bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired resistance to influenza infection in fish‐oil fed mice.
Authors: Schwerbrock Nicole MJ , Shi Qing , Beck Melinda A
Published: June 2021

Most of the long chain n‐3 polyunsaturated fatty acids (PUFA), such as EPA (20:5n‐3) and DHA (22:6n‐3), are obtained from dietary intake of fish oils. Fish oil has been shown to promote anti‐inflammatory activities. Although the anti‐inflammatory properties of fish oil may be beneficial during a chronic inflammatory illness, the same anti‐inflammatory properties may negatively influence host resistance to a pathogen, in which an inflammatory response is necessary to eradicate the agent. To test the impact of fish oil feeding on an infection, we fed C57BL/6 mice a diet with fish oil or a control diet without fish oil for 2 weeks. The fish oil diet was administered at a fish oil‐corn oil ratio of 4:1, w/w at 5g/100g diet. After 2 weeks on the diets, mice were infected with influenza virus (A/PR/8) and killed at days 0 (uninfected), 3, 7, 10, 15 and 21 post infection. Although the anti‐inflammatory properties of the fish oil diet resulted in reduced lung inflammation in the influenza infected mice, it also resulted in a higher mortality rate and slower recovery following infection. While splenic NK activity was suppressed in fish oil fed mice, lung NK activity was not affected. Flow cytometry of bronchioalveolar lavage cells revealed fewer CD8+ T cells in the fish oil fed mice compared with controls. These results suggest that the anti‐inflammatory properties of fish oil may be detrimental during a viral infection.

Grant Funding Source

DK 56350
White button, Shiitake, and Portabella mushrooms modulate the development of collagen‐induced arthritis in mice.
Authors: Kuvibidila Solo , Alexander Heather , Lim Yin , Christopher Lawrance , Lucas Edralin , Clarke Stephen , Smith Brenda J
Published: June 2021

Mushrooms have been used in ancient Chinese medicine for treatment and prevention of many diseases due to their immunomodulatory properties. However, less work has been conducted on the white button mushrooms, commonly found in US. The objective of this study was to examine the extent to which diets fortified with 5% white button mushrooms (WM), shiitake (SM), and portabella (PM), can prevent the development of collagen‐induced arthritis (CIA) in mice, an experimental model for the human disease. Eight‐week old DBA female mice (n=110) were fed either the AIN76 (baseline, n=37) diet or the experimental diets (n=19‐27/group) for 6 weeks. After intradermal injection of a single dose of 100 ug bovine collagen type II to 50% of the mice, a single dose of 50 ug LPS was given by intraperitoneal injection on 20d post immunization. Paw swelling was assessed by three different investigators between day 4, 5, and 6 after LPS injection. The percentage of mice that developed paw swelling was as follows: 100%, 83%, 54%, and 64% for PM, baseline, WM, and SM diets, respectively (p <0.05). None of the mice that received the vehicle developed CIA. The mean arthritis index (paw swelling severity) was also higher in PM fed mice (9.0) than in the other groups (5.67‐6.86). Mushrooms tended to decrease TNF‐a and IL‐6 levels in CIA mice by 22‐46%. Although mean body weights slightly decreased in CIA mice, they were not affected by mushroom fortification. Data suggest that WM and SM appear to provide protection from the development of CIA but may not alter the severity of the disease. Supp.: Grant # 580790706 (Mushroom Council/USDA/NutriCore) and funds from Oklahoma State University.
Effects of trans fatty acids on markers of inflammation
Authors: Rezamand Pedram , Hunt Katherine M , Williams Janet E , Shields Shannon , McGuire Mark A
Published: June 2021

Trans fatty acids (tFA) contribute to inflammation. The objective of this study was to investigate the effects of tFA on mRNA expression of pro‐inflammatory markers. Bovine mammary epithelial cells (MACT) were grown in DMEM containing 10% FBS. Cells were then subcultured in a medium void of FBS, to which incremental concentrations (up to 90 μM) of tFA: BSA (FA‐free) solution were added and cells were collected at specific time‐points over 48 h. RNA was extracted and converted to cDNA for quantitative real time PCR analysis of pro‐inflammatory genes. Presence of elaidic acid (trans 9 C18:1) caused increases in mRNA expression of IL‐1β (3.4‐fold; dose‐independently over 6 h period) and ICAM‐1 (up to 1.4‐fold, dose× time P=0.0003), relative to that for cells treated with no tFA whereas expression of IL‐6 and IL‐8 was reduced. Presence of linoleidic acid (trans 9, trans 12 C18:2) tended to increase mRNA expression of ICAM‐1 by 1.5‐fold and increased that of IL‐1 β (up to 4‐fold; dose× time P=0.003) but reduced mRNA expression of IL‐6 and IL‐8, relative to that for control (no tFA). Trans mono‐ and dienoic FA up‐regulated mRNA expression of IL‐1β and ICAM‐1 while down‐regulated expression of IL‐6 and IL‐8 in bovine mammary epithelial cells. Reducing dietary tFA in lactating cattle rations or tFA formation in the rumen during biohydrogenation may lower the risk for mammary gland inflammation. Supported by NIH‐NRRI grant P20 RR15587.
Calcitriol increases macrophage recruitment by adipocytes
Authors: Sun Xiaocun , Zemel Michael B
Published: June 2021

We have demonstrated that calcitriol stimulates the production of both ROS and inflammatory cytokines/chemokines in adipocytes, and that these effects are mediated by both mitochondrial uncoupling status and cytosolic Ca2+ signaling. Further, dietary calcium‐induced suppression of calcitriol attenuated diet‐induced oxidative and inflammatory stress in white adipose tissue. Since infiltration and differentiation of adipose tissue‐resident macrophages, which contribute to obesity related oxidative and inflammatory stress, are under the local control of adipocyte chemokines, we investigated the effect of calcitriol on macrophage adherence to mature adipocytes using an in vitro perfusion system. Calcitriol (10 nM) stimulated a two‐fold increase in MCP‐1 expression and secretion by 3T3‐L1 adipocytes (p=0.004), and cytokine array demonstrated corresponding increases in multiple additional chemokines. To evaluate the chemo‐attractant effect of calcitriol treatment, fluorescently labeled macrophages were continuously perfused across adherent adipocytes pre‐treated with or without calcitriol and the non‐adherent cells were washed off before imaging and quantification of macrophage adherence. Calcitriol increased macrophage adherence to differentiated adipocytes by 7‐fold, p<0.00008), indicating that calcitriol markedly stimulates macrophage recruitment by adipose tissue.
Eating disorders in Mexican female adolescent with normal weight, overweight, and obesity
Authors: Jiménez Alejandra , Escalante Erika , Shamah Teresa , Morales Carmen , Mundo Verónica
Published: June 2021

The objective was to explore eating disorders among Mexican female adolescent with normal weight, overweight, and obesity.

