bluuebunny/crossref_metadata_2025 huggingface dataset:
Race/ethnicity, family income, and education differentials in nutritional biomarkers in American children and adolescents: NHANES 2003–2006
Authors: Kant Ashima K. , Graubard Barry I.
Published: June 2021

Diet, an acknowledged correlate of health may mediate the known race/ethnic and socioeconomic differentials in the health of US children. However, few studies have systematically examined the independent association of ethnicity, income, and education with nutritional profiles of US children. We used the NHANES 2003–2006 data for 2–19 year old Americans to examine the independent associations of race/ethnicity, family income, and education with dietary intakes and serum concentrations of vitamins A, D, E, C, B‐6, B‐12, folate, and carotenoids (n ~ 2700 to 7500). Non‐ Hispanic blacks (NHB) had lower serum concentrations of vitamins A, B‐6, E, and alpha‐carotene relative to non‐Hispanic whites (NHW). Both NHB and Mexican‐Americans (MA) had higher serum vitamin C, beta‐cryptoxanthin and lutein/zeaxanthin, but lower folate and vitamin D concentrations relative to NHW. In NHB, the differences in mean dietary intakes of vitamins A, C, folate, alpha‐carotene, beta‐cryptoxanthin, and lutein/zeaxanthin were in a similar direction to that of biomarker concentrations. Family income and education predicted few biomarker or dietary outcomes and the observed associations were weak. In conclusion, race/ethnicity (but not family income or education) was a strong independent predictor of dietary intakes and serum concentrations of micronutrients in US children and adolescents. Supported by NIH grant award HD060217
The burden of malnutrition among school children in Kelantan, Malaysia
Authors: Lee Yi Yi , Muda Wan Abdul Manan Wan , Suzuki Masashige
Published: June 2021

The Third Malaysian National Health and Morbidity Survey conducted in 2006 reported that 15% of children aged 1 to 18 years were undernourished. This figure reflects a worrying public health problem in the country whereby there are still sizable number of children who are not achieving a healthy body weight during their growing years. Undernourished children are unable to meet their full genetic potential because their growth, immune functions, cognitive, psychological and intellectual developments are affected. A cross‐sectional study was carried out among school children aged 10 to 12 years‐old living in the district of Bachok, Kelantan, a rural district located in the East Coast of Peninsular Malaysia. The aim of the study was to determine the prevalence of malnutrition and its relationship with the children's academic achievements, socioeconomic conditions and dietary intakes. Results revealed that positive correlations between academic achievement and socioeconomic conditions with the children's nutritional status. The findings from this study can be used to develop suitable prevention strategies or intervention programs for parents, teachers, as well as governmental and non‐governmental agencies to promote healthier growth and development among children in Malaysia, especially those from poor households.

Grant Funding Source: Prof Masashige Suzuki
Effect of soluble fiber on blood lipid profiles in patients with type2 diabetes in Korea
Authors: Jung Sunyoon , Ha Jimin , Doo Miae , Kim Yangha
Published: June 2021

Ingestion of soluble fiber has been reported to improve dyslipidemia in patients with type2 diabetes. In this study, the effect of fibersol‐2, one of soluble fibers, on serum lipid profiles of patients with type2 diabetes was investigated in Korea. 56 subjects (men=25, women=29, mean age=59.5±11.3) were randomly divided into two groups; prescribed hospital diets (Control, n=25) or prescribed hospital diets supplemented with 12g of fibersol‐2 per day (High fiber, n=31). Anthropometric parameters, blood profiles and dietary intakes were measured before and after the treatment. The duration of diabetes, anthropometric variables, and blood profiles were not significantly different between groups. After the treatment, the subjects supplemented with fiber showed significant decrease in the blood levels of total cholesterol (TC), triglyceride (TG), and atherogenic index (AI) (P<0.05). The blood levels of TC and LDL cholesterol (LDL‐C) in the group supplemented with fiber were lower than those of control group (P<0.05). These results suggest that supplementation of soluble fiber may have positive effects on improving the blood lipid profiles in patients with type2 diabetes.
Food‐related behaviors of international college students
Authors: Dixon Zisca , Vaccaro Joan A. , Tellez Christine , Harper Meredith , Huffman Fatma G.
Published: June 2021

Objective

To examine adherence to dietary requirements in first‐time residential students.

Methods

Analysis of variance using data from 24‐hour recalls and MyPyramid tracker was performed for multiethnic students (N= 219) with informed consent.

Results

The ethnic composition was 46% Hispanic, 26% White non‐Hispanic, 22% Black non‐Hispanic, and 6% other. The majority of students did not adhere to the recommended guidelines (DGA) for daily calories (n=89, 65% females; n=63, 77% males) and sodium intake (n=93, 68% females; n=66, 81% males). Lack of adherence to DGA differed by ethnicity for female students: Black non‐Hispanic females consumed 149 Kcal more; whereas, White non‐Hispanics and Hispanic females consumed less [−3.0, – 250 Kcal, respectively (p=0.006)]. DGA differences in females by ethnicity were for meat and beans (p=0.009), carbohydrates (p=0.003), and sodium (p=0.002).

