scholarly journals Inhibition of Autotaxin and Lysophosphatidic Acid Receptor 5 Attenuates Neuroinflammation in LPS-Activated BV-2 Microglia and a Mouse Endotoxemia Model

2021 ◽  
Vol 22 (16) ◽  
pp. 8519
Author(s):  
Lisha Joshi ◽  
Ioanna Plastira ◽  
Eva Bernhart ◽  
Helga Reicher ◽  
Alexander Triebl ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Brain ◽  
Systemic Inflammation ◽  
Lysophosphatidic Acid ◽  
Microglia Activation ◽  
No Production ◽  
Type I ◽  
Neuroinflammatory Response ◽  
Cox2 Expression

Increasing evidence suggests that systemic inflammation triggers a neuroinflammatory response that involves sustained microglia activation. This response has deleterious consequences on memory and learning capability in experimental animal models and in patients. However, the mechanisms connecting systemic inflammation and microglia activation remain poorly understood. Here, we identify the autotaxin (ATX)/lysophosphatidic acid (LPA)/LPA-receptor axis as a potential pharmacological target to modulate the LPS-mediated neuroinflammatory response in vitro (the murine BV-2 microglia cell line) and in vivo (C57BL/6J mice receiving a single i.p. LPS injection). In LPS-stimulated (20 ng/mL) BV-2 cells, we observed increased phosphorylation of transcription factors (STAT1, p65, and c-Jun) that are known to induce a proinflammatory microglia phenotype. LPS upregulated ATX, TLR4, and COX2 expression, amplified NO production, increased neurotoxicity of microglia conditioned medium, and augmented cyto-/chemokine concentrations in the cellular supernatants. PF8380 (a type I ATX inhibitor, used at 10 and 1 µM) and AS2717638 (an LPA5 antagonist, used at 1 and 0.1 µM) attenuated these proinflammatory responses, at non-toxic concentrations, in BV-2 cells. In vivo, we demonstrate accumulation of PF8380 in the mouse brain and an accompanying decrease in LPA concentrations. In vivo, co-injection of LPS (5 mg/kg body weight) and PF8380 (30 mg/kg body weight), or LPS/AS2717638 (10 mg/kg body weight), significantly attenuated LPS-induced iNOS, TNFα, IL-1β, IL-6, and CXCL2 mRNA expression in the mouse brain. On the protein level, PF8380 and AS2717638 significantly reduced TLR4, Iba1, GFAP and COX2 expression, as compared to LPS-only injected animals. In terms of the communication between systemic inflammation and neuroinflammation, both inhibitors significantly attenuated LPS-mediated systemic TNFα and IL-6 synthesis, while IL-1β was only reduced by PF8380. Inhibition of ATX and LPA5 may thus provide an opportunity to protect the brain from the toxic effects that are provoked by systemic endotoxemia.

scholarly journals Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1906
Author(s):  
Hiroshi Ueda ◽  
Hiroyuki Neyama ◽  
Yosuke Matsushita
Keyword(s):  
Body Weight ◽  
Neuropathic Pain ◽  
Lysophosphatidic Acid ◽  
Body Weight Loss ◽  
Type I ◽  
Diabetic Neuropathic Pain ◽  
Pain Behaviors ◽  
Glucose Levels ◽  
Pain Models ◽  
Elevated Glucose

Lysophosphatidic acid (LPA) signaling is known to play key roles in the initiation and maintenance of various chronic pain models. Here we examined whether LPA signaling is also involved in diabetes-induced abnormal pain behaviors. The high-fat diet (HFD) showing elevation of blood glucose levels and body weight caused thermal, mechanical hyperalgesia, hypersensitivity to 2000 or 250 Hz electrical-stimulation and hyposensitivity to 5 Hz stimulation to the paw in wild-type (WT) mice. These HFD-induced abnormal pain behaviors and body weight increase, but not elevated glucose levels were abolished in LPA1−/− and LPA3−/− mice. Repeated daily intrathecal (i.t.) treatments with LPA1/3 antagonist AM966 reversed these abnormal pain behaviors. Similar abnormal pain behaviors and their blockade by daily AM966 (i.t.) or twice daily Ki16425, another LPA1/3 antagonist was also observed in db/db mice which show high glucose levels and body weight. Furthermore, streptozotocin-induced similar abnormal pain behaviors, but not elevated glucose levels or body weight loss were abolished in LPA1−/− and LPA3−/− mice. These results suggest that LPA1 and LPA3 play key roles in the development of both type I and type II diabetic neuropathic pain.

