bluuebunny/crossref_metadata_2025 huggingface dataset:
Iron Status in Multiples and Their Neonates
Authors: Ru Yuan , Pressman Eva K , Guillet Ronnie , Cooper Beth M , Katzman Philip J , Caveglia Sarah , O'Brien Kimberly
Published: June 2021

Women carrying multiples are at high risk for iron deficiency anemia. Low maternal iron (Fe) status may impact neonatal Fe stores and may have long‐term adverse functional consequences. In this study, maternal Fe status will be longitudinally followed across pregnancy in 125 women carrying multiples, all of whom receive standard Fe‐containing prenatal supplements. Data on 33 pregnant women are available to date, including 9 sets of triplets and 24 sets of twins. Average gestational age at delivery was 34 ± 3.72 weeks. Maternal and umbilical cord serum was analyzed for Fe status indicators and inflammatory markers. Maternal anemia was evident in 64.7% of women at term. Maternal ferritin values averaged 17.89 ± 7.28 μg/L; 71.4% of women had depleted ferritin stores (< 20 ug/L) by mid‐gestation. Transferrin receptor averaged 4.15 ± 3.08 mg/L; fully 35.7% of women had values indicative of tissue iron insufficiency (>; 4.4 mg/L). Mean neonatal umbilical cord hemoglobin concentrations at birth were 14.23 ± 3.37 g/dL; 25.8% of neonates were anemic (< 13.0 g/dL). Cord ferritin averaged 104.82 ± 66.51 μg/L (n=25) and cord hepcidin was positively associated with maternal mid‐gestation hepcidin (n=11 pairs, p<0.0001). More data in this high‐risk population is needed to assess determinants of anemia and risk factors for anemia in this group given the increase in multiple births in the United States.

Grant Funding Source: Gerber Foundation
Sociodemographic, clinical, and lifestyle factors associated with prostate cancer aggressiveness in a population‐based study
Authors: Vance Terrence M , Wang Ying , Su L. Joseph , Fontham Elizabeth T. H. , Bensen Jeannette T. , Mohler James L. , Chen Ming‐Hui , Chun Ock K.
Published: June 2021

This study aimed to determine the associations between sociodemographic, clinical, and lifestyle factors and prostate cancer (PCa) aggressiveness. Data are from the North Carolina‐ Louisiana Prostate Cancer Project, a population‐based study of incident PCa in African Americans (AA) (n=925) and Caucasian Americans (CA) (n=1,059). Medical record abstraction and structured questionnaires were used to collect data. PCa patients with higher aggressiveness were greater among AA than CA. Aggressive cases were greater among men older at diagnosis, not married, less educated, with lower income, without previous screenings or health insurance, and with greater BMI and waist‐hip ratio (WHR) than their counter parts (p<0.05). When stratified by race, several factors were found to differ between AA and CA, including age, marital status, education, poverty, health insurance status, PSA screening, and supplement use (p<0.05). These results suggest that differences in several sociodemographic, clinical, and lifestyle factors may contribute to the disparity in PCa aggressiveness observed between AA and CA.

Grant Funding Source: NIH Cancer Epidemiology Small Grant #1R03CA159421–01A1.
Dietary intake of sleep‐deprived, on‐call anesthesiology residents
Authors: Taylor Matthew Kenneth , Gibson Cheryl A. , Unruh Gregory K. , Ptomey Lauren T. , Spaeth Kendra R. , Sullivan Debra K.
Published: June 2021

BACKGROUND

Sleeping habits are relevant to the health of medical residents as sleep‐deprivation has been linked to increased energy intake and obesity risk.

OBJECTIVE

To evaluate effects of nights on call and amount of sleep time on dietary intake of anesthesiology residents.

METHODS

27 anesthesiology residents were recruited to participate in this crossover design study evaluating dietary intake on two occasions, 1) after receiving ≥8 hours of sleep and 2) after receiving ≤4 hours of sleep on‐call. Dietary data were collected at two breakfast buffets where participants were allowed to select food choices ad‐libitum. Food items were weighed previous to and after service, including plate waste. 24‐hour food recall was utilized to collect dietary intake data for the rest of that day. Participants were unaware that dietary intake was evaluated at each breakfast buffet.

RESULTS

20 participants (15 M, 12 F; 32 ± 5.6 years) completed the study. No significant difference was observed between total energy (791 ± 672.8 kcal vs. 737.5 ± 470.5 kcal) or macronutrient intake. Intake of fat as percent of energy greater than IOM recommendations was observed in the sleep‐deprived group (36.9 ± 8.3%).

CONCLUSION

Sleep‐deprivation related to on‐call shifts did not result in increased energy intake by anesthesiology residents; however, sleep‐deprivation was related to greater than IOM recommended fat intake as percent of energy.
Child and adolescent dietary intake of produce with high pesticide exposure
Authors: Kobernik Emily K , Branum Amy M
Published: June 2021

Widespread use of pesticides in agricultural and residential environments has led to frequent exposure, yet intake of pesticide‐contaminated foods among children and adolescents has not been thoroughly assessed. Dietary intake of produce most commonly contaminated with pesticides as established by the Environmental Working Group (EWG) is described. We analyzed 24‐hour dietary recall data from 106,970 children and adolescents (6–18 years) from the 2007–2010 National Health and Nutrition Examination Survey (NHANES). Population‐weighted proportions of the 14 highest ranking EWG fruits and vegetables were estimated. Approximately 42% of total fruit/vegetable intake came from foods on the EWG list. Consumption of EWG fruit accounted for 33% of total fruit intake, mostly in the form of apples. EWG vegetable consumption accounted for 47% of total vegetable intake, with potatoes (60.9%, SE: 2.0) and lettuce (18.6%, SE: 1.2) comprising the majority. Berries were most commonly consumed by Non‐Hispanic white (85.2%, SE: 3.8), and non‐poor (76.0%, SE: 3.6) children. Among Non‐Hispanic black and Mexican‐ American children, the greatest proportion of intake came from dark leafy greens and apples, respectively. Although most children eat less than the recommended amount of fruits and vegetables, these results indicate produce more commonly eaten by children are characterized by higher pesticide contamination.
Use of breast milk vitamin A concentration as an indicator of population vitamin A status in a national survey in Cameroon
Authors: Engle‐Stone Reina , Haskell Marjorie J , Nankap Martin , Ndjebayi Alex O , Brown Kenneth H
Published: June 2021

