bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of predictive equations for resting energy expenditure (REE) in Chinese and Korean young adults
Authors: Tsani A. Fahmy Arif , Ko Su-Young , Yeon Seo-Eun , Kim Myung-Hee , Kim Eun-Kyung
Published: June 2021

The aim of this study was to assess the accuracy of predictive equations for REE in Chinese and Korean young adults. Subjects were 96 healthy university students (47 Chinese, 49 Korean) aged 18–24y. REE (MREE) was measured by indirect calorimetry. Predicted REE (PREE) was calculated using the 7 equations (Harris‐Benedict, WHO‐WH, Schofield‐WH, Henry‐WH, Mifflin, Liu, and IOM equation). MREE of Chinese (1510.7¡¾231.6 kcal/day) was not significantly different with of Korean (1503.0¡¾307.8 kcal/day). The validity of the equations was evaluated on basis of prediction accuracy (the percentage of subjects predicted within 10% of the MREE), difference, RMSPE, % difference, and Bland‐Altman analyses. The most accurate for Chinese students was the IOM equation (prediction accuracy 96%, difference ‐1.0¡¾204.2 kcal/day, RMSPE 64.8 kcal/day, % difference 0.3%). Although the IOM equation was the most reliable in Korean students (difference −1.8¡¾245 kcal/day, RMSPE 115.7 kcal/day, % difference 1.2%), the prediction accuracy of the equation was only 63%. Thus, while Chinese and Korean are in the same region of Asia, they have different accuration in energy predictive equation, which may caused by different ethnicity.

This research was supported by Basic Science Research Program, National Research Foundation of Korea funded by the Ministry of Education, Science and Technology.
Indole compounds inhibits migration of breast cancer cell by suppressing MMPs via reduction of FAK expression
Authors: Park Soo Jeung , Ho Jin-Nyoung , Nam Da-Eun , Kim Ok Kyung , Jun Woojin , Lee Jeongmin
Published: June 2021

Indole‐3‐carbinol (I3C) and indole[3,2‐b] carazole (ICZ) are major bioactive food components in cruciferous vegetables. Although previous studies have shown anticancer activity of I3C and ICZ in various cancer cells, it has not been determined how indole compounds regulates migration and related signaling pathways. In this study, we investigated the effects of I3C and ICZ on migration using breast cancer cells (MCF‐7 and MDA‐MB231). The growth inhibition of breast cancer cells by I3C and ICZ was measured by MTT assay, and 10 ¥ìM was chosen as maximum dose for migration assay because at this concentration, no significant interference in the cell growth or morphology was observed. Our results showed that I3C and ICZ were dramatically inhibited migration of breast cancer cells in a dose‐dependent manner, as observed in monolayer scratch assay. The MMP‐2 and ‐9 activity were also reduced by I3C. In addition, pretreatment of I3C was decreased FAK mRNA expression. Taken together, indole compounds inhibits migration of breast cancer cells by reduction of MMPs activity and FAK expression.
Antiproliferative effects of Thioflavanone through p53‐ dependent Apoptosis induction in Human breast cancer cells
Authors: Kim Gun-Hee , Choi Eun Jeong , Kim Kyung Hee
Published: June 2021

Breast cancer is one of the most frequently diagnosed cancers in women and its occurrence has, in recent years, increased worldwide. The present study evaluated the anticancer activity of the synthetic anticancer drug candidate thioflavanone and thioflavone on human breast cancer cell lines. This study investigated the anticancer effects of thioflavanone and thioflvone on human breast cancer MCF‐7, MDA‐MB‐231, and MDA‐MB‐ 453 cell lines. Cells were treated with either thioflavanone or thioflavone from 1 to 100 μM for 24 h, and their antiproliferative activity and cytotoxicity was determined. Thioflavanone and thioflavone possessed similar antiproliferative activities; their IC50 values were 62–89 and 74–128μM, respectively, although the cytotoxicity of thioflavnone was significantly increased in a dose‐dependent manner. In a brief study of the underlying mechanism, thioflavanone, but not thioflavone, may induce apoptosis through the p53‐dependent expression of Bax. Although both thioflavanone and thioflavone cause apoptosis in MDA‐MB‐231 at their respective IC50 Value, thioflavanone and thioflavone may act through different pathways, this might explain the cytotoxic effect of thiolfavone. Taken together, our results indicate that thioflavanone significantly inhibited cellular proliferation with a weak cytotoxicity and induced apoptosis in human breast cancer cell lines. Moreover, we speculate that the mechanism by thioflavanone induced apoptosis was through the p53‐dependent pathway. The induction of apoptosis by thioflavanone may be novel strategy for cancer chemotherapy.
Benzyl isothiocyanate targets chemoresistant and metastatic head and neck squamous carcinoma cells
Authors: Wolf M. Allison , Palumbo Allison , Hardman W. Elaine , Claudio Pier Paolo
Published: June 2021

Approximately 500,000 cases of head and neck squamous cell carcinoma (HNSCC) are reported worldwide each year. Despite recent improvements in cancer treatment, the increase in overall survival of advanced HNSCC has not improved in the past 3 decades. Poor outcome of advanced HNSCC is mainly attributed to chemoresistance and metastasis. Consequently, the need for new therapeutic options to enhance survival of patients with advanced HNSCC is needed. Benzyl isothiocyanate (BITC), a natural compound found in cruciferous vegetables, is showing promising results in targeting chemoresistant and metastatic HNSCC cell lines. Our data suggests that BITC decreased the viability of two HNSCC cell lines (HN30 and HN12) greater when combined with cisplatin, than with treatment of BITC or cisplatin alone after 24, 48 and 72 hrs. A migration assay indicated that the HN12 and HN30 cell line are inhibited by BITC in a dose dependent manner. Additionally, the same wound‐healing assay also showed that 10μM BITC inhibited migration of the highly metastatic HN12 cell line, and when combined with 10μM cisplatin this effect appeared to be enhanced. Treatment with cisplatin alone resulted in migration rates that are similar to the vehicle control. These data altogether suggest that BITC is a novel treatment option for chemoresistant HNSCC.
Delta‐Tocotrienol enhances cisplatin‐induced inhibition of growth and invasion of Non‐Small Cell Lung Cancer Cells
Authors: Ji Xiangming , Gupta Smiti
Published: June 2021

