Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance

BackgroundProtein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with CKD. However, direct evidence for a role of these toxins in CKD-related vascular calcification has not been reported.MethodsTo study early and late vascular alterations by toxin exposure, we exposed CKD rats to vehicle, IS (150 mg/kg per day), or PCS (150 mg/kg per day) for either 4 days (short-term exposure) or 7 weeks (long-term exposure). We also performed unbiased proteomic analyses of arterial samples coupled to functional bioinformatic annotation analyses to investigate molecular signaling events associated with toxin-mediated arterial calcification.ResultsLong-term exposure to either toxin at serum levels similar to those experienced by patients with CKD significantly increased calcification in the aorta and peripheral arteries. Our analyses revealed an association between calcification events, acute-phase response signaling, and coagulation and glucometabolic signaling pathways, whereas escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Additional metabolic linkage to these pathways revealed that IS and PCS exposure engendered a prodiabetic state evidenced by elevated resting glucose and reduced GLUT1 expression. Short-term exposure to IS and PCS (before calcification had been established) showed activation of inflammation and coagulation signaling pathways in the aorta, demonstrating that these signaling pathways are causally implicated in toxin-induced arterial calcification.ConclusionsIn CKD, both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways and were strongly associated with impaired glucose homeostasis.

Download Full-text

The Effects of Warfarin and Direct Oral Anticoagulants on Systemic Vascular Calcification: A Review

Cells ◽

10.3390/cells10040773 ◽

2021 ◽

Vol 10 (4) ◽

pp. 773

Author(s):

Kalaimani Elango ◽

Awad Javaid ◽

Banveet K. Khetarpal ◽

Sathishkumar Ramalingam ◽

Krishna Prasad Kolandaivel ◽

...

Keyword(s):

Vascular Calcification ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Arterial Calcification ◽

Frequent Monitoring ◽

Cardiovascular Morbidity And Mortality ◽

Retrospective Cohort Studies ◽

History Of ◽

The Cost

Warfarin has been utilized for decades as an effective anticoagulant in patients with a history of strong risk factors for venous thromboembolism (VTE). Established adverse effects include bleeding, skin necrosis, teratogenicity during pregnancy, cholesterol embolization, and nephropathy. One of the lesser-known long-term side effects of warfarin is an increase in systemic arterial calcification. This is significant due to the association between vascular calcification and cardiovascular morbidity and mortality. Direct oral anticoagulants (DOACs) have gained prominence in recent years, as they require less frequent monitoring and have a superior side effect profile to warfarin, specifically in relation to major bleeding. The cost and lack of data for DOACs in some disease processes have precluded universal use. Within the last four years, retrospective cohort studies, observational studies, and randomized trials have shown, through different imaging modalities, that multiple DOACs are associated with slower progression of vascular calcification than warfarin. This review highlights the pathophysiology and mechanisms behind vascular calcification due to warfarin and compares the effect of warfarin and DOACs on systemic vasculature.

Download Full-text

Short-term exposure and long-term consequences of neonatal exposure to Δ9-tetrahydrocannabinol (THC) and ibuprofen in mice

Behavioural Brain Research ◽

10.1016/j.bbr.2016.04.001 ◽

2016 ◽

Vol 307 ◽

pp. 137-144 ◽

Cited By ~ 18

Author(s):

Gaëtan Philippot ◽

Fred Nyberg ◽

Torsten Gordh ◽

Anders Fredriksson ◽

Henrik Viberg

Keyword(s):

Neonatal Exposure ◽

Short Term ◽

Short Term Exposure ◽

Long Term Consequences

Download Full-text

Spatio-temporal associations of air pollutant concentrations, GP respiratory consultations and respiratory inhaler prescriptions: a 5-year study of primary care in the borough of Lambeth, South London

Environmental Health ◽

10.1186/s12940-021-00730-1 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Mark Ashworth ◽

◽

Antonis Analitis ◽

David Whitney ◽

Evangelia Samoli ◽

...