Conclusions

The results of this study suggest the need for campaigns on college campuses to promote healthy eating, targeting freshmen. These findings imply that restrictions for the amount of sodium in prepared foods on campus may need to be considered as a policy change.
Effects of consuming oxidized vegetable oils on amino acid metabolism
Authors: Wang Lei , Yao Dana , Chen Chi
Published: June 2021

Consumption of thermally‐stressed lipids through fried foods has been suggested as a contributing factor in various adverse health conditions, including obesity, insulin resistance and cardiovascular diseases. However, the underlying mechanism of this association is not well understood. In this study, the influences of consuming heated vegetable oils on the metabolic system were examined through the metabolomics‐guided biochemical analysis. Fresh soybean oil‐low fat (FSO‐LF) diet (contain 7% fresh oil), fresh soybean oil‐high fat (FSO‐HF) diet (contain 16.7% fresh oil), heated soybean oil‐low fat (HSO‐LF) diet (contain 7% heated oil), and heated soybean oil‐high fat (HSO‐HF) diet (contain 16.7% heated oil) were given to C57/B6 mice for 4 weeks, respectively. The results from targeted metabolite analysis indicated that, in addition to the significant changes in the cholesterol and triglyceride levels, HSO treatment also altered the homeostasis of amino acids, such as the decrease of tryptophan level and the increase of proline in the serum. Metabolomic analysis of urine samples further identified the metabolites of tryptophan as the prominent biomarkers that contributing to the separation of urine samples from FSO and HSO treatment. Nicotinamide N‐oxide, a metabolite from tryptophan‐NAD+ pathway, was increased by HSO, while xanthurenic acid, another metabolite of tryptophan, was reduced by HSO. All these observations warrant further investigation on the effects of thermally‐stressed oils on amino acid metabolism.
Glycemic index of native fructose extracted from fruits: a scientific‐based specificity
Authors: David Aurelie , Cazaubiel Murielle , Gendre David , Housez Béatrice
Published: June 2021

Research in nutrition has shown that consuming different carbohydrate‐based foods can elevate blood sugar levels differently for an equivalent carbohydrate intake. In the EFSA Scientific Opinion (ID 558) related to fructose and reduction of post‐prandial glycemic responses, the NDA Panel considers that “fructose should replace sucrose and glucose in foods or beverages in order to obtain the claimed effect”. While fructose generally results from a process of starch hydrolysis, a patented process has recently been developed to extract and purify the native fructose from fruits. To confirm the glycemic index (GI) of this native fructose, a randomized, controlled clinical trial was conducted. Subjects (N=12) consumed 50g of glycemic carbohydrate from native fructose (FructiLight®) compared to a referent (glucose) on 2 different days, separated by at least 48 hours. Blood glucose and insulin were assessed at t=−5 (before product consumption), 15, 30, 45, 60, 90, and 120 min. This protocol was based on FAO/WHO and ISO 26642:2010 recommendations for GI determination. Values for GI and the insulin index (II) were 11.93 and 22.67, respectively, for native fructose. These data confirm previous findings in mice, and demonstrate that this particular type of native fructose possesses an extremely low GI, which may be advantageous as an ingredient for reducing the blood sugar response of different food applications.
Physiological effects of Polydextrose (PDX) and Soluble Corn Fiber (SCF) in a randomized, placebo‐controlled, study of healthy adults
Authors: Timm Derek , Thomas Will , Williamson-Hughes Patricia , Boileau Thomas , Slavin Joanne
Published: June 2021

We have previously shown that PDX and SCF positively affect gut health by increasing fecal weight. In this study, we evaluated the ability of PDX and SCF to be fermented in the gut as measured by fecal short chain fatty acids (SCFA), fecal pH, breath hydrogen production, and stool consistency. Subjects (n = 36) consumed 20 grams of study fibers daily for 10 days and collected fecal samples during the final 5 days of each treatment. Total SCFA concentrations were significantly higher in the control (56 ± 17 μmol/g wet weight) compared to PDX (46 ± 16 μmol/g wet weight), but similar to SCF (50 ± 16 μmol/g wet weight). PDX had a lower (p = 0.02) fecal pH (6.37 ± 0.39) and SCF trended (p = 0.07) toward lower (6.41 ± 0.50) pH than the control (6.55 ± 0.36). Breath hydrogen levels were significantly higher for PDX and SCF compared to the control. The PDX caused a significantly softer stool consistency than the SCF and control treatments. We postulate that increased fecal weight from PDX and SCF consumption may have diluted the fecal SCFA concentrations, accounting for the higher total SCFA concentration in the control treatment. Despite this, our results show significantly increased fermentation measures of PDX and SCF with good tolerance compared to the control and demonstrate a physiological benefit of these functional fibers. This study was supported by General Mills Inc. and Tate & Lyle Health & Nutrition Sciences.

Grant Funding Source : General Mills and Tate & Lyle
Within subject variation of satiety hormone responses to a standard lunch
Authors: Forester Shavawn M. , Witbracht Megan , Horn William , Laugero Kevin , Keim Nancy L.
Published: June 2021

Background

Insulin (Ins), leptin (Lep), GLP‐1, and glucagon (Glg) are known regulators of glucose metabolism and food intake, but reproducibility in response to a meal challenge is not well characterized. We assessed within‐subject variation of these hormones in 14 young adult women.

Methods

Subjects were studied on 2 days during the follicular phase of the menstrual cycle. On test days blood was drawn at 20, 35, 50, 65 & 125 min after a standard lunch meal. Meso Scale Discovery assay system was used to measure the hormones in a multiplexed sandwich immunoassay.

Results

Analysis of variance revealed that there were no differences between test days for all 4 hormones. Correlations between values for test days 1 & 2 were significant for Ins (r = 0.68; p < 0.0001), Lep (r = 0.86; p < 0.0001) and GLP‐1 (r = 0.97; p < 0.0001) but not for Glg (r = 0.18; p = 0.143). Mean within‐subject variation (% of mean value at each time point) was 42, 37, 48, and 87 for Ins, Lep, GLP‐1 and Glg, respectively. Averaging values for 5 time points, to represent postprandial response, reduced within‐subject variation to 30, 37, 23, and 35% of mean value, respectively.

