bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre‐pregnancy BMI, physical activity and resting energy expenditure predicts body composition in pregnancy
Authors: Begum Fatheema , Colman Ian , McCargar Linda , Bell Rhonda C , APrON Study Team
Published: June 2021

A high proportion of women exceed gestational weight gain (GWG) recommendations, but the body composition of women and factors influencing these changes are not explicit. The study objective was to describe the association between pre‐pregnancy body mass index (BMI), lifestyle factors, resting energy expenditure (REE) and fat mass (FM) accretion during pregnancy. Pregnant women (n=600) were measured 2–3 times during pregnancy; data on weight, body composition (skin folds), diet (24 hour recall) and physical activity (questionnaire) were collected. Data was analysed by linear mixed regression. Women with normal and overweight BMI gained similar amounts of total FM while obese women gained less FM and had a slower rate of FM accretion (p<0.01). Sports score was inversely associated with FM (p<0.01), while REE was positively associated with FM (p<0.01). In longitudinal analyses, overweight and obese women had lower sports scores (p<0.05) and higher REE (p<0.01) compared to women with normal BMI. Energy and macronutrient intake did not differ among BMI groups. Energy intakes in overweight and obese women were less than their estimated energy requirements (p<0.01). Effective intervention programs promoting optimal GWG should account for variations in individual woman's energy expenditure. Future studies estimating energy intake requirements during pregnancy according to pre‐pregnancy BMI are warranted.

Grant Funding Source: Alberta Innovates‐Health Solutions
Reliability of adipose tissue quantification using water suppressed and non‐water suppressed MRI in obese women
Authors: Spencer Matthew D , Pineda Jesica N , Haller Sarah F , Moran Raksa B , Lorenzo Santiago , Bernhardt Vipa , Bassett J Todd , Weatherall Paul T , Babb Tony G
Published: June 2021

Evaluating fat distribution is important in the study of obesity; this requires valid, reliable measures of visceral (V) and subcutaneous (sQ) adipose tissue. This study compares V, sQ and total (T=V+sQ) adipose tissue using water suppressed (i.e., fat only; FO) and non‐water suppressed (NWS) MRI, and establishes test‐retest reliability on these measures.

20 obese women (36 ± 6 yr; 36 ± 6 kg•m−2) underwent FO and NWS scans to quantify V, sQ, and T adipose tissue at the 2nd/3rd lumbar vertebra. NWS and FO scans were analyzed twice (test‐retest), starting with threshold determination (partitioning fat/non‐fat pixels).

Test‐retest reliability was high (r>;0.99) for NWS values of V, sQ and T. V was similar (p>;0.05; r>;0.99) between NWS (0.117±0.054) and FO (0.118±0.057 kg). Small differences (p<0.05) were observed between NWS and FO for sQ (mean Δ: 0.012±0.012 kg; r>;0.99) and T (0.013±0.022 kg; r>;0.99). Test‐retest reliability of FO revealed minor differences (p<0.05) for V (mean Δ: 0.003±0.007 kg), sQ (0.001±0.003 kg) and T (0.005±0.010 kg; r>;0.99 for all); these were associated with differences in user‐determined threshold (V: r=−0.94; sQ: r=−0.89; T: r=−0.94). Differences were abolished (p>;0.05) when FO images were re‐analyzed (n=10) using original thresholds.

NWS and FO provide similar and reliable estimates of V, sQ and T in obese women. Thus, FO offers a reliable, convenient alternative to NWS.
Positive effect of white button mushrooms when substituted for meat on body weight and composition changes during weight loss and weight maintenance – A one‐year randomized clinical trial.
Authors: Poddar Kavita H , Ames Meghan , Chen Hsin‐Jen , Feeney Mary Jo , Wang Youfa , Cheskin Lawrence J
Published: June 2021

Decreasing the energy density (ED) of the diet is an important strategy for controlling obesity. This one‐year, randomized clinical trial examined the effect of substituting mushrooms for red meat, compared to a standard diet, on weight loss and maintenance among adults seeking weight loss. 64 women and 9 men; mean age 48.4yrs completed anthropometric measurements and 7‐day food records four times during a standardized weight loss and maintenance regimen. At the end of the 1‐year trial, participants who substituted mushrooms for meat (n=36) reported lower energy (kcals) and fat intake (g) (mean±[SE] = −123±113 and −4.25±6.88), lost more pounds and percent body weight (−7.03±3.34, 3.6% of their starting weight), achieved lower body mass index (−1.53±0.36), waist circumference (−2.6±3.5inches) and percent total body fat (−0.85±0.53) compared to participants on the standard diet. People following the mushroom‐rich diet maintained the weight loss well and weighed 7 lbs less than before starting their diet plan. Thus, encouraging adults to substitute edible mushrooms for red meat in three meals/week was found to be a useful strategy for enhancing weight loss and maintenance efforts among overweight/obese adults.
Deoxycholic acid is involved in the initiation and progression of atherosclerosis.
Authors: Shimizu Hidehisa , Hagio Masahito , Yoshitsugu Reika , Kikuchi Keidai , Joe Ga Hyun , Hara Hiroshi , Ishizuka Satoshi
Published: June 2021

Deoxycholic acid (DCA), a kind of bile acids, is elevated in serum of patients with chronic kidney disease (CKD). The present study examines the influence of DCA on the functions of vascular smooth muscle cells (VSMCs) because CKD is associated with cardiovascular diseases such as atherosclerosis. As a result, DCA induced JNK phosphorylation and migration of VSMCs whereas JNK inhibitor prevented DCA‐induced the migration. In addition, phosphorylation of c‐Jun, a downstream molecule of JNK, was promoted upon stimulation with DCA. On the base of this result, we checked whether DCA promotes the expression level of PDGFRβ that has a c‐Jun binding site in the promoter region. When VSMCs were incubated with DCA for 24 h, the expression level of PDGFRβ was upregulated. Furthermore, increased ERK phosphorylation by incubation with DCA for 24 h correlated with DCA‐induced the expression of PDGFRβ. These results demonstrate that DCA directly influences the functions of VSMCs. Taken together, elevated serum concentration of DCA is involved in the pathogenesis of atherosclerosis in patients with CKD. This work is supported by Regional Innovation Strategy Support Program of the MEXT, The Japanese Government.
Systemic fatty acid uptake and skeletal muscle inflammatory pathway activation may contribute to the variability in insulin sensitivity found in obesity
Authors: Van Pelt Douglas W. , Newsom Sean A. , Schenk Simon , Horowitz Jeffrey F.
Published: June 2021

