scholarly journals Renal Denervation Attenuates Neuroinflammation in the Brain by Regulating Gut-Brain Axis in Rats With Myocardial Infarction

2021 ◽  
Vol 8 ◽  
Author(s):  
Jun-Yu Huo ◽  
Wan-Ying Jiang ◽  
Yi-Ting Lyu ◽  
Lin Zhu ◽  
Hui-Hui Liu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Inflammatory Cytokines ◽  
Renal Denervation ◽  
Intestinal Barrier ◽  
Intestinal Injury ◽  
Microglia Activation ◽  
Barrier Permeability ◽  
Microbial Dysbiosis ◽  
Cardiac Functions ◽  
The Brain

Aims: The development of neuroinflammation deteriorates the prognosis of myocardial infarction (MI). We aimed to investigate the effect of renal denervation (RDN) on post-MI neuroinflammation in rats and the related mechanisms.Methods and Results: Male adult Sprague-Dawley rats were subjected to sham or ligation of the left anterior descending coronary artery to induce MI. One week later, the MI rats received a sham or RDN procedure. Their cardiac functions were analyzed by echocardiography, and their intestinal structures, permeability, and inflammatory cytokines were tested. The intestinal microbiota were characterized by 16S rDNA sequencing. The degrees of neuroinflammation in the brains of rats were analyzed for microglia activation, inflammatory cytokines, and inflammation-related signal pathways. In comparison with the Control rats, the MI rats exhibited impaired cardiac functions, intestinal injury, increased intestinal barrier permeability, and microbial dysbiosis, accompanied by increased microglia activation and pro-inflammatory cytokine levels in the brain. A RDN procedure dramatically decreased the levels of renal and intestinal sympathetic nerve activity, improved cardiac functions, and mitigated the MI-related intestinal injury and neuroinflammation in the brain of MI rats. Interestingly, the RDN procedure mitigated the MI-increased intestinal barrier permeability and pro-inflammatory cytokines and plasma LPS as well as ameliorated the gut microbial dysbiosis in MI rats. The protective effect of RDN was not significantly affected by treatment with intestinal alkaline phosphatase but significantly reduced by L-phenylalanine treatment in MI rats.Conclusions: RDN attenuated the neuroinflammation in the brain of MI rats, associated with mitigating the MI-related intestinal injury.

scholarly journals Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

2019 ◽  
Author(s):  
Sawako Shindo ◽  
Shih-Heng Chen ◽  
Saki Gotoh ◽  
Kosuke Yokobori ◽  
Hao Hu ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Inflammatory Cytokines ◽  
Estrogen Receptor Α ◽  
Microglia Activation ◽  
Immune Functions ◽  
Protein Levels ◽  
Brain Extracts ◽  
Anti Inflammatory ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Abstract Background Estrogen has been suggested to regulate anti-inflammatory signaling in brain microglia through estrogen receptor α (ERα), the only resident immune cells of the brain. The mechanism of how ERα regulates is not well understood. Previously, ERα is phosphorylated at Ser216 in mouse neutrophils, regulating their infiltration into the uterus. Therefore, ERα has now been examined as to its phosphorylation in microglia to regulate their inflammatory functions.MethodsAn antibody against an anti-phospho-S216 peptide of ERα (αP-S216) was used for double immunofluorescence staining to detect to ERα in cultured microglia. A knock-in (KI) mouse line bearing the phosphorylation-blocked ERα mutation S216A (ERα KI) was generated to examine whether this phosphorylation regulate immune functions of microglia.ResultsPhosphorylated ERα at Ser216 was present in microglia but not astrocytes. Staining with an anti-Iba-1 antibody showed that microglia activation was augmented in substantial nigra of ERα KI brains. Lipopolysaccharide (LPS) treatments aggravated microglia activation in ERα KI brains, pro-inflammatory cytokines were increased while anti-inflammatory cytokines were decreased at mRNA and protein levels in whole brain extracts. These increases and decreases of cytokine proteins were also observed in LPS-treated microglia cultured from brains of ERα KI neonates. FACS analysis revealed that ERα KI mutation increased number of IL-6 producing microglia and apoptosis. ERα KI mice decreased motor connection ability in Rotarod tests.ConclusionsBlocking of Ser216 phosphorylation aggravated microglia activation and inflammation of mouse brain, thus confirming that phosphorylated ERα exerts anti-inflammatory functions. ERα KI mice enable us to further investigate the mechanism by which phosphorylated ERα regulates brain immunity and inflammation.