Discussion

Despite controlled test meals, we observed large within‐subject variation that was partly reduced by using summary measures. Other contributors to variation may include pre‐test diet intake, environmental influences, or analytical error. Funding: USDA CSREES 2009‐35215‐05364.
Comparison of dietary supplementation with lutein diacetate and lutein
Authors: Landrum John , Bone Richard , Mendez Vanesa , Valenciaga Anisley , Babino Darwin
Published: June 2021

Problem

The responses of subjects taking a 20 mg/day lutein diacetate supplement were compared with that for a 20 mg/day crystalline lutein or a placebo.

Methods

Ten subjects, assigned to each of three groups, lutein diacetate (group 1), lutein (group 2), and a placebo (group 3), were supplemented for 24 weeks. Groups 1 and 2 consumed a dose equivalent to 20 mg per day of free lutein. Serum samples, collected at baseline, and at weeks 6, 12, 18, and 24 were analyzed by HPLC. Macular Pigment Optical Density (MPOD) was obtained by heterochromatic flicker photometry at baseline and weeks 6, 12, 18 and 24..

Results

The average serum lutein concentrations for weeks 6 to 24 expressed as a ratio to the baseline value (±SD) were 5.52 ± 2.88 for group 1, 4.43 ± 1.61 for group 2, and 1.03 ± 0.25 for group 3. The median rate of macular pigment increase (milli‐absorbance units/week) for groups 1, 2, and 3 were 2.35, 1.55, and 0.19 mAU/wk, respectively. P‐values for these serum and MPOD increases are both highly significant when compared to placebo.

Conclusions

The average serum response was ~25% higher for group 1 compared with group 2 and, the median MPOD response was 52% higher for group 1 than group 2. P‐values calculated for the differences in these increases were, p = 0.066, marginally significant, for serum, and p = 0.09 approaching significance, for MPOD. Financial Support: Industrial Organica S.A. de C.V.
Melatonin can attenuate HOCl‐mediated hemolysis, free iron release and heme degradation from hemoglobin
Authors: Maitra Dhiman , Abdulhamid Ibrahim , Diamond Michael P. , Saed Ghassan M , Abu-Soud Husam M
Published: June 2021

In inflammatory diseases, where hypochlorous acid (HOCl) is elevated, iron homeostasis is disturbed, resulting in iron accumulation. Free iron is toxic since it can lead to generation of other free radicals through the Fenton reaction. Recently, we have shown that HOCl binds to the heme moiety of hemoglobin (Hb) and generates a transient ferric species in which ultimately leads to heme destruction, free iron release and protein aggregation. HOCl is generated by myeloperoxidase, utilizing chloride and hydrogen peroxide as substrates. Melatonin, a neurohormone, has been shown to act as an inhibitor of MPO and is also know to scavenge HOCl. Here we show that HOCl mediated Hb heme destruction can be partially or completely prevented by pre‐incubation of Hb with increasing concentrations of melatonin prior to the addition of HOCl, as judged by UV‐Vis spectrophotometry and in‐gel heme staining. Melatonin also prevented HOCl‐mediated free iron release and protein aggregation. Similarly, pre‐incubation of erythrocytes with increasing concentrations of melatonin prior to the treatment with HOCl prevented HOCl‐mediated loss of erythrocyte viability, indicating the biological relevance of this finding. Melatonin prevents HOCl‐mediated Hb heme destruction by direct scavenging of HOCl or through the destabilization of the higher Hb oxidative states intermediates, ferryl porphyrin radical cation Hb‐Fe(IV)=O+π• (Compound I) and Hb‐Fe(IV)=O (Compound II), that are formed through the reaction of HOCl with Hb. This work also indicates that Hb/melatonin system can function as a catalytic sink for HOCl, establishing a direct mechanistic link between melatonin and its protective effect in chronic inflammatory diseases.

Grant Funding Source: NIH
The iron transporter ferroportin is regulated by ascorbate
Authors: Scheers Nathalie M , Hoffmann Karolina B , Sandberg Ann-Sofie
Published: June 2021

A few tightly regulated transport proteins mediate iron absorption across the intestinal epithelium. However, at the basolateral border of the intestinal cells there is only one identified transporter, ferroportin, for the transfer of intracellular iron to the vascular system. The aim was to investigate the effect of ascorbate (Vitamin C) on the regulation of ferroportin in human intestinal Caco‐2 cells. We observed increased ferroportin levels in the presence of basolateral ascorbate (150 μM) as measured by Western blot and ELISA. After 2 h of apical iron incubation, the expression of ferroportin protein was dramatically decreased. We also observed that higher ascorbate concentration (300 μM) decreased ferroportin levels. Thus, the effect of ascorbate was dose‐dependent. Interestingly, the level of iron regulatory protein 2 (IRP2) was closely following the levels of ferroportin. In conclusion, our results suggest that the functional protein level of ferroportin is regulated by ascorbate and that IRP2 is involved. In addition, the nature of the IRP2 response suggests that it could be iron‐independent. The Swedish Council for Environment, Agricultural Sciences and Spatial Planning funded this study.
Tracing iron balance from mouse to human
Authors: Wang Fudi
Published: June 2021

It is estimated that nearly one quarter of population worldwide are suffered from iron deficiency anemia. In contrast, iron overload induces hemochromatosis. Therefore, maintenance of iron homeostasis is crucial for human health. To explore the mechanistic network of iron regulators in maintenance of iron homeostasis, we initiated our investigations in functional characterization of iron exporter Fpn1 in mice. We generated tissue‐specific Fpn1 deletion mice, which lack Fpn1 in hepatocytes and macrophages. Our data suggest Fpn1 mediates iron mobilization, iron storage, and iron absorption to maintain systemic iron homeostasis. In addition, we observed metalloreductase Steap3 coordinates with TLR4 to regulate systemic iron homeostasis and inflammatory responses. Furthermore, in a large cohort of Chinese population study, we discovered the polymorphisms of TMPRSS6, which encodes protein matriptase‐2, is not only significantly associated with lower iron levels and hemoglobin level in sera, but also captured iron deficiency as high genetic risk factors in anemia and reduced risk to type 2 diabetes. From mouse to human, we aim to shed light on the molecular mechanisms of iron homeostasis in diseases. We believe our studies pave ways to translate the findings to therapeutic target stratification in iron related diseases.

