scholarly journals Phosphorus Supplementation Mitigates Perivascular Adipose Inflammation–Induced Cardiovascular Consequences in Early Metabolic Impairment

2021 ◽  
Author(s):  
Haneen S. Dwaib ◽  
Ghina Ajouz ◽  
Ibrahim AlZaim ◽  
Rim Rafeh ◽  
Ali Mroueh ◽  
...  
Keyword(s):  
Rat Model ◽  
Macrophage Polarization ◽  
Control Diet ◽  
Hypoxia Inducible Factor ◽  
Inorganic Phosphorus ◽  
Cardiovascular Complications ◽  
Metabolic Efficiency ◽  
Dependent Manner ◽  
Perivascular Adipose Tissue ◽  
Cardiovascular Damage

Background The complexity of the interaction between metabolic dysfunction and cardiovascular complications has long been recognized to extend beyond simple perturbations of blood glucose levels. Yet, structured interventions targeting the root pathologies are not forthcoming. Growing evidence implicates the inflammatory changes occurring in perivascular adipose tissue (PVAT) as early instigators of cardiovascular deterioration. Methods and Results We used a nonobese prediabetic rat model with localized PVAT inflammation induced by hypercaloric diet feeding, which dilutes inorganic phosphorus (Pi) to energy ratio by 50%, to investigate whether Pi supplementation ameliorates the early metabolic impairment. A 12‐week Pi supplementation at concentrations equivalent to and twice as much as that in the control diet was performed. The localized PVAT inflammation was reversed in a dose‐dependent manner. The increased expression of UCP1 (uncoupling protein1), HIF‐1α (hypoxia inducible factor‐1α), and IL‐1β (interleukin‐1β), representing the hallmark of PVAT inflammation in this rat model, were reversed, with normalization of PVAT macrophage polarization. Pi supplementation restored the metabolic efficiency consistent with its putative role as an UCP1 inhibitor. Alongside, parasympathetic autonomic and cerebrovascular dysfunction function observed in the prediabetic model was reversed, together with the mitigation of multiple molecular and histological cardiovascular damage markers. Significantly, a Pi‐deficient control diet neither induced PVAT inflammation nor cardiovascular dysfunction, whereas Pi reinstatement in the diet after a 10‐week exposure to a hypercaloric low‐Pi diet ameliorated the dysfunction. Conclusions Our present results propose Pi supplementation as a simple intervention to reverse PVAT inflammation and its early cardiovascular consequences, possibly through the interference with hypercaloric‐induced increase in UCP1 expression/activity.

Effect of a novel consensus bacterial 6-phytase variant in grower pigs fed corn-soybean meal-based diets formulated with a full nutrient matrix and no added inorganic phosphorus

2021 ◽  
Author(s):  
D E Velayudhan ◽  
M Gracia ◽  
O Casabuena Rincón ◽  
L Marchal ◽  
Y Dersjant-Li
Keyword(s):  
Growth Performance ◽  
Soybean Meal ◽  
Polynomial Regression ◽  
Control Diet ◽  
Average Daily Gain ◽  
Inorganic Phosphorus ◽  
Net Energy ◽  
Dependent Manner ◽  
Feed Conversion ◽  
Percentage Points

Abstract The capacity of a novel consensus bacterial 6-phytase variant (PhyG) to entirely replace dietary inorganic phosphorus (Pi) source in grower pigs fed diets with reduction of calcium (Ca), net energy (NE) and digestible amino acids (AA) was evaluated, using growth performance and apparent total tract digestibility (ATTD) of nutrients as outcome measures. A total of 352 mixed-sex pigs (initial BW 23.4 kg) were randomized to 4 treatments, 8 pigs/pen and 11 pens/treatment. Diets were corn-soybean meal-based and formulated by phase (grower 1, 25 to 50 and grower 2, 50 to 75 kg BW). The positive control diet (PC) provided adequate nutrients and a negative control diet (NC) was formulated without Pi (1.2 g/kg ATTD P) and reduced in Ca (-0.12 to -0.13 percentage points), NE (-32 kcal/kg) and digestible essential AA (-0.004 to -0.026 percentage points) vs. PC. Two further treatments comprised the NC plus 500 or 1,000 FTU/kg of PhyG. Data were analyzed by ANOVA, mean contrasts and orthogonal polynomial regression. Nutrient reductions in the NC reduced (P < 0.05) average daily gain (ADG) during grower 1 and overall (73 to 136 days of age), increased (P < 0.05) feed conversion ratio (FCR) during grower 1 and overall and tended to reduce (P < 0.1) average daily feed intake (ADFI) during grower 2 and overall, vs. PC. Phytase supplementation improved (P < 0.05) FCR during grower 1, ADG during grower 2 and overall, ATTD of DM and P, and tended to improve DE (P = 0.053) in a linear dose-dependent manner. PhyG at 1,000 FTU/kg resulted in growth performance (all measures, all phases) equivalent to PC. The findings demonstrate that PhyG at 1,000 FTU/kg totally replaced Pi in complex grower pig diets containing industrial co-products, compensated a full nutrient matrix reduction and maintained performance.

