AST-120 Reduces Neuroinflammation Induced by Indoxyl Sulfate in Glial Cells

Chronic kidney disease (CKD) involves multiple organ dysfunction, and the neurological complications that are often present in CKD patients support the idea of a crosstalk between the kidneys and the brain. Evidence suggests a possible role for products accumulating in these patients as uremic toxins in various CKD complications, including neurodegeneration. Indoxyl sulfate (IS), derived from tryptophan metabolism, is well-known as a uremic nephron-vascular toxin, and recent evidence suggests it also has a role in the immune response and in neurodegeneration. Inflammation has been associated with neurodegenerative diseases, as well as with CKD. In this study, we demonstrated that sera of CKD patients induced a significant inflammation in astrocyte cells which was proportional to IS sera concentrations, and that the IS adsorbent, AST-120, reduced this inflammatory response. These results indicated that, among the uremic toxins accumulating in serum of CKD patients, IS significantly contributed to astrocyte inflammation. Moreover, being also chronic inflammation associated with CKD, here we reported that IS further increased inflammation and oxidative stress in primary central nervous system (CNS) cells, via Nuclear Factor-κB (NF-κB) and Aryl hydrocarbon Receptor (AhR) activation, and induced neuron death. This study is a step towards elucidating IS as a potential pharmacological target in CKD patients.

Download Full-text

Spontaneous Subarachnoid Haemorrhage in a Case with Covid-19 Infection - Effect or Association? A Case Report

Journal of Evolution of Medical and Dental Sciences ◽

10.14260/jemds/2021/731 ◽

2021 ◽

Vol 10 (41) ◽

pp. 3607-3609

Author(s):

Sourya Acharya ◽

Samarth Shukla ◽

Pankaj Banode ◽

Shefali Sharma ◽

Abhijeet Wadekar

Keyword(s):

Subarachnoid Haemorrhage ◽

Severe Pneumonia ◽

Haemorrhagic Stroke ◽

Airway Disease ◽

Acute Disseminated Encephalomyelitis ◽

Neurological Complications ◽

Multiple Organ ◽

Chronic Obstructive ◽

Acute Necrotizing Encephalopathy ◽

The Brain

Covid-19 is a disease caused by the SARS-CoV-2 virus that usually causes mild flu-like illness in majority of the cases, but it can cause severe pneumonia and multiple organ dysfunction even death especially in elderly patients who also have comorbidities like hypertension, diabetes, chronic obstructive airway disease (COAD), asthma, and cardiac disease. The central and peripheral nervous systems are not spared, and neurological complications are frequently reported in severely ill patients who have comorbidities. The SARS-CoV-2 virus has the potential to invade the brain and it enters the brain via a haematogenous route or olfactory system through angiotensinconverting enzyme -2 receptors, present on endothelial cells of cerebral vessels. The most neurological manifestations, seen in Covid-19 infection are altered sensorium (agitation, delirium, and coma), ischemic or haemorrhagic stroke, acute disseminated encephalomyelitis or acute necrotizing encephalopathy, headaches, Guillain-Barré syndrome. Here is a case of a 70-year-old hypertensive female who presented to us with complaints of fever, headache and vomiting of 3 days duration and after investigations, a diagnosis of Covid -19 with hypertension and subarachnoid haemorrhage was made.

Download Full-text

Toxic Effects of Indoxyl Sulfate on Osteoclastogenesis and Osteoblastogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms222011265 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11265

Author(s):

Jia-Fwu Shyu ◽

Wen-Chih Liu ◽

Cai-Mei Zheng ◽

Te-Chao Fang ◽

Yi-Chou Hou ◽

...

Keyword(s):

Transcription Factor ◽

Dynamic Balance ◽

Osteoclast Differentiation ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Toxic Effects ◽

High Dose ◽

Activated T Cells ◽

Aryl Hydrocarbon ◽

Bone Damage

Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.