The aim of this study was to identify factors that may underlie differences in insulin sensitivity (Si) among a seemingly homogeneous cohort of obese women. We measured insulin sensitivity (IVGTT), basal fatty acid rate of disappearance (Rd), whole‐body fat oxidation, and performed a muscle biopsy in 21 obese women. Si was inversely related to fatty acid Rd (R2=0.21; P=0.04). We then compared a subset of these subjects with the lowest Si (LOW; = 2.1 (mU/L) −1·min−1; n=7) with a subset who had relatively normal Si (NORM; = 3.4 (mU/L) −1·min−1; n=8). Despite nearly identical adiposity and oxidative capacity in LOW vs NORM (BMI: 34±2 vs 34±1 kg/m2; %body fat: 48±1% vs 47±1%; waist circumference: 104±2 vs 104±2 cm; VO2max: 2.2±0.2 vs 2.3±0.1L/min), fatty acid Rd was nearly 40% greater in LOW (P=0.02). Activation of inflammatory pathways known to impair insulin action in skeletal muscle was also higher in LOW vs NORM (i.e. higher phosphorylated JNK, lower IκBα abundance; both P<0.05). In contrast, LOW and NORM exhibited no differences in systemic markers of inflammation (i.e. TNFα, IL‐6, MCP‐1), basal whole‐body fat oxidation, and intramyocellular lipid concentrations. In summary, increased fatty acid uptake may activate inflammatory pathways in skeletal muscle, which in turn may contribute to differences in Si among obese women who were otherwise largely indistinguishable.

Grant Funding Source: ADA (#1–03‐JF‐10) and NIH (#R01 DK077966)
Redox Regulation of eicosanoid metabolism is critical for the resolving inflammation in experimental colitis
Authors: KAUSHAL NAVEEN , Kudva Avinash K , Patterson Andrew D , Cantorna Margherita , Prabhu Sandeep
Published: June 2021

Increased levels of pro‐inflammatory lipid mediators called prostaglandins (PGs), particularly PGE2 in patients with active ulcerative colitis (UC) indicates its critical role in inflammatory bowel disease (IBD). Therefore, resolving inflammation by therapeutic strategies that can reduce PGE2 levels are promising to treat UC. Recently, we have reported that Se as a part of redox regulatory proteins can resolve inflammation by modulating the cyclooxygenase‐2 (COX‐2) dependent PG synthesis pathways. The aim of the present study is to dissect the redox sensitive inflammatory metabolic pathways leading to PGE2 inactivation that can help in the resolution of inflammation. Currently, we demonstrated that in a DSS induced experimental colitis model Se supplementation (0.4 and 1.0ppm), which is above the adequate limits (80ppb), completely relieved the classical signs of colitis‐associated inflammatory markers such as TNF‐α, IL‐1β and IFN‐γ. A concomitant increase in the expression of 15‐PGDH in the colons of these mice indicated that Se by regulating the metabolic pathways of pro‐inflammatory PGs can mitigate the inflammatory processes in IBDs. Studies in macrophage‐selenoproteins specific genetic knockouts indicated their critical role in activating resolution pathway of inflammation. Current study addresses the central role of redox equilibrium in the inflammatory processes associated with UC and the approaches to manipulate these redox networks to treat IBD. Understanding the role of Se in the resolution of inflammation and the molecular mechanisms underlying such protective effects of functional foods can be used as an adjunct therapy in colitis.

Grant Funding Source: NIH
Depolymerized cranberry proanthocyanidins attenuate TNFα‐induced inflammation in human adipocytes and induce paraptosis‐like cell death in HepG2 hepatoma cells
Authors: Okla Meshail , Ou Keqin , Gu Liwei , Chung Soonkyu
Published: June 2021

Cranberries are rich source of proanthocyanidins (PAC) that possess plethora health benefits including anti‐proliferative and anti‐inflammatory activities. However, 85% of PAC in Cranberries exist as polymers which cannot be absorbed. Recently, we have developed a depolymerization procedure to convert PAC polymers into absorbable oligomers. The aim of this study was to determine novel functions of depolymerized cranberry proanthocyanidins (dPAC). First, we evaluated the anti‐inflammatory potential of dPAC in primary human adipocytes. Our data showed that dPAC 1) reduced adipose‐derived stem cell differentiation in a dose‐dependent manner, 2) dampened the basal and TNFα‐stimulated pro‐inflammatory gene expressions and 3) inhibited MAP‐kinase ERK and JNK activation. Next, we assessed the anti‐proliferative and apoptotic potentials of dPAC on hepatocellular carcinoma HepG2 cells. Our data showed that dPAC effectively 1) reduced proliferation, 2) increased autophagy and 3) induced paraptosis‐like cell death in HepG2 cells. Collectively, dPAC exerted unique anti‐inflammatory effects in unmodified cells, and anti‐proliferative and pro‐apoptotic effects in modified cancer cells.