Breast milk vitamin A (BMVA) has been proposed as an indicator of population VA status but has rarely been applied in large surveys or compared with conventional VA biomarkers. We assessed the prevalence of, and risk factors for, low BMVA and its relationships with VA intake, plasma retinol‐binding protein (pRBP) and markers of inflammation in a national survey in Cameroon. We randomly selected 30 clusters in each of 3 strata (South, North, and Cities). Casual milk samples were collected from 5 women per cluster (n = 437 total). pRBP, C‐reactive protein (CRP), α1‐acid glycoprotein (AGP), and VA intake were assessed in a subset (n = 269). Mean BMVA was 3.80 (95% CI: 3.54 – 4.06) μmol/L and 23.4 (22.0 – 24.8) μg/g fat. Low BMVA was infrequent: 7.3% (4.7 – 9.9) of values were < 1.05 μmol/L and 9.4% (5.9 – 12.9) were < 8 μg/g fat, consistent with the low prevalence of pRBP < 0.78 μmol/L (< 5%). Risk factors for both low BMVA and pRBP included living in the North and low maternal education. BMVA was positively associated with inflammation‐adjusted pRBP among women in the lowest VA intake tertile (< 114 μg RAE/d, P < 0.01), but not in the highest tertile (>; 462 μg RAE/d, P >; 0.6). Controlling for milk fat, BMVA was negatively associated with CRP (P = 0.011) but not AGP (P = 0.53). BMVA and pRBP provide similar estimates of VA deficiency prevalence and identify the same risk groups among women in Cameroon. Data from populations with lower VA status are needed.

Grant Funding Source: Michael and Susan Dell Foundation; Sight & Life
Plasma n‐3/n‐6 PUFAs interact with FADS2 genetic variations to affect blood cholesterol concentrations in type 2 diabetes
Authors: Huang Meng‐Chuan , Huang Pei‐Chi , Chung Hsin‐Fang , Hsu Chih‐Cheng
Published: June 2021

Single nucleotide polymorphisms (SNPs) of fatty acid desaturase (FADS) and n‐3/n‐6 polyunsaturated fatty acids (PUFAs) have been linked to decreased risks of cardiovascular diseases. We aimed to examine whether FADS SNPs (rs2072114, rs1535, and rs174546) interacted with n‐3/n‐6 PUFAs status as plasma levels to affect blood lipid profiles in type 2 diabetes. In 2008, we selected 192 diabetic patients without using lipid‐lowering drugs from a diabetic (DMIDS) cohort established in Taiwan. After adjusting for confounding factors, FADS2 rs2072114 G‐variant correlated significantly with decreased total cholesterol (p‐trend=0.015), LDL (p‐trend=0.009), and HDL (p‐trend=0.007) only in the low (<50 percentile) alpha‐linolenic acid (ALA)/linoleic acids (LA) group but not in the high (≥50 percentile) ALA/LA group (p for interaction= 0.012, 0.012, and 0.181, respectively). Furthermore, the G‐variant was significantly associated with lower total cholesterol (p‐trend=0.049) and HDL (p‐trend=0.024), and marginally with LDL (p‐trend=0.067) in the low n‐3 long chain PUFA (LCPUFAs) group (<50 percentile) but not in the high n‐3 LCPUFAs (≥50 percentile) (p for interaction= 0.170, 0.053, and 0.015, respectively). Genetic variations of FADS2 may interact with n‐3/n‐6 PUFAs to affect cholesterol metabolisms in type 2 diabetes. Further investigation may be needed with larger sample size in this ethnic population.
No difference in protein leverage affecting energy intake between soy and whey protein
Authors: Martens Eveline , Lemmens Sofie , Westerterp‐Plantenga Margriet
Published: June 2021

The protein leverage hypothesis requires evidence that protein intake is regulated stronger than energy intake. Ad libitum energy intake, body weight changes and appetite profile were determined in response to protein to carbohydrate+fat ratio over 12 consecutive days, and in relation to type of protein. A crossover study was performed (n= 40/39 (m/f); age 34.0 ± 17.6 y; BMI 23.7 ± 3.4 kg/m2), using diets containing 5, 15, and 30 energy percent from soy or whey protein. Protein‐content effects did not differ by type of protein. In the soy and whey protein groups, total energy intake was lower in the high (7.21 ± 3.08 MJ/d) vs. the low (9.33 ± 3.52) and normal protein conditions (9.62 ± 3.51, p=0.001), predominantly from a lower energy intake from meals (p=0.001). Protein intake varied directly with the level of protein in the diet (p=0.001). AUC of appetite ratings did not differ; yet fluctuations in hunger (p=0.019) and desire to eat (p=0.026) over the day were attenuated in the high vs. the normal protein condition. Evidence supporting the protein leverage hypothesis has been obtained in that individuals, irrespective of type of protein, under‐ate relatively to energy balance from diets containing a higher protein to carbohydrate+fat ratio. No evidence for protein leverage effects from diets containing a lower ratio of protein to carbohydrate+fat was obtained. This may be due to the replacement of protein with carbohydrate, and might be different if fat‐replacement would have been applied. Supported by grants from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreements n° 266408 (Full4Health) and by food products from Kellogg's Nederland, FrieslandCampina, and Solae, LLC.

