability. (Supported by Ajinomoto Amino Acid Research Program).
Carbohydrate‐related dietary factors and plasma adiponectin levels in healthy adults in the Framingham Offspring Cohort.
Authors: McKeown Nicola Mary , Liu Enju , Meigs James B , Rogers Gail , D'Agostino Ralph , Jacques Paul
Published: June 2021

Diet may influence circulating adiponectin levels by improving insulin sensitivity. We examined the associations between carbohydrate‐related dietary factors and plasma adiponectin levels in healthy adults aged 26‐81 y (n= 979 men and 1227 women). Dietary intakes were assessed using a FFQ. Fasting plasma adiponectin was assayed with an immunoassay kit. After adjustment for age, sex, BMI, total energy intake, current smoking status, % energy from fat and alcohol consumption, higher intakes of dietary fiber were positively associated with plasma adiponectin (10 % difference between highest (Q5) and lowest (Q1) quintile; p trend= 0.04), while dietary glycemic index (DGI) inversely associated with plasma adiponectin (10% difference between Q5 and Q1; p trend <0.001). A marginally significant positive association was observed between cereal fiber and whole‐grain intakes and plasma adiponectin levels (p trend =0.06). However, only the association between DGI and plasma adiponectin levels remained significant after adjustment for fasting insulin. Total carbohydrate, fruit, vegetable, legume/nut fibers, glycemic load, and refined grain intakes were not associated with adiponectin levels. In conclusion, a high DGI may influence adiponectin by mechanisms independent of insulin.

Supported in part by funding from General Mills Bell Institute of Research, the USDA Agreement 58‐1950‐7‐707 and the Framingham Heart Study of the National Heart Lung and Blood Institute of the NIH (Contract N01‐HC‐25195)
Glucose lowering effect of lupin seed γ‐ conglutin in hyperglycaemic rats upon chronic treatment
Authors: Lovati Maria Rosa , Manzoni Cristina , Pizzagalli Anna , Duranti Marcello Maria , Castiglioni Silvia
Published: June 2021

Aim of the study was to evaluate the effect of a chronic oral administration of conglutin γ, a lupin seed protein, in male Sprague Dawley rats in which the hyperglicemia was induced by drinking water containing 10% d‐glucose. A dosage of 100 mg/kg b.w. of conglutin γ was administered daily to rats for 21 days. Conglutin γ administration induced a statistically significant reduction in plasma glucose (‐25%) and triglyceride (‐20%) levels as well as a reduction of glycemia after the oral glucose loading, comparable to that of metformin. In order to assess the mechanism underlining this biological effect, Hep G2 cells, grown in DMEM containing different glucose concentrations (5.5 mM, 11 mM and 17 mM) for 24, 48 and 72 h, were exposed, respectively to 0.5 mg/mL conglutin γ 10 mM metformin or 100nM insulin. Conglutin γ induced in Hep G2 cells, in all experimental conditions, an increased glucose consumption (from 1.5 to 2.5 fold ) which was more evident after 24h of incubation. Moreover, the addition of conglutin γ potentiated, in this in vitro model, the activity of insulin and metformin in cell glucose uptake. These findings represent the first molecular evidence of the possible use of a legume protein in the control of glycemia.

Supported in part by a grant of MIUR from Italy
Effects of Polyphenolics from Grape (Vitis rotundifolia) and acai (Euterpe oleracea Mart.) on the expresion of microRNAs relevant to inflammation in vascular diseases
Authors: Noratto Giuliana Doris , Angel Gabriela , Mertens‐Talcott Susanne U.
Published: June 2021

