scholarly journals Iso-α-Acids, the Bitter Components of Beer, Suppress Microglial Inflammation in rTg4510 Tauopathy

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3133 ◽  
Author(s):  
Yasuhisa Ano ◽  
Yuta Takaichi ◽  
Kazuyuki Uchida ◽  
Keiji Kondo ◽  
Hiroyuki Nakayama ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Amyloid Β ◽  
Phosphorylated Tau ◽  
Brain Disorders ◽  
Flow Cytometry Analysis ◽  
Wild Type ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
Aging Populations ◽  
Microglial Inflammation

Due to the growth in aging populations, prevention for cognitive decline and dementia are in great demand. We previously demonstrated that the consumption of iso-α-acids (IAA), the hop-derived bitter compounds in beer, prevents inflammation and Alzheimer’s disease pathology in model mice. However, the effects of iso-α-acids on inflammation induced by other agents aside from amyloid β have not been investigated. In this study, we demonstrated that the consumption of iso-α-acids suppressed microglial inflammation in the frontal cortex of rTg4510 tauopathy mice. In addition, the levels of inflammatory cytokines and chemokines, including IL-1β and MIP-1β, in the frontal cortex of rTg4510 mice were greater than those of wild-type mice, and were reduced in rTg4510 mice fed with iso-α-acids. Flow cytometry analysis demonstrated that the expression of cells producing CD86, CD68, TSPO, MIP-1α, TNF-α, and IL-1β in microglia was increased in rTg4510 mice compared with wild-type mice. Furthermore, the expression of CD86- and MIP-1α-producing cells was reduced in rTg4510 mice administered with iso-α-acids. Moreover, the consumption of iso-α-acids reduced the levels of phosphorylated tau in the frontal cortex. Collectively, these results suggest that the consumption of iso-α-acids prevents the inflammation induced in tauopathy mice. Thus, iso-α-acids may help in preventing inflammation-related brain disorders.

scholarly journals Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells

2011 ◽  
Vol 301 (2) ◽  
pp. C530-C539 ◽  
Author(s):  
Michael Romio ◽  
Benjamin Reinbeck ◽  
Sabine Bongardt ◽  
Sandra Hüls ◽  
Sandra Burghoff ◽  
...  
Keyword(s):  
T Cells ◽  
Proinflammatory Cytokines ◽  
Wild Type ◽  
Murine Splenocytes ◽  
Gm Csf ◽  
A2a Receptors ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
Ifn Γ ◽  
Macrophage Colony

CD73-derived adenosine acts as potent inhibitor of inflammation, and regulatory T cells (Treg) have been shown to express CD73 as a novel marker. This study explored the role of endogenously formed adenosine in modulating NF-κB activity and cytokine/chemokine release from murine Treg and effector T cells (Teff) including key enzymes/purinergic receptors of extracellular ATP catabolism. Stimulating murine splenocytes and CD4+ T cells with anti-CD3/anti-CD28 significantly upregulated activated NF-κB in CD73−/− T cells (wild type: 4.36 ± 0.21; CD73−/−: 6.58 ± 0.75; n = 4; P = 0.029). This was associated with an augmented release of proinflammatory cytokines IL-2, TNF-α, and IFN-γ. Similar changes were observed with the CD73 inhibitor APCP (50 μM) on NF-κB and IFN-γ in wild-type CD4+ T-cells. Treatment of stimulated CD4+ T-cells with adenosine (25 μM) potently reduced IFN-γ release which is mediated by adenosine A2a receptors (A2aR). AMP (50 μM) also reduced cytokine release which was not inhibited by APCP. In Teff, A2aR activation (CGS21680) potently inhibited the release of IL-1, IL-2, IL-3, IL-4, IL-12, IL-13, IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), CCL3, and CCL4. However, in Treg, CGS21680 did not alter cytokine/chemokine release. In summary, CD73-derived adenosine tonically inhibits active NF-κB in CD4+ T-cells, thereby modulating the release of a broad spectrum of proinflammatory cytokines and chemokines. Downregulation of P2X7 and upregulation of CD73 in Treg after antigenic stimulation may be an important mechanism to maintain the ability of Treg to generate immunosuppressive adenosine.

scholarly journals SARS-CoV-2 variants of concern infect the respiratory tract and induce inflammatory response in wild-type laboratory mice