Grant Funding Source: University of Florida, Institute of Food and Agricultural Sciences
Docosahexaenoic and eicosapentaenoic acid supplementation reduces growth of basal‐like and claudin‐low breast cancer subtypes in obese mice
Authors: Ford Nikki Ann , Barnett Kelsey , Hursting Stephen D
Published: June 2021

The prescription drug Lovaza® contains ethyl esters of the marine based omega 3 fatty acids docosahexaenoic acid (DHA; 38% w/w) and eicosapentanoic acid (EPA; 47%) which play major roles in inflammation, cell membrane fluidity and cell signaling. The effects of omega‐3 fatty acid supplementation on ER‐negative basal‐like and claudin‐low breast tumors, which are aggressive subtypes with poor prognoses, are not well characterized. Furthermore, the ability of EPA and DHA to offset the enhancing effects of obesity on these cancers is unknown. Female C57BL/6 mice were fed either a control (AIN‐76A) diet, diet‐induced obesity regimen (DIO; 60 kcal % fat diet), or DIO diet + Lovaza (2.5g / kg) for 6 weeks. All mice were then orthotopically injected with a tumor cell suspension derived from MMTV‐Wnt‐1 mammary tumors (Wnt‐1 basal‐like) or a clonal isolate from the same tumors shown to have a molecular profile similar to human claudin‐low breat tumors (M‐Wnt claudin low). Tumors were allowed to grow until one or more tumors reached 1 cm in diameter in any direction and then mice were killed and tumors were paraffin embedded or snap frozen for further analysis. Wnt‐1 and M‐Wnt mammary tumor weight was significantly reduced by Lovaza supplementation in obese mice in parallel with enhanced cellular apoptosis. This work was supported by a Breast Cancer Research Foundation Grant and Glaxo‐Smith Kline donated the Lovaza® capsules.

Grant Funding Source: Breast Cancer Research Fund
Cs‐5 modulating immune response in a normal adult model
Authors: Gao Ling , Zhang Yan , Lu Ji‐Hong , Tan Ning‐Zhi , Zhu Jia‐Shi
Published: June 2021

Cs‐5, a mycelia fermentation product of Cordyceps sinensis, has shown health benefits in several pharmacology areas. BABL/c mice (8‐mo) were randomized into 3 groups, receiving vehicle or Cs‐5 at a dose of 0.5 (LD) or 1.0 g/kg (HD) for 4 wks by gavage, to examine the Cs‐5's effect on splenocyte proliferation and cytokine secretions in response to PMA+Ionomycin. As compared to 2‐mo young controls, serum IgA and IgG were increased in 8‐mo controls (p<0.01). Compared to 8‐mo controls, serum IgA was decreased ~50% (P<0.01) and IgG increased (+46% & +27%, P<0.001) at both doses of Cs‐5. Splenocyte proliferation did not change with aging or with Cs‐5. Compared to 2‐mo controls, the 8‐mo adult controls showed increased ratio of IFN‐γ/IL‐4 as a measure of Th1/Th2 balance (P<0.01). Compared to 8‐mo controls, Cs‐5 (1) altered splenocyte response to stimuli in the HD group with enhanced IFN‐γ production (+292%, P<0.01); (2) decreased the ratio of IFN‐γ/IL‐4 in the LD group (−66%, P<0.01), but increased the ratio in the HD group (+1334%, P<0.01); (3) increased IL‐22 in the HD group (+281%, P<0.01); (4) decreased the TGF‐β secretion at both doses (−96% & −77%, P<0.01). In summary, in normal adult mice lacking inflammatory stimuli, Cs‐5 potentiates splenocytes towards Th1 immunity and suppresses responses of Th2, Th17 and Treg cells to the experimental stimuli. Thus Cs‐5 may modulate Th1/Th2/Th17 balance through down‐regulation of Treg.
Association between metabolic syndrome and serum vitamin D concentration in patients undergoing coronary artery bypass graft
Authors: ROMANELLI MASSIMILIANO MARCO CORSI , Dozio Elena , Dogliotti Giada , Barassi Alessandra , Vianello Elena , Malavazos Alexis Elias , D'Eril Gianlodovico Melzi
Published: June 2021

Vitamin D (VitD) concentration is suggested to be associated with obesity, metabolic syndrome (MS) and increased cardiovascular disease risk. In this study we evaluated 25‐OH‐VitD level in patients affected by coronary artery disease undergoing coronary artery bypass graft and we studied its association with MS.

Blood samples of patients and healthy controls (C) were collected to measure 25‐OH‐VitD level by direct competitive immunoluminometric assay. A complete biochemical blood profile and anthropometric measures were also taken.

Patients displayed lower 25‐OH‐VitD level compared to C. Patients were then classified as having or not MS according to ATPIII criteria. In the MS group 25‐OH‐VitD level resulted lower than in the group without MS. Patients were also subdivided in three groups according to 25‐OH‐VitD level (VitD deficiency: < 20 ng/mL; VitD insufficiency: 20–30 ng/mL; VitD adequate level: >; 30 ng/mL). Patients with VitD deficiency displayed increased fasting glucose, glycated hemoglobin, insulin resistance and lower HDL‐cholesterol. The percentage of patients with MS resulted also higher in this group.

In conclusion, although in patients with advanced coronary artery disease a general reduction in VitD level has been observed, it seems that this reduction resulted strongly related to the presence of MS.

DiaSorin S.p.A.,Vercelli, Italy
Oxidation of SERCA2 at cysteine 674 increases ER stress during hind limb ischemia in mice
Authors: Mei Yu , Thompson Melissa D. , Silver Marcy , Cohen Richard A.
Published: June 2021

Reversible glutathione adducts on the cysteine 674 (C674) thiol of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) stimulate Ca2+ uptake activity, endothelial cell (EC) angiogenic signaling, and migration. This study was to determine if oxidation of SERCA C674 and endoplasmic reticulum (ER) stress affects angiogenesis during hind limb ischemia. SERCA2 C674 serine mutant heterozygote knock in (SKI) mice, lacking one allele for the redox‐regulated C674 thiol, had impaired blood flow recovery after femoral artery ligation. Immunostaining demonstrated increased SERCA C674 thiol oxidation in microvascular endothelium of ischemic limbs, and double staining revealed increased BIP expression co‐localized with the EC marker isolectin B4. Staining was greater in SKI compared with WT, indicating thiol oxidation or mutation in ischemia is associated with ER stress activation. Western blotting showed ER stress markers p‐PERK and CHOP were greater in both non‐ischemic and ischemic SKI limbs compared to WT. Cultured SKI microvascular ECs showed smaller Ca2+ stores, and higher basal and hypoxia‐induced levels of BIP and CHOP. Collectively, these data suggest that lack of the SERCA C674 thiol caused by oxidation or mutation increases EC ER stress. Thus, oxidation of SERCA2 C674 and associated Ca2+ store depletion and ER stress during hind limb ischemia may contribute to impaired angiogenesis.