Data of Mexican female adolescent from the National Scholar Survey 2008 were analyzed. Classification of overweight and obesity was done in accordance with BMI cut points, recommended by the International Obesity Task Force (IOTF). An index was constructed to identify eating disorders (i.e. losing the eating control, restrictive practices, and self induced vomiting). Multiple‐logistic regression analysis was done adjusted by age, overcrowding, weight perceptions, violence, addictions, physical activity, and TV‐watching.

A total of 20,015 participants, who represented a 4,817,745 Mexican female adolescent from 10 to 17 (mean age 12.3 ± 1.6 y) were evaluated. 23.4% and 7.9% of female adolescent were overweight or obese, respectively. After adjusting it by confounding variables, those female adolescent who were overweight(OR: 2.14 CI95%: 1.87,2.45) or obese(OR: 3.81 CI95%: 3.13, 4.64) were more likely to have eating disorders with respect to those female adolescent who had normal weight.

In this study, Mexican female adolescent eating disorders, were strongly associated with overweight or obesity.

Supported by the Rio Aronte Foundation, and Fondo de Apoyo al Programa Intersectorial de Educación Saludable.
The incorporation of a protein‐rich breakfast on appetite sensations and subsequent food intake in “breakfast‐skipping” adolescents
Authors: Leidy Heather J , Racki Erin M , Coffey Candice R
Published: June 2021

Purpose

To examine the impact of a protein‐rich breakfast (in solid vs. beverage form) on appetite and subsequent food intake in breakfast‐skipping adolescents. Methods: 15 healthy adolescents (age 14 ± 1 y; BMI 79 ± 4 %ile; breakfast 2 ± 1 occasions/wk) randomly consumed, on 4 separate days, a 500 kcal breakfast consisting of a normal protein meal (18 ± 1 g protein) in solid form (PN‐S), a protein‐rich meal (48 ± 2 g protein) in solid (PR‐S) or beverage (PR‐B) form, or no meal (NM). Pre and post‐meal appetite was measured over 5 h followed by an ad libitum lunch.

Results

PR‐S was the only meal to exhibit significant reductions in post‐meal hunger vs. NM (p<0.01). Post‐meal fullness was greater after each meal vs. NM (all comparisons; p<0.05) but not different between meals. All meals led to significant reductions in prospective food consumption vs. NM (all comparisons; p<0.05); PR‐S led to greater reductions vs. PN‐S (p=0.06). Fewer calories were consumed at lunch following the PR‐S (363 ± 51) vs. NM (490 ± 63; p< 0.01), PN‐S (504 ± 66; p<0.01), and PR‐B (464 ± 83 kcal; p=0.10).

Conclusions

The incorporation of a protein‐rich breakfast beneficially impacts appetite & subsequent food intake in breakfast‐skipping adolescents suggesting a potential role in the management of obesity. However, protein‐rich beverages may not elicit the same positive effects compared to solid versions. Support: M01 RR023940; SAH Research Award, KUMC
Nutritional profile of primary school children in Lima and Callao, Peru
Authors: Liria Maria Reyna , Mispireta Mónica , Lanata Claudio F. , Creed‐Kanashiro Hilary M
Published: June 2021

The nutritional profile of 1766 school children in grades 3 to 6 was evaluated in a random sample of 80 coeducational primary schools in Lima and Callao. Anthropometry, body fat composition, hemoglobina, food frequency and physical activity were evaluated. Results showed 20.6% children were overweight and 15.5% obese, with higher prevalences in private schools and boys. 7.7% of children had growth retardation, higher in state schools and in boys. 13.7% of children were anemic. Half of the children had little physical activity, children in public schools and boys were more active. Children with greater height for age had higher BMI, less anemia, taller mothers, fewer siblings, greater birth weight and lower SES. These children also consumed milk products less frequently and food from social programs more frequently. Overweight or obese children had mothers with greater BMI, fewer siblings, higher SES, consumed milk products more frequently with less frequent use of food from social programs. The principal nutritional problem found in these school children was overweight and obesity, followed by anemia. An important factor related to overweight and obesity in this population of children was the low level of physical activity.

Funding: ILSI‐Sur Andino
The Relationship Between Whole Grain Consumption and Body Measures in American Children Ages 6‐18 Years: Results From NHANES 1999‐ 2004
Authors: Albertson Ann Marie , Holschuh Norton M. , Gugger Carolyn K.
Published: June 2021

One‐day food intake from NHANES 1999‐04 coupled with the MyPyramid Equivalents Database, 2.0 for USDA Survey Foods was used to estimate whole grain (WG) intake of children ages 6‐18 years (n=8695). Weighted data were analyzed using SUDAAN. Children with a reported BMI were classified into groups based on their WG intake: 0 ounce equivalents (oz. eq.), >0 & <1 oz eq and >=1oz eq per day. BMI Z‐score, waist‐to‐height ratio (WHR) and percent overweight/obese were compared across groups. Children in the highest WG group had significantly lower unadjusted BMI Z‐scores and WHR than the lower 2 WG groups (p<0.005) and a significantly lower percent overweight/obese than the 0 WG group (p=0.002). Regression modes for BMI Z‐score and WHR as a of WG groups intake adjusted for age, gender, ethnicity, energy, physical activity and dietary fiber showed a significant predicted decrease in BMI Z‐Score with increasing WG intake (p<0.01). A logistic regression model adjusted for the same variables predicted a decline in percent overweight/obese with increasing WG intakes (p=0.07). Major sources of WG included ready‐to‐eat cereals (38% of total intake), grain snacks (24%) and yeast breads (18%). These data suggest increased WG intake may contribute to a healthy body measures in American children.
Nutrition Knowledge among first‐year Kuwait University students
Authors: El‐Sabban Farouk , Badr Hanan
Published: June 2021