Grant Funding Source: The MOST of China (2009CB941400, 2011CB966200), NSFC of China (10979071, 30970665, 31030039), CAS (KSCX2‐YW‐R‐141) and Science & Technology Commission of Shanghai Municipality grant (10JC1416800)
Glutamine activates heat shock transcription factor‐1 (HSF1) gene transcription
Authors: Xue Hongyu , Slavov Dobromir , Wischmeyer Paul
Published: June 2021

We have demonstrated that glutamine (GLN) enhances cytoprotective heat shock protein (HSP) expression. Heat shock transcription factor‐1 (HSF1) is the master regulator for HSP gene expression. We are aimed to explore GLN's effects on HSF1's activity and expression. Non‐stressed or heat‐stressed YAMC colonic epithelial cells were exposed to GLN at 0, 0.5 or 2mM. HSF1 expression, nuclear localization, trimerization and DNA binding were determined. HSF1 promoter‐driven reporter assay and deletion analysis of HSF1 gene promoter were conducted. GLN upregulated HSF1's transactivation activity by increasing its trimerization, nuclear localization and DNA binding. Further, GLN increased HSF1 protein and mRNA expression in both non‐stressed and stressed cells. Deletion analysis of HSF1 promoter shows that the key cis‐ element responsible for GLN response is present between bp −331 to −200. Within this region, deletion of the putative CCAAT enhancer binding protein (C/EBP) binding site resulted in decreased GLN response. In absence of glutamine, HSF1 expression was de‐repressed in C/EBPβ‐silenced cells. Over‐expression of the inhibitory dominant‐negative isoform of C/EBPβ repressed HSF1 expression in presence of adequate glutamine. We for the first time show that GLN not only activates HSF1's transactivation activity, but also activates HSF‐1 gene transcription per se in a C/EBPβ‐dependent manner.
Identification of three promoters in the human holocarboxylase synthetase (HCS) gene
Authors: Xia Mengna , Malkaram Sridhar Achary , Zempleni Janos
Published: June 2021

HCS catalyzes the binding of biotin to carboxylases, which play essential roles in macronutrient metabolism. HCS also appears to play a role in a multiprotein repressor complex in human chromatin. Little is known about the transcriptional regulation of HCS. This study sought to identify and characterize human HCS promoter(s). An in silico search (ensembl genome browser) revealed 3 potential promoters, positioned at bp 2888 to 5253 (P1), 12877 to 14926 (P2), and 28055 to 29336 (P3) in the HCS gene (NG_016193). The promoters were cloned from human IMR90 cells and subcloned into the pGL3 luciferase reporter plasmid to create HCS‐P1GL3, HCS‐P2GL3, and HCS‐P3GL3. All 3 constructs exhibited promoter activity when transfected into human HEK293 kidney cells, HCT116 colon cells, and MCF7 mammary cells. Typically, promoter activities followed the pattern P1 > P3 > P2, but some tissue specificity was apparent. For example, the activity of P3 was about 3 times the activities of P1 and P2 in MCF7 cells. Analysis of the Encode database (genome.ucsc.edu) revealed a significant enrichment of the activation mark H3K4me3, suggesting that HCS is transcribed from all 3 promoters. Both enhancers and repressors were identified in all 3 promoters. We conclude that we have identified novel, functional promoters for human HCS, and that P1 is the strongest promoter in most tissues. (ARD Hatch Act, NIH DK063945, DK077816, and DK082476.)
Saturated fat intake interacts with HDL‐c genes to influence plasma HDL‐c of Filipino women
Authors: Zubair Niha , Adair Linda , Feranil Alan
Published: June 2021

Low HDL‐c is highly prevalent among Asian populations. We aimed to determine whether a HDL‐c gene score interacts with dietary intake of saturated fat, non‐saturated fat, and carbohydrates to influence fasting HDL‐c levels in Filipino women participating in the 2005 Cebu Longitudinal Health and Nutrition Survey (n = 1,687, age =35.7–68.8 y). The gene score summed the number of effect alleles (range: 5–14) in 8 genes shown previously to be associated with higher HDL‐c in this sample. HDL‐c (mean = 41.0 mg/dL) was regressed on gene score, macronutrient intake, and the interaction of score with macronutrient, adjusting for age, physical activity and BMI. In a main effects model, gene score was positively related to HDL‐c (1.69 mg/dL per risk allele, 95% CI: 1.36–2.02; p = 0.00). Gene score significantly interacted with saturated fat intake (p =0.03), but not non‐saturated fat or carbohydrate intake. Predicted HDL‐c levels did not differ between low and high saturated fat intake among women with a low gene score. In contrast, with a high gene score (=12), HDL‐c was 4 mg/dL higher when saturated fat was at the 15thvs. the 85th percentile of population intake (difference of 6 g/d). The more favorable HDL‐c levels seen in women with higher gene score and higher saturated fat intake may reflect the intake of coconut oil, the main source of saturated fat in the Filipino diet, which has been previously shown to relate to higher HDL‐c levels.