scholarly journals Gujiansan Ameliorates Avascular Necrosis of the Femoral Head by Regulating Autophagy via the HIF-1α/BNIP3 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jie Han ◽  
Yuan Chai ◽  
Xiao-yun Zhang ◽  
Feng Chen ◽  
Zhi-wei Xu ◽  
...  
Keyword(s):  
Femoral Head ◽  
Avascular Necrosis ◽  
Rat Model ◽  
Type I Collagen ◽  
Hypoxia Inducible Factor ◽  
Time Dependent ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Dependent Manner ◽  
Bone Specific Alkaline Phosphatase

Background. Clinically, the traditional Chinese medicine compound Gujiansan has been widely used in the treatment of steroid-induced avascular necrosis of the femoral head (SANFH). The present study aimed to investigate the mechanisms underlying the therapeutic effect of Gujiansan. Methods. A rat model of SANFH was established by the injection of dexamethasone (DEX) at a high dosage of 25 mg/kg/d. Then, Gujiansan was intragastrically administered for 2 weeks, 4 weeks, and 8 weeks, and histological examination of the femoral head was performed. The expression levels of related mRNAs and proteins were analyzed by qRT-PCR, Western blotting, and immunohistochemistry, and the levels of bone biochemical markers and cytokines were detected with ELISA kits. Results. Gujiansan administration ameliorated SANFH and induced the expression of hypoxia-inducible factor-1α (HIF-1α), Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), LC3, and Beclin-1 in the rat model in a dose- and time-dependent manner, and Gujiansan promoted osteocalcin secretion at the femoral head. In addition, Gujiansan increased the levels of bone formation- and bone resorption-specific markers (osteocalcin (OC), bone-specific alkaline phosphatase (BAP), tartrate resistant acid phosphatase-5b (TRACP-5b), N-terminal telopeptides of type I collagen (NTX-1), and C-terminal telopeptide of type I collagen (CTX-1)) and decreased the levels of proinflammatory cytokines (TNF-α, IL-6, and CRP) in a dose- and time-dependent manner. Conclusions. Gujiansan accelerates the formation of a new bone, promotes the absorption of the damaged bone, inhibits the inflammatory response, induces autophagy of the femoral head via the HIF-1α/BNIP3 pathway, and ultimately ameliorates SANFH.

scholarly journals The Influence of Diet and Sex on the Gut Microbiota of Lean and Obese JCR:LA-cp Rats

2021 ◽  
Vol 9 (5) ◽  
pp. 1037
Author(s):  
Craig Resch ◽  
Mihir Parikh ◽  
J. Alejandro Austria ◽  
Spencer D. Proctor ◽  
Thomas Netticadan ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Control Diet ◽  
Bacterial Species ◽  
Alpha Diversity ◽  
Short Chain Fatty Acids ◽  
Female Rats ◽  
Dependent Manner ◽  
Male And Female ◽  
Ground Flaxseed ◽  
The Impact

There is an increased interest in the gut microbiota as it relates to health and obesity. The impact of diet and sex on the gut microbiota in conjunction with obesity also demands extensive systemic investigation. Thus, the influence of sex, diet, and flaxseed supplementation on the gut microbiota was examined in the JCR:LA-cp rat model of genetic obesity. Male and female obese rats were randomized into four groups (n = 8) to receive, for 12 weeks, either (a) control diet (Con), (b) control diet supplemented with 10% ground flaxseed (CFlax), (c) a high-fat, high sucrose (HFHS) diet, or (d) HFHS supplemented with 10% ground flaxseed (HFlax). Male and female JCR:LA-cp lean rats served as genetic controls and received similar dietary interventions. Illumine MiSeq sequencing revealed a richer microbiota in rats fed control diets rather than HFHS diets. Obese female rats had lower alpha-diversity than lean female; however, both sexes of obese and lean JCR rats differed significantly in β-diversity, as their gut microbiota was composed of different abundances of bacterial types. The feeding of an HFHS diet affected the diversity by increasing the phylum Bacteroidetes and reducing bacterial species from phylum Firmicutes. Fecal short-chain fatty acids such as acetate, propionate, and butyrate-producing bacterial species were correspondingly impacted by the HFHS diet. Flax supplementation improved the gut microbiota by decreasing the abundance of Blautia and Eubacterium dolichum. Collectively, our data show that an HFHS diet results in gut microbiota dysbiosis in a sex-dependent manner. Flaxseed supplementation to the diet had a significant impact on gut microbiota diversity under both flax control and HFHS dietary conditions.