2021 ◽  
Author(s):  
Shannon Stone ◽  
Hussin A. Rothan ◽  
Janhavi P. Natekar ◽  
Pratima Kumari ◽  
Shaligram Sharma ◽  
...  
Keyword(s):  
Immune Escape ◽  
Mrna Levels ◽  
Laboratory Mice ◽  
Wild Type ◽  
The Public ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
New Hosts ◽  
High Concentrations ◽  
Old Mice

AbstractThe emergence of new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern poses a major threat to the public health due to possible enhanced virulence, transmissibility and immune escape. These variants may also adapt to new hosts in part through mutations in the spike protein. In this study, we evaluated the infectivity and pathogenicity of SARS-CoV-2 variants of concern in wild-type C57BL/6 mice. Six-week-old mice were inoculated intranasally with a representative virus from the original B.1 lineage or emerging B.1.1.7 and B.1.351 lineages. We also infected a group of mice with a mouse-adapted SARS-CoV-2 (MA10). Viral load and mRNA levels of multiple cytokines and chemokines were analyzed in the lung tissues on day 3 after infection. Our data show that unlike the B.1 virus, the B.1.1.7 and B.1.351 viruses are capable of infecting C57BL/6 mice and replicating at high concentrations in the lungs. The B.1.351 virus replicated to higher titers in the lungs compared to the B.1.1.7 and MA10 viruses. The levels of cytokines (IL-6, TNF-α, IL-1β) and chemokine (CCL2) were upregulated in response to the B.1.1.7 and B.1.351 infection in the lungs. Overall, these data indicate a greater potential for infectivity and adaptation to new hosts by emerging SARS-CoV-2 variants.

scholarly journals SARS-CoV-2 Variants of Concern Infect the Respiratory Tract and Induce Inflammatory Response in Wild-Type Laboratory Mice

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 27
Author(s):  
Shannon Stone ◽  
Hussin Alwan Rothan ◽  
Janhavi Prasad Natekar ◽  
Pratima Kumari ◽  
Shaligram Sharma ◽  
...  
Keyword(s):  
Immune Escape ◽  
Mrna Levels ◽  
Laboratory Mice ◽  
Wild Type ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
New Hosts ◽  
High Concentrations ◽  
Old Mice ◽  
Viral Nucleocapsid

The emergence of new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern pose a major threat to public health, due to possible enhanced virulence, transmissibility and immune escape. These variants may also adapt to new hosts, in part through mutations in the spike protein. In this study, we evaluated the infectivity and pathogenicity of SARS-CoV-2 variants of concern in wild-type C57BL/6 mice. Six-week-old mice were inoculated intranasally with a representative virus from the original B.1 lineage, or the emerging B.1.1.7 and B.1.351 lineages. We also infected a group of mice with a mouse-adapted SARS-CoV-2 (MA10). Viral load and mRNA levels of multiple cytokines and chemokines were analyzed in the lung tissues on day 3 after infection. Our data show that unlike the B.1 virus, the B.1.1.7 and B.1.351 viruses are capable of infecting C57BL/6 mice and replicating at high concentrations in the lungs. The B.1.351 virus replicated to higher titers in the lungs compared with the B.1.1.7 and MA10 viruses. The levels of cytokines (IL-6, TNF-α, IL-1β) and chemokine (CCL2) were upregulated in response to the B.1.1.7 and B.1.351 infection in the lungs. In addition, robust expression of viral nucleocapsid protein and histopathological changes were detected in the lungs of B.1.351-infected mice. Overall, these data indicate a greater potential for infectivity and adaptation to new hosts by emerging SARS-CoV-2 variants.

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

2019 ◽  
Vol 16 (8) ◽  
pp. 710-722 ◽  
Author(s):  
Xiao-Ying Sun ◽  
Quan-Xiu Dong ◽  
Jie Zhu ◽  
Xun Sun ◽  
Li-Fan Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Maze Test ◽  
N2a Cells ◽  
Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

scholarly journals 4-(Phenylsulfanyl) Butan-2-One Attenuates the Inflammatory Response Induced by Amyloid-β Oligomers in Retinal Pigment Epithelium Cells

Marine Drugs ◽  
2020 ◽  
Vol 19 (1) ◽  
pp. 1
Author(s):  
Peeraporn Varinthra ◽  
Shun-Ping Huang ◽  
Supin Chompoopong ◽  
Zhi-Hong Wen ◽  
Ingrid Y. Liu
Keyword(s):  
Retinal Pigment Epithelium ◽  
Inflammatory Response ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Epithelial Cell Line ◽  
Age Related ◽  
Tnf Α ◽  
Cox 2