Lung cancer is the leading cause of death among all cancers. Non‐small cell lung cancer (NSCLC) accounts for 80% of lung cancer with a five‐year survival rate of 16%. Although a subset of NSCLC patients benefit from the development of target therapies, cisplatin remains the standard chemotherapeutic drug. Previously, we demonstrated that delta‐tocotrienolinhibits NSCLC cell proliferation, invasion and induces apoptosis by down‐regulation of the Notch‐1 signaling pathway. The objective of this study was to investigate whether delta‐tocotrienol, a naturally occurring isoform of Vitamin E, could enhance the cisplatin‐induced inhibition of growth and invasion of NSCLCcells. Treatment of NSCLCcells with delta‐tocotrienoland cisplatin in combination resulted in a dose dependent inhibition of cell growth, cell migration, tumor cell invasiveness, and induction of apoptosis in NSCLC cells. Real‐time RT‐PCR and western blot analysis showed that antitumor activity by the combination of delta‐tocotrienol and cisplatin was associated with decreases in Notch‐1, Hes‐1, Survivin, and Bcl‐XLand increases in cleaved PARP, Caspase‐3 expressions. In addition, there was a decrease in NF‐κB‐DNA binding activity. These results suggest that down‐regulation of Notch‐1, via inhibition of NF‐κB signaling pathways by delta‐tocotrienol and cisplatin, could provide a potential novel approach for prevention of tumor progressionin non‐small cell lung cancer.

This research was supported by funds provided by Wayne State University.

Grant Funding Source: Wayne State University
A Comparison of Lycopene, Anthocyanins, and Proanthocyanidins Consumption between College Students and their Respective Older Generations Living in the Same Household
Authors: Li Kenneth , Tam Chick F
Published: June 2021

Carotenoid (lycopene LC) and flavonoids (anthocyanins AN and proanthocyanidins PA) are effective antioxidants found in daily diets. 94 pairs of college students (CS) and their respective older generations (OG) living in the same household were recruited with their self‐reported three‐day dietary records to determine intakes of LC, AN, and PA. USDA National Nutrient Database for LC (2011) and for PA (2004) were employed to determine LC and PA contents. AN content was determined by Wu et al. (J. Agric Food Chem V.64, 2006). The variables, such as subjects’ BMIs and three day total energy intakes were used to determine the statistical correlations between the intakes of these three compounds and the variables. The results showed that CS consumed more LC and AN (LC: CS vs OG 4179.25 mcg ± S.E. 748.39 vs 2928.56 mcg ± S.E. 475.57 respectively, p=0.14) (AN: CS vs OG 92.95 mg ± S.E. 20.10 vs 57.69 mg ± S.E. 12.72 respectively, p=0.11) and CS consumed slightly lower PA than OG (CS vs OG 333.82 mg ± S.E 49.38 and 371.46 mg ± S.E 92.61 respectively, p=0.55) and no significant differences were found. Whereas there were no significant correlations were found between variables and these compounds, except there was a significant positive correlation found between LC consumption and three day total energy intakes in the CS (p=0.01) but not found significance in the OG (p=0.08). The adequate intakes of these compounds are important for their health.

Grant Funding Source: Self‐support
Anti‐inflammatory Effects of 4′‐Hydroxy Nobiletin, the Major Metabolite of Nobiletin
Authors: WU XIAN , Guo Shanshan , Xu Guang , Zheng Jinkai , Xiao Hang
Published: June 2021

Nobiletin, a citrus flavonoid has been associated with various biological activities including anti‐inflammation. We have found that 4′‐hydroxy nobiletin (4′HN) was a major colonic metabolite in mice fed with nobiletin, and the colonic levels of 4′HN were much higher than those of nobiletin. Herein, we studied anti‐in&# 64258;ammatory effects of 4′HN in lipopolysaccharide (LPS)‐treated RAW264.7 macrophages. Treatments of 4′HN at non‐cytotoxic concentrations dose‐dependently inhibited LPS‐induced nitric oxide production in macrophages. These inhibitory effects were much stronger than those produced by nobiletin. Western blot analysis showed that 4′HN drastically decreased protein expression levels of iNOS and COX‐2. Furthermore, 4′HN also inhibited LPS‐induced activation of Iκβ‐α, Akt and SAPK/JNK. Real‐time qRT‐PCR showed that 4′HN decreased mRNA levels of iNOS and COX‐2. Heme oxygenase‐1 (HO‐1, an antioxidant enzyme) has been reported to suppress inflammatory responses. Our results demonstrated that 4′HN significantly increased the both protein and mRNA levels of HO‐1, which may contribute to its anti‐inflammatory effects. Overall our results demonstrated that 4′HN is a potent anti‐inflammatory colonic metabolite of nobiletin, which provide a scientific basis for using nobiletin as a nutraceutical ingredient to inhibit inflammation‐related diseases such as colitis and colon cancer.