The cardio‐protective and anti‐innflammatory effects of polyphenolics have been demonstrated. It was the objective to investigate the anti‐inflammatory effects of polyphenolics from grape (Gp) and açai (Ac) in human umbilical vein endothelial cells (HUVEC). Cells were treated with Ac or Gp phenolics (5‐20 mg/L) and inflammation was induced with glucose (Gluc) (25mM) or lipopolysaccharide (LPS) (1ng/mL). The generation of reactive oxygen species (ROS) was determined with the dichlorofluorescein assay. MicroRNAs and mRNAs were quantified by RT‐PCR. Ac and Gp phenolics (5‐40mg/L) did not inhibit cell proliferation and moreover protected cells against Gluc induced ROS (Ac: 21‐ 57% and Gp: 37‐ 40%). Ac and Gp reversed Gluc‐induced 7.2‐fold increased expression of mir‐146a down to control levels in a dose‐dependent manner. Additionally, Ac and Gp reduced the mRNA expression of tumor necrosis factor receptor I (TNFRI) (up to 66%) and interleukin (IL‐8) (up to 68%). Gp and Ac decreased LPS‐induced expression of ICAM (up to 40‐60%) and angiotensin II (AGII) (up to 15%), and correspondingly increased expression of mir‐126 and mir‐155 (up to 3.8 and 4.4 fold, respectively) which are known inhibitors of ICAM and AGII, respectively. Overall, the investigated microRNAs may play a key role in the underlying mechanisms of the anti‐inflammatory effects of Gp and Ac polyphenolics.
Moderate Copper Deficiency Affects Liver Metallothionein and Resistance to Chemical Hepatotoxicity
Authors: DiSilvestro Robert A , Joseph Elizabeth
Published: June 2021

Neonates have different liver copper metabolism than in later life. The differences include neonates having high levels of total and copper‐metallothionein (MT). The present study found that moderate copper deficiency in neonate rats produced low liver MT, apparently due in part to altered gene expression for MT (in older rats, copper deficiency has no such effect). Copper status also had some effect on activities of liver Cu‐Zn superoxide dismutase and serum ceruloplasmin, a liver secreted copper enzyme. The effects of moderate copper deficiency on copper proteins were associated with impaired resistance to liver injury stimulated by treatment with carbon tetrachloride. Injury was assessed by serum values for liver enzymes and bile acids. It is not certain how much the carbon tetrachloride resistance change could be assigned to alterations in any one copper protein. However, MT likely played a role since in a parallel study, MT KO mice showed high injury upon exposure to low dose carbon tetrachloride. In summary, moderate copper deficiency in neonate rats affects both liver metallothionein levels and resistance to a hepatotoxin. This could hold importance for human infants in liver stress.
Role of Copper Transport System for Extracellular Superoxide Dismutase in Angiotensin II‐Induced Hypertension
Authors: Fukai Tohru , Ozumi Kiyoshi , Kim Ha Won , McKinney Ronald D. , Ushio‐Fukai Masuko
Published: June 2021

Vascular extracellular superoxide dismutase (SOD3), a secretory copper enzyme, blunts angiotensin II (Ang II)‐induced hypertension by reducing the extracellular superoxide (O2▸‐) levels. We previously demonstrated that Ang II upregulates SOD3 expression and activity; however, underlying molecular mechanisms remain unclear. Here we show that SOD3 expression and activity are markedly decreased in fibroblasts lacking the copper chaperone/transcription factor Atox1 or the copper uptake transporter Ctr1. Chronic Ang II infusion increases nuclear staining of Atox1 as well as SOD3 protein expression and activity in mouse aorta, which are abolished in Atox1‐deficient (Atox1‐KO) mice. In cultured vascular smooth muscle cells, Ang II stimulates nuclear translocation of Atox1 and SOD3 promoter activity through its binding to the Atox1 responsive element, which are abolished in cells lacking Ctr1. Finally, Atox1‐KO mice infused with Ang II show enhanced systolic blood pressure as well as vascular O2▸‐ levels, which are rescued by the SOD mimetic tempol. In summary, copper‐dependent transcription factor function of Atox1 plays an important role in Ang II‐induced upregulation of SOD3 expression and activity through Ctr1‐Atox1 pathway, which may contribute to preventing oxidant‐stress‐dependent Ang II‐induced hypertension. This work was supported by 5R01HL070187‐08.
In vivo proton NMR spectroscopy reveals an altered neurochemical profile in copper deficient rat brain
Authors: Prohaska Joseph , Gybina Anna
Published: June 2021