Assessing nutrition knowledge (NK) of populations assists in drawing strategies for nutrition awareness and education programs. Nutrition‐related problems are common in Kuwait, thus the significance of needed data on NK. This study involved 1037 freshmen, 374 males and 653 females, representing all Kuwait University colleges. A questionnaire was devised which included sections on demographics and knowledge about: general nutrition, proteins, carbohydrates, lipids, minerals and vitamins and water. The survey was conducted during March‐May 2008 and data analysis utilized SPSS for social sciences, version 16. Scores for responses to each question were as follows: do not know (0), wrong answer (1) and correct answer (2) with possible total score of 126. Attained scores were referenced to the highest possible for each section and expressed as a percentage. Sectional score percentages were: general nutrition (78), proteins (73), carbohydrates (76), lipids (70), minerals and vitamins (70) and water (69); with an overall result of 73%. A scale for total NK score percentages was as follows: poor (<50), fair (50‐75) and good (>75). Based on this scale, the overall NK score percentage is rated as fair. Further analysis of responses to each question of the questionnaire should reveal the weak areas that would require more attention towards enhancing such knowledge. This study could be of help to authorities involved to devise specialized nutrition awareness and education programs.

This work was supported by Kuwait University Research Grant No. [WF01/06].
Counseling on mashing local foods for infants increases nutrient intakes but less than supplementation with a fortified spread in rural Zimbabwe.
Authors: Paul Keriann , Muti Monica , Madzima Rufaro , Humphrey Jean H , Stoltzfus Rebecca J
Published: June 2021

Fortified spread, Nutributter® (NB), is promoted as a supplement to prevent childhood malnutrition. Prior to a community based trial, we conducted formative research to see how local diets of 6‐12 month olds in rural Zimbabwe could be improved and then further improved when providing NB. We carried out 2 sets of Trials of Improved Practices (TIPs), with and without NB. The first set identified feeding problems and acceptable improved practices using behavior change and available foods (n=16 mother/infant dyads). The second set was similar to the first, but it also assessed the acceptability of NB (n=16 dyads). TIPs included 5 interviews over 2 wk and 24‐hr dietary recalls (2 pre‐ and 2 post‐counseling). Poor variety was the major feeding problem due to little awareness about what foods infants could eat. Recommendations to mash local foods such as vegetables, fruits, insects, and seeds were most frequently accepted, tried, and practiced. Nutributter was well accepted when added to the new foods tried by the mothers. While intakes from complementary foods of energy, protein, Vitamin A, and calcium increased regardless of NB (p<0.05), intakes of fat, folate, iron, and zinc increased only (fat) or more so (all others) with the provision of NB (<0.05). Significantly increasing nutrient intakes using local food is possible in Zimbabwe, but provision with NB helps ensure adequate intakes, especially of micronutrients.
Education and improved iron intakes for treatment of mild iron deficiency anemia in adolescent girls in southern Benin
Authors: Alaofè Halimatou , Zee John , Dossa Romain , Turgeon O'Brien Huguette
Published: June 2021

The impact of a nutrition education program combined with an increase in bioavailable dietary iron to treat iron deficiency anemia (IDA) has never been studied in adolescent girls. The impact of an intensive dietary program for the treatment of IDA was studied in 34 intervention and 34 control boarding girls aged 12 to 17 years from Benin. A quasi‐experimental design comprising 4 weeks of nutrition education combined with an increase in the content and bioavailability of dietary iron for 22 weeks was implemented in the intervention school, but not in the control school. A nutrition knowledge questionnaire, 24‐h dietary recalls, anthropometric measurements, iron status indices and screening for malarial and intestinal parasitic infections (IPI) were obtained in both groups. Nutrition knowledge scores and mean intakes of nutrients including dietary iron, absorbable iron and vitamin C were higher in the intervention group (p < 0.05) compared to the control group after 26 weeks. Also, mean hemoglobin and serum ferritin values were higher (122 vs. 113g/L; p = 0.0002; 32 vs. 19µg/L; p = 0.04) in the intervention group, whereas the incidence of anemia (32 vs 85%; p = 0.005) and IDA (26 vs. 56%; p = 0.04) was significantly lower. This study is the first, to our knowledge, to demonstrate in adolescent girls that a multi‐dietary strategy aiming to improve available dietary iron can reduce iron deficiency anemia.
Vitamin C deficiency is associated with obesity in rural Mexican women
Authors: García Olga Patricia , Ronquillo Dolores , Elian Shadia , de la Torre Karina , Caamaño María del Carmen , Rosado Jorge Luis
Published: June 2021

The objective of this cross‐sectional study was to evaluate the associations of the antioxidant vitamins C and E deficiencies with BMI, central adiposity, body fat, and leptin concentration. Women aged 37±7.5 years (n=549) from a rural community in Mexico were evaluated. Anthropometrical measurements included weight, height, and waist and hip circumference. A fasting blood sample was taken for the analysis of leptin, and vitamins C and E. Body composition was determined by DEXA (Hologic Mod Explorer). The prevalence of overweight and obesity measured as BMI was 36% and 44% respectively. Central obesity was present in more than 80% of the subjects and 96% of the subjects had a body fat content higher than 30%. The prevalence of vitamin C deficiency in overweight and obese women was significantly higher (37%) than normal weight women (29%) (p<0.05). Vitamin C was negatively associated with BMI (p=0.035, β=‐0.219;95%CI:‐0.422,‐0.016) and leptin concentration (p<0.044, β=‐0.219;95%CI:‐0.082,‐0.001); no associations were found with %body fat or abdominal fat (g). Vitamin E deficiency was similar in overweight and obese women (70%) compared to normal weight women (76%). No associations were found between vitamin E and any of the variables studied. In conclusion, vitamin C deficiency, and not vitamin E, is associated with increased body mass intake and higher leptin concentrations in women living in rural areas.
Cys‐loop ion channels and G‐protein coupled receptors as targets for structure‐inspired drug discovery
Authors: Hendrickson Wayne A.
Published: June 2021