Grant Funding Source:Supported by grants from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreements n° 266408 (Full4Health) and by food products from Kellogg's Nederland, FrieslandCampina, and Solae, LLC.
Comparison of Watermelon and Carbohydrate Beverage on Exercise‐Induced Oxidative Stress, Inflammation, and Immune Dysfunction, and Augmentation Index
Authors: Shanely R. Andrew , Nieman David C. , Knab Amy M. , Perkins‐Veazie Penelope , Henson Dru , Cialdella‐Kam Lynn , Sha Wei , Meaney Mary Pat
Published: June 2021

Watermelon (WM) is a rich source of carbohydrate (CHO) and L‐citrulline. WM may support exercise (EX) performance and act as a countermeasure to EX‐induced inflammation, oxidative stress, and immune dysfunction, and arterial stiffness. Cyclists (n = 20, 48±2 y) participated in a randomized, placebo controlled, crossover study. Subjects completed two 75km time trials after either 2 wk ingestion of 980 mL/d WM or no treatment. Subjects drank either 0.2 gm/kg CHO from WM or 6% CHO drink every 15 min during EX. Augmentation index (AIx) was calculated from radial artery waveforms using applanation tonometry pre‐study and pre‐, post‐, 1h post‐EX. WM ingestion vs no treatment for 2 wk did not alter blood biomarkers but decreased AIx 38% (p= 0.007). EX performance did not differ between WM or 6% CHO (p= 0.194). WM vs 6% CHO resulted in a similar pattern of increase in blood glucose, and greater increases in post‐EX FRAP (13%), ORAC (12%), and total nitrate (29%) (all p< 0.017), but did not alter the pattern of change in the other biomarkers. EX resulted in lower central and peripheral pressures and WM attenuated the 1hr post‐EX decrease in augmentation pressure and AIx (all p< 0.01). In conclusion, 2 wk WM decreased resting AIx, fully supported the energy demands of EX, and increased post‐EX blood anti‐oxidant capacity and total nitrate. Counter to our hypothesis, WM blunted the post‐EX drop in AIx.

Funding, National Watermelon Promotion Board
Low‐dose methotrexate (MTX) inhibits methionine S‐adenosyltransferase (MAT) in vitro and in vivo
Authors: Wang Yi‐Cheng , Chiang En‐Pei
Published: June 2021

MAT catalyzes the only reaction that produces the major methyl donor in mammals. Low‐dose MTX is a commonly used DMARD. We tested the hypothesis that MTX inhibits MAT in vitro and in vivo. HepG2 cells were cultured under folate restriction or low‐dose MTX with and without folate or methionine supplementation. Mice received MTX regimens that reflected low‐dose clinical use in humans. We found that methionine or folate supplementation greatly improved SAM in folate‐depleted cells but not in cells preexposed to MTX. MTX but not folate depletion suppressed MAT genes, proteins and activity. Low‐dose MTX inhibited MAT1A and MAT2A genes, MATI/II/III proteins and MAT enzyme activities in mouse tissues. Concurrent folinate supplementation with MTX ameliorated MAT2A reduction and restored SAM in cells. However, posttreatment folinate rescue failed to restore MAT reduction or SAM level in cells preexposed to MTX. We provide both in vitro and in vivo evidence that lowdose MTX inhibits MAT genes, proteins, and enzyme activity independent of folate depletion. Because polyglutamated MTX stays in the hepatocytes, if MTX inhibits MAT in the liver, the efficacy of clinical folinate rescue with respect to maintaining hepatic SAM would be limited. The study raise concerns on perturbed methylation reactions in humans on low‐dose MTX. Well‐designed trials for optimizing SAM and methylation status in patients taking MTX are warranted

Grant Funding Source: National Science Council
The effects of folate, choline and betaine on transmethylation in a methionine restricted piglet
Authors: Robinson Jason L , McBreairty Laura E. , Brunton Janet A. , Bertolo Robert F.
Published: June 2021

Methionine is an essential amino acid that is incorporated into protein and is also the primary methyl donor for transmethylation reactions via S‐adenosylmethionine (SAM), SAM is demethylated to S‐adenosylhomocysteine (SAH) with the majority of methyl groups either being transferred to DNA or used for synthesis of creatine (CR) and phosphatidylcholine (PC). SAH is converted to homocysteine (HCY) which can be oxidized or remethylated back to methionine by the methyl donors folate and choline (via betaine). 4–8 d old neonatal piglets were fed a diet devoid (n=8) or replete (n=7) of these methyl donors. After 5 d, dietary methionine was reduced to 80% of requirement. On day 8, animals received a constant infusion of [3H]methyl‐methionine for 6 h to measure flux to PC, CR, and DNA. Methyl deficient pigs had a lower SAM/SAH ratio and higher plasma HCY (p<0.05). Methylation to CR, but not PC and DNA, was lower in methyl deficiency, suggesting this methylation reaction is most sensitive to methyl supply. Moreover, methylation of phosphatidylethanolamine to PC tended to be higher with methyl deficiency suggesting this pathway is upregulated when choline is deficient. Severe restriction of remethylation in piglets reduces methionine availability for creatine synthesis. (CIHR funded).

Grant Funding Source:CIHR
Influence of lactation and choline intake on one‐carbon biomarkers in women
Authors: Davenport Crystal , Shields Kelsey , Yan Jian , Jiang Xinyin , Malysheva Olga , Caudill Marie , Stabler Sally , Allen Robert
Published: June 2021

Objective

We sought to quantify the effects of lactation and maternal choline intake on maternal indicators of one‐carbon metabolism.