Grant Funding Source : National Institutes of Health DK078150, HL085144
Identification of biotin‐ and holocarboxylase synthetase‐dependent microRNAs in human fibroblasts
Authors: Wijeratne Subhashinee Samudra , Malkaram Sridhar Achary , Zempleni Janos , Pabian Michael Dylan , Granatowicz Andrew Daniel
Published: June 2021

MicroRNAs (miRs) regulate their target genes by binding to the 3′‐UTR. Previously we reported that the expression of miR‐539 depends on biotin, thereby regulating the expression of holocarboxylase synthetase (HCS) in human kidney cells. HCS appears to be part of a multiprotein gene repression complex in human chromatin. We hypothesized that both biotin and HCS play important roles in regulating miRs. IMR‐90 primary human fibroblasts were cultured in media containing deficient, normal, and high biotin concentrations; in addition, HCS mutant fibroblast were cultured in high biotin medium to mimic the scenario in HCS‐deficient patients receiving biotin supplements. miRs were sequenced using the SOLiD platform. Expression analyses were performed using edgeR, R software. The expression of miR‐378 and miR‐34a* was greater in biotin‐deficient and ‐supplemented IMR‐90 cells, respectively, compared with biotin‐normal controls (p < 0.01). The expression of miR‐2110 and miR‐150 was lower, in biotin‐deficient and supplemented cells, respectively, compared with controls (p < 0.01). The expression of 58 miRs increased or decreased in HCS‐mutant fibroblasts compared to IMR‐90 cells in biotin‐normal medium (p < 0.01). We conclude that HCS activity is of greater importance than biotin supply in regulating miR expression. (SSW and SAM contributed equally.)

(UNL ARD Hatch Act, NIH DK063945, DK077816, and DK082476)
Green tea supplementation during gestation and lactation modulates heart lipid metabolism and oxidative status in rat offspring born of high ‐ fat diet ‐ fed dams.
Authors: Lam Ben Chun Yip , Li Edmund Tsze Shing
Published: June 2021

Hepatic glucose and lipid metabolism, and insulin sensitivity of offspring born to high‐fat (HF) diet fed dams could be improved by supplementing green tea extract (GTE) to the dam's diet either during gestation or lactation. This study further examined the effects of developmental programming on lipid metabolism and oxidative status in the heart. Dams were fed low‐fat (LF), HF, or HF with 0.75% GTE (GT) throughout gestation. During lactation, half of the HF dams were given the GT diet and vice versa. All pups were fed with LF or HF diet for 16 wk. 3‐way ANOVA was used to analyze for diet effect in gestation, lactation and postweaning periods. GTE effects were more prominent during lactation than gestation. Heart triglyceride, cholesterol and free fatty acid levels were higher (P < 0.01) in offspring of dams fed GT compared with those fed HF diet during lactation. The former group also had up‐regulated mRNA expression of proliferators – activated receptor alpha and its downstream genes (P < 0.05). Concurrently, activities of catalase, glutathione peroxidase and glutathione transferase in the heart were elevated (P < 0.05). The data suggested that with increase in lipid utilization (anabolic and catabolic), the heart of offspring born of GT dams is protected by improved oxidative status. Developmental programming triggered by maternal GTE supplementation appears to be time and organ specific. (Supported by HKU grant)
Collapsing Glomerulopathy in Two Renal Transplant Recipients: A Rare Pattern of Glomerular Injury
Authors: Sheikh Umer N , Herman Sara , Qu Hong
Published: June 2021

Introduction

Collapsing Glomerulopathy (CG) can be seen in native and allograft kidneys and is characterized by collapsing glomerular capillaries with hypertrophic and hyperplastic podocytes. It can occur idiopathically or as a secondary process associated with HIV infection.

Methods

We describe two cases of CG in renal allografts. The patients were 57 and 69 years of age and presented 5 and 2 years after transplantation, respectively. Both patients had high creatinine levels but only modest proteinuria. Both patients were on sirolimus, tacrolimus, and mycophenolate.

Results

Renal biopsies showed GBM collapse with cellular lesions in a few glomeruli. There were diffuse interstitial neutrophilic and lymphoplasmacytic infiltrates. There was arteriopathy with focal neo‐media formation suggestive of chronic rejection. EM showed total effacement of podocytic foot processes with microvillous transformation. Immunohistochemical stains were negative for C4d in peritubular capillaries and viral nephritis.

Conclusions

The morphologic pattern of CG in renal allografts cannot be defined by mere presence of collapsing glomeruli. Instead CG represents a pattern of glomerular injury which may morphologically mimic crescent formation or acute pyelonephritis. These findings emphasize that CG may result from diverse pathogenic mechanisms including drugs, such as sirolimus.
RAGE signaling influences smoke‐induced secretion of pro‐inflammatory cytokines by primary alveolar macrophages
Authors: Johnson KacyAnn D , Robinson Adam B. , Reynolds Paul R.
Published: June 2021

Our research has implicated RAGE, a pattern recognition receptor, in inflammation induced by pulmonary epithelial cells exposed to cigarette smoke (CS). However, precise pro‐inflammatory contributions by alveolar macrophages (AMs) in the respiratory compartment remained unknown. Primary AMs were isolated from bronchoalveolar lavage fluid (BALF) and immunohistochemistry was employed using Mac‐3, a macrophage‐specific marker, to ensure the purity of the cell population. Employing quantitative PCR, we discovered that RAGE mRNA was significantly increased by primary AMs from wild type C57Bl/6 mice following CS exposure. Because CS exposure increased RAGE, we exposed freshly isolated primary AMs from RAGE null and wild type mice to CS and assessed pro‐inflammatory molecule secretion. Using a PCR based cDNA amplification approach, we discovered that Eotaxin, IL‐12, and IL‐ 3 were all up‐regulated in wild type primary AMs exposed to CS compared to CS‐exposed AMs from RAGE null mice. Furthermore, ELISAs revealed that RAGE might also regulate the secretion of these pro‐inflammatory cytokines by primary AMs that encounter CS. The data reveal that acute secretion of pro‐inflammatory cytokines by primary AMs exposed to CS occurs, at least in part, via RAGE signaling. This work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU Mentoring Environment Grant (PRR).
Genetic variation in CARD15 and allergy
Authors: Katenta Anna , Guerra Stefano
Published: June 2021