Download Full-text

Pilot Study of Probiotic Supplementation on Uremic Toxicity and Inflammatory Cytokines in Chronic Kidney Patients

Current Nutrition & Food Science ◽

10.2174/1573401315666190215111402 ◽

2020 ◽

Vol 16 (4) ◽

pp. 470-480

Author(s):

Cristina T. Roth-Stefanski ◽

Carla Dolenga ◽

Lia S. Nakao ◽

Roberto Pecoits-Filho ◽

Thyago P. de Moraes ◽

...

Keyword(s):

Pilot Study ◽

Inflammatory Cytokines ◽

Lactobacillus Acidophilus ◽

Serum Levels ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Bacterial Metabolism ◽

Probiotic Supplementation ◽

Primary Endpoints ◽

Inflammatory Profile

Background: Bacterial metabolism contributes to the generation of uremic toxins in patients with chronic kidney disease (CKD). It has been investigated the use of probiotics in the reduction of uremic toxins intestinal production. Objective: The aim of this pilot study was to evaluate the effect of probiotic supplementation on reducing the production of uremic toxins and the inflammatory profile of CKD patients. Methods: We performed a randomized, blind, placebo-controlled, crossover study on patients with CKD stages 3 and 4. The intervention was a probiotic formulation composed of Lactobacillus acidophilus strains given orally three times a day for 3 months. Changes in uremic toxins (p-Cresylsulfate and Indoxyl Sulfate) and serum inflammatory cytokines were the primary endpoints. Results: Of the 44 patients randomized, 25 completed the study (mean age 51 ± 9.34, 64% female, mean eGFR 36 ± 14.26 mL/min/1.73m², mean BMI 28.5 ± 5.75 kg/m²). At 3 months, there were no significant changes in any of the studied biomarkers including p-cresylsulfate (p = 0.57), Indoxyl sulfate (p = 0.08) and interleukin-6 (p = 0.55). Conclusion: Lactobacillus acidophilus strains given as probiotic were not able to reduce serum levels of uremic toxins and biomarkers of inflammation in CKD patients in stage 3 and 4.

Download Full-text

Respiratory Hypoxia and Oxidative Stress in the Brain. Is the Endogenous Erythropoietin an Antioxidant?

Current Chemical Biology ◽

10.2174/2212796810903030238 ◽

2009 ◽

Vol 3 (3) ◽

pp. 238-252

Author(s):

Teresa Carbonell ◽

Ramon Rama

Keyword(s):

Oxidative Stress ◽

Endogenous Erythropoietin ◽

The Brain ◽

And Oxidative Stress

Download Full-text

SARS-CoV-2: is there neuroinvasion?

Fluids and Barriers of the CNS ◽

10.1186/s12987-021-00267-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Conor McQuaid ◽

Molly Brady ◽

Rashid Deane

Keyword(s):

Respiratory Distress ◽

Vascular Dysfunction ◽

Multiorgan Failure ◽

Neurological Complications ◽

Wide Distribution ◽

The Body ◽

Health Conditions ◽

Main Body ◽

Beneficial Effects ◽

The Brain

Abstract Background SARS-CoV-2, a coronavirus (CoV), is known to cause acute respiratory distress syndrome, and a number of non-respiratory complications, particularly in older male patients with prior health conditions, such as obesity, diabetes and hypertension. These prior health conditions are associated with vascular dysfunction, and the CoV disease 2019 (COVID-19) complications include multiorgan failure and neurological problems. While the main route of entry into the body is inhalation, this virus has been found in many tissues, including the choroid plexus and meningeal vessels, and in neurons and CSF. Main body We reviewed SARS-CoV-2/COVID-19, ACE2 distribution and beneficial effects, the CNS vascular barriers, possible mechanisms by which the virus enters the brain, outlined prior health conditions (obesity, hypertension and diabetes), neurological COVID-19 manifestation and the aging cerebrovascualture. The overall aim is to provide the general reader with a breadth of information on this type of virus and the wide distribution of its main receptor so as to better understand the significance of neurological complications, uniqueness of the brain, and the pre-existing medical conditions that affect brain. The main issue is that there is no sound evidence for large flux of SARS-CoV-2 into brain, at present, compared to its invasion of the inhalation pathways. Conclusions While SARS-CoV-2 is detected in brains from severely infected patients, it is unclear on how it gets there. There is no sound evidence of SARS-CoV-2 flux into brain to significantly contribute to the overall outcomes once the respiratory system is invaded by the virus. The consensus, based on the normal route of infection and presence of SARS-CoV-2 in severely infected patients, is that the olfactory mucosa is a possible route into brain. Studies are needed to demonstrate flux of SARS-CoV-2 into brain, and its replication in the parenchyma to demonstrate neuroinvasion. It is possible that the neurological manifestations of COVID-19 are a consequence of mainly cardio-respiratory distress and multiorgan failure. Understanding potential SARS-CoV-2 neuroinvasion pathways could help to better define the non-respiratory neurological manifestation of COVID-19.