G‐protein coupled receptors (GPCRs) and ion channels predominate among molecular targets for approved drugs (Imming et al., Nat. Rev. Drug Discov. 5, 821, 2006; Overington et al., Nat. Rev. Drug Discov. 5, 993, 2006). Structural biologists and many medicinal chemists find that atomic‐level structures of molecular targets can be very helpful in identifying and optimizing drug leads, but membrane proteins have been difficult subjects for structural analysis and they are woefully underrepresented in the Protein Data Bank. Fortunately, there has been a recent surge in structures of GPCRs and ion channels. I will describe our structural studies of ligand complexes with the α9 acetylcholine receptor, a Cys‐loop ion channel, and with the 5HT2c sertotonin receptor, a GPCR.
Characterizing the chelatable/labile iron pool in mammalian cells
Authors: Hill Natasha , Rojas Ben , Thon Vireak , Beck Albert , Ton‐nu Lena , Planutyte Lina , Mason Andrew Z. , Linder Maria C.
Published: June 2021

Iron shuttling in and out of cellular proteins and compartments comprises a chelatable or labile pool. Attempts at characterizing this pool have been largely unsuccessful. Using 3h labeling with tracer 59Fe, we identified a 1600 Da component in ultrafiltrates of cultured cell lysates that degraded to 600 Da over time (if not separated from the bulk of the cellular protein) and could be converted from 1600 to 600 Da with proteinase K. Both the 1600 and 600 Da components were negatively charged at pH 7+ and separated from cellular 59Fe‐labeled ferritin (Ft) in native PAGE. 59Fe in the unknown versus Ft varied inversely with total cellular Fe. However, analysis of Centricon 10 ultrafiltrates from human HepG2 and Caco2 cells showed that the Fe content did not vary appreciably with cellular Fe status (pretreatment with 180 uM Fe or 30 uM DFO for 24h, or untreated). Concentrations in this pool were 90‐ 200 ng/mg cell protein, with total iron contents ranging from 200 to1600 ng/mg. Mass spectrometry after laser fragmentation released multiple units of 44 Da (consistent with COO‐). We conclude that the cellular labile Fe pool stays quite constant despite changes in Fe status and may primarily consist of a complex of Fe with a small peptide plus carboxylate units. Supported in part by PHS Grant No. RO1 HD 46949.
High‐risk Human Papilloma Virus infection (HPV) among women attending Women's Hospital (HMC) in Qatar
Authors: Al Thani Asma A , Abu –Rub Aisha I. , Al‐Khanji Moza A , Afifi Nahla M. , Al‐Ansari Nasser A
Published: June 2021

Human papillomavirus (HPV) causes a variety of infections. Recent studies indicated that high‐risk types of HPV cause cervical neoplasia. This study aims to investigate the prevalence of high‐risk Human (HPV) genotype (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) infection and its characteristics in Qatar's female by using High Risk Screen Real‐TM SC" test. Ninety five cervical swabs from women attending the Gynae‐oncology clinic at HMC (August 2007‐ May 2008) were enrolled in this study. Cytology results indicated that 31.8% of women had normal smear and 64.28% of them were HPV DNA positive, Upon the whole study population with abnormal smear 46.6% of them had ASCUS {60.7% of them were HPV DNA positive}, 34.9% had LGSIL {85.9% of them were HPV DNA positive}, 13.5% had HGSIL {61.7% of them were HPV DNA positive}, the remaining 5% had squamous cell carcinoma {66.7% of them were HPV DNA positive}.

Of the overall study population; 11 samples were found to be positive by Pap smear and RT‐ PCR and 33 samples were found to be negative in both tests. On the other hand, no samples have being positive by Pap smear and negative by RT‐PCR. However, 44 samples which have shown to be negative by Pap smear but they found to be positive with RT‐PCR. In conclusion, results of this study have proved that detection of HPV infection using molecular technique is more sensitive than the use of conventional methods. This project is supported by QU & UREP.
The anti‐estrogenic activity of peptide AFPep is dependent on its mechanism of entry into breast cancer cells
Authors: Lennon Josh , Andersen Tom , Bennett James , Barroso Margarida
Published: June 2021

AFPep is a cyclic 9‐amino acid peptide derived from the active site of alpha‐fetoprotein that is effective for the treatment and prevention of ER(+) breast cancer. Understanding how AFPep enters breast cancer cells is critical to characterize its mechanism of action. To test whether AFPep anti‐estrogenic activity is dependent on its manner of cellular entry, we conjugated AFPep with Alexa546 or BodipyTR‐X, a hydrophilic or hydrophobic fluorophore, respectively. Internalization of these AFPep conjugates into T47D cells was tested under various conditions, using confocal microscopy. Our results suggest that AFPep‐Alexa is internalized into human breast cancer cells via the endocytic/lysosomal pathway, while AFPep‐Bodipy enters directly into the cytosol. We also tested these AFPep conjugates in a uterine growth inhibition (UGI) assay to test their anti‐estrogenic properties. Whereas AFPep‐Bodipy retained its UGI activity, AFPep‐Alexa had little uterine growth inhibition. We conclude that conjugation of AFPep to hydrophilic labels targets the peptide to degradation in the lysosomes, effectively blocking its anti‐estrogenic activity. Conjugation of AFPep to hydrophobic labels allows its entry into the cytosol, therefore retaining AFPep's anti‐estrogenic activity. This information will facilitate characterization of the mechanism of action of AFPep and translation of AFPep to clinical trials.
Neuroprotectin D1 exerts potent anti‐apoptotic and anti‐amyloidogenic effects in human neural cell models of Alzheimer's disease
Authors: ZHAO YUHAI , LUKIW WALTER J , BAZAN NICOLAS G
Published: June 2021