scholarly journals Sargassum Horneri (Turner) C. Agardh Regulates Neuroinflammation via Inhibition of LPS-stimulated Microglia Activation in Vitro and in Vivo

2021 ◽  
Author(s):  
Jun Sik Lee ◽  
Jun Hwi Cho ◽  
Mi Eun Kim
Keyword(s):  
Protein Expression ◽  
Brown Algae ◽  
Microglia Activation ◽  
Sargassum Horneri ◽  
No Production ◽  
Mapk Phosphorylation ◽  
Mice Brain ◽  
Cox 2

Abstract Previously we reported that Sargassum horneri (Turner) C. Agardh (S. horneri) is a brown algae species that exerts anti-inflammatory activity toward murine macrophages. However, the anti-neuroinflammatory effects and the mechanism of S. horneri on microglia cells are still unknown. We investigated the anti-neuroinflammatory effects of S. horneri extract on microglia in vitro and in vivo. In present study, we found that S. horneri was not cytotoxic to BV-2 microglia cells, and it significantly decreased lipopolysaccharide (LPS)-induced NO production. Moreover, S. horneri also diminished the protein expression of iNOS, COX-2, and cytokines production including IL-1b, TNF-a, and IL-6 on LPS-stimulated microglia activation. S. horneri elicited anti-neuroinflammatory effects by inhibiting phosphorylation of p38 MAPK and NF-kB. In addition, S. horneri inhibited astrocytes and microglia activation in LPS-challenged mice brain. Therefore, these results suggested that S. horneri exerted anti-neuroinflammatory effects on LPS-stimulated microglia cells activation by inhibiting MAPK phosphorylation and NF-kB signaling.

Effects of Pentoxifylline on Peritoneal Fibroblasts and Silica-Induced Peritoneal Fibrosis

2003 ◽  
Vol 23 (3) ◽  
pp. 228-236 ◽  
Author(s):  
Cheng-Chung Fang ◽  
Ming-Nan Lai ◽  
Chiang-Ting Chien ◽  
Kuan-Yu Hung ◽  
Chien-Chen Tsai ◽  
...  
Keyword(s):  
Body Weight ◽  
Collagen Synthesis ◽  
Control Group ◽  
Type Iii Collagen ◽  
Type I ◽  
Dependent Manner ◽  
Peritoneal Fibrosis ◽  
Group 1

♦ Background Peritoneal fibrosis is a long-term complication following continuous ambulatory peritoneal dialysis (CAPD). Peritoneal fibroblasts may play an important role in peritoneal fibrosis. Up to now, the treatment of peritoneal fibrosis in patients with CAPD remains unsatisfactory. Pentoxifylline (PTX) is a xanthine derivative and is used in the treatment of peripheral vascular and cerebrovascular diseases. Several studies have demonstrated that PTX can ameliorate fibrosis of the skin, liver, and kidney. ♦ Objective To investigate the effect of PTX on in vitro growth and collagen synthesis of human peritoneal fibroblasts (HPFBs), and to evaluate the effects of PTX on silica-induced peritoneal fibrosis in vivo. ♦ Design and Measurements In the in vitro study, HPFBs were cultured from human omentum. The effect of PTX on the growth of serum-stimulated HPFBs was evaluated by MTT assay. The effect of PTX on the collagen synthesis of HPFB was measured by [3H]-proline incorporation. Expression of type I and type III collagen mRNA was evaluated by Northern blotting. The effects of PTX on matrix metalloproteinase (MMP) activity and cAMP level in HPFBs were measured by immunoassays. In the in vivo study, Wistar rats were randomly divided into five groups. All rats received intraperitoneal (IP) injection of silica suspension (250 mg/100 g body weight) on day 0. The rats of group 1 (control group) were injected with vehicle IP every day for 14 days. The rats of groups 2, 3, and 4 were injected with PTX (4 mg/100 g body weight) IP every day for 3, 7, and 14 days, respectively. The rats in group 5 received an intravenous infusion of PTX (8 mg/100 g body weight) every day for 7 days. On the 15th day after silica injection, all rats were sacrificed. Their parietal and visceral peritoneums were removed and processed for pathology, and the severity of fibrosis was measured and scored. ♦ Results: In vitro, PTX inhibited serum-stimulated HPFB growth (maximum was 93% at 1 mg PTX/mL) in a dose-dependent manner. Collagen synthesis by HPFB was reduced (47% at 1 mg PTX/mL), and collagen I and III mRNA expression in HPFBs was suppressed by PTX. The PTX did not affect the MMP (including MMP-1, MMP-8, and MMP-13) activities of HPFBs. The mechanism of PTX was through increasing cAMP by its phosphodiesterase inhibiting activity. In vivo, the severity of fibrosis was significantly reduced in groups 4 and 5 compared to group 1 ( p < 0.05). ♦ Conclusion These results suggest that PTX can inhibit growth of and collagen synthesis by HPFBs in vitro. The fibrosis derived from silica-induced peritonitis in vivo was also ameliorated by PTX. Therefore, pentoxifylline may have the potential to be used to treat peritoneal fibrosis in patients on CAPD.