Grant Funding Source : NIH: CA139174, AICR: 10A044
Comparison of the effects of paired organic and conventional wines with different total polyphenol concentrations on plasma antioxidant status
Authors: Ricklefs Kristin , Rasmussen Kristen , Martin Keith R
Published: June 2021

Dietary polyphenols are ubiquitous phytochemicals with antioxidant activity, which may reduce the risk of chronic diseases. Organically grown plants, i.e., grapevines, with greater pathogen exposure may have even higher levels of polyphenols, e.g., resveratrol, than conventionally grown plants, which could increase plasma antioxidant capacity in humans without affecting sensory qualities. To test this, we randomized 18 females (21–50 y) to 1 of 5 groups each assigned a geographically paired organic (OW) and conventional wine (CW), and a placebo (PW) wine. At 3 independent visits and after a baseline blood draw for each, participants consumed 5 oz of 1 wine of the 3 within 15 min followed by a blood draw at 30 min post‐consumption. Total polyphenol (TP) concentrations, antioxidant capacity, i.e., FRAP, and sensory surveys were determined and collected. Results demonstrated that in 2 pairings the OW had significantly higher concentrations of TP (3.49, 5.8 g/L) vs. CW (2.63, 4.63 g/L). In 2 pairings, TP in CW was higher (5.23, 8.38 g/L) vs. OW (4.55, 3.70 g/L). The mean of the PW was 1.26±0.20. No significant differences in antioxidant capacity of plasma or sensory qualities were demonstrated between OW and CW. We conclude that OW and CW produced in the same vineyards in the SW US have similar antioxidant capacities even with significantly different TP concentrations.
Anti‐inflammatory action of Liriope platyphylla (LP) on LPS‐stimulated RAW 264.7 macrophage
Authors: Kim NaYeon , Kim Min Jee , Kim Mee Ree
Published: June 2021

Liriope platyphylla (LP) is one of the well‐known herb use in eriental medicine for treatment asthma and bronchial and lung inflammation. In this study, we investigated the anti‐inflammatory effect of water extract of Liriope platyphylla (LP) on lipopolysaccharide (LPS)‐induced inflammation using RAW 264.7 macrophage cells. And for induction of inflammation in macrophages, RAW 264.7 cells (1×104) were stimulated with 3 ug/ml of LPS for 24 hr. Treatment of LP was carried out 15 hr before LPS stimulation in splenic RAW 264.7 cells. Anti‐inflammatory effect of LP on LPS‐induces inflammation in RAW 264.7 cells was measured the level of pro‐inflammatory cytokines (IL‐6 and TNF‐α), nitric oxide (NO) and PGE2 produced from LPS‐stimulated RAW 264.7 cells. Treatment of LP suppressed the production of NO and pro‐inflammatory cytokines such as IL‐6 and TNF‐α from LPS‐treated RAW 264.7 cells. In addition, treatment with LP showed a significant decrease of PGE2, another inflammation parameter. In RT‐PCR analysis, it was ascertained that LP down‐regulated the expression of mRNA for iNOS, IL‐6 and TNF‐α in LPS‐stimulated RAW 264.7 cells. Furthermore, LP inhibited the NF‐κB activation induced by LPS, which was associated with the abrogation of IκB degradation. Moreover, treatment of LP suppressed the phosphorylation of ERK. JNK and p38 MAP kinases in LPS‐stimulated RAW 264.7 cell. It was of significant that administration of LP suppressed LPS‐induced endotoxemia in an animal model using mice.

These results show that LP is able to suppress the production of IL‐4 and IFN‐γ inhibit LPS‐induced inflammation of RAW 264.7 macrophages. The anti‐inflammatory effect of LP on RAW 264.7 cells might be attributed to the inhibition of the expression of NO and pro‐inflammatory cytokines through the down‐regulation of NF‐κB activation and MAP kinase phosphorylation in macrophages. These findings suggest a possibility that LP is a good candidate available for endotoxin‐induced inflammation by macrophages.
Protective effects of emodin against cisplatin‐induced oxidative stress in cultured human kidney (HEK 293) cells
Authors: Waly Mostafa , Ali Badreldin H , Al-Lawati Intisar , Nemmar A
Published: June 2021

Recent studies indicated that emodin reduces cellular oxidative stress induced by various insults and drugs. Cisplatin is an anticancer drug that is associated with nephrotoxicity and induces oxidative stress in cultured human kidney (HEK 293) cells. This study aimed to assess the in‐vitro antioxidant properties of the emodin against cisplatin‐induced oxidative stress in HEK 293 cells. Our study revealed that emodin acted as a potent free radical scavenger and provided nephroprotection against cisplatin‐induced oxidative stress. Emodin as low as 0.5 μM did not decrease cells viability and restored the cisplatin‐induced glutathione (GSH) depletion and total antioxidant capacity (TAC) in a dose‐dependent manner. Emodin augmented the cisplatin‐induced inhibition of antioxidant enzymes [(catalase (CAT), glutathione peroxidase (GPx), glutathione S‐transferase (GST), glutathione reductase (GR) and superoxide dismutase (SOD)]. These results suggest that modin has the potential to be used as an adjunct therapeutic agent in patients receiving cisplatin treatment.
A comparison of Attitudes and Reports of Health‐Related Behavior of Type 2 Diabetes Patients between the United States and Mexico City
Authors: Veringa Eelco M.G. , Cháirez-Jiménez Carolina , Glasser Michael , Pérez-Lizaur Ana Bertha
Published: June 2021

OBJECTIVE

The main purpose of this study was to compare the characteristics of Mexican and United States patients with a diagnosis of type 2 diabetes in primary care settings.

METHODS

A cross‐sectional, cross‐national study was conducted from June 2008 to January 2011. A survey was sent to 1079 patients in the United States and 155 in Mexico City.

RESULTS

Response rates were 17.1% (n=187) for United States participants versus 89.0% (n=138) in Mexico City. The Mexican population scored significantly worse on general health status with 48.9% reporting good health status compared to 72.0% in the United States (p<0.001). Percentages of patients who had an HbA1c test performed and also knew what it measures and reported a correct target value were respectively 38.0% and 68.2% (p<0.001). For patients from both countries, training of health care personnel and the patient value of tight control are correlated with better treatment satisfaction.