The 42 amino acid amyloid‐ ? (A ?42) peptide is widely considered as a key molecule implicated in pathogenesis of Alzheimer's disease (AD). Recent studies suggest that neuroprotectin D1 (NPD1), an enzymatic metabolite of docosahexaenoic acid (DHA), may help counteract pathological changes occurring in neurodegenerative disorders such as AD. In this study we sought to investigate the mechanism of NPD1's neuroprotective actions and effects on beta amyloid precursor protein ( ?APP) processing. In a cellular model of AD involving A ?42‐stressed human neural (HN) cells in primary culture, NPD1 significantly ameliorated A ?42‐induced cell death and apoptosis as measured by MTT, caspase‐3 assay, TUNEL and Hoechst 33258 staining. A ?42‐induced expression of the pro‐inflammatory cyclooxygenase‐2 (COX‐2) and cytokine tumor necrosis factor a (TNF‐a) were also reduced by NPD1. In HN cells over‐expressing ?APP, NPD1 significantly suppressed A ? peptide release while the generation of neurotrophic sΑPPα peptides was elevated. Our most recent data suggest that peroxisomal proliferator‐activated receptor ? (PPAR?) might be implicated in the neuroprotective actions of NPD1. In conclusion, NPD1 demonstrated potent anti‐apoptotic, anti‐inflammatory and anti‐amyloidogenic effects in HN cell models of AD, in part, via the targeting of PPAR? and the α‐ and β‐secretase systems.
Analysis of oxidative stress in mouse model of cerebral amyloid angiopathy (CAA)
Authors: Fernandez‐Kim Sun Ok , Zhang Le , Liu Ying , Dasuri Kalavathi , Ebenezer Philip J. , Bruce‐Keller Annadora , Van Nostrand William E. , Keller Jeffrey N.
Published: June 2021

Cerebral amyloid angiopathy (CAA) is an important cause of cerebral hemorrhage stroke and dementia in the elderly. CAA is mediated in part by the effects of amyloid β‐protein (Aβ), with the Tg‐SWDI transgenic mouse model closely recapitulating key aspects of CAA in humans.

In this report we measured the levels of key oxidative stress indices within the frontal cortex of Tg‐SWDI mice (6‐8 months) and age‐matched non‐transgenic mice of the same background (C57Bl/6). Specifically we report on the level of oxidative stress by measuring the amount of protein carbonyls, protein nitroxylation, antioxidant enzyme levels, and the levels of the transcription factor Nrf2. Taken together these data indicate a role for oxidative stress in the development of CAA, and suggest that strategies which ameliorate increases in oxidative stress may be beneficial in the treatment and management of CAA.

This work was supported by a grant from the Alzheimer's Association and NIA (P01AG005119) to Dr. Jeffrey Keller
Role of tumor and host PIN1 status on Lewis Lung Carcinoma growth
Authors: Schneider Ryan A. , Liu Tongzheng , Shah Vaibhav , Keshvara Lakhu , Hoyt Dale G.
Published: June 2021

The peptidyl‐proline isomerase, PIN1, is overexpressed in many cancers. Its depletion slowed the growth of human prostate tumors in athymic mice. Contrary to this, we found that PIN1 depletion in EMT6 murine mammary adenocarcinoma cells increased their growth in the mammary fat pad of wildtype BALB/c mice. Here we investigated the effect of tumor and of host PIN1 status on growth of another tumor in immunocompetent mice. We hypothesized that PIN1 depletion in Lewis Lung Carcinoma (LLC1) cells would increase growth in wildtype C57/BL6 mice, and that tumor growth would be further enhanced in pin1 ‐/‐ mice. Stable PIN1 knockdown or control LLC1 cells were produced by viral transduction. As with EMT6 cells, PIN1 knockdown in LLC1 cells decreased proliferation in vitro, compared to control (p<0.001). The effect of host PIN1 on tumor growth was then tested by subcutaneously injecting PIN1 knockdown or control LLC1 cells in pin1 wildtype or ‐/‐ mice. Like EMT6 tumors in BALB/c mice, PIN1 knockdown increased LLC1 tumor growth in wildtype mice (p<0.05). Interestingly, PIN1 knockdown tumors grew even faster in ‐/‐ than in wildtype mice (p<0.05), while growth of control tumors was unaffected by host PIN1 status. Thus, reductions in tumor and host PIN1 increased tumor growth. PIN1 may regulate host and tumor factors or the microenvironment to promote growth in immunocompetent mice.
Transcription coactivator PBP/MED1 is required for diethylnitrosamine‐induced hepatocarcinogenesis in the mouse
Authors: Matsumoto kojiro , Jia Yuzhi , Viswakarma Navin , Rao M Sambasiva , Reddy Janardan K
Published: June 2021

Nuclear receptor coactivator PBP (peroxisome proliferator‐activated receptor (PPAR)‐binding protein/MED1) functions as an anchor for mediator multisubunit cofactor transcription complex. Disruption of this gene in the mouse results in embryonic lethality. Using PBP liver conditional null (PBPΔLiv) mice, we reported that PBP is essential for PPARα ligand, Wy‐14,643‐induced liver tumorigenesis. We now examined the role of PBP in diethylnitrosamine‐initiated/phenobarbital promoted liver tumor induction. PBPΔLiv mice subjected to this protocol for 1, 4, and 12 weeks, revealed a striking proliferative response and clonal expansion of few residual PBP positive hepatocytes. No proliferative expansion of PBP null hepatocytes was noted. Liver tumors developed in wild‐type and PBPΔLiv mice after 1 year treatment but all hepatocellular carcinomas that developed in PBPΔLiv mice were PBP positive although the surrounding non‐tumor portions of liver in PBPΔLiv mice did not express PBP. These data indicate that PBP is essential for the development of hepatocellular carcinoma. (This work was supported by NIH Grant DK083163).
Transcriptional Regulation of Cardiomyocyte PPAR‐Alpha by Stretch
Authors: Rodriguez Jessica , Case Natasha , Li Luge , Rubin Janet , Willis Monte S
Published: June 2021