Keyword(s):

Primary Care ◽

Negative Binomial ◽

Hospital Admissions ◽

Air Pollutant ◽

Respiratory Morbidity ◽

Short Term ◽

Short Term Exposure ◽

Short And Long Term ◽

Spatio Temporal

Abstract Background Although the associations of outdoor air pollution exposure with mortality and hospital admissions are well established, few previous studies have reported on primary care clinical and prescribing data. We assessed the associations of short and long-term pollutant exposures with General Practitioner respiratory consultations and inhaler prescriptions. Methods Daily primary care data, for 2009–2013, were obtained from Lambeth DataNet (LDN), an anonymised dataset containing coded data from all patients (1.2 million) registered at general practices in Lambeth, an inner-city south London borough. Counts of respiratory consultations and inhaler prescriptions by day and Lower Super Output Area (LSOA) of residence were constructed. We developed models for predicting daily PM2.5, PM10, NO2 and O3 per LSOA. We used spatio-temporal mixed effects zero inflated negative binomial models to investigate the simultaneous short- and long-term effects of exposure to pollutants on the number of events. Results The mean concentrations of NO2, PM10, PM2.5 and O3 over the study period were 50.7, 21.2, 15.6, and 49.9 μg/m3 respectively, with all pollutants except NO2 having much larger temporal rather than spatial variability. Following short-term exposure increases to PM10, NO2 and PM2.5 the number of consultations and inhaler prescriptions were found to increase, especially for PM10 exposure in children which was associated with increases in daily respiratory consultations of 3.4% and inhaler prescriptions of 0.8%, per PM10 interquartile range (IQR) increase. Associations further increased after adjustment for weekly average exposures, rising to 6.1 and 1.2%, respectively, for weekly average PM10 exposure. In contrast, a short-term increase in O3 exposure was associated with decreased number of respiratory consultations. No association was found between long-term exposures to PM10, PM2.5 and NO2 and number of respiratory consultations. Long-term exposure to NO2 was associated with an increase (8%) in preventer inhaler prescriptions only. Conclusions We found increases in the daily number of GP respiratory consultations and inhaler prescriptions following short-term increases in exposure to NO2, PM10 and PM2.5. These associations are more pronounced in children and persist for at least a week. The association with long term exposure to NO2 and preventer inhaler prescriptions indicates likely increased chronic respiratory morbidity.

Download Full-text

Effects of Long-Term Triclosan Exposure on Microbiota in Zebrafish

Frontiers in Microbiology ◽

10.3389/fmicb.2021.604313 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ning Tang ◽

Pianpian Fan ◽

Xiaogang Yu ◽

Rui Ma ◽

Yexuan Tao ◽

...

Keyword(s):

Gastrointestinal Tract ◽

Early Adulthood ◽

Rrna Gene ◽

Adult Zebrafish ◽

Short Term ◽

Microbial Composition ◽

Short Term Exposure ◽

Embryonic Life ◽

A Minor

Background: Triclosan (TCS) is a widely used antibacterial agent in personal care products and is ubiquitous in the environment. We aimed to examine whether TCS exposure affects microbiota in the gastrointestinal tract of zebrafish.Methods: After exposure to TCS 0 (Dimethyl Sulphoxide, DMSO control), 0.03, 0.3, 3, 30, 100, and 300ng/ml, respectively, from day 0 to 120days post fertilization (dpf), or for 7days in adult 4-month zebrafish, the long- and short-term impact of TCS exposure on the microbiome in the gastrointestinal tract was evaluated by analyzing 16S rRNA gene V3-V4 region sequencing.Results: The top two most dominant microbiota phyla were Proteobacteria and Fusobacteria phylum in all zebrafish groups. In TCS exposure 0–120 dpf, compared with DMSO control, the mean number of microbial operational taxonomic units (OTUs) was 54.46 lower (p<0.0001), Chao indice 41.40 lower (p=0.0004), and Ace indice 34.10 lower (p=0.0044) in TCS 300ng/ml group, but no change was observed in most of the other TCS concentrations. PCoA diagram showed that the microbial community in the long-term TCS 300ng/ml exposure group clustered differently from those in the DMSO control and other TCS exposure groups. A shorter body length of the zebrafish was observed in the long-term TCS exposure at 0.03, 100, and 300ng/ml. For 7-day short-term exposure in adult zebrafish, no difference was observed in alpha or beta diversity of microbiota nor the relative abundance of Proteobacteria or Fusobacteria phylum among DMSO control and any TCS levels, but a minor difference in microbial composition was observed for TCS exposure.Conclusions: Long-term exposure to high TCS concentration in a window from early embryonic life to early adulthood may reduce diversity and alter the composition of microbiota in the gastrointestinal tract. The effect of short-term TCS exposure was not observed on the diversity of microbiota but there was a minor change of microbial composition in adult zebrafish with TCS exposure.