CONCLUSION

More frequent attention to HbA1c control in Mexico City and better patient knowledge are key factors in achieving better diabetes control in Mexico City, as well as better patient satisfaction in both countries.

Grant Funding Source : Student Prize of the International Nutrition Council (INC)
Vitamin D supplementation results in higher numbers of Clostridium coccoides in the feces of female but not male mice with intestinal inflammation
Authors: Glenn Andrea J. , Fielding Kristina A. , Chen Jianmin C. , Comelli Elena M. , Ward Wendy E.
Published: June 2021

Vitamin D may have immunomodulatory effects in the intestine and potential to target the gut microbiota. Our objective was to determine if exposure to supplemental levels of vitamin D mitigates intestinal inflammation in interkeukin‐10 knockout (IL‐10 KO) mice. Mice were randomized to a diet containing 25 IU (low levels) or 5000 IU (supplemental levels) of vitamin D/kg of diet in utero until necropsy at 3 months of age when colonic and fecal samples were collected. Colon inflammation severity and IL‐8 levels (males only) were assessed by histological analysis and ELISA, respectively, and fecal microbiota composition was determined by qPCR. Vitamin D had no effect on IL‐8 levels in males, or body weight and inflammation severity in either gender. Vitamin D had no effect on microbiota composition in males, but females in the supplemental group had higher (p<0.05) counts of Clostridium coccoides than females in the low group. All other bacteria measured were unaffected. Moreover, female mice had lower (p<0.05) colonic inflammation scores and more (p<0.05) C. coccoides than males. Clostridia are major butyrate producers and promote Treg cell activity in the colon. Therefore, vitamin D may favourably modulate microbiota composition without attenuating inflammation in female IL‐10 KO mice.

Funding sources: Dairy Farmers of Canada, NSERC and Ontario Graduate Scholarship
Effects of galactooligosaccharides (GOS) on the gut microbiota of aged adults
Authors: Culpepper Tyler , Girard Stephanie-Anne , Dahl Wendy , Langkamp-Henken Bobbi , Mai Volker
Published: June 2021

A decrease in gut microbiota diversity in aged adults has been linked to reduced immune function, and attempts have been made to increase the numbers of beneficial microbes in these individuals. The effects of specific dietary substrates on microbiota, especially in aged adults, are largely unknown. Here we report on a randomized double‐blinded placebo‐controlled microbiota study in 80 healthy adults aged at least 60 years. Microbiota composition was analyzed in fecal samples taken at baseline and two weeks into the intervention using various 16S rRNA based methods. Quantitative PCR (qPCR) showed an increase in the proportion of bifidobacteria in subjects consuming 5 g/day GOS (p<0.05). 16S rRNA sequence analysis of 719964 sequence reads resulted in 11455, 20623, and 27597 operational taxonomic units (OTUs) at the 95%, 97%, and 98% similarity levels, respectively. The prevalence of 74 OTUs was significantly affected by GOS treatment (14 OTUs at the 95% similarity level, 23 at the 97% similarity level, and 37 at the 98% similarity level).75% of the OTUs whose prevalence was associated with GOS intake matched to the order Clostridiales. At the genus level, the numbers of sequences in OTUs matching to Ruminococcus increased with GOS intake. Our results suggest that gut microbiota, including potentially beneficial bacteria, in aged adults can be modified by intake of 5g/day GOS. Supported by Corn Products International.
Calcium effects on bodyweight appear to be mediated in part by changes in gut microflora and altered by dietary matrix
Authors: Walzem Rosemary L. , Dowd Scot E. , Thomas Anthony P. , Dunn Tamara N. , Adams Sean H. , Pillai Suresh D.
Published: June 2021

Calcium (Ca) intake variably affects bodyweight (BW) regulation. Delivery matrix may affect Ca effects. Gut microflora is now a considered variable in BW regulation. Three isonitrogenous, isocaloric, 45 kcal% fat diets were fed to male C57/BL6J mice (n=10/group) in two diet‐induced obesity tests. Isolated soy protein was used for diets containing adequate (0.5 wt%, D1) or high (1.5 wt%, D2) amounts of Ca as CaCO3, while non‐fat dry milk was used in a second 1.5 wt% Ca diet (NFDM), providing 0.5 wt% Ca as intrinsic dairy Ca. Test 1: 5 wk old mice were fed test diets for 12 wks. Mice fed D1 and NFDM consumed similar amounts of feed, but NFDM fed mice gained less BW and body fat (p<0.05). Mice fed D2 consumed the most feed, gained the most BW and body fat (p <0.05). Gut microflora community structure was determined by 16SrRNA pyrosequencing of feces collected during the last 48 hrs of study. UniFrac analysis and PCA clustering of mice with similar microflora clearly separated D1, D2, and NFDM at the genera level. Test 2: Test 1 protocol, except that mice were pre‐fed D1 for 12wks prior to being fed D1, D2, or NFDM for an additional 8wk period. Similar responses in feed intake, BW, body fat and microflora shifts were seen. Dairy was most effective in obesity prevention (Test 1) and its effects were correlated to changes in gut microflora. 1.5 wt% CaCO3 increased obesogenic tendencies. Funded by the Dairy Research Institute.
Omega‐3 supplementation prevents intestinal inflammation by inhibiting the expansion of an intestinal pathobiont in IL10−/− mice
Authors: Devkota Suzanne , Leone Vanessa , Wang Yunwei , Musch Mark , Antonopoulos Dion , Chang Eugene
Published: June 2021