Release of Erythrocyte-Derived ATP, a Recognized Stimulus of Nitric Oxide Production, Is Increased upon Incubation of Erythrocytes with C-Peptide.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1567-1567
Author(s):  
Dana M. Spence ◽  
Jennifer A. Meyer
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Type I Diabetes ◽  
Atp Release ◽  
Mechanical Deformation ◽  
Type I Diabetes Mellitus ◽  
No Production ◽  
Type I ◽  
C Peptide

Abstract Red blood cells (RBCs), when traversing microvascular beds, are subjected to mechanical deformation. It is established that RBCs release nanomolar to micromolar amounts of adenosine triphosphate (ATP), a recognized stimulus of nitric oxide (NO) production in vivo. The finding that ATP is released from RBCs in response to mechanical deformation, suggests that the RBC may be an important determinant of NO production as these cells traverse the intact circulation. An example of this potential importance of the RBC exists in diabetic complications. It is well established that patients with Type I diabetes mellitus, when compared to non-diabetics, have RBCs that are less deformable and more susceptible to oxidant stress. In conjunction with these findings, it has recently been reported that RBCs obtained from Type II diabetics release less ATP (91 +/− 10 nM) upon deformation than subjects without the disease (190 +/− 8 nM). These findings suggest that a membrane flexibilizer capable of increasing RBC-derived ATP in response to mechanical deformation may prove beneficial in improving microvascular flow. C-peptide, a 31 amino acid peptide, that connects the A and B chains of insulin, has been thought to have no significant biological role in vivo. Recently, it has been reported that C-peptide increases the deformability of erythrocytes obtained from the whole blood of patients with Type I diabetes mellitus. However, there has been no previous study to determine if C-peptide will actually increase the deformation-induced release of ATP from RBCs. Here, data is presented showing that adding nanomolar concentrations of C-peptide RBCs obtained from rabbits increases the ability of these cells to release ATP over time. When a 7% hematocrit of RBCs was incubated with a solution containing 6.6 nM C-peptide and pumped through tubing having an inside diameter that approximates resistance vessels in vivo (i.e., ~50 μm), the amount of ATP released from the RBCs increased from 0.246 ± 0.033 μM to 0.692 ± 0.140 μM (n = 10 rabbits, p<0.001) over a period of 8 hours. In the absence of the peptide, an aliquot from the same sample resulted in no significant increase in ATP release. Under conditions of non-flow, RBCs incubated with the peptide showed no statistically significant increase in ATP release. Additionally, RBCs that were incubated in the peptide containing 1 mM glybenclamide, a proven inhibitor of RBC-derived ATP, released 50% less ATP than a solution of RBCs in the absence of the inhibitor. Our results suggest that adding C-peptide to rabbit RBCs increases their ability to release ATP. Subsequent studies have shown the activity of C-peptide is depleted within 3–4 days after the solution is prepared. However, spectra obtained from a MALDI-TOF spectrometer clearly indicate that the peptide is still present in the solution exactly as it was on the day it was prepared. This suggests that there may be an activated form of the peptide that is responsible for the increase in RBC deformability and deformation-induced ATP release from these cells. In conclusion, these results suggest that C-peptide should not be considered as a biomarker alone and may have important interactions with RBCs in vivo.

scholarly journals Immunohistochemical study of dental pulp cells with 3D collagen type I gel in demineralized dentin tubules in vivo

2020 ◽  
Author(s):  
Sultan Zeb Khan ◽  
Sana Mirza ◽  
Samina Karim ◽  
Takashi Inoue ◽  
Mohammed S. Bin-Shuwaish ◽  
...  
Keyword(s):  
Body Weight ◽  
Dental Pulp ◽  
Collagen Gel ◽  
Male Rats ◽  
Type I ◽  
Dental Pulp Cells ◽  
Pulp Cells ◽  
Dentin Tubules ◽  
Demineralized Dentin