scholarly journals Preventive Effects of Bacillus licheniformis on Heat Stroke in Rats by Sustaining Intestinal Barrier Function and Modulating Gut Microbiota

2021 ◽  
Vol 12 ◽  
Author(s):  
Lei Li ◽  
Man Wang ◽  
Jikuai Chen ◽  
Zhuoran Xu ◽  
Shaokang Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Inflammatory Cytokines ◽  
Bacillus Licheniformis ◽  
Barrier Function ◽  
Heat Stroke ◽  
Intestinal Barrier ◽  
Intestinal Injury ◽  
Organ Injury ◽  
Intestinal Barrier Function ◽  
Preventive Effects

Heat stroke (HS) models in rats are associated with severe intestinal injury, which is often considered as the key event at the onset of HS. Probiotics can regulate the gut microbiota by inhibiting the colonization of harmful bacteria and promoting the proliferation of beneficial bacteria. Here, we investigated the preventive effects of a probiotic Bacillus licheniformis strain (BL, CMCC 63516) on HS rats as well as its effects on intestinal barrier function and gut microbiota. All rats were randomly divided into four groups: control (Con) + PBS (pre-administration with 1 ml PBS twice a day for 7 days, without HS induction), Con + BL group (pre-administration with 1 ml 1 × 108 CFU/ml BL twice a day for 7 days, without HS induction), HS + PBS (PBS, with HS induction), and HS + BL (BL, with HS induction). Before the study, the BL strain was identified by genomic DNA analysis. Experimental HS was induced by placing rats in a hot and humid chamber for 60 min until meeting the diagnostic criterion of HS onset. Body weight, core body temperature, survival rate, biochemical markers, inflammatory cytokines, and histopathology were investigated to evaluate the preventive effects of BL on HS. D-Lactate, I-FABP, endotoxin, and tight-junction proteins were investigated, and the fluorescein isothiocyanate-dextran (FD-4) test administered, to assess the degree of intestinal injury and integrity. Gut microbiota of rats in each group were analyzed by 16S rRNA sequencing. The results showed that pre-administration with BL significantly attenuated hyperthermia, reduced HS-induced death, alleviated multiple-organ injury, and decreased the levels of serum inflammatory cytokines. Furthermore, BL sustained the intestinal barrier integrity of HS rats by alleviating intestinal injury and improving tight junctions. We also found that BL significantly increased the ratios of two probiotic bacteria, Lactobacillus and Lactococcus. In addition, Romboutsia, a candidate biomarker for HS diagnosis, was unexpectedly detected. In summary, BL pre-administration for 7 days has preventative effects on HS that may be mediated by sustaining intestinal barrier function and modulating gut microbiota.

P2X7 Receptor as a Potential Target for Major Depressive Disorder

2021 ◽  
Vol 22 ◽  
Author(s):  
Zeyi Huang ◽  
Sijie Tan
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Chronic Stress ◽  
Inflammatory Cytokines ◽  
P2x7 Receptor ◽  
Microglia Activation ◽  
Major Depressive ◽  
Bbb Permeability ◽  
The Brain

Major depressive disorder (MDD) is a common mental disorder. Although the genetic, biochemical, and psychological factors have been related to the development of MDD, it is generally believed that a series of pathological changes in the brain caused by chronic stress is the main cause of MDD. However, the specific mechanisms underlying chronic stress-induced MDD are largely undermined. Recent investigations have found that increased pro-inflammatory cytokines and changes in the inflammatory pathway in the microglia cells in the brain are the potential pathophysiological mechanism of MDD. P2X7 receptor (P2X7R) and its mediated signaling pathway play a key role in microglia activation. The present review aimed to present and discuss the accumulating data on the role of P2X7R in MDD. Firstly, we summarized the research progress in the correlation between P2X7R and MDD. Subsequently, we presented the P2X7R mediated microglia activation in MDD and the role of P2X7R in increased blood-brain barrier (BBB) permeability caused by chronic stress. Lastly, we also discussed the potential mechanism underlying P2X7R expression changes after chronic stress. In conclusion, P2X7R is a key molecule regulating the activation of microglia. Chronic stress activates microglia in the hippocampus by secreting interleukin-1β (IL-1β) and other inflammatory cytokines, and increasing the BBB permeability, thus promoting the occurrence and development of MDD, which indicated that P2X7R might be promising therapeutic target for MDD.