Download Full-text

Short-term exposure to air pollution (PM2.5) induces hypothalamic inflammation, and long-term leads to leptin resistance and obesity via Tlr4/Ikbke in mice

Scientific Reports ◽

10.1038/s41598-020-67040-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Clara Machado Campolim ◽

Lais Weissmann ◽

Clílton Kraüss de Oliveira Ferreira ◽

Olivia Pizetta Zordão ◽

Ana Paula Segantine Dornellas ◽

...

Keyword(s):

Air Pollution ◽

Leptin Resistance ◽

Short Term ◽

Short Term Exposure ◽

Hypothalamic Inflammation

Download Full-text

Intestinal Explant Cultures from Gilthead Seabream (Sparus aurata, L.) Allowed the Determination of Mucosal Sensitivity to Bacterial Pathogens and the Impact of a Plant Protein Diet

International Journal of Molecular Sciences ◽

10.3390/ijms21207584 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7584

Author(s):

David Sánchez Peñaranda ◽

Christine Bäuerl ◽

Ana Tomás-Vidal ◽

Miguel Jover-Cerdá ◽

Guillem Estruch ◽

...

Keyword(s):

Immune Response ◽

Phase Ii ◽

Plant Protein ◽

Gilthead Seabream ◽

Growth Stages ◽

Short Term ◽

Short Term Exposure ◽

Cox 2 ◽

The Impact

The interaction between diet and intestinal health has been widely discussed, although in vivo approaches have reported limitations. The intestine explant culture system developed provides an advantage since it reduces the number of experimental fish and increases the time of incubation compared to similar methods, becoming a valuable tool in the study of the interactions between pathogenic bacteria, rearing conditions, or dietary components and fish gut immune response. The objective of this study was to determine the influence of the total substitution of fish meal by plants on the immune intestinal status of seabream using an ex vivo bacterial challenge. For this aim, two growth stages of fish were assayed (12 g): phase I (90 days), up to 68 g, and phase II (305 days), up to 250 g. Additionally, in phase II, the effects of long term and short term exposure (15 days) to a plant protein (PP) diet were determined. PP diet altered the mucosal immune homeostasis, the younger fish being more sensitive, and the intestine from fish fed short-term plant diets showed a higher immune response than with long-term feeding. Vibrio alginolyticus (V. alginolyticus) triggered the highest immune and inflammatory response, while COX-2 expression was significantly induced by Photobacterium damselae subsp. Piscicida (P. damselae subsp. Piscicida), showing a positive high correlation between the pro-inflammatory genes encoding interleukin 1β (IL1-β), interleukin 6 (IL-6) and cyclooxygenase 2(COX-2).

Download Full-text

Pharmacological and Nutritional Modulation of Vascular Calcification

Nutrients ◽

10.3390/nu12010100 ◽

2019 ◽

Vol 12 (1) ◽

pp. 100 ◽

Cited By ~ 4

Author(s):

Liv M. Vossen ◽

Abraham A. Kroon ◽

Leon J. Schurgers ◽

Peter W. de Leeuw

Keyword(s):

Cardiovascular Disease ◽

Drug Therapy ◽

Vascular Calcification ◽

Vitamin K ◽

Vascular Function ◽

Clinical Importance ◽

Arterial Calcification ◽

Channel Blockers ◽

Cardiovascular Morbidity And Mortality ◽

Prevention And Treatment

Vascular calcification is an independent predictor of cardiovascular disease, and therefore, inhibition or regression of this processes is of clinical importance. The standard care regarding prevention and treatment of cardiovascular disease at this moment mainly depends on drug therapy. In animal and preclinical studies, various forms of cardiovascular drug therapy seem to have a positive effect on vascular calcification. In particular, calcium channel blockers and inhibitors of the renin–angiotensin–aldosteron system slowed down arterial calcification in experimental animals. In humans, the results of trials with these drugs are far less pronounced and often contradictory. There is limited evidence that the development of new atherosclerotic lesions may be retarded in patients with coronary artery disease, but existing lesions can hardly be influenced. Although statin therapy has a proven role in the prevention and treatment of cardiovascular morbidity and mortality, it is associated with both regression and acceleration of the vascular calcification process. Recently, nutritional supplements have been recognized as a potential tool to reduce calcification. This is particularly true for vitamin K, which acts as an inhibitor of vascular calcification. In addition to vitamin K, other dietary supplements may also modulate vascular function. In this narrative review, we discuss the current state of knowledge regarding the pharmacological and nutritional possibilities to prevent the development and progression of vascular calcification.

Download Full-text

Short-term exposure of Chinook salmon (Oncoryhnchus tshawytscha) to o,p-DDE or DMSO during early life-history stages causes long-term humoral immunosuppression.