Copper deficiency in mammals is associated with impaired brain development and mitochondrial dysfunction. Although the precise mechanisms are unknown disturbances in energy metabolism due to lower cytochrome c oxidase is a common hypothesis. Perinatal copper deficiency was produced in Holtzman rat dams and evaluated in male offspring. Biochemical analyses of rat brains indicated that compared to copper adequate (CuA) rats copper‐deficient (CuD) rats had lower copper and iron levels. In vivo proton NMR spectroscopy was used to quantify 18 cerebellar and hippocampal metabolites on postnatal day 21 (P21). Lower concentration of ascorbate was measured in both brain regions in CuD rats, which was in good agreement with previously published in vitro HPLC data. Both regions also demonstrated lower N‐acetylaspartate levels suggestive of impaired mitochondrial function and/or delayed brain development. For other metabolites, the P21 neurochemical profile of CuD rats was remarkably similar to CuA rats but uniquely different from iron‐deficient or chronic hypoxia models. Further research is needed to determine the neurochemical consequences of copper deficiency.

Supported in part by NIH HD‐39708 to JP and Center for Magnetic Resonance Research is in part supported by NIH grants P41 RR008079, P30 NS057091 and W.M. Keck Foundation.
The tumor suppressor SOCS3 limits STAT3 binding to the TNFR2 promoter and promotes proteasomal degradation of TNFR2
Authors: Hamilton Kathryn Elizabeth , Simmons James G. , Rigby Rachael J. , Lund P. Kay
Published: June 2021

In the AOM/DSS model of inflammation‐associated colon cancer, intestinal epithelial cell‐specific (IEC)‐SOCS3 deletion increases tumor load, enhances STAT3 and NF¿B activation, and up‐regulates TNFR2. TNFR2 mediates proliferation and reduces apoptosis of IEC, and is increased in inflammatory bowel diseases and colon cancer. Little is known about direct functional effects of SOCS3 in colon cancer cells or molecular mechanisms that regulate TNFR2 expression. This study tested the hypothesis that SOCS3 limits anchorage‐independent growth of colon cancer cells and down‐regulates TNFR2 at transcriptional and post‐transcriptional levels. Colon cancer cell lines were infected with empty or SOCS3‐expressing adenovirus (AdEmpty or AdSOCS3). Anchorage‐independent growth, TNFR2 mRNA and protein were measured. Cytokine‐induced STAT3 or NF¿B binding to consensus sequences in the TNFR2 promoter was evaluated using chromatin immunoprecipitation (ChIP). AdSOCS3 dramatically reduced anchorage‐independent growth, and decreased TNFR2 mRNA and protein. Pre‐treatment with proteosome inhibitors prevented this decrease. STAT3, but not NF¿B binds to consensus sites in the TNFR2 promoter, and AdSOCS3 decreases this binding. SOCS3‐mediated inhibition of TNFR2 expression may contribute to its tumor suppressor role during inflammatory bowel disease. NIH DK47769.
Teaching and learning anatomy interactively online in the new digital age of 21st century
Authors: Ding Yang , Wilson Timothy Dale
Published: June 2021

To address decreasing in‐class hours and lack of cadaveric dissection time dedicated to anatomical education, the authors propose a new interactive methodology for teaching anatomy online. This new curriculum will implement virtual reality technology through the open source software called realXtend to provide an engaging learning experience for students as well as allowing greater educational access for learners and educators alike. The can take place inside or outside the traditional learning environment. Once fully operational, realXtend allows users to freely interact with the digital models within a virtual three‐ dimensional world and examine the fine detail of anatomical structures which may not be clearly visible in cadaveric dissections. In addition, realXtend grants users the freedom to freely scale, move and rotate any of the anatomical structures to facilitate spatial perception. This curriculum is ideally implemented concurrently with cadaveric dissections to mutually complement each other, thus maximizing overall effectiveness in a rich learning environment for students. We plan to incorporate this technology in the upcoming year in Health Science undergraduate anatomy curriculum to complement the lack of actual dissections in the anatomy courses.