scholarly journals Embryonal Carcinoma P19 Cells Produce Erythropoietin Constitutively But Express Lactate Dehydrogenase in an Oxygen-Dependent Manner

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1185-1195 ◽  
Author(s):  
Taiho Kambe ◽  
Junko Tada ◽  
Mariko Chikuma ◽  
Seiji Masuda ◽  
Masaya Nagao ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Binding Site ◽  
Embryonal Carcinoma ◽  
Hypoxia Inducible Factor ◽  
Embryonic Stem ◽  
Gene Promoter ◽  
Dependent Manner ◽  
P19 Cells ◽  
Independent Manner ◽  
Hep3b Cells

Abstract Embryonic stem cells and embryonal carcinoma P19 cells produce erythropoietin (Epo) in an oxygen-independent manner, although lactate dehydrogenase A (LDHA) is hypoxia-inducible. To explore this paradox, we studied the operation of cis-acting sequences from these genes in P19 and Hep3B cells. The Epo gene promoter and 3′ enhancer from P19 cells conveyed hypoxia-inducible responses in Hep3B cells but not in P19 cells. Together with DNA sequencing and the normal transcription start site of P19 Epo gene, this excluded the possibility that the noninducibility of Epo gene in P19 cells was due to mutation in these sequences or unusual initiation of transcription. In contrast, reporter constructs containing LDHA enhancer and promoter were hypoxia inducible in P19 and Hep3B cells, and mutation of a hypoxia- inducible factor 1 (HIF-1) binding site abolished the hypoxic inducibility in both cells, indicating that HIF-1 activation operates normally in P19 cells. Neither forced expression of hepatocyte nuclear factor 4 in P19 cells nor deletion of its binding site from the Epo enhancer was effective in restoring Epo enhancer function. P19 cells may lack an unidentified regulator(s) required for interaction of the Epo enhancer with Epo and LDHA promoters.

scholarly journals Dietary conjugated linoleic acid (CLA) induces apoptosis of colonic mucosa in 1,2-dimethylhydrazine-treated rats: a possible mechanism of the anticarcinogenic effect by CLA

2001 ◽  
Vol 86 (5) ◽  
pp. 549-555 ◽  
Author(s):  
Hyun S. Park ◽  
Ji H. Ryu ◽  
Yeong L. Ha ◽  
Jung H. Y. Park
Keyword(s):  
Linoleic Acid ◽  
Conjugated Linoleic Acid ◽  
Control Diet ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Tumour Incidence ◽  
Sprague Dawley Rats ◽  
Dietary Conjugated Linoleic Acid

One of the objectives of the present study was to investigate whether 1 % conjugated linoleic acid (CLA) in the diet reduced tumour incidence in the colon of 1,2-dimethylhydrazine (DMH)-treated rats. Colon cancer was induced by injecting 6-week-old, male, Sprague–Dawley rats with 15 mg/kg DMH twice per week for 6 weeks. They were fed either 1 % CLA or a control diet ad libitum for 30 weeks. Dietary CLA significantly decreased colon tumour incidence (P<0·05). Our second objective was to investigate whether apoptosis in the colon mucosa of DMH-treated rats was affected by the amount of dietary CLA and whether the changes in apoptosis were related to those in fatty acid-responsive biomarkers. For this purpose, rats were killed after being fed a diet containing 0 %, 0·5 %, 1 % or 1·5 % CLA for 14 weeks. CLA was undetected in the mucosa of rats fed the 0 % CLA diet and increased to 5·9 mg/g phospholipid in rats fed the 0·5 % diet. The apoptotic index estimated by the terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling technique was increased by 251 % and the 1,2-diacylglycerol content was decreased by 57 % in rats fed 0·5 % CLA. No further changes in these variables were observed when CLA in the diet was raised to 1·0 % or 1·5 %. However, dietary CLA decreased mucosal levels of prostaglandin E2, thromboxane B2 and arachidonic acid in a dose-dependent manner. The present data indicate that dietary CLA can inhibit DMH-induced colon carcinogenesis by mechanisms probably involving increased apoptosis.