Caspase‐recruitment domain containing protein 15 (CARD15) functions as a cytosolic receptor involved in bacterial recognition by antigen‐presenting cells. It was hypothesized that through the use of data analysis and statistical software, CARD15 polymorphisms would be determined to have significant association with asthma and atopy‐related phenotypes, using a large Tucson‐based cohort. Five Single Nucleotide Polymorphisms (SNPs) were genotyped in CARD15 and the Hardy‐Weinberg equilibrium (HWE) was evaluated. Chi square tests were run for each SNP that passed HWE using the following variables: ever asthma, allergic rhinitis, ever atopy. Statistical significance for associations with asthma, allergic rhinitis, and atopy was set at p < 0.05. Our results suggest that there is no association between the SNPs RS2066842 and RS5743291 with asthma and allergic rhinitis. However there is a possibility that these SNPs may be associated with atopy. These results need to be replicated in other populations to reduce the risk of spurious results. In the future, if SNPs RS2066842 and RS5743291 are confirmed to have significant association with atopy, patients can be screened for them and their risk of developing atopy can be determined.
Lysophosphatidic acid induces reactive oxygen species generation through protein kinase C in PC‐3 prostate cancer cells
Authors: Lin Chu-Cheng , Lin Chuan-En , Lin Yueh-Chien , Lee Hsinyu
Published: June 2021

Prostate cancer is one of the most frequently diagnosed cancers in males. PC‐3 cell is a popular cell model for investigating late stage prostate cancer behaviors. Lysophosphatidic acid (LPA) is a lysophospholipid regulates multiple cell processes including proliferation, migration and other aggressive cell behaviors in different cancers. In our previous study, we demonstrated that LPA enhances VEGF‐C expression in PC‐3 cell through activating the generation of reactive oxygen species (ROS), which is known to be important in the development of many different cancers. Using flow cytometry, we measured the relative ROS levels in PC‐3 cells. LPA triggers ROS generation within ten minutes. This ROS production can be suppressed by antioxidants, N‐acetylcysteine, TEMPO and Tiron, respectively. By using LPA1/3 antagonist Ki16425, we confirmed that LPA induced ROS is mediated through LPA1/3‐dependent pathway. Moreover, pretreatment with PKC inhibitors can block the ROS generation stimulated by LPA treatment. Overall, we first demonstrated that LPA induces ROS generation in a PKC dependent manner in PC‐3 prostate cancer cell line.
A case of JAK‐2 positive essential thrombocythemia followed by mantle cell lymphoma
Authors: Sheikh Umer N , Socec Catherine , Snower Daniel
Published: June 2021

Introduction

A switch from chronic myeloproliferative neoplasm (MPN) to lymphoid malignancy is not an uncommon phenomenon. However, progression from a JAK‐2 positive essential thrombocythemia (ET) to mantle cell lymphoma (MCL) has not been reported.

Methods

We describe the case of a 69 year old man who developed colonic MCL, 44 months after the diagnosis of an MPN, which was classified according to WHO criteria as JAK‐2 positive ET. The patient was treated for ET with hydroxyurea (HU) for 66 months and with etanercept (anti‐TNF‐α) for ankylosing spondylitis for approximately six years, during which time he was diagnosed with MCL.

Results

The transformation from ET to MCL was accompanied by clonal evolution from a normal to a complex karyotype that included deletions of 6q and 11q, loss of 12p and 20p, monosomies 13 and 14, and structural rearrangement of 14q32.

Conclusions

Diverse pathways must be considered in this transformation process. Although therapeutic induction of MCL by anti‐TNF‐α therapy is extremely rare, MCL in this case might have been related to anti‐TNF‐α therapy. Chance coincidence of both disorders seems improbable, especially given the short interval from the diagnosis of ET to the development of MCL, but nonetheless may be considered. A third explanation might be provided by a spontaneous switch, which would further support the theory that MPNs are disorders of a pluripotent stem cell.
Human Mesenchymal Stem Cell Modulates the Stretch‐induced Inflammatory Response in Bronchial Epithelial Cells
Authors: Kuo Carol Y.-C. , Li Julie Y.-S. , Lee Oscar K.-S. , Chien Shu
Published: June 2021

Asthma involves abnormalities of bronchial epithelial cells (BECs) and smooth muscle cells, as well as their interaction. Research in pulmonary pathology has generally focused on inflammatory reactions initiated by immunological responses to allergens and irritants. In addition to biochemical stimuli, physical forces also play an important role in regulating the structure and function of the lung, and abnormal stretching force exerted on lung tissues can contribute to the pathogenesis of asthma. However, the mechanisms of mechanically induced inflammation in lung remain unclear. Human mesenchymal stem cells (hMSCs) are emerging as a therapeutic regime in various inflammatory diseases, including inflammation in the lung. Our results demonstrated that excessive mechanical stretch causes (a) increases of epithelial cell secretion of inflammatory cytokines (e.g. IL‐8 and IL‐6) through the activation of mitogen‐activated protein kinase (MAPK) signaling pathways and (b) decreases of anti‐inflammatory cytokine (IL‐10) synthesis. Co‐culture with hMSCs reversed the stretch‐induced epithelial inflammatory responses by increasing IL‐10 secretion. In summary, we have demonstrated that mechanical stretch modulates the homeostasis of the bronchial epithelial cell secretome and that MSCs administration can be used as a potential therapeutic approach for bronchial epithelial cell inflammation.
Humanizing the lambda light chain of the human/murine mixed‐chain anti‐cocaine monoclonal antibody 2E2
Authors: Ball William J. , Tabet Michael R. , Wilton Rosemarie , Norman Andrew B.
Published: June 2021