Grant Funding Source

Internal
Prion Proteins: One Surprise After Another
Authors: Lindquist Susan Lee , Alberti Simon , Halfmann Randal , Jackson Walker
Published: June 2021

Proteins must fold into the right shape to do their jobs. When misfolded proteins persist, the consequences can be deadly, leading to devastating diseases. In the case of prion proteins, altered forms can template their change in shape to other proteins of the same type, leading to transmissible spongiform encephalopathies. We engineered mice to express the mammalian prion protein PrP with a mutation linked to human FFI (fatal familial insomnia). These mice develop pathology that is very similar to that of FFI, and the disease phenotype was readily transmitted to mice expressing wild‐type PrP, demonstrating that a point mutation in PrP is sufficient not only to cause a distinct neurodegenerative disease but also the spontaneous appearance of prion infectivity.

In yeast cells, prions are not toxic, but can provide helpful new phenotypes. The prion state involves conversion of a protein domain into an amyloid fold, and this occurs through a molten oligomeric intermediate. We identified the critical nucleating contacts involved in the conversion of Sup35, a yeast prion involved in translation termination. Using peptide arrays, we determined that this region also controls two previously mysterious properties of prion biology: the species barrier and the formation of distinct prion strains.
Single Molecule FRET of Protein Folding Dynamics
Authors: Schuler Ben
Published: June 2021

We have been using single molecule Förster resonance energy transfer (FRET) for the investigation of protein folding, with a focus on non‐native states of proteins; these are conformationally more heterogeneous than native structures and have thus been more difficult to access experimentally. Single molecule FRET has allowed us to map long‐range distance distributions in the unfolded state of the small cold shock protein CspTm1, even at low concentrations of denaturant, where the unfolded molecules are collapsed, and where the majority of protein molecules are already folded. Using advanced correlation methods, we determined the reconfiguration time of unfolded CspTm2 and found a decrease in its intramolecular diffusion coefficient upon collapse. This increase in the roughness of the free energy surface is accompanied by the formation of some secondary structure, as determined with kinetic synchrotron circular dichroism experiments1. Complete fluorescence intensity correlation functions from picoseconds to seconds are an increasingly important tool to investigate protein dynamics3 and quantify previously inaccessible characteristics of the free energy surfaces for folding. In a next step, the same methods now allow us to investigate the folding and dynamics of proteins in the context of cellular factors, such as molecular chaperones.4
Effects of P deficiency on growth and tissue specific stem cell proliferation in neonatal pigs
Authors: Alexander Lindsey S , Mahajan Avanika , Flann Kyle L. , Rhoads Robert P. , Odle Jack , Stahl Chad H.
Published: June 2021

Dietary phosphorus (P) deficiency reduces both muscle and bone growth in growing pigs. While satellite cells and mesenchymal stem cells are essential to postnatal muscle and bone growth, respectively, no work has investigated the possible effects of P nutrition on the proliferation of these cells. To determine the effect of dietary P deficiency during early‐postnatal growth, twenty 1‐day old pigs were fed either a P adequate (PA) or 20% P deficient (PD) liquid diet for 15d. By Day 5 and throughout the trial, plasma P and PTH concentrations were reduced (P < 0.05) in PD fed pigs. At Day 5 the PD pigs also had higher (P < 0.05) plasma Ca concentrations; however this difference was no longer significant by Day 10. Despite similar feed intakes, pigs fed the PA diet gained approximately 80% more weight (P < 0.05) than their PD fed counterparts. Additionally, PA fed pigs had radial bones with greater (P < 0.05) fresh, dry, and ash weight than the PD fed pigs, however the percentage of bone mineral content was not altered based on diet. The PD fed pigs had reduced (P < 0.05) proliferation of both satellite cells isolated from the loin muscle and mesenchymal stem cells isolated from bone marrow. The reduction in satellite cell and mesenchymal stem cell proliferation in P deficient animals may help explain the mechanism by which dietary P deficiency negatively affects muscle and bone growth.
Estimating distributions of usual total nutrient intake: A comparison of available methods
Authors: Dodd Kevin W , Bailey Regan , Wilger Jaime , Sempos Chris , Dwyer Johanna , Radimer Kathy , McDowell Margaret , Johnson Cliff , Picciano Mary Frances
Published: June 2021