The human microbiome of Western populations has changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Previously we showed consumption of a diet high in saturated (anhydrous milkfat‐derived) fat (MF) but not polyunsaturated (safflower oil‐derived)‐fat (PUFA) changes the conditions for microbial assemblage and promotes expansion of a rare, immunogenic, sulfite‐reducing pathobiont, Bilophila wadsworthia. This was associated with a proinflammatory TH1 immune response and development of colitis in genetically susceptible IL‐10−/− mice in both specific pathogen free (SPF) and germ‐free environments. The current study examines whether omega‐3 supplementation can attenuate the effect of the MF diet by reducing the bacterial load of B. wadsworthia and subsequent inflammation. SPF IL10−/− mice were adapted to either a low‐fat (LF), high saturated milk‐fat (MF), fish oil supplemented (FO), or safflower oil supplemented (SO) diets. All three high fat diets were isocaloric with fat comprising 37% total kcal, with the supplemented groups representing 32% MF + 5% FO or SO. After 10wk, 454 pyrosequencing of cecal contents and subsequent principal component analysis revealed colonic bacterial communities of mice on the FO diet were significantly different than those on MF and SO diets. Particularly noticeable was the decrease in abundance of B. wadsworthia in the FO treated mice. This observation was accompanied by reduced levels of IL‐6, IL‐17, IL12p70, and IFNγ, as well as reduced histological colitis scores compared to MF and SO fed mice. Together these data suggest omega‐3 supplementation may decrease risk for inflammatory bowel diseases by suppressing pro‐inflammatatory pathobionts such as B. wadsworthia. Supported by NIH F31.

Grant Funding Source : NIH
Increased microvessel density in the pituitarires of pregnant women
Authors: Rotondo Fabio , Rotondo Angelo , Scheithauer Bernd W , Syro Luis V , Cusimano Michael , Kovacs Kalman
Published: June 2021

Pituitary enlargement, development of pregnancy cells and prolactin cell hyperplasia are known to occur in pregnancy. In the present work, we assessed microvessel densities in the 20 pituitaries of pregnant women who passed away. Twenty pituitaries of age matched non‐pregnant women who died from non‐endocrine diseases were used as controls. The autopsy obtained pituitaries were formalin fixed and paraffin embedded. Slides were immunostained for adenohypophysial hormones and for CD‐34, an endothelial cell biomarker using the streptavidin‐biotin‐ peroxidase complex method. Microvessel densities were evaluated quantitatively in 10 random high‐ power fields. For statistical analysis, the chi‐square and Fisher exact tests were applied.

The results confirmed that the pituitaries of pregnant women increased in weight and contained more PRL immunopositive cells compared to the controls. The formation of pregnancy cells was also evident. In the pituitaries of pregnant women compared to the control, microvessel densities were significantly higher. The cause of increased vascularity remains to be evaluated.

This work was supported by the Jarislowsky and Lloyd Carr‐Harris Foundations.
Hypertension and CaMKII isoforms in the endothelium of murine mesenteric arteries
Authors: Charbel Chimène , Toussaint Fanny , Blanchette Alexandre , Villeneuve Louis Robert , Ledoux Jonathan
Published: June 2021

Crucial to endothelial functions, Ca2+ homeostasis in native endothelial cells has been studied using hypertensive mice (chronic infusion of phenylephrine; PE). Localized spontaneous endothelial Ca2+ oscillations, termed Ca2+ pulsars, appear to be altered in hypertensive mice. Interestingly, calmodulin‐dependent protein kinase II (CaMKII) is involved in endothelial function and is uniquely characterized by its ability to decode oscillatory Ca2+ signals such as Ca2+ pulsars. The objective of this study is to determine the impact of Ca2+pulsars stimulation in hypertension on CaMKII isoforms in endothelial cells from mesenteric arteries. The expression of all four CaMKII isoforms (α, β, δ and γ) is significantly decreased (47–57%) in hypertensive mice compared to controls. Western Blot revealed the presence of CaMKIIα, β, δ but not γ in mesenteric arteries. Consistently, CaMKIIα, β and δ were specifically detected in endothelial cells by immunofluorescence experiments. Furthermore, hypertension is correlated with an exacerbated distribution of endothelial CaMKII in clusters compared to control. Additionally, confocal imaging showed that acute stimulation of Ca2+ pulsars with PE stimulates clustering of CaMKII in both groups. Our data suggest that endothelial CaMKII can play a significant role in hypertension. Supported by CIHR, FRSQ, CFI and HSFC.
The effects of caffeine on vascular injury‐induced neointimal hyperplasia
Authors: White Ryan Dean , Chang Yingzi
Published: June 2021

Vascular restenosis after angioplasty is a major hindrance to the lasting success of surgical revascularization as a treatment of myocardial infarction. Chronic inflammation stimulates vascular smooth muscle cell migration and proliferation leading to neointimal hyperplasia. It is reported that chronic caffeine use suppresses inflammation by upregulating adenosine receptors. Our current study was designed to test the hypothesis that caffeine decreases vascular injury‐induced neointimal hyperplasia by suppressing inflammation. Male Sprague‐Dawley rats were fed 10 mg/kg caffeine, 20 mg/kg caffeine, or vehicle for two weeks followed by balloon catheter‐induced carotid artery injury. Rats were sacrificed after two weeks of continued treatment. Carotid arteries were collected and neointimal formation was compared. Rats that received caffeine showed a significant reduction of intima thickening (P<0.001) and neointima to media ratio (P<0.05) when compared to control rats. No significant differences were found between 10 mg/kg and 20 mg/kg caffeine treatment groups. Our results indicate that chronic caffeine use decreases vascular injury‐induced neointimal hyperplasia. Research support provided by the ATSU Graduate Program.
Preclinical efficacy and safety of Kv7 potassium channel openers in the treatment of cerebral vasospasm
Authors: Mani Bharath K , O'Dowd James , Kumar Lalit , Ross Masey , Byron Kenneth
Published: June 2021