Funding NIH RO1 HL31607
Trichostatin A epigenetically increases calpastatin expression, and inhibits calpain activity and calcium‐induced SH‐SY5Y neuronal cell toxicity: implication of histone deacetylase inhibitors in Alzheimer¡ s disease
Authors: Jo sangmee , Seo Jungwon , Byun Catherine Jeonghae , Park Jinsil , Lee Hyeon Ju , Hwang Soojin , Jo Inho
Published: June 2021

Calpains are involved in calcium‐induced neuronal cell toxicity. The activity of calpains is regulated by an inhibitor calpastatin, and increased activity of calpains and marked decreased calpastastin are often found in Alzheimer's disease (AD). Here, we examined whether and how Histone deacetylase (HDAC) inhibitor trichostatin A (TSA) inhibits calcium‐induced neuronal cell death using differentiated SH‐SY5Y neuroblastoma cells. TSA significantly increased both mRNA and protein level of calpastain, but caused no change of calpain 1 and calpain 2. Furthermore, TSA‐stimulated increase of calpastatin was accompanied by a significant attenuation of ionomycin‐induced autolysis of calpain 1, but not of calpain 2, and calpain‐dependent spectrin cleavage. A chromatin immunoprecipitation assay revealed the increased levels of acetylation at lysine 5 of histone H4 (H4K5‐ace), H3K9‐ace, and H3K14‐ace within a promoter region of calpastatin in TSA‐treated cells. Finally, TSA significantly decreased cell toxicity induced by ionomycin. This study demonstrated that TSA attenuates calcium‐induced neuronal cell death by the inhibition of calpain activity which is mediated in part by increased calpastatin expression via histone hyperacetylation within calpastatin promoter region. (Supported by a grant of the Korean Health Technology R&D Project, MHW, Republic of Korea (A120004))
THE ANTAGONISM OF TRPV1 RECEPTORS PREVENT THE CARDIOVASCULAR CHANGES DURING SEPTIC SHOCK
Authors: Alves Fernando Ferrari , dos Reis Daniel Gustavo , Resstel Leonardo , Correa Fernando Morgan
Published: June 2021

Introduction

During sepsis there are changes in the cardiovascular system that is characterized by a drop in blood pressure (BP), an increase in heart rate (HR). It has been descript that during the septic shock the endocannabinoid system is active and in high concentrations they could act in vaniloids receptors (TRPV1). Moreover the endocannabinoids, acting in TRPV1 receptors are potent vasodilators, however, your participation has not been fully studied in the septic shock induced by cecal ligation and puncture (CLP).

Methods

Wistar rats had a radio‐telemetry probe introduced in a descendent aortic to measure cardiovascular activity. At the same time the sepsis was induced by CLP. The TRPV1 antagonist SB366791 in a dose of 2ml/kg was injected intravenous immediately after the end of surgery and the cardiovascular parameters is measured by 8h. Institution's Animal Ethics Committee (N‐082/2010)

Results

The intravenous treatment with SB366791 a TRPV1 antagonist did not alter the (BP) or (HR), PAM (97±4 vs 96±3 mmHg; t= 0.6, p>;0.05 n=5) and HR (343±4 vs 345±4 bpm; t=0.2; p>;0.05). The treatment with SB366791 was able to decrease the fall in (BP) (F(1,294)= 88, p<0.0001) and the increase in (HR) (F(1,294)=17, p<0,0001) during the septic shock caused by CLP.

Conclusions

The present results indicate that the TRPV1 participate in the genesis of cardiovascular changes during septic shock caused by CLP.
In Vitro and In Vivo Characterization of the Novel Opioid Antagonists NAP and NAQ
Authors: Braithwaite Amanda , Giuvelis Denise , Streicher John , Yuan Yunyun , Zhang Yan , Bilsky Edward
Published: June 2021

Opioid use, abuse and addiction have risen dramatically over the past few years. Opioid antagonists are used to manage acute opioid withdrawal, addiction, and peripheral side effects of opioid therapy. We have developed reversible and selective mu opioid neutral antagonists to aid in opioid overdose therapy while potentially minimizing withdrawal as compared to inverse agonists. We characterized two novel 6β‐N‐heterocyclic naltrexamine derivatives (NAP and NAQ) in mouse models of opioid‐mediated antinociception, locomotor activity, gastrointestinal transit, physical dependence and acetic acid writhing and also in an in vitro beta‐arrestin2‐GFP translocation assay. NAQ produced dose‐and time‐dependent reversal of morphine‐induced antinociception and hyperlocomotion and suppressed writhing behavior after acetic acid administration. In chronic morphine treated mice, NAQ produced modest withdrawal at higher doses that was much lower in intensity compared to equivalent doses of naloxone. NAP and NAQ antagonized DAMGO induced beta‐arrestin2 recruitment in MOR expressing cells. NAP also had a different pharmacokinetic profile, having a longer time to reach peak effect and a longer duration of action. NAP and NAQ demonstrate a unique pharmacology and may represent new and improved therapies for managing opioid overdose, addiction, and side effects associated with opioid analgesics.
Peroxisome Proliferator Activated Receptor‐δ Agonist GW0742 Prevents the Development of Paclitaxel‐induced Peripheral Neuropathy in Mice
Authors: Esposito Emanuela , Crupi Rosalia , Paterniti Irene , Campolo Michela , Cuzzocrea Salvatore
Published: June 2021