Abstract TP336: The Intestinal Barrier Dysfunction Induced by Intracerebral Hemorrhage Contributes to the Brain Edema

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Tian Wang ◽  
Bing Han ◽  
Yingjie Han ◽  
Ting Li ◽  
Fenghua Fu
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Intestinal Permeability ◽  
Sham Group ◽  
Intestinal Barrier ◽  
Intestinal Injury ◽  
Brain Water Content ◽  
Barrier Dysfunction ◽  
The Brain ◽  
Brain Water

Background and Purpose: This study aims to investigate whether intracerebral hemorrhage (ICH) can lead to intestinal barrier dysfunction, and whether ICH-induced intestinal injury plays a role in brain edema. Methods: ICH mice model was prepared by an intrastriatal injection of bacterial collagenase. The following parameters were investigated at 3 h, 6 h, 12 h, 1 d, 2 d, 3 d, or 7 d after ICH preparation. Mice were given intragastrically with FITC-dextran and the intestinal permeability was evaluated by serum fluorescence measurement. Serum lipopolysaccharide (LPS) level was assayed with ELISA kits. Ileum and jejunum were stained with hematoxylin and eosin. Intestinal mucosal injuries were graded according to the scoring method (grade 0 to grade 4). Brain water content was evaluated via a wet/dry weight method. Correlations of intestinal injury, intestine permeability, LPS, and brain edema were analyzed using Pearson’s correlation analysis. Results: Compared with the Sham group, Ileum and jejunum damage occurred at 6 h after ICH, and the ICH-induced intestinal injury continued until 7 d. In line with the histopathological findings, the degree of ileum and jejunum injury was significantly increased at 6 h after ICH, showing mostly scores in Grade 1 to Grade 3 ( P < 0.05 or P < 0.01). After 6-h ICH, the intestinal permeability to FITC-dextran was higher compared to the Sham group, and the increase of intestinal permeability lasted 7 d ( P < 0.01). From 6 h to 7 d, serum LPS was significantly augmented ( P < 0.01). The brain content of the ipsilateral hemispheres was increased at 12 h, 1 d, 2 d, and 3 d after ICH ( P < 0.05 or P < 0.01), and the brain content of the contralateral hemispheres was also enhanced at 1 d, 2 d, and 3 d after ICH ( P < 0.01). The ileum and jejunum injury were positively associated with intestine permeability (r = 0.625, P < 0.01, r = 0.465, P < 0.01, respectively). The intestine permeability was positively associated with the serum level of LPS (r =0.585, P < 0.01). The LPS levels were positively associated with brain water content (r = 0.338, P < 0.01). Conclusion: ICH can cause intestinal mucosal injury. Consequently, the increase of intestinal permeability results in the translocation of endotoxins, which contributes to ICH-induced brain edema.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Passive Diffusion ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Different Types ◽  
The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

scholarly journals Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

2021 ◽  
Vol 22 (15) ◽  
pp. 7847
Author(s):  
Anthony Fringuello ◽  
Philip D. Tatman ◽  
Tadeusz Wroblewski ◽  
John A. Thompson ◽  
Xiaoli Yu ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Hemorrhagic Stroke ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Interleukin 7 ◽  
Poor Outcomes ◽  
Patient Prognosis ◽  
The Brain

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery.

scholarly journals Obeticholic Acid Inhibits Anxiety via Alleviating Gut Microbiota-Mediated Microglia Accumulation in the Brain of High-Fat High-Sugar Diet Mice

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 940
Author(s):  
Li Wu ◽  
Yuqiu Han ◽  
Zhipeng Zheng ◽  
Shuai Zhu ◽  
Jun Chen ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Intestinal Barrier ◽  
Behavioral Performance ◽  
High Fat ◽  
Barrier Dysfunction ◽  
Obeticholic Acid ◽  
Promising Agent ◽  
Serum Biochemical ◽  
Lipid Metabolites ◽  
The Brain