Cocaine abuse is a serious world‐wide health problem. No pharmacological agonist or antagonist of cocaine‐mediated CNS effects has yet been approved as a therapeutic to treat cocaine abuse relapse. However, human sequence monoclonal antibodies (mAb) that bind cocaine with high affinity and selectivity may provide an effective immunotherapy by blunting the addictive effects of cocaine in treated patients. Our laboratory has generated a mAb, designated 2E2, that meets several criteria for in vivo efficacy. Interestingly, 2E2 is composed of a human gamma heavy (H) and a murine lambda light (L) chain. Therefore, to further humanize 2E2's structure we have engineered a chimeric L chain consisting of the murine Lv variable domain and a human Lc constant region. Expression of the re‐engineered, recombinant mAb, denoted h2E2, in Chinese hamster ovary cells (CHO) and its physical characterization has been achieved. Binding studies indicate that h2E2 retains a high affinity (~4nM) and specificity for cocaine and cocaethylene. Studies determining and comparing the thermal and pH stability of h2E2 and its unfolding transitions as measured by differential scanning calorimetry to the parent 2E2 and other murine anti‐cocaine mAbs indicate that h2E2's stability is modestly improved. These results indicate that h2E2 is a suitable lead candidate therapeutic replacing mAb 2E2. Work supported by NIH grant 1DP1A031386.
Effects of subtype selective dopamine receptor agonists on progressive ratio responding for cocaine‐ and remifentanil‐paired stimuli
Authors: Bertz Jeremiah William , Woods James Henry
Published: June 2021

Pretreatment with dopamine D3 receptor preferring agonists (e.g., pramipexole) has been shown to increase rats’ operant responding for stimuli previously paired with self‐administered cocaine. Presently, we assessed the ability of (1) agonists with different dopamine receptor preferences to increase responding for cocaine‐paired stimuli and (2) pramipexole to increase responding for opioid‐paired stimuli. Rats were trained to nose‐poke for IV infusions of cocaine or remifentanil under a progressive ratio (PR) schedule. Lights above the active manipulandum provided infusion‐paired conditioned stimuli (CS). Animals were then tested in extinction: nose‐poking produced the CS alone under the PR schedule, and a pretreatment of saline; pramipexole; the D2 preferring agonist, sumanirole; or the D1‐like agonist, SKF81297, was given before each session. Compared to saline, pramipexole and sumanirole, but not SKF81297, dose‐dependently increased responding for cocaine‐paired CS. Pramipexole also significantly increased responding for remifentanil‐paired CS. These increases depended on CS presentation: when the CS were also omitted from test sessions, pramipexole's effects were significantly attenuated. Thus, the response‐increasing effects of D2‐like agonists are not limited to D3 preferring compounds and cocaine‐paired CS. Funding: NIDA R01 DA024897 and R01 DA020669.
Cognitive‐Disrupting Effects of Cocaine as an Effect of Menstrual Cycle Phase
Authors: Kromrey Sarah Allyson , Gould Robert W , Czoty Paul W
Published: June 2021

Cocaine exposure is associated with reduced dopamine (DA) function that presents as behavioral and cognitive dysregulation. In both human and animal studies, cocaine use is linked to poor cognitive performance in cognitive tasks involving behavioral flexibility. Additionally, fluctuating estrogen levels across the menstrual cycle affect DA levels and influence cognitive performance. The current study examined cognitive performance using a 3‐stimulus visual discrimination and reversal task in cocaine‐naïve female cynomolgus macaques (n=3) and monkeys with a cocaine self‐administration (SA) history (n=4). Monkeys with a history of cocaine SA required a greater number of sessions to learn the reversal task compared to cocaine‐naïve monkeys. Preliminary data suggest that noncontingent cocaine administration prior to cognitive testing increased the number of trials needed to learn both visual discrimination and reversal tasks. In ongoing studies, cocaine is being administered during the follicular (days 5–10) and luteal (days 18–24) phases of the menstrual cycle. These data will extend our understanding of the cognitive‐disrupting effects of cocaine in females as an effect of menstrual cycle phase and cocaine SA history and may provide sex‐specific treatment strategies for cocaine dependence. Support: DA 29178, DA 007246
Age difference in behavior induced from co‐administration of nicotine and alcohol
Authors: Larraga Armando , Chew Chanel N , Gadalla Christina , Belluzzi James D. , Leslie Frances M
Published: June 2021

Alcohol (EtOH) and tobacco are the two most concurrently used recreational drugs. Initiation of use of these two drugs is typically seen during adolescence, a period of critical brain maturation and increased vulnerability to drug abuse. We have established a novel model in which adolescent or adult rats self‐administer EtOH, nicotine, or the combination of the two (Combo). Illustrated by significantly higher reinforced responses, we concluded adolescent, but not adult, rats find Combo more reinforcing than EtOH or nicotine alone. In addition, nonreinforced responses were also significantly different between drug treatment and age. We hypothesized concurrent administration of EtOH and nicotine will induce locomotion in adolescent, but not adult rats. To test this, we acutely administered low doses of nicotine (30 μg/kg) and/or alcohol (4 mg/kg) to adolescent rats, aged postnatal day (P) 32, and adult rats aged P90, then monitor locomotor activity in a novel open field for 30 minutes. Nicotine and Combo induced locomotion in adolescent, but not adult rats. Furthermore, it seems Combo uniquely increases center‐time in adolescent rats. This suggests that concurrent use of EtOH and nicotine has a reinforcing, stimulatory, and anxiolytic effect in adolescent, but not adult rats. Our results imply adolescents are more vulnerable to initiate concurrent use of alcohol and nicotine, and are supported by clinical data.
Characterization of Dopamine D3 receptor‐selective compounds on unconditioned behaviors and food/drug choice in cocaine and methamphetamine self‐administering rhesus monkeys
Authors: Nader Susan H , Blaylock BL , Wilson WD , Banala A , Newman AH , Nader MA
Published: June 2021