Peroxisome proliferator activated receptor (PPAR)‐δ is found in all the areas of origin of the spinoreticulothalamic and spinothalamic tracts, but also in the terminal fields. PPAR‐δ could be implicated both in the regulation of pain sensation and in pain transmission acting as immediate early gene controlling the transcription of genes encoding protein implicated in the facilitated spinal transmission and the central sensitization, such as COX‐2 or iNOS. Painful neuropathy was induced in male mice by administration of paclitaxel (2 mg/kg, i.p.) on 4 alternate days. Paclitaxel‐treated animals received PPAR‐δ agonist (GW0742; 0.3mg/kg, i.p.) daily for 14 days (days −1 to 13). Both the activation of glial cells at day 29 and the time course of proinflammatory cytokine release within the spinal cord were also determined. Repeated administration of GW0742 prevented the development of thermal hyperalgesia and mechanical allodynia in paclitaxel‐treated mice. GW0742 treatment prevented spinal microglial and astrocytic activation evoked by paclitaxel at day 29 and attenuated the early production of spinal proinflammatory cytokines IL‐1β, IL‐6 and TNF‐α. Our results confirm changes in the reactivity of glial cells during the development of peripheral neuropathy induced by paclitaxel and support a preventive effect of GW0742, probably via glial cells reactivity reduction, on the development of this neuropathy.
Effect of charcoal treatment on rats with adenine‐induced chronic renal failure
Authors: Ali Badreldin H. , Al Za'abi M. , Waly M. I. , Ramkumar A. , Madanagopal T. , Lawati I. , Nemmar A.
Published: June 2021

Charcoal, the black residue comprising of carbon and ashes, produced by slow pyrolysis of biological substances, has been used to cure toxicity by binding to the toxic substance and precluding its absorption by the gastro intestinal tract, thereby, preventing the toxicity caused by oral ingestion. In this work we analyzed the effect of charcoal given in the feed at concentrations of 5%, 15% or 20% in rats with adenine‐induced chronic renal failure (CRF). Eight groups, of six rats each, were treated with normal feed (controls), 0.75% adenine in feed, charcoal 5%, 15% or 20%, either alone or with adenine for 28 consecutive days. At the end of the treatment, samples of urine, blood and kidney were collected from all the rats to measure several biochemical, structural and functional parameters. The results showed that adenine induced changes in urine, plasma and kidney tissues of rats typical of CRF. These changes were significantly ameliorated by charcoal given at a concentration of 20%. The mitigation of toxicity induced by lower doses of charcoal was not statistically significant. The results suggest that charcoal (20%) is a useful sorbent agent in adenine‐induced CRF in rats.

This work was supported by SQU.
Attenuation of 1,2,3‐trichloro‐4‐nitrobenzene nephrotoxicity by antioxidants and inhibitors of biotransformation
Authors: Racine Christopher , Ferguson Travis , Preston Deborah , Anestis Dianne , Rankin Gary
Published: June 2021

Chloronitrobenzenes (CNBs) are chemical intermediates used to manufacture a wide variety of compounds. CNBs are also nephrotoxicants in a rat renal cortical slice model. The purpose of this study was to explore the effects of antioxidants and inhibitors of renal biotransformation systems on 1,2,3‐trichloro‐4‐ nitrobenzene's (1,2,3‐TC4NB) nephrotoxic potential using isolated renal cortical cells (IRCC) from male Fischer 344 rats. Nephrotoxic potential was determined by incubating 1, 2, 3 – TC4NB (0 or 1 mM) with the IRCC (4 × 106 cells/ml) for 60 minutes and measuring lactate dehydrogenase (LDH) release. In some experiments, the cells were pretreated with an antioxidant [glutathione (1.0mM), α‐tocopherol (1.0 mM), N‐acetyl‐L‐cysteine (2.0 mM) or ascorbate (2.0 mM)], a cytochrome P450 inhibitor [piperonyl butoxide, isoniazid or metyrapone (1.0 mM)], a FMO inhibitor [N‐octylamine (0.2 mM) or methimazole (1.0 mM)], a peroxidase inhibitor [mercaptosuccinate (0.1 mM)] or a cyclooxygenase inhibitor [indomethacin (1.0 mM)]. 1,2,3‐TC4NB nephrotoxicity was reduced by all antioxidants, N‐octylamine, metyrapone and mercaptosuccinate. These results suggest that free radicals play a role in 1,2,3‐TC4NB nephrotoxicity and may result from multiple biotransformation pathways/intermediates. (Supported in part by NIH Grant 5P20RR016477 to the West Virginia IDeA Network for Biomedical Research Excellence)
Antioxidant effect of phycobiliproteins on proteins and DNA exposed to a reactive oxygen species generating system.
Authors: Olvera‐Ramirez Roxana , Estrada_Perez Alan , Alcalde_Vazquez Raul , Muñoz Jose Luis
Published: June 2021

It is well known that cyanobacteria has been used as antioxidants in some toxicological models, as well as fluorescent markers and as natural pigments in food industry, but little is known about its role in oxidative stress protection. The aim of this study is to assess the possible protective effect of phycobiliproteins (PBP's) on proteins (BSA) and DNA exposed to a reactive oxygen species (ROS) generating system. A raw extract of PBP's was obtained from the cyanobacteria Arthrospira maxima and was used like antioxidant. A series of tubes with Bovine seroalbumine (BSA) were exposed to 10 μl of Cu (II) and 100 μL of ascorbic acid like a ROS generating system, also plasmidic DNA PGLO was exposed. Using spectrophotometry was demonstrated that BSA and DNA were affected. Another series of tubes were incubated under the same conditions but were added with different concentrations of the PBP's raw extract. The results showed that PBP's exhibit some protective effect against oxidative damage using 30 μL from FBP's extract in BSA and 100 μL in plasmidic DNA. Also was demonstrated that DNA plasmidic electrophoretic pattern was conserved when the PBP's extract was added.
Effect of claudin on cytochrome P450 activity
Authors: Shimizu Yoshimi , Kondoh Masuo , Watari Akihiro , Fukasawa Masayoshi , Yagi Kiyohito
Published: June 2021