Anxiety is one of the complications of metabolic disorders (MDs). Obeticholic acid (OCA), the bile acids (BAs) derivative, is a promising agent for improving MDs in association with gut dysbiosis. Yet, its protective effect on MDs-driven anxiety remains unknown. Here, we assessed the serum biochemical parameters and behavioral performance by open field and Morris water maze tests in HFHS diet-induced MDs mice after OCA intervention for nine and 18 weeks. Moreover, antibiotics intervention for microbial depletion was conducted simultaneously. We found that OCA treatment inhibited the initiation and progression of anxiety in HFHS diet-MDs mice via a microbiota–BAs–brain axis: OCA decreased the neuroinflammatory microglia and IL-1β expression in the hippocampus, reversed intestinal barrier dysfunction and serum proinflammatory LPS to a normal level, modified the microbial community, including the known anxiety-related Rikenellaceae and Alistipes, and improved the microbial metabolites especially the increased BAs in feces and circulation. Moreover, the OCA-reversed bile acid taurocholate linked disordered serum lipid metabolites and indole derivatives to anxiety as assessed by network analysis. Additionally, microbial depletion with antibiotics also improved the anxiety, microgliosis and BAs enrichment in the experimental MDs mice. Together, these findings provide microbiota–BAs–brain axis as a novel therapeutic target for MDs-associated neuropsychiatric disorders.

Microglia activation in the hypothalamic PVN following myocardial infarction

2010 ◽  
Vol 1326 ◽  
pp. 96-104 ◽  
Author(s):  
Indrajeetsinh Rana ◽  
Martin Stebbing ◽  
Andrew Kompa ◽  
Darren J. Kelly ◽  
Henry Krum ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Microglia Activation

Regulation of components of the brain and cardiac renin-angiotensin systems by 17β-estradiol after myocardial infarction in female rats

2006 ◽  
Vol 291 (1) ◽  
pp. R155-R162 ◽  
Author(s):  
Stephanie A. Dean ◽  
Junhui Tan ◽  
Roselyn White ◽  
Edward R. O’Brien ◽  
Frans H. H. Leenen
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Female Rats ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Brain Nuclei ◽  
Renin Angiotensin ◽  
Lv Dysfunction ◽  
17Β Estradiol ◽  
The Brain

The present study tested the hypothesis that 17β-estradiol (E2) inhibits increases in angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT1R) in the brain and heart after myocardial infarction (MI) and, thereby, inhibits development of left ventricular (LV) dysfunction after MI. Age-matched female Wistar rats were treated as follows: 1) no surgery (ovary intact), 2) ovariectomy + subcutaneous vehicle treatment (OVX + Veh), or 3) OVX + subcutaneous administration of a high dose of E2 (OVX + high-E2). After 2 wk, rats were randomly assigned to coronary artery ligation (MI) and sham operation groups and studied after 3 wk. E2 status did not affect LV function in sham rats. At 2–3 wk after MI, impairment of LV function was similar across MI groups, as measured by echocardiography and direct LV catheterization. LV ACE mRNA abundance and activity were increased severalfold in all MI groups compared with respective sham animals and to similar levels across MI groups. In most brain nuclei, ACE and AT1R densities increased after MI. Unexpectedly, compared with the respective sham groups the relative increase was clearest (20–40%) in OVX + high-E2 MI rats, somewhat less (10–15%) in ovary-intact MI rats, and least (<10–15%) in OVX + Veh MI rats. However, because in the sham group brain ACE and AT1R densities increased in the OVX + Veh rats and decreased in the OVX + high-E2 rats compared with the ovary-intact rats, actual ACE and AT1R densities in most brain nuclei were modestly higher (<20%) in OVX + Veh MI rats than in the other two MI groups. Thus E2 does not inhibit upregulation of ACE in the LV after MI and amplifies the percent increases in ACE and AT1R densities in brain nuclei after MI, despite E2-induced downregulation in sham rats. Consistent with these minor variations in the tissue renin-angiotensin system, during the initial post-MI phase, E2 appears not to enhance or hinder the development of LV dysfunction.

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