Methods

Lactating (n = 28; 30‐d post‐partum) and nonlactating (NL, n = 21) women were randomized to choline intakes of 480 or 930 mg/d for 10 weeks. Blood and urine were collected at baseline, study midpoint, and study end for analysis of one carbon metabolites.

Results

Compared to NL women, lactating women exhibited elevated plasma choline (p=0.04) and decreased urinary dimethylglycine losses (p=0.008). Within lactating women, a higher choline intake yielded greater plasma betaine (p=0.015), greater plasma dimethylglycine (p=0.037), greater plasma methylglycine (p=0.036), and decreased plasma cystathionine (p=0.012). However, higher choline intake did not affect plasma concentrations of homocysteine, cysteine, methionine, or glycine.

Conclusions

Lactation and choline intake influence biomarkers of 1‐C metabolism with some evidence of a greater demand for choline during lactation and a positive effect of a higher choline intake on methyl group supply.
Improved insulin sensitivity and reduced adiposity with aP2 driven TLR4 overexpression in transgenic mice
Authors: Ono‐Moore Kikumi D , Zhao Ling , Huang Shurong , Kim Jeong‐a , Rutkowsky Jennifer M , Snodgrass Ryan G , Schneider Dina A , Quon Michael J , Hwang Daniel H
Published: June 2021

Chronic low grade inflammation is associated with obesity and diabetes. The underlying causes and mechanisms mediating chronic low grade inflammation in metabolic disorders are not well understood. Toll‐like receptor 4 (TLR4) mediates both infection‐induced and sterile inflammation by recognizing pathogen‐associated molecular patterns (PAMPs) and endogenous molecules, including saturated fatty acids, respectively. It has been shown that saturated fatty acids can activate TLR4 (Lee et al. 2001), and that TLR4 deficient mice were protected from high fat diet (HFD)‐ induced obesity and insulin resistance suggesting that TLR4‐ mediated inflammation may cause insulin resistance (Shi, Kokoeva et al. 2006). Thus, we made transgenic (Tg) mice expressing a constitutively active TLR4 driven by aP2 promoter to determine whether these Tg mice would have increased insulin resistance. Surprisingly, these Tg mice fed a normal chow diet had improved insulin sensitivity with reduction of food intake, adiposity, and body weight gain when compared with wild type littermates. These results raise an important question of whether TLR4‐ mediated inflammation is a direct cause of insulin resistance or promotes secondary changes including adaptive response to reduce energy (food) intake. (USDA‐ARS‐WHNRC Program Funds and NIH‐DK 064007, ADA 1–12‐BS‐99 to J.K).
Cigarette Smoke‐Induced Myocardial Inflammation and Contractile Dysfunction Is Mediated by Unsaturated Aldehydes and TRPV1
Authors: He Emily Y , Wu Zhenbiao , Scott Glenda I , Ren Jun
Published: June 2021

Cigarette smoking triggers proinflammatory response through stimulating the capsaicin‐sensitive transient receptor potential cation channel TRPV1. Recent evidence suggests that smoking is associated with an overtly increased prevalence of heart diseases. This study was designed to examine the effect of 2 α,β‐unsaturated aldehydes present in cigarette smoke, namely crotonaldehyde and acrolein, on myocardial insulin sensitivity and contractile function. Our results revealed that in vitro short‐term exposure of crotonaldehyde, and acrolein provoked myocardial inflammatory response and dampened insulin signaling manifested as accumulation of the cytokines TNF‐α and NFκB as well as reduced insulin‐stimulated glucose uptake. These responses were accompanied with compromised cardiomyocyte contractile function including depressed peak cardiomyocyte contractile capacity, prolonged duration of relaxation, decreased intracellular Ca2+ release and slowed intracellular Ca2+ clearing. Activation of TRPV1 was enhanced in response to aldehyde exposure. Interestingly, the crotonaldehyde and acrolein‐induced pro‐inflammatory response, loss of insulin sensitivity and cardiomyocyte contractile function were significantly attenuated or mitigated by the aldehyde scavenger glutathione and the TRPV1 antagonist capsazepine. Both aldehydes and capsaicin increased the activity of Nox3 NADPH oxidase activity and STAT1. Inhibition of Nox3 and STAT1 independently blunt the crotonaldehyde and acrolein‐induced cardiomyocyte dysfunction. Inhibition of TRPV1 protected against the aldehyde cytotoxicity. Taken together, our data suggest a role of α,β‐unsaturated aldehydes as the main causative agents in cigarette smoke in the pathogenesis of cigarette smoke‐induced heart diseases possibly via a Nox3/STAT1‐ and TRPV1‐dependent mechanism.
Cav1 is a Key Mediator of Tumor‐Stromal Interactions in Melanoma
Authors: Trimmer Casey , Capozza Franco
Published: June 2021

Several lines of experimental evidence have demonstrated the importance of the tumor microenvironment in controlling melanoma tumor growth and melanoma metastasis. Cav1, the main structural component of the plasma membrane microdomains termed Caveolae, is emerging as an important signaling molecule in the stroma of several tumor types. However, Cav1's role in the melanoma microenvironment remains argely unexplored. Here, we utilize various experimental approaches to elucidate the function of stromal Cav1 in the development of melanoma in mice. We show that loss of Cav1 (but not Cav2) in mice promotes the growth of orthotopically implanted melanoma cells. We use cocultures of fibroblasts and melanoma cells coupled with cytokine analysis to identify various Cav1 regulated factors that function in a paracrine fashion to promote the growth of melanoma cells in vitro and in vivo. In summary, these studies reveal previously undefined functions for this protein in the melanoma microenvironment that could potentially be targeted for therapy.
Lipopolysaccharide increases agonist‐induced contractile responses in Sprague Dawley rat corpus cavernosum
Authors: Stallmann‐Jorgensen Inger Susanne , Webb R. Clinton
Published: June 2021