Cerebral vasospasm is a sequel to subarachnoid hemorrhage (SAH) that leads to death or disability due to cerebral ischemia. The persistent constriction of the conduit arteries in the brain is due to sustained depolarization of myocytes lining the arteries, resulting in continuous influx of calcium (Ca2+) through voltage‐gated Ca2+ channels. Ca2+ channel blockers (CCB) or potassium (K+) channel openers that oppose membrane depolarization are expected to dilate the arteries and reduce ischemia. CCBs have limited efficacy because of heterogenous expression of Ca2+ channel subunits in myocytes and their propensity to induce hypotension. We recently reported that Kv7channels are expressed in rat basilar artery myocytes and Kv7 channel openers reverse the constriction of rat basilar artery produced by spasmogens — endothelin, serotonin and vasopressin. Here we demonstrate that Kv7 channel activators, retigabine and celecoxib significantly attenuate basilar artery spasm in a rat SAH model, when administered intraperitoneally every 12 hours for 48 hours. Both Kv7 channel openers induced hypothermia, an effect expected to limit neuronal damage. They also induced a transient drop in blood pressure (BP) generally lasting 30–60 min after each administration, but mean 24‐h BP measured using radio‐telemetry in normal rats was not changed. These results indicate that Kv7 channel openers can attenuate vasospasm without sustained hypotension.
The NAMPT Inhibitor FK866 Reverts The Damage In Spinal Cord Injury
Authors: Esposito Emanuela , Impellizzeri Daniela , Mazzon Emanuela , Fakhfouric Gohar , Rahimian Reza , Travelli Cristina , Tron Gian Cesare , Genazzani Armando A , Cuzzocrea Salvatore
Published: June 2021

Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.

We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI in mice. Twenty‐four hr following SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in cytokines, PAR, NAMPT, Bax, MPO activity, NF‐κB activation, astrogliosis and microglial activation was observed. Meanwhile, levels of neurotrophins and anti‐apoptotic Bcl‐2 significantly decreased. Treatment with FK866 (10 mg/kg), the best characterized NAMPT inhibitor, at 1h and 6h after SCI rescued motor function, preserved prelesional gray and white matter, restored anti‐apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF‐α, IL‐1β, Bax levels and NF‐κB activity. We show for the first time that FK866, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.
Oral arsenic exposure induces UGT1A1 expression in neonatal humanized UDP‐Glucuronosyltransferase‐1 mice through changes in cellular morphology associated cytotoxicity
Authors: Konopnicki Camille , Fujiwara Ryoichi , Nguyen Nghia , Tukey Robert H
Published: June 2021

Arsenic, which is commonly found in drinking water, is a human toxicant and carcinogen. Abnormal cell cycle regulation, as well as changes in cell morphology due to arsenic‐induced cytotoxicity, can lead to changes in cell signaling that ultimately affect gene expression patterns. In this study, we address the contribution of oral arsenic exposure on the induction of small intestinal UDP‐glucuronsyltransferase 1A1 expression in humanized UGT1 (hUGT1) mice. Neonatal hUGT1 mice develop hyperbilirubinemia, which returns to normal as adults. When arsenic (10mg/kg) was administered to neonatal hUGT1 mice by oral gavage, intestinal UGT1A1 gene expression was induced followed by reduced levels of serum bilirubin. Induction of the Cyp2b10 gene and the oxidative stress marker, Gsta1 was also observed following exposure. Analysis of intestinal gene markers indicated that arsenic treatment led to intestinal proliferation and injury. Hematoxylin & eosin (H&E) and Periodic Acid Schiff (PAS) staining revealed abnormal vacuole formation of intestinal enterocytes and signs of cellular proliferation. Increased expression of proliferative gene markers was also seen in arsenic treated mice. We conclude that early intestinal damage by arsenic is linked to induction of intestinal xenobiotic metabolism. (Supported by grants GM086713 and ES010337)
Subcutaneous tissue response of mice to calcium hydroxide‐based pastes combined with chlorhexidine or to chlorhexidine gel used as intracanal medication
Authors: Faria Gisele , Pereira Maristela SS , Silva Lea AB , Kuga Milton C , Tanomaru-Filho Mário , Tanomaru Juliane MG , Rossi Marcos A
Published: June 2021

The purpose of this study was to evaluate the response of subcutaneous connective tissue of mice to calcium hydroxide‐based pastes with chlorhexidine digluconate (CHX) or to CHX gel. Seventy‐five mice were assigned to 5 groups. Each animal received 2 polyethylene tube implants as follows: Group I (n=10 tubes) ‐ calcium hydroxide paste (Calen®), Group II (n=10) ‐ Calen mixed with 0.5% CHX (n=10), Group III (n=10) ‐ Calen mixed with 2% CHX, Group IV (n=10) −2% CHX gel, Group V (n=10) empty tube for 7, 21, and 63 days. The tissues were removed and submitted to histological processing and analysis. On days 7, group IV showed more inflammatory cells then groups I, II and III (p<0.05 ‐ ANOVA and Tukey test). On days 21, there was no difference between groups I and II (p>0.05) and between groups III and IV (p>0.05), and the number of inflammatory cells was higher in these last two groups (p<0.05). On days 63, groups I and II showed less inflammatory cells, followed by III (p<0.05) and IV (p<0.05). On days 63, groups I, II and III showed regression of the initial inflammation and signs of repair. In group IV there was no regression of inflammation suggesting a persistent residual aggression from the material, even 63 days. In conclusion, the Calen and Calen + 0.5% CHX allowed best adequate tissue response, whereas the Calen + 2% CHX showed an intermediate tissue response and 2% CHX gel showed worst tissue response. Supported by PROPe‐UNESP.
Novel Orally Active Epoxyeicosatrienoic Acid (EET) Analogs Attenuate Cisplatin Nephrotoxicity
Authors: Khan Md. Abdul Hye , Meyer Jessica L , Walsh Katherine A , Falck John R , Jat Jawahar L , Manthati Vijay L , Imig John D
Published: June 2021