Epithelial cells (ECs) cover the surfaces of the body and form the first‐line of defense against xenobiotics. The defense barrier comprises the intercellular seals, known as tight junctions (TJs), between adjacent epithelial cells and the intracellular defense systems, including cytochrome P450s (CYPs) and transporters. However, cross‐talk between the intercellular and the intracellular defense systems has not been investigated. Here, we investigated the effects of a TJs‐seal component, claudin (CL), on CYPs in Huh7 cells. A Huh7 sub‐cell line (S7d6) was screened for resistance to hepatitis C virus infection, which involves the CL‐1 co‐receptor. Western blot and quantitative PCR (qPCR) analyses revealed that CL‐1 was deficient in S7d6 cells. CYP3A4 activity was higher in S7d6 cells than in Huh7 cells and qPCR analysis confirmed that CYP3A4 mRNA was higher in S7d6 cells than in Huh7 cells. To evaluate functional CYP3A4 activity, we investigated the cytotoxicity of cyclophosphamide (CPA) in S7d6 cells because CPA is a substrate of CYP3A4 and is toxified by CYP3A4. S7d6 cells were more sensitive than Huh7 cells to CPA. These results suggest that CL‐seals might be associated with the activity of CYPs in the epithelial defense system. This work was supported by grants from MEXT (24390042) and from the Ministry of Health, Labor, and Welfare of Japan.
Influence of Short‐term High Salt Diet and Acute Exercise on Microvascular Reactivity in Humans
Authors: Cavka Ana , Grizelj Ivana , Goslawski Melissa , Drenjancevic Ines , Bian Jing‐Tan , Phillips Shane A
Published: June 2021

High salt diet contributes to the development of hypertension. The deleterious effects of high salt diet (HSD) may occur independent of and prior to the development of high blood pressure. We hypothesized that 1) microvascular flow induced dilation (FID) and acetylcholine induced dilation (AChID) are impaired after short‐term HSD and 2) acute exercise reverses endothelial function after short term salt loading. Healthy, inactive woman (N=15) were fed 6 g of NaCl for 7 days and then underwent a single progressive 15 min leg press WL session. Subcutaneous fat tissue biopsies were obtained before and after HSD and acute exercise. Resistance arteries from biopsies were cannulated for vascular reactivity measurements in response to flow (pressure gradient 10–100 cmH2O) and in response to acetylcholine (ACh, 10–9‐10–4 M). All subjects were normotensive before and urinary sodium was increased after HSD and exercise. Plasma renin activity and plasma aldosterone levels were reduced after HSD. FID and AChID were reduced after 7 days of HSD compared to pre‐HSD. Acute exercise restored FID and AChID post HSD. The presence of L‐NAME reduced FID and AChID at baseline and after exercise. However, there was no effect of L‐NAME on FID and AChID after HSD. These data suggest that 1) one week of HSD impairs microvascular FID and AChID and 2) acute exercise restores microvascular NO‐dependent dilation to flow and ACh.
A mechanistic collagen recruitment model can explain passive property differences in resistance arteries from salt sensitive, fawn hooded and brown norway rats on low salt diets
Authors: Hao Qing , Weinberg Brian D. , Lombard Julian H. , Carlson Brian E.
Published: June 2021

A mechanistic model for collagen recruitment and passive response was developed which predicts the stress of elastin and collagen fibers in middle cerebral arteries based on available pressure‐diameter data for salt sensitive (SS/JrHsdMcwi, n=8), fawn hooded (FHH/EurMcwi, n=11) and brown norway (BN/NHsdMcwi, n=10) male rats, all maintained on a low salt (0.4% NaCl) diet. In this model, which describes total vessel wall stress as a sum of elastin and collagen stresses, a Weibull distribution function is assumed to describe gradual recruitment of collagen fibers in the vessel wall. It was found that the peak recruitment strain parameter for collagen was relatively invariant within each rat strain based on independent analysis of the experimental data. Subsequently with the peak recruitment strain parameter fixed, the remaining parameters describing ratios of cross sectional elastin and collagen area to total vessel wall area and shape of the recruitment distribution can be determined by fitting the model to experimental data. Applying this model to SS, BN and FH rat data shows that average elastin tension is 2.91 N/m for BN, 2.9 N/m for FH and 3.2N/m for SS and average collagen tension is 49.3 N/m for BN, 76.0 N/m for FH and 86.0 N/m for SS. Therefore we can conclude that cerebral arteries of the SS rat have stiffer passive properties than those of FH and BN rats, even before onset of any difference in hypertensive phenotype.
SKA‐31, a positive modulator of SKCa and IKCa channels, increases systemic conductance and lowers arrterial pressure in an anesthetized pig model
Authors: Mishra Ramesh C , Mitchell Jamie , Wulff Heike , Belenkie Israel , Tyberg John V , Braun Andrew P
Published: June 2021

SKA‐31 regulates microvascular tone, tissue perfusion and blood pressure by acting on endothelial SKCa and IKCa channels. In this study, we have examined the hemodynamic effects of SKA‐31 in comparison to the established vasodilator sodium nitroprusside (SNP) in anesthetized domestic pigs. We measured left ventricular (LV), aortic and inferior vena cava (IVC) pressures and monitored levels of blood flow in the ascending aorta, right carotid, left anterior descending coronary and left renal arteries during acute intravenous infusions of SKA‐31 (0.1 to 5 mg/kg), followed by a single dose of SNP (5 μg/kg). SKA‐31 dose‐dependently and reversibly decreased mean aortic pressure (mPAO) to a level comparable to that produced by SNP (−23±3 vs. −28±4 mmHg). Mean IVC pressure did not change. Both SKA‐31 (1 to 5 mg/kg doses) and SNP increased systemic conductance, along with coronary and carotid artery conductances; renal conductance did not change. There was no change in LV stroke volume (SV) for any infusion, and heart rate was not altered following SKA‐31 administration (132±14 vs. 128±13 bpm). With no change in SV, the significant decrease in LV stroke work (SW) observed with either SKA‐31 or SNP was largely attributed to decreased mPAO. In summary, SKA‐31 significantly decreased mPAO by increasing systemic conductance, and did not appear to reduce cardiac contractility. Supported by the CIHR (JVT and APB) and the NIH (HW).
Adipose tissue artery‐derived TNF impairs dilation of skeletal muscle resistance arteries in obesity
Authors: Feher Attila , Szabo Andras , Bagi Zsolt
Published: June 2021