Chronic inflammatory conditions are frequent co‐morbidities of erectile dysfunction (ED) and elevated lipopolysaccharide (LPS) levels may increase inflammation via Toll‐like receptor 4 (TLR4) activation. An imbalance between vascular dilatation and contraction underlies ED. We hypothesized that LPS increases the agonist‐induced contractile response in corpus cavernosum (CC). The CC tissues were isolated, incubated for 6 hours in tissue culture media with 1 ug/mL LPS or vehicle, before being mounted in a muscle strip myograph for studies of isometric force generation. Contraction to 120 mM KCl did not differ between LPS and vehicle treated CC. KCl‐induced contraction data were used to normalize contraction data from the serotonin concentration response curve (30 nM‐100 uM). The CC tissue exposed to LPS exhibited enhanced contraction to serotonin (as % of KCl contraction) compared to control values. At 30 uM concentration: 67.34±5.15 vs. 43.34±6.67% (p<0.05), and at 100 uM: 77.61±5.4 vs. 56.61±6.98% (p<0.05). These results show that treatment with the TLR4 ligand LPS increased the contractile response to serotonin in rat corpus cavernosum. Thus, TLR4 activation may play a role in the etiology of ED which is a condition that has been shown to predict cardiovascular disease.

Support: NIH and SMSNA.
Losartan Protection Against CCL4 Induced Hepatic Fibrosis Involves Changes In Adhesion Molecules and Inflammatory Markers
Authors: Nassar Noha N , El Wakeel Sara A. , El Sayed Moushira I. , El‐Denshary Ezzeldein S. M.
Published: June 2021

The role of Angiotensin II (AgII) receptor blockers in the limitation of progression of hepatic fibrosis remains yet to be explored. In the current study we investigated the anti‐inflammatory, antioxidant and antifibrotic effect of 3 ascending doses (5,10, and 20 mgkg−1) of an agiotensin II receptor blocker losartan (LOS) in a model of CCl4 induced hepatic fibrosis. To this end, 60 male Wistar rats were divided into 5 groups; Gp I received olive oil and served as vehicle, Gp II received CCL4 (3.1gkg−1,i.p in olive oil 1:1) twice weekly for 8 weeks. GP III, IV and V received CCL4 + LOS 5, 10 and 20mgkg−1,p.o, respectively. LOS was given one hour before CCL4 insult daily for 10 weeks starting from the first day of CCL4 administration.LOS (5,10 and 20 mgkg− 1) significantly reduced serum transaminases (ALT, AST), hepatic content of TBARS,NO, MPO, ICAM‐1 and TNF‐α in a dose dependent manner. LOS significantly raised the levels of hepatic NPSH and TAC in a dose dependent manner. The results showed that losartan has improved CCL4 induced hepatic fibrosis throughout its anti‐inflammatory and antioxidant mechanisms. These biochemical changes correlated positively with histopathological changes induced by CCL4.
Tolerance and cross‐tolerance among high‐efficacy synthetic cannabinoids JWH‐018 and JWH‐073 and low‐efficacy phytocannabinoid Δ9‐THC
Authors: Fantegrossi William E , Franks Lirit N , Vasiljevik Tamara , Prather Paul L
Published: June 2021

Repeated administration of cannabinoid agonists has been shown to result in tolerance to several central and peripheral effects in laboratory animals, and to cellular effects observed in vitro. Intrinsic efficacy is known to modulate pharmacodynamic tolerance at several central receptor systems, but whether this phenomenon also applies to cannabinoid receptors has not been adequately explored. In these studies, daily injections of the high‐efficacy synthetic cannabinoids JWH‐018 and JWH‐073, or the low‐efficacy phytocannabinoid Δ9‐THC were administered to mice previously prepared with radiotelemetry probes capable of simultaneously monitoring core temperature and locomotor activity. In separate groups of mice, the effects of JWH‐018 and JWH‐073 were assessed in subjects with or without a history of Δ9‐ THC administration. Repeated administration of all three cannabinoids resulted in almost complete tolerance to hypothermic effects within 5 days, and when re‐challenged with the same dose after a 14‐day drug abstinence period, some degree of tolerance was still evident for all three cannabinoids. Interestingly, no tolerance to locomotor suppression was noted for any of the cannabinoids. Mice made tolerant to the hypothermic effects of Δ9‐ THC after 4 daily administrations also exhibited near complete tolerance to the hypothermic effects of JWH‐018 and JWH‐073 on day 5, and in both cases, residual tolerance was still apparent after a 14‐day drug abstinence period. Potential mechanisms for these observed in vivo effects were investigated in vitro using assays of CB1 receptor expression and function. These studies suggest that intrinsic efficacy at CB1 receptors is not a primary variable in eliciting tolerance to hypothermic effects in mice. This work supported by RR020146 and RR029884.
The effects of tropisetron on cocaine‐induced conditioned taste aversions
Authors: Briscione Maria , Serafine Katherine , Merluzzi Andrew , Rice Kenner , Riley Anthony
Published: June 2021

Cocaine, like other drugs of abuse, has both rewarding and aversive effects, and the balance between these effects may influence a drug's overall abuse potential. The conditioned taste aversion (CTA) preparation is an animal model used to assay the aversive effects of drugs. In this procedure, animals avoid consumption of a novel taste after it has been paired with a drug, a decrease in consumption indicative of the drug's aversive effects. The present study addressed whether pharmacological antagonism of 5‐HT would result in attenuated cocaine‐induced CTAs indicating a role of 5‐HT in cocaine's aversive effects. The specific 5‐HT receptor, 5‐HT3, was analyzed given that it is implicated in a variety of behavioral effects of cocaine. This series of investigations assessed the aversive effects of the 5‐HT3 antagonist tropisetron alone and in combination with cocaine. Tropisetron failed to attenuate cocaine‐induced CTAs, suggesting that cocaine's aversive effects are not mediated by 5‐HT, or at least this specific receptor subtype. This research was supported in part by a grant from the Mellon Foundation, the Mathias Research Award and American University's Scholars and Artists Fellowship.
Effects of two‐week chronic treatment with phendimetrazine on choice between cocaine and food in rhesus monkeys
Authors: Banks Matthew L , Blough Bruce E , Negus Sidney S
Published: June 2021