Download Full-text

UV-induced neuronal degeneration in the rat cerebral cortex

Cerebral Cortex Communications ◽

10.1093/texcom/tgab006 ◽

2021 ◽

Author(s):

Mariko Nakata ◽

Masayuki Shimoda ◽

Shinya Yamamoto

Keyword(s):

Uv Irradiation ◽

Neuronal Degeneration ◽

Uv Light ◽

Brain Lesion ◽

Terminal Deoxynucleotidyl Transferase ◽

Heme Oxygenase 1 ◽

Dependent Manner ◽

Focal Brain Injury ◽

The Brain ◽

And Oxidative Stress

Abstract Irradiation with ultraviolet (UV) light on the cortical surface can induce a focal brain lesion (UV lesion) in rodents. In the present study, we investigated the process of establishing a UV lesion. Rats underwent UV irradiation (365 nm wavelength, 2.0 mWh) over the dura, and time-dependent changes in the cortical tissue were analyzed histologically. We found that the majority of neurons in the lesion started to degenerate within 24 hours and the rest disappeared within 5 days after irradiation. UV-induced neuronal degeneration progressed in a layer-dependent manner. Moreover, UV-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity and heme oxygenase-1 (HO-1) immunoreactivity were also detected. These findings suggest that UV irradiation in the brain can induce gradual neural degeneration and oxidative stress. Importantly, UV vulnerability may vary among cortical layers. UV-induced cell death may be due to apoptosis; however, there remains a possibility that UV-irradiated cells were degenerated via processes other than apoptosis. The UV lesion technique will not only assist in investigating brain function at a targeted site but may also serve as a pathophysiological model of focal brain injury and/or neurodegenerative disorders.

Download Full-text

SHR/NCrl rats as a model of ADHD can be discriminated from controls based on their brain, blood, or urine metabolomes

Translational Psychiatry ◽

10.1038/s41398-021-01344-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Camille Dupuy ◽

Pierre Castelnau ◽

Sylvie Mavel ◽

Antoine Lefevre ◽

Lydie Nadal-Desbarats ◽

...

Keyword(s):

Oxidative Stress ◽

Attention Deficit Hyperactivity Disorder ◽

Animal Model ◽

Metabolic Pathways ◽

Neurodevelopmental Disorder ◽

Hyperactivity Disorder ◽

Pathophysiological Condition ◽

The Brain ◽

And Oxidative Stress ◽

Peripheral Samples

AbstractAttention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorder characterized by inattention, impulsivity, and hyperactivity. The neurobiological mechanisms underlying ADHD are still poorly understood, and its diagnosis remains difficult due to its heterogeneity. Metabolomics is a recent strategy for the holistic exploration of metabolism and is well suited for investigating the pathophysiology of diseases and finding molecular biomarkers. A few clinical metabolomic studies have been performed on peripheral samples from ADHD patients but are limited by their access to the brain. Here, we investigated the brain, blood, and urine metabolomes of SHR/NCrl vs WKY/NHsd rats to better understand the neurobiology and to find potential peripheral biomarkers underlying the ADHD-like phenotype of this animal model. We showed that SHR/NCrl rats can be differentiated from controls based on their brain, blood, and urine metabolomes. In the brain, SHR/NCrl rats displayed modifications in metabolic pathways related to energy metabolism and oxidative stress further supporting their importance in the pathophysiology of ADHD bringing news arguments in favor of the Neuroenergetic theory of ADHD. Besides, the peripheral metabolome of SHR/NCrl rats also shared more than half of these differences further supporting the importance of looking at multiple matrices to characterize a pathophysiological condition of an individual. This also stresses out the importance of investigating the peripheral energy and oxidative stress metabolic pathways in the search of biomarkers of ADHD.