Despite its critical importance, factors responsible for altering the vasomotor behaviour of resistance arteries in obesity is poorly understood. We tested the hypothesis that soluble inflammatory mediators are released from arteries of adipose tissue (ATA), which act remotely on skeletal muscle resistance arteries (SMRA) to interfere with their dilator function. ATA and SMRA were dissected from the heart and gracilis muscle of lean or obese mice (60% of fat feeding, 3‐month), and changes in diameter was measured in pressurized (80 mmHg) arteries with video‐microscopy. The endothelium‐dependent dilation to acetylcholine (ACh) was significantly reduced in SMRA of obese mice. When SMRA from lean mice were serially connected to ATA from obese mice with a glass capillary, we found that dilation of SMRA to ACh was greatly reduced. When the ATA from obese mice were pre‐incubated with TIMP‐3, an inhibitor of ADAM‐17, ACh‐induced dilation of SMRA was significantly enhanced. Similarly, preservation of dilation was observed when ATA and SMRA were pre‐incubated with a TNF blocking antibody. Taken together, we identified ATA as the direct source of TNF, which via ADAM‐17‐dependent sheddase activity manner is released from ATA to interfere with dilation of skeletal muscle resistance arteries in obesity.
Novel methodology to simultaneously image endothelial and smooth muscle function in pressurized arteries
Authors: Wilson Calum , Saunter Christopher , Girkin John M , McCarron John G
Published: June 2021

Communication between the endothelium and smooth muscle is central to the control of vascular function. However, understanding this communication has been hampered by an inability to simultaneously measure the various signalling events that occur in endothelial and smooth muscle cells in arteries at physiological pressures. Here we describe the development of a novel imaging methodology to address this issue. Gradient‐index (GRIN) optics provides miniature, cylindrical rod lenses with flat faces and were inserted into the lumen of pressurised arteries. Endothelial imaging was enabled by a side‐viewing lens, fabricated by fixing a micro‐prism to the GRIN rod. GRIN imaging of the endothelium was combined with conventional epi‐fluorescent microscopy for smooth muscle intracellular measurements. By selectively loading the endothelium and smooth muscle with different Ca2+ indicator dyes, simultaneous measurements have been obtained from the two different cell types within the vessel wall. These results highlight the difference in time course and amplitude of Ca2+ signals between endothelial and smooth muscle cells. This work has been support by the Wellcome Trust, the British Heart Foundation, and an EPSRC doctoral training grant.
Central blockade of TLR4 improves cardiac function and attenuates pro‐inflammatory cytokines and oxidative stress in hypertensive rats
Authors: Dange Rahul Babulal , Agarwal Deepmala , Vila Jorge , Wilson Brad , Teruyama Ryoichi , Francis Joseph
Published: June 2021

Role of pro‐inflammatory cytokines (PICs) and oxidative stress within the paraventricular nucleus (PVN) in the pathogenesis of hypertension (HTN) is well established. Although role of toll‐like receptor 4 (TLR4) in various cardiovascular diseases is becoming evident, role of brain TLR4 in the pathogenesis of HTN has never been explored. We hypothesized that TLR4 upregulation within the PVN contributes to the development of HTN. Male SD rats were infused with Angiotensin II (AngII) (200 ng/kg/min) or vehicle by subcutaneous miniosmotic pumps; a subgroup of rats were given intracerebroventricular infusion of Viral Inhibitory Peptide (VIPER, a specific TLR4 blocker) or control peptide for 14 days. Mean arterial pressure (MAP) and cardiac function were evaluated by radio‐telemetry and echocardiography, respectively. PVN and heart tissues were analyzed by RT‐PCR and western blot. TLR4 expression was dramatically upregulated within the PVN of hypertensive rats. VIPER infusion attenuated MAP and improved cardiac function in hypertensive rats. Interestingly, VIPER infusion prevented the increase in PICs (TNF‐α and IL‐1β) and reduced oxidative stress markers (gp91phox and iNOS) in hypertensive rats. These results suggest that the brain TLR4 plays an important role in hypertensive response by modulating PICs and oxidative stress and that the central blockade of TLR4 exerts beneficial effects in HTN. Funding: LSU
Differential effects of pravastatin on secretion of pro‐ and anti‐angiogenic factors from trophoblast and endothelial cells
Authors: Gillham Haley Elizabeth , Banek Christopher Todd , Needham Karen , Gilbert Jeffrey
Published: June 2021

We recently reported pravastatin (Prav) lowers blood pressure but does not improve circulating angiogenic balance (↑soluble fms‐like tyrosine kinase‐1, sFlt‐1; ↑soluble endoglin, sEng; and ↓vascular endothelial growth factor, VEGF) in rats with placental ischemia induced hypertension. Since the placenta is thought to be the primary source of sFlt‐1 and sEng, we hypothesized Prav would have pro‐angiogenic effects in human umbilical vein endothelial cells (HUVEC) but anti‐angiogenic effects in trophoblast cells. Cells were cultured in atmospheric O2 (19%), physiologic normoxic (8%) and hypoxic (1.5%) conditions and treated with Prav (0, 10, 20 μmol/L) for 12 hours. Data analysis was by two‐way ANOVA and significance accepted when P<0.05. Hypoxia stimulated (P<0.05) VEGF and sEng but not sFlt‐1 concentrations in the media of BeWo trophoblast cells. An interaction between O2 and Prav was observed such that sEng decreased (P<0.05) with increasing doses of Prav. In Jar cells, hypoxia did not affect VEGF or sFlt‐1 but decreased sEng secretion into culture media. Prav increased (P<0.05) sEng secretion from both normoxic and hypoxic Jar cells in a dose dependent manner. Hypoxia and Prav had no effect on VEGF, sFlt‐1 or sEng in HUVECs. These data indicate Prav has cell‐type, O2 concentration and dose‐dependent effects on VEGF and sEng secretion in placental and endothelial cells that may not be beneficial in preeclampsia.
Zinc activates KCNQ1 and KCNN4 K+ channels in T84 secretory epithelial cells
Authors: Mongiardo Krystin M , Crane John K , Duffey Michael E
Published: June 2021