Distributions of usual nutrient intake are used to monitor a population's nutritional status. It is vital to consider nutrient intakes from all sources, including dietary supplements (DS). This study compared strategies for estimating distributions of total nutrient intake based on data from the National Health and Nutrition Examination Survey (NHANES). In the 2003‐2004 NHANES, two 24‐hour dietary recalls (24HR) were collected; detailed information about type, consumption frequency, and amount of nutrients from DS was collected through an interviewer‐administered questionnaire. A simulation study compared several approaches for combining the 24HR and DS data for calcium intake. Four methods (ISU, NAS, BCP, and NCI) for adjusting 24HR nutrient data were extended to use DS data in three ways by adding:

average intake from DS to adjusted 24HR intakes,

average intake from DS to each 24HR intake before adjustment, or

single‐day DS dosages to none, some, or all of the 24HRs before adjustment.

We find that adding average DS intake to adjusted 24HR intakes leads to unbiased estimates for percentiles, but adding DS intake to 24HR intakes before adjusting can lead to substantial bias. These results suggest that complex relationships existing between DS use and habitual diet must not be ignored.
n‐3 Fatty Acids Decrease LDL‐Cholesterol Delivery and Lipoprotein Lipase in the Arterial Wall in Insulin Resistant Mice
Authors: Chang Chuchun Liz , Seo Toru , Accili Domenico , Deckelbaum Richard J
Published: June 2021

We reported that saturated fat enriched diets (SAT) increase arterial LDL‐cholesteryl ester (CE) deposition from LDL selective uptake (SU) ‐ a process of LDL‐CE uptake without concomitant uptake of whole particle, and this was associated with increased arterial lipoprotein lipase (LpL) levels. We now questioned how n‐3 fatty acid (n‐3 FA) rich diets influence arterial cholesterol (Ch) delivery and LpL levels. Mixed‐background rescued insulin receptor knockout mice were used as an insulin resistant (IR) model and fed chow or high fat diets enriched in n‐3 or SAT for 12 wk, followed by bolus injection of fluorescent BODIPY‐CE and Alexa labeled human LDL to independently trace LDL‐CE and ‐apoB/whole particle uptake. In contrast to SAT, n‐3 diets markedly reduced all plasma lipids (p<0.05), ameliorating IR. As opposed to SAT, n‐3 reduced arterial LDL uptake, CE deposition and SU (1.12±0.14, 2.94±0.17, n‐3 vs. SAT, p<0.05). Disparate patterns of CE deposition between diets were comparable with arterial LpL distributions; SAT induced high LpL throughout aortic media; LpL was limited to intima only in n‐3 mice. These studies indicate dietary n‐3 FA reduces arterial LDL‐Ch delivery and deposition with changing arterial LpL levels and distribution. We hypothesize one mechanism whereby n‐3 FA diminishes adverse cardiovascular disease outcomes in IR, is by diminishing arterial LDL‐Ch deposition early in atherogenesis.

Grant Funding Source

NIH grant T32‐DK007647‐18
Dietary fatty acid determinants of human milk fatty acids.
Authors: Innis Sheila M , King D Janette
Published: June 2021

Human milk provides fatty acids (FA) for energy and essential n‐6 and n‐3 FA to support infant growth and development. The n‐3 FA docosahexaenoic acid (DHA) particularly important because of its crucial role in neural development and function. Low milk DHA is associated with poor infant visual and neural development. Using a longitudinal blinded intervention with 400mg/d DHA or placebo in gestation, we addressed the relationship between maternal n‐6 and n‐3 fatty acid status in gestation and DHA secretion in milk, and dietary determinants fatty acid intake and milk fatty acids. Blood was collected at 16 and 36 wks gestation, then breast milk collected at 1 mth postpartum for 156 mothers who exclusively breast fed term infants. FA was determined using 100m capillary column GLC. Fatty acid methodology, recovering trans and medium chain FA, impacts the number and accuracy of FA quantization, and data interpretation. Milk DHA was positively correlated to maternal DHA in gestation, varied from 0.06 to 1.25% milk FA, and was inversely related to milk trans FA. Medium chain FA from mammary gland synthesis, varied 3 fold, and were inversely related to milk 18:2n‐6 and 18:3n‐3, but not DHA, 20:5n‐3 or 20:4n‐6. Milk FA vary widely; diets high in hydrogenated fats are associated with low milk DHA, while diets rich in unsaturated vegetable oils may lower MCFA secretion in human milk. Supported by CIHR.
The effect of a weight reducing low carbohydrate vegan diet on apolipoproteins and blood pressure
Authors: Wong Julia M W , Kendall Cyril W C , Esfahani Amin , Ng Vivian W Y , Greaves Kathryn A , Paul Greg , Jenkins David J A
Published: June 2021