The heart is a highly metabolically active organ that derives its energy from mainly the oxidation of fatty acids (70‐80%) and to a lesser extent glucose (20‐30%). During the development of heart failure, cardiomyocytes metabolically adapt by switching its energy substrate preference to glucose. While members of the PPAR (peroxisome proliferator‐activated receptor) transcription factor family are required for this metabolic switch, the external factors that regulate PPAR activity have not been identified. In the present study, we identify that biomechanical stretch of cardiomyocytes leads to the transcriptional regulation of PPAR family members. The HL‐1 cardiomyocyte cell line was subjected to a 24 hour time course of cyclical (20 cycles/minute) unidirectional stretch (15%) using the Flexcell® Tension Plus(tm) System. By Real Time PCR analysis, we identified characteristic responses of the early response genes to stretch, with significant increases in cFos and BNP mRNA peaking at 15‐30 mins. In response to stretch, mRNA levels of PPAR‐α and PPAR‐ β/d decreased in a time dependent manner, however, only PPAR‐α protein levels were modulated. These studies identify for the first time a model to investigate how biomechanical stretch is transduced into changes in cardiomyocyte metabolism, a key process in the development of heart failure.
Accumulation of type VI collagen in cardiomyopathic monkey hearts
Authors: Suzuki Osamu , Ageyama Naohide , Terao Keiji
Published: June 2021

To clarify the etiology of cardiomyopathy, we compared heart protein profiles between normal and cardiomyopathic monkeys, which Ageyama et al. of the Tsukuba Primate Research Center discovered as a monkey model for human cardiomyopathy. Heart proteins from normal and cardiomyopathic monkeys were extracted sequentially from left ventricles into soluble, less soluble, and least soluble fractions according to their solubility using a ReadyPrep sequential extraction kit (Bio‐Rad). These fractions were separated by SDS‐PAGE. On staining the gels with SyproRuby (Invitrogen), the bands were the same for the soluble and less soluble fractions in the two groups of monkey hearts, while one unique band (~200 kDa) was found in the least soluble fraction of the cardiomyopathic hearts. Mass spectrometry and Western blot analyses suggested that the ~200 kDa protein was a collagen type VI α3‐subunit that was produced from an immature ~300 kDa form after C‐terminus cleavage. Western blot analyses confirmed the increase in collagen type VI α1‐ and α2‐subunits as well. These results suggest that the accumulation of type VI collagen is involved in the etiology of cardiomyopathy.
UT‐B Deficient Mice Develop Cardiac Hypertrophy and Cardiac Dysfunction Associated with Aging
Authors: Meng Yan , Zhao Dan , Li Yang , Yang Baoxue , Zhao Xuejian
Published: June 2021

Urea transporter B (UT‐B) is a urea transporter protein expressed in kidney, heart, testis, etc. To determine whether UT‐B could play an important role in cardiac function, we evaluated the morphological and functional difference between wild‐type mice and UT‐B null mice by histological analysis, electrocardiogram and left ventricular (LV) hemodynamics measurement. RT‐PCR and immunofluorescence showed UT‐B expression in cardiomyocytes in wild‐type mice and no UT‐B expression in UT‐B null mice. Urea concentration in heart tissue and serum were significantly higher in UT‐B null mice than that in wild‐type mice , and became much higher with aging. Aging UT‐B null mice had significant cardiac hypertrophy with severe interstitium fibrosis compared to age‐matched wild‐type mice. M‐model echocardiographic images of hearts showed increased AWd, AWs, PWd and PWs in 52‐weeks‐old UT‐B null mice compared with age‐matched wild‐type mice. But LVDd and LVDs in UT‐B null mice did not differ from those of wild‐type mice (P > 0.05). E/A ratio was decreased and LVEDP was increased in UT‐B null mice. Our results provide the first evidence that UT‐B deletion causes accumulation of urea in heart tissue, cardiac hypertrophy and progressive cardiac dysfunction in mice, which suggests that UT‐B play an important role in cardiac function. This work was supported by grants from the National Natural Science Foundation of China (30370572).
The role of VAV guanine nucleotide exchange factor in Dectin‐1 mediated phagocytosis
Authors: Johnstone Jill Kathleen , Morin Nicole A , Cioffi William G , Reichner Jonathan S
Published: June 2021

Phagocytosis involves the cellular recognition and engulfment of foreign particles by a diverse number of cell surface receptors on phagocytes. Particle recognition by phagocytic receptors is accompanied by polymerization of the actin cytoskeleton, which has regulatory pathways that are complex and may be receptor dependent. VAV is a guanine nucleotide exchange factor (GEF) that regulates RhoGTPases, which in turn regulate cytoskeleton rearrangement. We tested the hypothesis that in peritoneal macrophages, VAV GEFs are essential for Dectin‐mediated phagocytosis, and are not needed for Fc‐mediated phagocytosis. Peritoneal macrophages were obtained from wild type (WT) and VAV‐knockout mice by peritoneal lavage, and were assayed for phagocytosis of zymocel (Dectin‐1 dependent), and IgG opsonized latex beads (FcR‐dependent) for 30 minutes at 37oC. Intracellular particles were then enumerated per 100 cells. In the Dectin‐1 phagocytic assay, VAV‐knockout macrophages ingested fewer zymocel particles than WT macrophages (p<0.05). In the Fc‐mediated phagocytic assay, VAV‐knock‐out macrophages ingested a similar amount of IgG‐opsonized latex beads as WT (p>0.05). These findings are the first demonstration for the role of VAV in Dectin‐1 mediated phagocytosis and further define the complex regulation of phagocytosis by highlighting a receptor‐specific intracellular signaling mechanism.
Regulation of Antiviral Immunity Synergistically Controls Autoimmunity in Type 1 Diabetes
Authors: Filippi Christophe M , Estes Elizabeth A , Oldham Janine E , Larsson Par , Wolfe Tom , von Herrath Matthias G
Published: June 2021