Environmental Health Perspectives ◽

10.1289/ehp.6171 ◽

2003 ◽

Vol 111 (13) ◽

pp. 1601-1607 ◽

Cited By ~ 41

Author(s):

Ruth H Milston ◽

Martin S Fitzpatrick ◽

Anthony T Vella ◽

Shaun Clements ◽

Deke Gundersen ◽

...

Keyword(s):

Life History ◽

Chinook Salmon ◽

Early Life ◽

Early Life History ◽

Short Term ◽

Life History Stages ◽

Short Term Exposure

Download Full-text

Contrasting seed germination responses to red and far-red light in Leptospermum scoparium and Melicytus ramiflorus

Functional Plant Biology ◽

10.1071/pp00024 ◽

2000 ◽

Vol 27 (11) ◽

pp. 1069

Author(s):

Helen Herron ◽

John Clemens ◽

Dennis H. Greer

Keyword(s):

Seed Germination ◽

Red Light ◽

Green Light ◽

Photon Flux ◽

Short Term ◽

Short Term Exposure ◽

Subsequent Exposure ◽

R:Fr Ratio ◽

Leptospermum Scoparium

Effects of red light (R) and far-red light (FR), and selected photon flux densities (PFD) of photosynthetically active radiation (PAR) on seed germination in the photoblastic, primary colonising species Leptospermum scoparium J. R. et G. Forst. and the late secondary successional Melicytus ramiflorus J. R. et G. Forst. were studied. A continuous R dose response curve forL. scoparium germination was developed, unifying data from experiments using long-term exposure to PAR with those following short-term exposure to R. The threshold R dose needed to effect germination was ~0.1 mmol m –2 , and the response was saturated at 1000 mmol m –2 . Stimulation of germination by R was reversed by a subsequent exposure to FR. These features are consistent with a low-fluence response mediated by phytochrome B. FR reversal of germination was achieved at a dose two orders of magnitude lower than that of R required to induce initial germination. However, when both R and FR were provided simultaneously, the FR dose needed to even partially inhibit germination (34% compared to > 95% in controls) was two orders of magnitude higher than the R dose (R:FR ratio = 0.007). Germination in L. scoparium was also stimulated in up to 12% of seed upon diurnal exposure to FR, or by green light (~2 mol m –2 ), indicating a very-low-fluence response mediated by phytochrome A also operating in this species. In contrast, seed germination in M. ramiflorus was relatively unresponsive to R, and secondary dormancy was induced by high PFD (515 mol m –2 s –1 ).

Download Full-text

Long-term regulation of hexose uptake by isoproterenol in cultured 3T3 adipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1985.248.6.e706 ◽

1985 ◽

Vol 248 (6) ◽

pp. E706-E711 ◽

Cited By ~ 2

Author(s):

J. P. van Putten ◽

H. M. Krans

Keyword(s):

Protein Synthesis ◽

Prolonged Exposure ◽

Term Effect ◽

Long Term Effects ◽

Fat Cell ◽

Short Term ◽

Long Term Effect ◽

Short Term Exposure ◽

Hexose Uptake

Catecholamines are known to have short-term regulatory effects on fat cell hexose uptake. We examined the long-term effects of catecholamines on the insulin-sensitive 2-deoxyglucose (dGlc) uptake in cultured 3T3-L1 adipocytes. Prolonged exposure (48 h) to isoproterenol (beta-adrenergic agonist) stimulated the basal dGlc uptake up to 90%. The effect was specific, time, concentration, and protein synthesis dependent and reversible. The effect of insulin was unaltered and superimposed on the increase in basal dGlc uptake. The long-term effect of isoproterenol was mimicked by epinephrine, dibutyryl cAMP (DBcAMP), and 1-methyl-3-isobutylxanthine (IBMX). By contrast, short-term exposure to isoproterenol (and epinephrine) induced a protein synthesis-independent increase in basal dGlc uptake (30%) not accompanied by an increase in insulin responsiveness. Moreover, on short-term basis, DBcAMP and IBMX suppressed both the basal and insulin-stimulated uptake up to 50%. Determination of the intracellular nonphosphorylated dGlc during the uptake and of the hexokinase activity revealed that the long-term effect of isoproterenol was most likely due to alterations low in dGlc transport. In conclusion, long-term regulators of hexose uptake are in cultured 3T3-L1 adipocytes, isoproterenol, and other cAMP stimulators. The long-term effect is independent from the short-term regulatory effect of the agents and from the effect of insulin.

Download Full-text