Objective

To determine the effect of a weight reducing low carbohydrate vegan diet, high in soy protein and vegetable oil, on apolipoproteins (apo) and blood pressure (BP) under metabolic conditions.

Method

Forty‐seven hypercholesterolemic subjects (19M, 28F; 56.9±7.5y; 30.9±2.7kg/m2) were instructed to take a low carbohydrate (26%) high protein vegan diet (test) or a low saturated fat National Cholesterol Education Program ATP III diet (control). For one month, with all food provided, subjects consumed 60% of their estimated energy requirements.

Results

Forty‐four subjects completed the study. Body weight fell equally by 3.5% on both diets. LDL‐C was reduced more on the test than the control diet (‐20.4±2.8% vs. ‐12.3±2.6%, P=0.002). The corresponding values for apoB and the apoB:apoA‐1 ratio were ‐21.1±2.8% vs. ‐13.2±2.2% (P=0.001) and ‐13.8±3.4% vs. ‐4.2±2.1% (P=0.001). Blood pressure was also reduced on the test than the control diet (systolic BP: ‐4.6±1.0% vs. ‐2.7±1.2%, P=0.046; diastolic BP: ‐5.8±1.0% vs. ‐3.1±1.4, P=0.014).

Conclusion

Weight loss reduces apoB, the apoB:apoA‐1 ratio and blood pressure more on a low carbohydrate vegan diet, high in vegetable protein and oil, than on a standard therapeutic diet. Funding: The Solae Company, Loblaw Companies Limited

Grant Funding Source

Canadian Institutes of Health Research
Comparative regulation of novel porcine selenoprotein gene expression in endocrine tissues and liver by dietary selenium
Authors: Lei X G , Zhou J C , Zhao H , Li J G , Wang K N , Xia X , Zhang Y J , Liu Y , Zhao Y
Published: June 2021

Expression and function of selenoproteins in endocrine tissues remain unclear. We conducted 2 experiments: 1) to clone 5 novel selenoprotein genes from pig tissues, and 2) to compare effects of dietary Se on mRNA levels of 12 selenoproteins, activities of 4 antioxidant enzymes, and Se concentrations in testis, thyroid, and pituitary with those in liver of pigs. In Exp. 1, porcine Gpx2, Sephs2, Sep15, Sepn1 and Sepp1 were cloned and demonstrated 84 to 94% of open reading frame homology to human genes. In Exp. 2, 30 weanling male pigs were fed a Se‐deficient (0.02 mg/kg) diet supplemented with 0, 0.3 or 3.0 mg Se/kg as Se‐enriched yeast (Angel Yeast, Hubei, China) for 8 wks. While dietary Se resulted in dose‐dependent increases in Se concentrations and GPX activities in all 4 tissues, its effects on gene expression of the 12 selenoproteins fell into 3 categories. Dietary Se exhibited no significant effect on the mRNA levels of any gene in thyroid and pituitary or 7 genes in any tissue. Testis mRNA levels of Txnrd1 and Sep15 were decreased by supplementing 3.0 mg of Se/kg compared with the 0.3 mg Se/kg group. In conclusion, dietary Se deficiency and supranutrition produced similar responses of Se concentrations and GPX activities in endocrine tissues and liver, but exerted essentially no impact on mRNA abundances of all 12 selenoprotein genes in thyroid and pituitary (Chinese Natural Science Foundation Projects 30628019 & 30700585).