The clinically available schedule III anorectic phendimetrazine is a prodrug for the monoamine releaser phenmetrazine and a candidate “agonist” medication for treatment of cocaine dependence. This study examined effects of continuous 14‐day treatment with phendimetrazine on cocaine vs. food choice in nonhuman primates. Rhesus monkeys (n=4) initially responded during daily 2‐hr sessions under a concurrent schedule of food delivery (1‐g pellets, fixed‐ratio 100 schedule) and cocaine injections (0 – 0.1 mg/kg/injection, fixed‐ratio 10 schedule). During 14‐day treatment blocks, saline or (+)‐phendimetrazine (0.32 – 1.0 mg/kg/hr) was continuously infused 23 hrs/day. During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01 mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1 mg/kg/inj). After 14 days of 1.0 mg/kg/hr phendimetrazine, tolerance developed to initial depression of food‐maintained responding, and there was a significant rightward shift in the cocaine choice dose‐effect function such that choice of 0.032 mg/kg/injection cocaine was significantly decreased by approximately 50%. Phendimetrazine was not more efficacious than 14‐day treatment with d‐amphetamine (0.032–0.1 mg/kg/hr) to decrease cocaine vs. food choice. Funded by NIH grants R01DA026946 and R01DA012790.
Physical dependence liability of nicotine in mice ‐ possible involvement of endogenous opioid system located on the downstream of α 7 nicotinic acetylcholine receptor
Authors: Kishioka Shiroh , Kiguchi Norikazu , Kobayashi Yuka , Wakida Naoki , Yamamoto Chizuko
Published: June 2021

We reported that nicotine‐induced analgesia, but not corticosterone (CS) increase, was suppressed by opioid antagonist (naloxone; NLX), and that nicotine‐induced CS increase was inhibited by α4β2 nicotinic acetylcholine receptor (nAChR) antagonist, but not α7. Thus, we predicted that endogenous opioid system might be located on the downstream of α7 nAChR, but not α4β2. On the other hand, it is well known that nicotine has physical dependence liability, but its mechanism is still unclear. Hence, we examined whether physical dependence on nicotine was developed by the stimulation of endogenous opioid system through α7 nAChR in ICR mice. We evaluated CS increase as an indicator of nicotine withdrawal. NLX elevated CS levels in mice receiving chronic nicotine in a dose of NLX‐dependent manner, and the NLX‐induced CS increase was correlated with the doses and the days of chronic nicotine. When opioid antagonist was administered together with chronic nicotine, NLX‐induced CS increase was not elicited, indicating that endogenous opioid system involved in the development of physical dependence on nicotine. Concomitant administration of α7 nAChR antagonist with chronic nicotine, but not α4β2, did not elicit the CS increase by NLX. These results suggest that physical dependence on nicotine was, at least in part, developed by the stimulation of endogenous opioid system, which was located on the downstream of α7 nAChR.
Anatabine Significantly Decreases Nicotine Self‐ Administration
Authors: Mello Nancy K. , Fivel Peter A. , Kohut Stephen J. , Caine S. Barak
Published: June 2021

Anatabine is one of the most abundant of the minor tobacco alkaloids but relatively little is known about its interactions with the abuse‐related effects of nicotine. The acute effects of anatabine (0.18–3.2 mg/kg, IM) or saline on nicotine‐ and food‐maintained responding were examined in four rhesus monkeys. Nicotine (0.01 mg/kg/inj, base) and banana‐flavored food pellets (1g) were available under a second‐order schedule (FR 2, VR 16:S). Anatabine or saline injections were administered 15 min before the food self‐administration session began. Saline control treatment was in effect after administration of each anatabine dose until monkeys returned to baseline levels of responding. Anatabine dose‐dependently reduced nicotine self‐administration (P<0.05) with no significant effects on food‐maintained responding. There was no evidence of sedation or other adverse side effects. These data suggest that anatabine could be an effective medication for treatment of nicotine addiction. Supported by DA026892 from the National Institute on Drug Abuse, NIH.
Further characterization of varenicline (VAR) and mecamylamine (MEC) and effects on self‐administration (SA) of cocaine (COC) and nicotine (NIC)
Authors: Kromrey Sarah Allyson , Nader Sue , Nader Michael
Published: June 2021

Studies investigating NIC SA in nonhuman primates is limited despite NIC being one of the most commonly used drugs which is often used in combination with other drugs of abuse. Previous studies in our laboratory found that neither VAR, a nicotinic α4β2 receptor partial agonist, nor NIC functioned as reinforcers when substituted for COC, although both drugs, along with MEC, a nonselective and noncompetitive NIC receptor antagonist, potentiated the discriminative stimulus effects of COC. The present studies further characterize the effects of VAR and MEC in male rhesus monkeys SA NIC (0.001–0.1 mg/kg/injection) on a fixed‐ratio 30 schedule of reinforcement; these animals had a prior history of COC SA. Preliminary results show MEC (0.03–0.3 mg/kg) and VAR (0.1–1.0 mg/kg) functioned as reinforcers when substituted for NIC, suggesting that a history of NIC SA was necessary for MEC and VAR to maintain SA. These results emphasize the importance of evaluating drug history and current drug use when assessing abuse potential of drugs. When given in combination with the dose of NIC that maintained peak response rates, both VAR and MEC attenuated NIC SA. The observation that the behavioral effects of NIC receptor partial agonists and antagonists appear to attenuate NIC‐related behaviors and potentiate COC‐related behaviors supports the hypothesis of a unique role for NIC receptors in stimulant abuse. DA12460
Where are kids getting their empty calories? The role of stores, schools, and fast food restaurants
Authors: Poti Jennifer M , Slining Meghan M , Popkin Barry M
Published: June 2021