The dopamine D3 receptor (D3R) continues to be a promising novel treatment target for addiction. Recent studies suggest that the in vivo efficacy of D3R‐preferring compounds is dependent on the behavioral assay and previous exposure to drugs of abuse or diet. The present study examined the effects of a D3 agonist quinpirole (Qp), a selective D3 partial agonist PG 619 (PG) and the D2/D3 antagonist buspirone (Bus), in unconditioned behaviors (agonist‐elicited yawning and hypothermia) and food/drug choice self‐administration (SA) in male rhesus monkeys. In drug‐naïve monkeys, Qp (0.01–0.3 mg/kg, i.m.) elicited yawning in an inverted‐U shaped function with the descending limb characterized by hypothermia. In this assay, PG (0.1–0.3 mg/kg, i.m.) antagonized the ascending limb for yawning without affecting hypothermia, while Bus (0.03–0.056 mg/kg, i.m.) only attenuated hypothermia, suggesting limited activity at the D3R, In food/drug choice SA, Qp (0.03 mg/kg, i.v., 10‐min pretreat) and PG (0.1–0.3 mg/kg, i.v., 10‐min pretreat) robustly attenuated COC and MA SA following 5 days of treatment, but Bus (0.01–0.03 mg/kg, i.v., 10‐min pretreat) did not alter drug SA. Altogether, these findings supporting continued exploration of novel D3R compounds for treatment of COC and MA addiction. DA12460 and NIDA‐IRP
Pro‐social effects of 3,4‐methylenedioxymethamphetamine in mice
Authors: Curry Daniel Walker , Murnane Kevin Sean , Howell Leonard Lee
Published: June 2021

The drug 3,4‐methylenedioxymethamphetamine (MDMA, “ecstasy”) has been shown to increase feelings of closeness and empathy in humans. Despite evidence of MDMA‐induced neurotoxicity, these unusual pro‐social effects have continued to generate interest in the drug's therapeutic potential. Therefore, determining the mechanisms by which MDMA engenders these effects may allow for the development of novel, pro‐social medications that do not exhibit neurotoxicity. A number of genetic and molecular techniques that may be critical for understanding these mechanisms are primarily available in mice, yet the effects of MDMA on murine social behavior have not previously been described. To this end, in the present study, we characterized the effects of (+/−)‐MDMA in mice across a range of doses (3–30mg/kg, IP) on dyadic social behavior when mice in a pair were treated with the same dose of MDMA. We found that MDMA increased the duration of time the pair spent in close proximity, an effect that is consistent with the previously reported effects of MDMA in rats. In subsequent experiments, we will use selective receptor antagonists to further elucidate the mechanisms underlying this effect. Understanding these mechanisms may provide insight into the etiology of disorders exhibiting social deficits and help identify targets for their treatment. This study was supported with funds from the USPHS: DA020645 and RR00165.
Antinociceptive and anti‐inflammatory effects of Essential oil of Nepeta pogonosperma Jamzad et Assadi in rats
Authors: Ali Taskina , Javan Mohammad , Sonboli Ali , Semnanian Saeed
Published: June 2021

Pain management is a common but difficult medical challenge. Species richness, variation in chemical properties and diversified use in folk medicine attracted much research on the Nepeta genus of Iran. This study was designed to evaluate the antinociceptive effects of essential oil of Nepeta pogonosperma Jamzad et Assadi (NP) by tail flick and formalin tests and its anti‐inflammatory activity in rat paw edema model by water plethysmometer. Total 24 male Wister rats weighing 225±25gm were studied. Essential oil of NP was introduced intraperitoneally at the doses of 50mg/kg (in 6 rats), 100mg/kg (in 6 rats) and 200mg/kg (in 6 rats) for the experimental groups. Six (6) rats were treated with equal volume (200μl/100gm of body weight) of normal saline (control group). Antinociception was assessed by tail flick test (after 30 minutes) and by formalin test (for further 60 minutes) followed by paw edema test for anti‐inflammation by water plethysmometer (after sacrifice). All the doses of NP showed antinociception and anti‐inflammation, though higher two doses were significant in most cases in comparison to control. This study reveals that the essential oil of NP may minimize both the acute and chronic forms of nociception and may have potent role against inflammation, but the dose should be maintained precisely to obtain the intended effect. This study was supported by Iranian Society of Physiology and Pharmacology (ISPP).
Antinociceptive effects of novel GalR2‐specific analogs
Authors: Metcalf Cameron S , Klein Brian D , McDougle Daniel R , Bulaj Grzegorz , White H Steve
Published: June 2021

Neuropeptide‐based therapeutics represent an area of growing interest and potential utility in the treatment of a variety of neurologic diseases. The neuropeptide galanin has well‐established antinociceptive properties. Recent evidence suggests that peripheral GalR2 agonists may confer analgesic activity. We rationally designed GalR2‐preferring analogs that are active in the central and/or peripheral nervous systems. We used the carrageenan model of thermal hyperalgesia for screening of novel compounds and representative analgesics in mice. ED50 values (mg/kg) for the galanin analogs were: NAX 505‐5 (3.9), NAX 409‐9 (6.6), and NAX 810‐2 (3.1); values for other analgesics were: morphine (0.2), ibuprofen (10.5), acetylsalicylic acid (49.3), and gabapentin (28.6). The centrally‐and peripherally‐acting, GalR1‐preferring agonist NAX 505‐5 shows potent analgesic activity. The GalR2‐preferring analogs NAX 409‐9 (peripherally acting) and NAX 810‐2 (centrally‐and peripherally‐acting) also show potent antinociceptive activity. The efficacy of NAX 409‐9 and NAX 810‐2 in the carrageenan assay suggests a role for central and peripheral GalR2 receptors in antinociception. This work was supported in part by the NIH R21 grant NS059669.