Basolateral membrane K+ channels establish the electrical driving force for anion secretion by epithelial tissues. We determined the effects of Zn2+, an inhibitor of anion secretion, on these channels in T84 human colonic epithelial cells. After Cl− secretion was stimulated in monolayers by chlorophenylthio‐cAMP (50 μM), serosal Zn2+ (2mM, zinc acetate) rapidly increased the short circuit current (Isc) from 32±5 to 93±8 μA/cm2, followed by inhibition to 17.1±3.2 (n=6). To determine the mechanisms of activation, tissues were pretreated with the KCNQ1 inhibitor 293B (100 μM) in the serosal solution, which reduced the Zn2+‐activated Isc by 57%. The KCNN4 inhibitor TRAM‐34 (10 μM) reduced activation by 76%. Thus, Zn2+ activated both KCNQ1 and KCNN4 K+ channels. Activation of K+ current by Zn2+was seen in isolated voltage‐clamped cells (233±103 pA, n=4). Fura‐2 fluorescence ratio measurements in isolated cells showed Zn2+ caused a slow rise in Ca2+ which was blocked by the intracellular Zn2+ chelator, pyridylmethylethylenediamine (TPEN), suggesting that Zn2+ can act on intracellular sites. Since Zn2+can modify disulfide bonds, we exposed T84 monolayers to the thiol reagent, dithiothreitol (DTT, 5mM), and like Zn2+, DTT transiently stimulated Isc (43±4 to 82±2 μA/cm2, n=3). These results suggest Zn2+activates basolateral membrane K+ channels, probably via effects on disulfide bonds. (Supported by NIH AI 181528)
Smoothelin‐like 1 knock‐out is associated with altered CPI‐17 expression and myogenic tone.
Authors: Turner Sara Rose , Chappellaz Mona , Cole William C , MacDonald Justin A
Published: June 2021

We examined the role of the smoothelin‐like 1 (SMTNL1) protein in mediating vascular smooth muscle contractile responses to pressure in resistance vessels. Arterioles from wild type (WT) and SMTNL1 global knock‐out (KO) mice were examined with pressure myography, and tissues were analyzed by western blotting. Mesenteric arterioles (3rd order) from Smtnl1 KO mice exhibited strikingly enhanced myogenic tone potential compared to WT littermates. Vessels from KO animals are more responsive to acute pressure changes, (i.e., exhibit greater contractile response to increasing luminal pressure). Specifically, vessels from Smtnl1 KO animals were able to generate pressure induced constriction down to 75% of their passive diameter over pressures ranging from 40–120mmHg. Conversely, wild type vessels generate only modest tone. SMTNL1 was previously shown to regulate the activity of smooth muscle myosin phosphatase by altering MYPT1 expression levels. In this regard, WT and KO mesenteric arterioles showed no differences in total MYPT1 expression; however, a 4‐fold increase in CPI‐17 expression (transcript and protein) was associated with SMTNL1 KO. Based on these findings, we conclude that SMTNL1 contributes to the regulation of pressure induced contractility through modulation of the activity of the myosin light chain phosphatase, both directly and indirectly (via CPI‐17).
Essential role of TRPC3 channel as both NF‐κB upstream and downstream signaling molecule in asthmatic airway hyperresponsiveness and remodeling
Authors: Song Tengyao , Zheng Yun‐Min , Vincent Peter , Wang Yong‐Xiao
Published: June 2021

Canonical transient receptor potential (TRPC) channels are known to be crucial for numerous cellular responses in a variety of cells; however, their functional importance is unknown in airway smooth muscle cells (ASMCs). We recently demonstrate among all identified 7 members, TRPC3 channel predominantly shows a constitutively functional activity in ASMCs, and its expression and activity are significantly augmented in asthmatic ASMCs. Our more recent works reveal that intravenous injection of lentivirus encoding TRPC3 shRNAs into mice via a hydrodynamic delivery technique can effectively silence TRPC3 channel expression and activity in ASMCs. More excitingly, asthmatic airway hyper‐responsiveness, determined by the increased respiratory resistance and enhanced airway muscle contraction, is fully blocked in TRPC3 gene silencing mice. In support of its imperative role, TRPC3 channel shows the remarkably increased activity in response to the intracellular second messengers inositol 1,4,5‐trisphosphate, diacylglycerol and calcium, and all these responses are completely blocked in TRPC3 channel silencing mouse cells. The asthmatic airway remodeling, gauged by the augmented ASMCs proliferation rate revealed by Ki67 and increased ASMCs layer assessed by α‐smooth muscle actin, is abolished as well in TRPC3 silencing mice. We have further found that TRPC3 silencing inhibits the asthmatic increase in NF‐κB activity and cyclin D1 expression, the two vital molecules involved in asthmatic airway remodeling. Equally fascinatingly, inhibition of NF‐κB by silencing its indispensable component p65 prevents the asthmatic increase in TRPC3 expression and activity in ASMCs. Collectively, we conclude that TRPC3 channel may function as both the NF‐κB upstream and downstream signaling molecule to play an essential role in asthmatic airway hyper‐responsiveness and remodeling.