scholarly journals Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks

2019 ◽  
Vol 20 (5) ◽  
pp. 1223 ◽  
Author(s):  
Rüdiger Hardeland
Keyword(s):  
Amyloid Β ◽  
Sirtuin 1 ◽  
Toll Like Receptor 4 ◽  
System A ◽  
Age Related ◽  
Microglia Polarization ◽  
Inflammatory Phenotype ◽  
Secretory Phenotype ◽  
Anti Inflammatory ◽  
Stimulatory Agent

Aging and various age-related diseases are associated with reductions in melatonin secretion, proinflammatory changes in the immune system, a deteriorating circadian system, and reductions in sirtuin-1 (SIRT1) activity. In non-tumor cells, several effects of melatonin are abolished by inhibiting SIRT1, indicating mediation by SIRT1. Melatonin is, in addition to its circadian and antioxidant roles, an immune stimulatory agent. However, it can act as either a pro- or anti-inflammatory regulator in a context-dependent way. Melatonin can stimulate the release of proinflammatory cytokines and other mediators, but also, under different conditions, it can suppress inflammation-promoting processes such as NO release, activation of cyclooxygenase-2, inflammasome NLRP3, gasdermin D, toll-like receptor-4 and mTOR signaling, and cytokine release by SASP (senescence-associated secretory phenotype), and amyloid-β toxicity. It also activates processes in an anti-inflammatory network, in which SIRT1 activation, upregulation of Nrf2 and downregulation of NF-κB, and release of the anti-inflammatory cytokines IL-4 and IL-10 are involved. A perhaps crucial action may be the promotion of macrophage or microglia polarization in favor of the anti-inflammatory phenotype M2. In addition, many factors of the pro- and anti-inflammatory networks are subject to regulation by microRNAs that either target mRNAs of the respective factors or upregulate them by targeting mRNAs of their inhibitor proteins.

scholarly journals Short-chain fatty acids contribute to neuropathic pain via regulating microglia activation and polarization

2021 ◽  
Vol 17 ◽  
pp. 174480692199652
Author(s):  
Feng Zhou ◽  
Xian Wang ◽  
Baoyu Han ◽  
Xiaohui Tang ◽  
Ru Liu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Thermal Hyperalgesia ◽  
Short Chain Fatty Acids ◽  
Antibiotic Administration ◽  
Tnf Α ◽  
Microglia Polarization ◽  
Inflammatory Phenotype ◽  
Phenotype Markers ◽  
Anti Inflammatory

Microglia activation and subsequent pro-inflammatory responses play a key role in the development of neuropathic pain. The process of microglia polarization towards pro-inflammatory phenotype often occurs during neuroinflammation. Recent studies have demonstrated an active role for the gut microbiota in promoting microglial full maturation and inflammatory capabilities via the production of Short-Chain Fatty Acids (SCFAs). However, it remains unclear whether SCFAs is involved in pro-inflammatory/anti-inflammatory phenotypes microglia polarization in the neuropathic pain. In the present study, chronic constriction injury (CCI) was used to induce neuropathic pain in mice, the mechanical withdrawal threshold, thermal hyperalgesia were accomplished. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), pro-inflammatory phenotype markers including CD68, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and anti-inflammatory phenotype markers including CD206, IL-4 in the hippocampus and spinal cord were determined on day 21 after CCI. The results showed that CCI produced mechanical allodynia and thermal hyperalgesia, and also increased the expressions of microglia markers (Iba1, CD11b) and pro-inflammatory phenotype markers (CD68, IL-1β, and TNF-α), but not anti-inflammatory phenotype marker (CD206, IL-4) in the hippocampus and spinal cord, accompanied by increased SCFAs in the gut. Notably, antibiotic administration reversed these abnormalities, and its effects was also bloked by SCFAs administration. In conclusion, data from our study suggest that CCI can lead to mechanical and thermal hyperalgesia, while SCFAs play a key role in the pathogenesis of neuropathic pain by regulating microglial activation and subsequent pro-inflammatory phenotype polarization. Antibiotic administration may be a new treatment for neuropathic pain by reducing the production of SCFAs and further inhibiting the process of microglia polarization.

Inhibition of Histamine H3 receptor Attenuates Neuroinflammation and Cognitive Impairments in Alzheimer’s Disease via activating CREB Pathway

2020 ◽  
Author(s):  
Jiangong Wang ◽  
Bin Liu ◽  
Yong Xu ◽  
Chaoyun Wang ◽  
Meizi Yang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Interleukin 4 ◽  
Histamine H3 Receptor ◽  
Creb Phosphorylation ◽  
H3 Receptor ◽  
Age Related ◽  
Anti Inflammatory ◽  
Histamine H3