Age-related macular degeneration (AMD) is a progressive eye disease that causes irreversible impairment of central vision, and effective treatment is not yet available. Extracellular accumulation of amyloid-beta (Aβ) in drusen that lie under the retinal pigment epithelium (RPE) has been reported as one of the early signs of AMD and was found in more than 60% of Alzheimer’s disease (AD) patients. Extracellular deposition of Aβ can induce the expression of inflammatory cytokines such as IL-1β, TNF-α, COX-2, and iNOS in RPE cells. Thus, finding a compound that can effectively reduce the inflammatory response may help the treatment of AMD. In this research, we investigated the anti-inflammatory effect of the coral-derived compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) on Aβ1-42 oligomer (oAβ1-42) added to the human adult retinal pigment epithelial cell line (ARPE-19). Our results demonstrated that 4-PSB-2 can decrease the elevated expressions of TNF-α, COX-2, and iNOS via NF-κB signaling in ARPE-19 cells treated with oAβ1-42 without causing any cytotoxicity or notable side effects. This study suggests that 4-PSB-2 is a promising drug candidate for attenuation of AMD.

scholarly journals Hypoxia-Induced S100A8 Expression Activates Microglial Inflammation and Promotes Neuronal Apoptosis

2021 ◽  
Vol 22 (3) ◽  
pp. 1205
Author(s):  
Ji Sun Ha ◽  
Hye-Rim Choi ◽  
In Sik Kim ◽  
Eun-A Kim ◽  
Sung-Woo Cho ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Neuronal Apoptosis ◽  
Microglial Cells ◽  
Molecular Pattern ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Cox 2 ◽  
Necrosis Factor ◽  
Microglial Inflammation ◽  
Tlr4 Receptor

S100 calcium-binding protein A8 (S100A8), a danger-associated molecular pattern, has emerged as an important mediator of the pro-inflammatory response. Some S100 proteins play a prominent role in neuroinflammatory disorders and increase the secretion of pro-inflammatory cytokines in microglial cells. The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action. In this study, we reported that the S100A8 protein expression was increased in mouse neuronal and microglial cells when exposed to hypoxia, and induced neuroinflammation and neuronal apoptosis. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia. Also, phosphorylation of ERK via the TLR4 receptor induced the priming of the NLRP3 inflammasome. The changes in Cyclooxygenase-2 (COX-2) expression, a well-known inflammatory activator, were regulated by the S100A8 expression in microglial cells. Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia. These results suggested that S100A8 may be an important molecule for bidirectional microglia-neuron communication and a new therapeutic target for neurological disorders caused by microglial inflammation during hypoxia.

Blockage of angiotensin II type 1 receptor regulates TNF-α-induced MAdCAM-1 expression via inhibition of NF-κB translocation to the nucleus and ameliorates colitis

2010 ◽  
Vol 298 (2) ◽  
pp. G255-G266 ◽  
Author(s):  
Takashi Mizushima ◽  
Makoto Sasaki ◽  
Tomoaki Ando ◽  
Tsuneya Wada ◽  
Mamoru Tanaka ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Activity Index ◽  
Body Weight Loss ◽  
Disease Activity Index ◽  
Wild Type ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Novel Target ◽  
Colitis Model

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to α4β7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R−/−) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-α, but did not inhibit phosphorylation of p38 MAPK or of IκB that modulate MAdCAM-1 expression. However, NF-κB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R−/− than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R−/− than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-κB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1.

scholarly journals Relation of Endothelial Dysfunction and Adipokines Levels to Insulin Resistance in Metabolic Syndrome Patients

2009 ◽  
Vol 63 (4-5) ◽  
pp. 222-227
Author(s):  
Pēteris Tretjakovs ◽  
Antra Jurka ◽  
Inga Bormane ◽  
Indra Miķelsone ◽  
Dace Reihmane ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Endothelial Dysfunction ◽  
Doppler Imaging ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Cytokines And Chemokines ◽  
Tnf Α ◽  
Artery Disease ◽  
D 20