While the inflammatory immune response mounted against viral infections is usually believed to enhance autoimmune processes, we discovered that it triggers two key regulatory phenomena that synergize to promote tolerance in type 1 diabetes (T1D). Acute infection of prediabetic non‐obese diabetic (NOD) mice with lymphocytic choriomeningitis virus (LCMV) significantly delayed autoimmune diabetes and reduced disease incidence. The delay of T1D was due to transient up‐regulation of Programmed death‐ligand 1 (PD‐L1) which was induced, at least in part, by interferon, and caused the elimination of PD‐1‐expressing, diabetogenic CD8+ T cells. The reduction of T1D incidence was due to increased number and function of CD4+CD25+Foxp3+ regulatory T cells (Tregs) which produced TGF‐β and maintained long‐term tolerance. PD‐L1 and virally enhanced Tregs conferred marked protection from T1D by acting together in synergy. LCMV induced the regulatory mechanisms that prevented T1D by utilizing Toll‐like receptor 2 and dendritic cells. These results reconcile current discordance about the role of viruses in T1D and provide novel insight into disease etiology and potential treatment.
Fructose/losartan interactions: Effects on renal ACE2
Authors: Senador Danielle , Key Mary , Elased Khalid M , Morris Mariana
Published: June 2021

Fructose diet enhances losartan's hypotensive effect in mice. Angiotensin‐converting enzyme 2 (ACE2) has emerged as an important component of the renin angiotensin system. We examined the interactions between fructose diet and losartan on renal ACE/ACE2 balance. Male C57BL mice were fed a 60% fructose diet for 10 weeks and losartan (Los, 30mg/kg/day) was given in the drinking water for the last wk. Renal ACE and ACE2 activity were measured by radiofluorescent and fluorogenic assays, respectively. Renal Ang II levels were measured by RIA. Renal ACE and ACE2 protein expression were measured by Western blots. There was no alteration in renal ACE activity or protein expression between groups. Renal Ang II, ACE2 activity and ACE2 protein expression were increased in fructose group (Ang II: 112 ± 40 vs. 440 ± 114 pg/μg protein; ACE2 activity: 2.8 ± 0.2 vs. 3.9 ± 0.2 pmol/hr/ ?g protein; ACE2 protein expression: 0.6 ± 0.1 vs. 1.3 ± 0.1 AU). Los had no effect on renal Ang II or ACE protein or activity. Los increased ACE2 protein in controls (0.7 ± 0.1 vs. 1.4 ± 0.2, AU) with no change in activity. In fructose mice, Los decreased renal Ang II (440 ± 114 vs. 190 ± 85 pg/µg protein). Fructose produced consistent activation of the renal ACE2 system while Los produced no additional effects. Results suggest that interaction between Los and fructose is not mediated by changes in the renal ACE/ACE2 balance.
COX mediates impaired estrogen‐induced relaxation in resistance arteries from postpartum rats
Authors: Royal Crista R , White Richard E
Published: June 2021

Premenopausal women exhibit less hypertension than men, possibly due in part to the vasodilatory influence of estrogen (E2). However, clinical trials indicate that E2 may increase cardiovascular risk in postmenopausal women. E2 relaxes conductance vessels by generating NO from nitric oxide synthase; however, the mechanism(s) whereby E2 relaxes resistance arteries is largely unknown. To address this controversy we harvested first‐ and second‐order mesenteric arteries from ovariectomized (Ovx), nulliparous (N), and postpartum (PP) female rats, and studied E2‐induced vasodilation in vitro. Inhibiting NOS activity with either 10−4M L‐NAME (n=4), L‐NMMA (n=5), or the more nNOS‐selective inhibitor L‐NPA (n=4), had no effect on E2 relaxation in Ovx mesenteric resistance arteries vs N. Thus E2‐induced relaxation of Ovx does not appear to require NO. E2(10−6M)‐induced relaxation in PP was impaired significantly (15.37 ± 3%; p<0.001; n=7) vs N (31.70 ± 3%; n=6) or Ovx (32.51 ± 3%; n=6). In contrast, incubating arteries from PP rats (n=3) with indomethacin (10−4M) completely restored E2‐induced relaxation (30.87 ± 18.9%). This suggests that E2‐induced relaxation of resistance arteries from PP rats is impaired by a cyclooxygenase derivative. This contractile prostaglandin, likely a COX‐2 metabolite, may attenuate normal responses to E2 and thereby counteract its expected hypotensive effect. [NIH HL073890]
Activation of MEK1/ERK1/2/iNOS/sGC/PKG pathway contributes to the fall in blood pressure and vascular reactivity in endotoxemic rats
Authors: Korkmaz Belma , Buharalioglu Kemal , Demiryurek A. Tuncay , Sahan‐Firat Seyhan , Cuez Tuba , Tunctan Bahar
Published: June 2021