Little is known about the contribution of stores, schools, and fast food restaurants to excess empty calorie intake for US children. This analysis studied children aged 2–18 years (n=22,103) from 5 nationally representative surveys of dietary intake to identify the top sources of empty calories for each location and to compare trends from 1994–2010 by location for these key food groups.

The percent of total intake from empty calories at stores (33%), schools (32%), and fast food restaurants (35%) was not significantly different in 2009–2010. Sugar sweetened beverages (SSBs), grain desserts, high fat milk, pizza, and sandwiches were top sources of empty calories at all three locations. From 1994–2010, improvements occurred as the % empty calories in milk, pizza, fries, and SSBs decreased at schools and stores. SSBs from schools were lower in % added sugar than fast food SSBs as schools replaced caloric colas with fruit juice drinks. However, large increases in the % added sugar in school‐bought milk resulted in higher % empty calories for school compared to store‐bought milk across time. Fries from schools were higher in % solid fat than store‐bought fries, and school pizza was no better than fast food pizza in % empty calories.

In 2009–10, schools resembled fast food restaurants in their contributions to empty calories; nevertheless, stores remain the major source of empty calorie intake (436 ± 8.4 kcal/d) for US children.

Grant Funding Source: Funding for this study comes from the Robert Wood Johnson Foundation (Grant 67506) and the National Institutes of Health (R01 HL104580 and CPC 5 R24 HD050924).
Modulated light wave tumor therapy [MLW]: case study
Authors: Tulp Orien L , Einstein George P , Chow Tin , Wnuk Michael P , Branly Rolando
Published: June 2021

MLW was developed as the GP Einstein optical system as an alternative to conventional approaches to tumor therapy where such conventional therapies may not be indicated. By application of MLW we were able to shrink an abdominal tumor mass from 37 mm to 5 mm without chemotherapy or invasive surgical treatment. A controlled dose of modulated light irradiation, resulting in a change of the physiologic properties of the targeted tissue and bring their characteristic frequencies to the levels characteristic of corresponding healthy tissues. In MLW the Electromagnetic wave emitted by a modulated light wave and absorbed by a human tissue may serve as a “messenger” so that pathologic changes may be corrected by natural tissue repair mechanisms. With individualization of MLW frequencies, the condition and degree of pathology and the time‐dependent properties of MLW it may be able to treat a wide range of abdominal tumors. Institutional Support
Induction of apoptosis in MCF‐7 and NCI/ADR‐RES cells by triazole‐containing estradiol analogs
Authors: Schneider Ryan A , Reiff Lindsey N , Dudley Richard W
Published: June 2021

A series of triazole‐containing estradiol analogs (A‐D) was designed and synthesized in an attempt to generate compounds with increased D‐ring bulk. We hypothesized that these compounds would function as estrogen receptor (ER) antagonists and reduce proliferation of ER dependent cells. These compounds possessing varying degrees of lipophilicity and sterics were screened for anti‐proliferative activity in ER‐positive MCF‐7 cells and ER‐negative NCI/ADR‐RES cells. Visual examination of cells following increasing concentrations of C and D revealed gross morphology suggestive of apoptosis, whereas A and B elicited no apparent effects. Treatment with 50 μM of C and D reduced cell number by 41% and 58% respectively compared to control in MCF‐7 cells. Interestingly, NCI/ADR‐RES cell number was reduced by 61% and 69% with 50 μM of C and D respectively, suggesting that C and D function in an ER independent mechanism. Western blotting analysis demonstrated that C and D increased expression of cleaved caspases‐3 and ‐7 in NCI/ADR‐RES cells and cleaved caspase‐7 in MCF‐7 cells. C and D also increased expression of cleaved caspase‐9, but not caspase‐8, demonstrating induction of an intrinsic apoptotic pathway. These results suggest structural modifications affording increased bulk and lipophilicity to the D‐ring of estradiol generate compounds that function to induce intrinsic apoptosis in an ER independent mechanism.
The role of reactive oxygen species in the apoptotic effects of curcumin and simvastatin on lung cancer cell line
Authors: Lee Sang Haak , Kim In Kyoung , Lee Hye In , Lee Hwa Young , Ban Woo Ho , Kim Sei Won , Kang Hyeon Hui , Moon Hwa Sik
Published: June 2021

Curcumin is known to have anti‐inflammatory properties and induce apoptosis of cancer cells. The statins have been proven as effective anticancer agents through inhibition of cell proliferation and induction of apoptosis. However, the precise molecular anticancer mechanisms and synergic effects of these agents have not been elucidated in lung cancer cells.

Curcumin and simvastatin caused morphologic changes in A549 cells and inhibited the growth of the cell in a concentration dependent manner, especially the synergistic inhibition of cell proliferation with simvastatin (1 uM) and curcumin (20 uM). Curcumin promoted the expression of apoptosis related genes such as active caspase‐3, 9, p53 and p21 after 24 hrs. Intracellular reactive oxygen species (ROS) were significantly increased after treatment with curcumin and simvastatin up to 24 hrs in a dose dependent manner. Cells were treated with antioxidant N‐acetyl‐L‐cystein (NAC) before the simvastatin and curcumin, and the results showed that NAC decreased the intracellular ROS level and reversed the decreased cellular viability induced by the agents.