Relation of Endothelial Dysfunction and Adipokines Levels to Insulin Resistance in Metabolic Syndrome Patients Obese metabolic syndrome (MS) patients were categorised into three groups: 44 with type 2 diabetes mellitus (T2DM)(D); 20 with T2DM and coronary artery disease (CAD) (DC), and 26 with MS alone (M). Eighteen healthy subjects were selected as controls (C). Insulin resistance (IR) was assessed by HOMA-IR. Adiponectin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) concentrations were measured by xMAP technology. Endothelin-1 (ET-1) was determined by ELISA. We used laser Doppler imaging for evaluating cutaneous endothelium-dependent vasodilatation in the hand. D and DC groups had significantly elevated IR compared with M or C group (P < 0.01). TNF-α, IL-6, IL-8, MCP-1 and ET-1 levels in DC were significantly elevated compared with other groups (P < 0.001). IL-6, IL-8, MCP-1 and ET-1 in D group were higher than those in C group (P < 0.05). TNF-α, IL-6, IL-8, MCP-1 and ET-1 concentrations were correlated with HOMA-IR indexes and adiponectin levels. All patients had lower adiponectin concentrations than controls (P < 0.001), but there were no differences between the patient groups. Only D and DC groups demonstrated a significant and similar decrease in LDI-Ach marker compared to C group (P < 0.001). LDI-Ach values were significantly correlated with HOMA-IR indexes and adiponectin levels (P < 0.001). Our findings show that obese MS patients have significantly increased HOMA-IR, TNF-α, IL-6, MCP-1 and IL-8 levels, decreased adiponectin concentration, and endothelial dysfunction, but the presence of T2DM and CAD in these patients is associated with more pronounced endothelial dysfunction and increased production of inflammatory cytokines and chemokines.

scholarly journals Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2843
Author(s):  
Stefan Saretz ◽  
Gabriele Basset ◽  
Liridona Useini ◽  
Markus Laube ◽  
Jens Pietzsch ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Pharmaceutical Research ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Blood Brain ◽  
Secretase Activity ◽  
Number Of Patients ◽  
Aging Populations ◽  
A Cell

All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer’s disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood–brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood–brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These findings demonstrate the potential of carboranes as phenyl mimetics also in AD research.

Contributions of angiotensin II and tumor necrosis factor-α to the development of renal fibrosis

2001 ◽  
Vol 280 (5) ◽  
pp. F777-F785 ◽  
Author(s):  
Guangjie Guo ◽  
Jeremiah Morrissey ◽  
Ruth McCracken ◽  
Timothy Tolley ◽  
Helen Liapis ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Tumor Necrosis Factor ◽  
Renal Fibrosis ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Wild Type ◽  
Tnf Α ◽  
Factor Α ◽  
Tgf Β1 ◽  
Necrosis Factor

Angiotensin II upregulates tumor necrosis factor-α (TNF-α) in the rat kidney with unilateral ureteral obstruction (UUO). In a mouse model of UUO, we found that tubulointerstitial fibrosis is blunted when the TNF-α receptor, TNFR1, is functionally knocked out. In this study, we used mutant mice with UUO in which the angiotensin II receptor AT1a or the TNF-α receptors TNFR1 and TNFR2 were knocked out to elucidate interactions between the two systems. The contribution of both systems to renal fibrosis was assessed by treating TNFR1/TNFR2-double knockout (KO) mice with an angiotensin-converting enzyme inhibitor, enalapril. The increased interstitial volume (Vvint) in the C57BI/6 wild-type mouse was decreased in the AT1a KO from 32.8 ± 4.0 to 21.0 ± 3.7% ( P < 0.005) or in the TNFR1/TNFR2 KO to 22.3 ± 2.1% ( P < 0.005). The Vvint of the TNFR1/TNFR2 KO was further decreased to 15.2 ± 3.7% ( P < 0.01) by enalapril compared with no treatment. The induction of TNF-α mRNA and transforming growth factor-β1 (TGF-β1) mRNA in the kidney with UUO was significantly blunted in the AT1a or TNFR1/TNFR2 KO mice compared with the wild-type mice. Treatment of the TNFR1/TNFR2 KO mouse with enalapril reduced both TNF-α and TGF-β1 mRNA and their proteins to near normal levels. Also, α-smooth muscle actin expression and myofibroblast proliferation were significantly inhibited in the AT1a or TNFR1/TNFR2 KO mice, and they were further inhibited in enalapril-treated TNFR1/TNFR2 KO mice. Incapacitating the angiotensin II or the TNF-α systems individually leads to partial blunting of fibrosis. Incapacitating both systems, by using a combination of genetic and pharmacological means, further inhibited interstitial fibrosis and tubule atrophy in obstructive nephropathy.

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