Nephrotoxicity severely limits the use of the anti‐cancer drug cisplatin. Oxidative stress and inflammation contribute to cisplatin‐nephrotoxicity. Recently, EET analogs have been developed and demonstrate kidney protection in hypertension. Robust orally active EET analogs (EET‐A & EET‐B) were developed by modifying the carboxylate, olefins, and epoxide. We hypothesized that EET analogs would decrease cisplatin‐nephrotoxicity. Cisplatin was injected (7mg/kg) in rats pretreated with EET analogs (10mg/kg/d) for 7 days. On day 5 following cisplatin injection, urine, plasma and kidney were collected. Cisplatin‐nephrotoxicity is manifested by a 3–5‐fold increase in BUN, plasma creatinine (PCr), urinary N‐acetyl‐(D)‐glucosaminidase activity (NAG), and renal tubular cast formation. EET analogs attenuated cisplatin‐induced increases in BUN (EET‐A: 108±30 & EET‐B: 120±33 vs Veh: 241±51 mg/dL), PCr (2.0±0.2 & 1.4±0.2 vs. 3.1±0.2 mg/dL), and NAG (0.5±0.1 & 0.6±0.2 vs 3.0±0.6 U/d). EET analogs also reduced renal cast by 50%. EET analogs reduced cisplatin‐induced kidney TBARS (EET‐A: 7±1; EET‐B: 8±1 vs Veh. 16±2 μmol/g). Cisplatin‐nephrotoxicity was accompanied by elevated renal inflammation and apoptosis and EET analogs reduced their expression. Collectively, these data demonstrate that orally active EET analogs protect from cisplatin‐nephrotoxicity by reducing oxidative stress and inflammation.
Combination photodynamic therapy + sphingolipid analog LCL85 leads to autophagy, defective apoptosis and long‐term sensitization
Authors: Separovic Duska , Joseph Nicholas , Breen Paul , Saad Ziad H. , Bielawska Alicja
Published: June 2021

Two anticancer agents, LCL85 and photodynamic therapy (PDT) were combined to test whether the combination PDT/LCL85 evokes changes in the sphingolipid (SL) profile and promotes cell death. Short‐term exposure to PDT/LCL85 led to enhanced levels of C18‐, C20‐, and C20:1‐ceramide, and C18‐DHceramide, enhanced autophagy and defective apoptosis, without affecting cell viability. In contrast, long‐term clonogenic survival was reduced not only after PDT or LCL85, but even more after PDT/LCL85, supporting translational potential of PDT/LCL85.
Glucose infusion (3g/kg) increases nerve vascular conductance through an insulin‐mediated nitric oxide mechanism in rats
Authors: Olver T Dylan , Mattar Louis M , Grise Ken N , Twynstra Jasna , Lacefield James C , Noble Earl G , Shoemaker J Kevin
Published: June 2021

We tested the hypothesis that acute hyperglycemia will reduce nerve vascular conductance (NVC) in rats. Sprague‐Dawley rats (N=25) were anaesthetised, blood pressure (MAP) was monitored with a pressure transducer and the left sciatic nerve was exposed from the dorsal side. Doppler ultrasound (40‐MHz: Vevo 2100 ‐ VisualSonics) was used to measure nerve blood flow velocity in an arterial segment along the nerve. Rats underwent one of four systemic intravenous glucose infusion protocols (1: 1g/kg body mass glucose; 2) 3g/kg glucose; 3) 3g/kg + 15mg/kg of L‐NAME and 4) 15mg/kg of L‐NAME alone + 3g/kg of glucose after 20min), as well as an isovolumetric saline infusion (saline did not affect NVC). An additional group was injected with streptozotocin (60mg/kg) with an insulin pellet implanted subcutaneously to produce a normoglycemic, non‐insulin responsive condition; these animals also underwent the 3g/kg glucose infusion. Relative to baseline 3g/kg increased (P<0.01) NVC (NBVF/MAP; ~ 125%). This dilation was blunted in the L‐NAME and non‐insulin responsive groups (both NS). Therefore, hyperglycemia‐induced increases in NVC appear to be mediated by an insulin‐stimulated NO mechanism.

Funded by a CIHR
Sphingosine‐1‐phosphate from erythrocytes modulates water and macromolecule permeability in rat microvessels
Authors: Curry Fitz-Roy E , Clark Joyce F , Adamson Roger H
Published: June 2021

Exogenous sphingosine‐1‐phosphate (S1P) attenuates acute increases in vascular permeability acting through receptor S1P1 to stabilize the endothelial barrier. Recent evidence shows that S1P is synthesized, stored in and released from erythrocytes. This study directly evaluates the contribution of erythrocyte derived S1P to maintain basal permeability to serum albumin in intact individually perfused venular microvessels of rat mesentery. Permeability coefficients (Ps) to albumin, α‐lactalbumin and the hydraulic conductivity (Lp) of mesenteric venules were measured in the presence or absence of perfusates containing rat erythrocytes (RBCs) or RBC conditioned media. Under these conditions RBCs added to the perfusate were the principal source of S1P in the microvessel. Albumin Ps values were stable and within the range expected of blood perfused microvessels (mean 0.5 × 10−6 cm/sec) when RBCs or RBC conditioned media were present. When absent, Ps to albumin or α‐lactalbumin was increased up to 10 fold. The S1P1 receptor antagonist (W146) reversed the stabilizing action of RBCs and Ps increased to the same extent as in the absence of RBCs. W146 also increased Lp in the presence of RBCs used as flow markers. We conclude that erythrocytes are the primary source of S1P that maintains normal venular microvessel permeability. Disease states which reduce RBC derived S1P may increase basal permeability. Supp NIH HL28607
Microvascular permeability in the absence of Epac1 activity
Authors: Karlsen Tine Veronica , Kopperud Reidun , Lidén Åsa , Rygh Cecilie Brekke , Reed Rolf K , Døskeland Stein Ove
Published: June 2021