Safflower injection inhibits pulmonary arterial remodeling in a monocrotaline-induced pulmonary arterial hypertension rat model

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Aifeng Chen ◽  
Shibiao Ding ◽  
Liangliang Kong ◽  
Jianpu Xu ◽  
Fei He ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Cardiac Muscle ◽  
Rat Model ◽  
Dependent Manner ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
Dose Dependent

AbstractPulmonary arterial hypertension (PAH) is a group of diseases with an increase of pulmonary artery pressure (PAP) and pulmonary vascular resistance. Here, the effects of safflower injection, a preparation of Chinese herbs, was investigated in a monocrotaline (MCT)-induced PAH rat model. PAP, carotid artery pressure (CAP), and the right ventricular hypertrophy index (RVHI) increased in the PAH group, while safflower injection was able to inhibit this increase to similar levels as observed in the normal group. The arteriole wall of the lungs and cardiac muscle were thickened and edema was observed in the PAH group, while these pathologies were improved in the herb-treated group in a dose-dependent manner. MCT treatment induced proliferation of pulmonary artery smooth muscle cells (PASMCs), which was inhibited by safflower injection in a dose-dependent manner. Our experimental results demonstrated that safflower injection can regulate pulmonary arterial remodeling through affecting the expression of connective tissue growth factor, transforming growth factor-β, integrin, collagen or fibronectin, which subsequently affected the thicknesses of the arteriole walls of the lungs and cardiac muscle, and thereby benefits the control of PAH. This means safflower injection improved the abnormalities in PAP, CAP and RVHI, and pulmonary arterial remodeling through regulation of remodeling factors.

Abstract 2671: Thymosin Beta 4 Induced Oligodendrogenesis Is Associated With Upregulation Of Serum Response Factor

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Daniel C Morris ◽  
Benjamin Buller ◽  
Manoranjan Santra ◽  
Michael Chopp ◽  
Zheng Gang Zhang
Keyword(s):  
Western Blot ◽  
Progenitor Cells ◽  
Rat Model ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Embolic Stroke ◽  
Early Gene ◽  
Dependent Manner ◽  
Thymosin Beta 4 ◽  
Serum Response

Background: Thymosin beta 4 (Tβ4) is a G-actin sequestering peptide that improves neurological functional outcome when administered 24 hours after onset of stroke to a rat model of embolic stroke. Tβ4 increases the number of oligodendrocyte progenitor cells (OPCs) as well as mature oligodendrocytes (OLs). Mechanisms of Tβ4 induced oligodendrogenesis (OLG) remain unclear. Serum response growth factor (SRF) is a transcriptional factor which binds with ternary complex co-factors to primarily convey an immediate early gene response to influence and orchestrate neuronal migration and differentiation. Hypothesis: We tested the hypothesis that Tβ4 upregulates SRF with subsequent increase in the markers of OL differentiation. Results: We employed a mouse OPC line (N20.1) to investigate the mechanisms of Tβ4-induced OLG. The cells were plated at a density of 100,000 cells/ml and grown in the presence of 0, 12.5, 25 and 50 ng/ml of Tβ4 (RegeneRx Biopharmaceuticals, Inc.) for 14 days (n=3). Western blot analysis revealed that SRF was dose-dependently upregulated by a factor of 4. Quantitative real time PCR and Western blot analysis showed that Tβ4 treatment induced myelin basic protein (MBP) and 2’, 3’-cyclic nucleotide, 3’-phosphodiesterase (CNPase) expression in a dose-dependent manner by ∼2 fold, indicating the stimulation of OLG. In order to independently demonstrate that SRF promotes the differentiation of progenitor cells into mature oligodendrocytes, SRF was over expressed in the N20.1 cells using a plasmid encoding the SRF gene. After six days SRF over expressed N20.1 cells (n=3) demonstrated an increase of expression of MBP (26 ± 3%) and CNPase (23 ± 3%) when compared to cells transfected with an empty expression plasmid (n=3, MBP, 14 ± 3% and CNPase, 10 ± 4%, p<0.05). Conclusions: In this mouse model of OPCs, SRF was upregulated by Tβ4 and may be involved in Tβ4 induced OLG. Further in vivo investigation of SRF is warranted in our rat model of embolic stroke.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

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