Our data indicates that combination of curcumin and simvastatin has synergistic anti‐proliferative effects. Therefore, we suggest that curcumin and simvastatin may have anticancer and potential chemopreventive actions through ROS‐mediated apoptosis pathway.
Differential effects of cisplatin on lung cancer cells and primary neurons: roles of small GTPase RhoA
Authors: Weng Zhiying , Friesland Amy , Lu Zhe , Chen Yan‐Hua , Longo Frank M , Boykin Christi , Lu Qun
Published: June 2021

Cisplatin‐induced peripheral neurotoxicity poses a major clinical problem, however cisplatin's mechanism of injury to nonmitotically active neurons is not clear. This study examined differential effects of cisplatin on human lung cancer cell lines and primary mouse neurons. In cancer cells, cisplatin disrupts filamentous‐actin organization and increases G‐actin in the nucleus. Mitochondria aggregated in the cytoplasm yet its matrix components became accumulated in the nucleus accompanying the translocation of actin. In addition, cisplatin selectively activated intrinsic apoptosis pathways of cancer cells but did not activate caspase‐8 mediated cell death, or activate the small GTPase RhoA. LM11A‐31 and Y‐27632, which suppress RhoA signaling, had no effect on lung cancer cell proliferation. The apoptosis pathway activated by cisplatin was also not regulated by LM11A‐31 or Y‐27632. However, in neurons, cisplatin reduced neuronal branching, disrupted growth cone organization, and decreased the amount of G‐actin, all of which can be reversed by RhoA inhibitors. Cisplatin treatment induced mitochondria aggregation and the matrix accumulation in the nucleus. Our studies suggest cisplatin‐induced neurodegeneration correlates with RhoA activation and support RhoA suppression as a potential target for ameliorating cisplatin‐induced neurotoxicity. Supported by NIHCA111891 and NIHCA165202.
Differential Expression of Renin‐Angiotensin System Components in the Choroid Plexus of Betamethasone Exposed and Control Sheep
Authors: Marshall Allyson Catherine , Shaltout Hossam A , Pirro Nancy T , Rose James C , Diz Debra I , Chappell Mark C
Published: June 2021

The use of antenatal betamethasone (BM) is a widely accepted therapy to accelerate lung development and improve survival in preterm infants. We have developed an experimental model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. Past studies show BM‐exposed (BMX) offspring develop elevated blood pressure and altered baroreflex sensitivity by 6‐months of age. In this study, we compared the synthesizing components of the renin‐angiotensin system (RAS) including renin, angiotensinogen, ACE, ACE2, and neprilysin (NEP) in the choroid plexus from the 4th ventricle (ChP4) of male BMX and control offspring at 6‐months. No difference in the three peptidase activities was evident between BMX and control offspring; however, ACE2 activity was 3‐fold higher than either NEP or ACE. Moreover, all three enzymes were equally enriched ~2.5 fold in ChP4 brush border membranes (BBM) by Ca2+ precipitation. Both prorenin and active renin expression were detected in the ChP4; renin protein was significantly lower in the ChP4 of BMX animals (0.41 ± 0.03 vs 0.20 ± 0.03, p<0.05, N=4) and negatively correlated to Ang I‐intact angiotensinogen content (r = 0.78; p<0.01). We conclude that the ChP4 expresses all components of the RAS that would lead to local production of Ang II and Ang‐(1–7), although BMX may downregulate this system through the reduced expression of renin. HD47584
Pharmacological evaluation of Cissus quadrangularis fractionated extracts for bronchodilatory activity using Guinea pigs
Authors: Patil Savita Dattatray , Kumavat Narender Kumar
Published: June 2021

BACKGROUND AND PURPOSE

The bronchospasm in bronchial smooth muscle was the most studied feature of asthma and COPD. In the present study, we characterized the pharmacological activity of successively extracted CQME and CQEAE.

MATERIALS AND METHODS

The Bronchodilatory activity of CQME and CQEAE were investigated in a guinea pig bronchoconstriction model using restrained double chamber plethysmograph respectively.

RESULTS

Histamine induced bronchoconstriction in guinea pigs, exhibited marked inhibitory activity against histamine challenge with specific airway resistance (RxV) 3.07, and 4.12 in comparison to RxV of salbutamol 1.87 and histamine control group 6.48 on CQME and CQEAE administration.

CONCLUSION

These results demonstrate that CQME induced remarkable bronchodilator activity, so CQME may be beneficial in treating airway obstructive pulmonary diseases.
Genetic influences in the development of Amiodarone‐induced pulmonary fibrosis (AIPF)
Authors: Hartog Matthew , Herron Bruce , Lawrence David , Ding Xinxin
Published: June 2021

Amiodarone (AMI) is a class III antiarrhythmic drug that is known to cause irreversible pulmonary fibrosis within a subset of humans. The mechanism of toxicity is currently unknown but is thought to involve an immune response component. As there is no clear relationship between dose received and time of onset, and in light of known drug susceptibilities due to DNA polymorphisms, we propose that there may be a genetic predisposition to the development of AIPF. In order to model the genetic diversity of the human population a diverse panel of ten inbred mouse strains was selected. Sub‐acute and chronic treatment models were developed to identify genetically dependent responses predictive of AIPF onset. The toxicity phenotypes will be correlated with previously gathered microarray data from the inbred mouse panel to identify genetic factors relevant to the onset and development of AIPF. Divergent responses in multiple markers of pulmonary immune function, such as total cell count recovered, using bronchoalveolar lavage, total number of macrophages and lymphocytes, and CD4/CD8 T cell ratio, have segregated by genetic background and demonstrate a genetic component in response to AMI treatment.