Epac1 is a cAMP binding protein which through intrinsic guanine nucleotide exchange factor activity couples cAMP production to activation of Rap. Epac1 is abundant in blood vessel endothelium, and may contribute in the cAMP mediated attenuation of inflammatory leakage by stabilizing the endothelial barrier. To establish how basal vascular permeability is affected in the absence of Epac1 in vivo we measured blood‐to‐tissue albumin clearance and plasma volumes with a dual‐label isotope technique in isofluorane anesthetized Epac1 knockout (KO) and wt mice. Albumin permeability, calculated as the ratio of albumin clearance to local vascular volume, was significantly increased in back skin, quadriceps muscle, inguinal fat and brown fat of Epac1 KO compared to wt mice. Furthermore, there was a significant increase in water content in inguinal fat of Epac1 KO mice and with a similar tendency observed in back skin. We conclude that intact signaling through Epac1 may be of importance to maintain the basal endothelial barrier integrity in vivo and thus prevent excessive protein leakage into the interstitium of skin, muscle and fat under steady‐state conditions.

The work was supported by The Research Council of Norway and The Western Norway Health Authority. The following have contributed to produce and characterize the Epac1 KO mouse: C. Krakstad, K. Kristiansen, and L. Madsen.
ASSESSMENT OF OCCUPATIONAL RISK OF DEATH FROM LUNG CANCER IN WORKERS OF URANIUM PRODUCTION
Authors: Makhambetov Kairat , Tkachyev Viktor , Atigayeva Saule
Published: June 2021

The analysis of morbidity among workers of uranium production in Northern Kazakhstan in the period from 1971 to 2009, revealed a high proportion of lung cancer, which from the overall structure of oncological met in 68,7% of the case. This is especially evident in the age group of 50–59 years, where the experience of work more than 30 years. The differences in the number of expected and actual observed cases of death of the workers of uranium mines from lung cancer are comparable, and the ratio of observed and expected values indicate a rise in the nosology of about 1.4 times. The excess incidence of lung cancer in workers per unit of radiation exposure was 4.6 cases per one equivalent equilibrium emana for a month and was in direct dependence on the level of cumulative radiation exposure of daughter products of radon decay. The comparison of the frequency of occurrence and polymorphisms of alleles and genotypes of introns 3 and 6 of the p53 gene among the workers of a uranium mine and those of a control group. People who professionally exposed to radiation and toxic components of uranium are relatively high risk of development of oncological on the background of a decline in the immune reactivity of the organism.
Effect of Systemic Hematocrit on Blood Velocity Profiles in Arterioles
Authors: Yalcin Ozlem , Lee Chao-yu , Ranu Sunny , Jivani Manoj , Johnson Paul , Cabrales Pedro
Published: June 2021

Systemic hematocrit (Hctsys) is an important determinant of cardiac output and flow in the peripheral circulation. The cell free layer, by virtue of its location at the interface between the wall and the blood stream, very likely plays a key role in this relationship. We aimed to determine blood's velocity profile in arterioles with an emphasis on the hemodynamics near vessel walls at different Hctsys. The velocity profiles of 0.5 μm fluorescent labeled microspheres were assessed in rat cremaster arterioles (~35 μm) during systemic hemodilution and hemoconcentration with high speed video intravital microscopy. Hctsys was increased by 5% from 40 to 75% or decreased by 5% from 40 to 20%. Velocity was determined using single frame analysis of multiple images obtained with a gated imaging system. Velocities were filtered, normalized, and fit to a linear regression to calculate the parabolic coefficient (K). The data showed a positive correlation between Hct and the K value, where increased Hctsys resulted in blunted velocity profiles (K>2) across the flow stream. Analysis of profiles indicates a velocity discontinuity near the vessel wall, plasma only boundary layer and a microsphere free layer near the wall. These results confirm the presence of a finite size structure between the vascular endothelium and the flowing plasma, suggesting a hemodynamic function for the endothelium glycocalyx.
Sexual dimorphism of vascular mechanics in rats
Authors: Mattar Louis M , Zamir Mair , Shoemaker J. Kevin
Published: June 2021

The purpose of this study was to test the hypotheses that male and female rats would exhibit dimorphic mechanical properties of the hindlimb vasculature and that these differences would persist in hypertension. Vascular resistance (R), compliance (C), and tissue viscoelasticity (K) of the hindlimb vascular bed were quantified from concurrent femoral artery blood flow and pressure waveforms (lumped Windkessel model) in age‐matched Wistar‐Kyoto (WKY) and spontaneously hypertensive rats (SHR) male (n=10 each) and female (n=6 each). Female WKY rats displayed greater R (15.4±5.7 vs 7.7±3.3mmHg/mL/min; P<0.05) and K (3.4±2.4 vs 1.1±2.7mmHg/mL/min; P<0.05) with lower C (3.4E‐3±0.8E‐3 vs 4.9E‐3±0.9E‐3mL/mmHg/g; P<0.05) compared to males, respectively. Similarly, female SHRs had higher R (31.5±8.5 vs 17.6±7.8mmHg/mL/min; P<0.05) and K (7.3±2.5 vs 2.9±1.0mmHg/mL/min; P<0.05) with lower C (4.8E‐3±2.0E‐3 vs 6.8E‐3±3.5E‐3mL/mmHg/g; P<0.05) than their male counterparts. Main effects of strain and sex were observed for each of R, K and C variables (all P<0.05). Therefore, sex differences are apparent in the indices of steady state (R) and oscillatory (K and C) hindlimb vascular mechanics and these persist in hypertension.

Supported by CIHR.