Increased production of iNOS‐derived NO contributes to fall in blood pressure (BP) and vascular reactivity (VR) during endotoxemia. Inhibition of ERK1/2 activity also reverses the endotoxin (ET)‐induced hypotension via decreased NO production. We investigated whether an increase in protein expression and/or activity of the enzymes involved in MEK1/ERK1/2/iNOS/sGC/PKG pathway contributes to the decrease in BP and VR to norepinephrine (NE) in endotoxemic rats. An inhibitor of ERK1/2 phosphorylation by MEK1/2, U0126, and an inhibitor of iNOS, 1,3‐PBIT, prevented the ET‐induced decrease in BP and VR to NE. sGC inhibitor, ODQ, and PKG inhibitor, KT5823, reversed the decreasing effect of ET on the contractile responses to NE in vitro. ET caused an increase in p‐MEK1, p‐ERK1/2, iNOS and pVASP proteins, and NOx and cGMP levels. U0126 and 1,3‐PBIT did not reverse the ET‐induced increase in p‐MEK1 protein levels. The ET‐induced increase in ERK1/2, iNOS, sGC and PKG protein expressions and activities were prevented by U0126, while 1,3‐PBIT opposed the effect of ET on NOx, p‐VASP protein and cGMP levels. These data demonstrate that activation of MEK1/ERK1/2/iNOS/sGC/PKG pathway contributes to the fall in BP and VR in endotoxemic rats. This study was supported by Mersin Univ (BAP SBE EMB (RBK) 2006‐3 DR) and TUBITAK (SBAG‐3508, 106S299) projects.
Vascular relaxation stimulated with acetylcholine involves inducible and constitutive NO‐synthases and cyclooxygenase activation six hours after cecal ligation and perforation (CLP).
Authors: Bendhack Lusiane Maria , Araújo Alice Valença , Ferezin Camila Zarinello , Bonaventura Daniella , Vercesi Juliana Aparecida
Published: June 2021

Several studies have demonstrated a systemic hypotension in septic shock induced by CLP that is mainly attributed to nitric oxide (NO). The present work aimed to study the endothelium‐dependent vascular relaxation induced by acetylcholine (ACh) in CLP and sham‐operated (SO) rat aortic rings and to identify the NO‐synthase (NOS) isoform involved in this response by the selective inhibitors (eNOS, L‐NNA 100 μM), (nNOS, 7‐NI 100 μM) and inducible iNOS (1400W 10 μM), and the non‐selective L‐NAME 100 μM and the role of cyclooxygenase (COX). Mean arterial pressure was progressively reduced 6h after CLP. Rats were killed 6h after CLP and concentration‐effect curves for ACh were constructed in aortic rings in the absence or after incubation for 30 min with the given inhibitor. Both maximum relaxation (ME) and potency (pD2) induced by ACh were similar in CLP (99.4±1.3%; pD2 7.20±0.15, n=7) and in SO (95.9±3.0%, pD2 7.36±0.15, n=4). The relaxation was more inhibited in SO (L‐NAME 3.2±6.8%; L‐NNA 4.5±5.2%; 7‐NI 61.3±3.9%) than in CLP (L‐NAME 13.9±7.5%; L‐NNA 12.0±2.4%; 7‐NI 95.4±1.5%). However, these responses were similar after the combination of the COX and NOS inhibitors. In the presence of 1400W, the potency but not the ME of ACh was reduced in CLP. In conclusion, ACh induces aorta relaxation via iNOS and constitutive NOS and product(s) of COX 6h after CLP. Supported by CAPES, CNPq and FAPESP.
Chronic Angiotensin II cardiovascular effects are inversely related to α1D‐adrenoceptors expression in aorta of adult Wistar rat
Authors: Gallardo‐ Ortiz Itzell Alejandrina , IBARRA MAXIMILIANO , LOPEZ‐SANCHEZ PEDRO , VILLALOBOS‐MOLINA RAFAEL
Published: June 2021

Angiotensin II plays an important role in regulating blood pressure, it provokes cardiovascular remodeling and hypertension, as well as an increase in α1‐adrenoceptors mRNA and protein. In the cardiovascular system α1‐adrenoceptors regulate processes like cardiac and arterial smooth muscle contraction and they have been implicated in pathological processes. We explored the in vivo Ang II continuous effect on α1‐adrenoceptors function and expression in aorta of Wistar rats. Osmotic minipumps filled with Ang II (200 ng/kg/min/day) were subcutaneously implanted in male Wistar rats. Blood pressure was measured and after 2 weeks aorta was isolated for contractile experiments. α1‐Adrenoceptors mRNA expression and protein were measured. Ang II increased blood pressure. Phenylephrine‐induced contraction in aorta was greater (Emax, 4.2g) in Ang II‐treated rats than in controls (2.7g). PCR and Western Blot data showed that α1B,1A‐adrenoceptors did not change with Ang II while α1D‐adrenoceptors were lower. Histological data showed hypertrophy in aortas with Ang II. The data suggest a crosstalk between Ang II and α1‐adrenergic pathways, nevertheless this effect seems not related with hypertension and hypertrophy induced by Ang II.
Effects of cooling on α2‐adrenoceptor mediated contraction of rat tail vein
Authors: Yao Mingyi , Abel Peter W
Published: June 2021

a2‐Adrenoceptor (a2‐AR) mediated venous contraction plays an important role in thermoregulation. We investigated how cooling of rat tail vein, in vitro, affects a2‐AR mediated contraction. Tail veins were isolated, endothelium removed, and incubated at 37°C or 28°C for 2.5 hrs. At 37°C the a2‐AR agonist UK14304 caused contraction with an EC50 of 11.9 nM. Cooling to 28°C decreased the EC50 to 1.5 nM and increased maximal response by 46%. The same pattern was found with other a2‐AR agonists BHT933, guanabenz and dexmedetomidine; but not with 5‐HT, angiotensin II, arginine vasopressin, and phenylephrine. The affinities (KB's in nM) of a2‐AR antagonists determined from Schild plot were increased after cooling: RX821002 (non‐selective, 2 at 37°C, 0.2 at 28°C), MK912 (a2C‐AR selective, 0.1 at 37°C, 0.06 at 28°C), rawolscine (a2A/C‐AR selective, 11 at 37°C, 1 at 28°C), ARC239 (a2B‐AR selective, 181 at 37°C, 68 at 28°C). KB's for antagonists were consistent with the a2C‐AR subtype. UK14304 contraction was nearly eliminated by pertussis toxin at 37°C, however; pertussis toxin had little effect at 28°C. Cooling selectively increased α2C‐AR mediated contraction that may be due, in part, to increased affinity of α2C‐AR's and/or a change in α2C‐AR coupling to a Gi protein independent pathway. Thus the development of α2C‐AR selective agents may be useful to modulate venous function in diseases of altered thermoregulation.