Download Full-text

Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models

Antioxidants ◽

10.3390/antiox10020229 ◽

2021 ◽

Vol 10 (2) ◽

pp. 229

Author(s):

JunHyuk Woo ◽

Hyesun Cho ◽

YunHee Seol ◽

Soon Ho Kim ◽

Chanhyeok Park ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Computational Models ◽

Neuronal Damage ◽

Living Organism ◽

The Body ◽

Mitochondrial Functions ◽

A Cell ◽

The Brain ◽

And Oxidative Stress

The brain needs more energy than other organs in the body. Mitochondria are the generator of vital power in the living organism. Not only do mitochondria sense signals from the outside of a cell, but they also orchestrate the cascade of subcellular events by supplying adenosine-5′-triphosphate (ATP), the biochemical energy. It is known that impaired mitochondrial function and oxidative stress contribute or lead to neuronal damage and degeneration of the brain. This mini-review focuses on addressing how mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease. In addition, we discuss state-of-the-art computational models of mitochondrial functions in relation to oxidative stress and neurodegeneration. Together, a better understanding of brain disease-specific mitochondrial dysfunction and oxidative stress can pave the way to developing antioxidant therapeutic strategies to ameliorate neuronal activity and prevent neurodegeneration.

Download Full-text

The relationship of indoxyl sulfate and p-cresyl sulfate with target cardiovascular proteins in hemodialysis patients

Scientific Reports ◽

10.1038/s41598-021-83383-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ping-Hsun Wu ◽

Yi-Ting Lin ◽

Yi-Wen Chiu ◽

Gabriel Baldanzi ◽

Jiun-Chi Huang ◽

...

Keyword(s):

Hemodialysis Patients ◽

Complement Component ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Free Form ◽

Negatively Associated ◽

Coronary Syndrome ◽

Increased Risk ◽

Related Proteins ◽

The Relationship

AbstractProtein-bound uremic toxins (Indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) are both associated with cardiovascular (CV) and all-cause mortality in subjects with chronic kidney disease (CKD). Possible mechanisms have not been elucidated. In hemodialysis patients, we investigated the relationship between the free form of IS and PCS and 181 CV-related proteins. First, IS or PCS concentrations were checked, and high levels were associated with an increased risk of acute coronary syndrome (ACS) in 333 stable HD patients. CV proteins were further quantified by a proximity extension assay. We examined associations between the free form protein-bound uremic toxins and the quantified proteins with correction for multiple testing in the discovery process. In the second step, the independent association was evaluated by multivariable-adjusted models. We rank the CV proteins related to protein-bound uremic toxins by bootstrapped confidence intervals and ascending p-value. Six proteins (signaling lymphocytic activation molecule family member 5, complement component C1q receptor, C–C motif chemokine 15 [CCL15], bleomycin hydrolase, perlecan, and cluster of differentiation 166 antigen) were negatively associated with IS. Fibroblast growth factor 23 [FGF23] was the only CV protein positively associated with IS. Three proteins (complement component C1q receptor, CCL15, and interleukin-1 receptor-like 2) were negatively associated with PCS. Similar findings were obtained after adjusting for classical CV risk factors. However, only higher levels of FGF23 was related to increased risk of ACS. In conclusion, IS and PCS were associated with several CV-related proteins involved in endothelial barrier function, complement system, cell adhesion, phosphate homeostasis, and inflammation. Multiplex proteomics seems to be a promising way to discover novel pathophysiology of the uremic toxin.

Download Full-text