Dental pulp cells (DPCs) represent good candidates for the regeneration of dental tissue. This study aimed to evaluate the growth and differentiation potential of DPCs cultured inside demineralized dentin tubules in vivo. Six green fluorescent protein (GFP)-transgenic rats (body weight 100 g each) and thirty-two Sprague-Dawley (SD) male rats (body weight 250 g each) were used for DPC collection and dentin tubules preparation and transplantation, respectively. Third-passage DPCs with or without collagen gels were loaded into demineralized dentin tubules. Both types of grafts were transplanted into the rectus abdominis muscles of SD rats and were harvested after 21 days. The expression of alkaline phosphatase (ALP), bone sialoprotein (BSP), osteopontin (OPN), nestin, and dentin sialoprotein (DSP) were analyzed by immunohistochemistry. Histological analysis showed that DPCs in the collagen gel formed an osteodentin-like hard tissue matrix after 21 days. Increased positive immunoreactivity for ALP, BSP, OPN, nestin, and DSP was observed in experimental groups compared with control. Our results demonstrate that DPCs in collagen gel inside demineralized dentin tubules show increased growth and differentiation.

Differential up-regulation of hypoxia-inducible vasoactive factors in fetal mouse brain in vivo upon intrauterine hypoxia

2006 ◽  
Vol 37 (03) ◽  
Author(s):  
R Trollmann ◽  
K Strasser ◽  
J Soliz ◽  
D Wenzel ◽  
W Rascher ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Fetal Mouse ◽  
Vasoactive Factors ◽  
Intrauterine Hypoxia

Overtraining of aerobic physical exercise reduce rats (Rattus norvegicus) memory

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Ni Made Ridla Parwata
Keyword(s):  
Body Weight ◽  
Physical Exercise ◽  
Rattus Norvegicus ◽  
Research Method ◽  
Male Rat ◽  
Control Group ◽  
Adult Male Rat ◽  
The Subject ◽  
Heavy Training

Overtraining syndrome is a decrease in physical capacity, emotions and immunity due to training that is too often without adequate periods of rest. Overtraining is often experienced by athletes who daily undergo heavy training with short break periods. This research aims to look at the effect of overtraining aerobic physical exercise on memory in mice. The research method was experimental in vivo with the subject of adult male rat (Rattus Norvegicus) Winstar strain aged 8-10 weeks, body weight 200-250 gr. Divided into three groups, namely the control group, aerobic group and overtraining group. The results of memory tests with water E Maze showed an increase in the duration of travel time and the number of animal errors made by the overtraining group (p = 0.003). This study concludes that overtraining aerobic physical exercise can reduce memory in rat hippocampus.

Neuropharmacological Profile and Chemical Analysis of Moroccan Ormenis mixta L.

2018 ◽  
Vol 16 (S1) ◽  
pp. S55-S64
Author(s):  
G. Hajjaj ◽  
A. Bahlouli ◽  
M. Tajani ◽  
K. Alaoui ◽  
Y. Cherrah ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Body Weight ◽  
Traditional Medicine ◽  
Behavioral Tests ◽  
Phytochemical Screening ◽  
Activity Profile ◽  
Acute Toxicity Study ◽  
Pharmacological Studies

Ormenis mixta L. is traditionally used for central nervous system (CNS)-related diseases. Its anti-stress properties have received attention in Moroccan traditional medicine and aromatherapy. However, no pharmacological studies have yet been undertaken on this plant in Morocco. The present study provides a preliminary phytochemical screening and psychopharmacological profile of the essential oil and aqueous extract from Ormenis mixta L. by using behavioral tests in vivo, at graded doses. The result of this research shows that Ormenis mixta L. was safe up to 2 g/kg b.w. (body weight) in the acute toxicity study, possesses potential psychostimulant effect, and has antianxiety and antidepressant-like activity. This activity profile of Ormenis mixta L. was similar to the typical psychostimulant, caffeine. The exact mechanism of action underlying this stimulant-like effect should be clarified with further detailed studies. These results explained the extensive use of Ormenis mixta L. as a traditional medicine in Morocco.

Peculiarities of the course of type I allergic reactions in patients with blood diseases

2020 ◽  
pp. 40-50
Author(s):  
A. Nikitina
Keyword(s):  
Search Engines ◽  
Anaphylactic Shock ◽  
Type I ◽  
Allergic Reactions ◽  
Common Cause ◽  
Blood Diseases ◽  
Treatment Regimens ◽  
Modern Methods

Analysis of literature data presented in search engines — Elibrary, PubMed, Cochrane — concerning the risk of developing type I allergic reactions in patients with blood diseases is presented. It is shown that the most common cause of type I allergic reactions is drugs included in the treatment regimens of this category of patients. The article presents statistics on the increase in the number of drug allergies leading to cases of anaphylactic shock in patients with blood diseases. Modern methods for the diagnosis of type I allergic reactions in vivo and in vitro are considered.

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