Abstract BackgroundAlzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation and neuroprotection on APP/PS1 Tg mice remains unclear. MethodsIn this study, microgliosis, astrogliosis, A1 type astrocytes and A2 type astrocytes in APP/PS1 Tg mice were measured by immunostaining by Iba1, GFAP, C3 and S100A10 with and without treatment of thioperamide, an H3R antagonist. Inflammatory response of APP/PS1 Tg mice and effects of thioperamide were studied by measuring levels of pro-inflammatory cytokines (tumor necrosis factor α [TNFα] and interleukin-1β [IL-1β]) and anti-inflammatory cytokines (interleukin-4 [IL-4]). Protein levels of p-CREB and p-P65 NF-kB was tested by western blot to study the mechanism of thioperamide on AD. H89 was applied to study whether the mechanism offered by thioperamide was dependent on CREB activating. The effect of thioperamide and H89 on Aβ deposition was measured by immunostaining and ELISA. The cognitive function was tested by novel object recognition, Y maze and morris water maze. ResultsInhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice. Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated nuclear factor kappa B (NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of Aβ and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89. ConclusionsTaken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aβ clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.

scholarly journals Elucidation of the Mechanism Underlying the Anti-Inflammatory Properties of (S)-(+)-Carvone Identifies a Novel Class of Sirtuin-1 Activators in a Murine Macrophage Cell Line

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 777
Author(s):  
Cátia Sousa ◽  
Bruno Miguel Neves ◽  
Alcino Jorge Leitão ◽  
Alexandrina Ferreira Mendes
Keyword(s):  
Cell Line ◽  
Sirtuin 1 ◽  
Low Grade ◽  
Murine Macrophage ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Murine Macrophage Cell Line ◽  
Protein Levels ◽  
Age Related ◽  
Anti Inflammatory

The signaling pathways involved in age-related inflammation are increasingly recognized as targets for the development of preventive and therapeutic strategies. Our previous study elucidated the structure–activity relationship of monoterpene compounds derived from p-menthane as potential anti-inflammatory drugs and identified (S)-(+)-carvone as the most potent among the compounds tested. This study aims at identifying the molecular mechanism underlying the anti-inflammatory properties of (S)-(+)-carvone. The murine macrophage cell line, Raw 264.7, was stimulated with bacterial lipopolysaccharide (LPS) to simulate inflammation. Western blot was used to assess protein levels and post-translational modifications. The subcellular localization of NF-κB/p65 was visualized by immunocytochemistry. An in vitro fluorometric assay was used to measure Sirtuin-1 (SIRT1) activity. (S)-(+)-carvone inhibited LPS-induced JNK1 phosphorylation, but not that of p38 and ERK1/2 and also did not affect the phosphorylation and degradation of the NF-κB inhibitor, IκB-α. Accordingly, (S)-(+)-carvone did not affect LPS-induced phosphorylation of NF-κB/p65 on Ser536 and its nuclear translocation, but it significantly decreased LPS-induced IκB-α resynthesis, a NF-κB-dependent process, and NF-κB/p65 acetylation on lysine (Lys) 310. Deacetylation of that Lys residue is dependent on the activity of SIRT1, which was found to be increased by (S)-(+)-carvone, while its protein levels were unaffected. Taken together, these results show that (S)-(+)-carvone is a new SIRT1 activator with the potential to counteract the chronic low-grade inflammation characteristic of age-related diseases.

scholarly journals Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

2019 ◽  
Author(s):  
Shoshik Amram ◽  
Tal Iram ◽  
Ekaterina Lazdon ◽  
Robert Vassar ◽  
Ittai Ben-Porath ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cellular Senescence ◽  
Amyloid Β ◽  
Dependent Manner ◽  
Inflammatory Phenotype ◽  
Secretory Phenotype ◽  
5Xfad Mice ◽  
Tgf Β1

ABSTRACTAlterations in astrocyte function such as a pro-inflammatory phenotype are associated with Alzheimer’s disease (AD). We had shown impairments in the ability of aged astrocytes isolated from 5xFAD mice to clear and uptake amyloid-β (Aβ) as well as to support neuronal growth. Senescent cells accumulate with age and exhibit a senescence-associated secretory phenotype, which includes secretion of pro-inflammatory cytokines. In this study, we predicted that with age, astrocytes in 5xFAD mice would exhibit a cellular senescence phenotype that could promote neurodegeneration. We found an age-dependent increase in senescent astrocytes adjacent to Aβ plaques in 5xFAD mice. Inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells reduced interelukin-6 secretion by senescent astrocytes and resulted in improved neuronal support. Moreover, senescent astrocytes exhibited an increase in the induction of the TGF-β1-SMAD2/3 pathway, and inhibition of this pathway resulted in a reduction of cellular senescence. We also discovered that soluble Aβ42 induced astrocyte senescence in young naïve mice in a SMAD2/3-dependent manner. Our results suggest an important role of astrocyte senescence in AD and its role in mediating the neurotoxicity properties of astrocytes in AD and related neurodegenerative diseases.

scholarly journals Lipopolysaccharide induces placental mitochondrial dysfunction by reducing MNRR1 levels via a TLR4-independent pathway

2021 ◽  
Author(s):  
Neeraja Purandare ◽  
Yusef Kunji ◽  
Yue Xi ◽  
Roberto Romero ◽  
Nardhy Gomez-Lopez ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Redox Homeostasis ◽  
Toll Like Receptor 4 ◽  
Atm Kinase ◽  
Unfolded Protein ◽  
Inflammatory Phenotype ◽  
Placental Inflammation ◽  
Anti Inflammatory ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Mitochondria play a key role in the growth and development of the placenta, an organ essential for pregnancy in eutherian mammals. Mitochondrial dysfunction has been associated with pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals at a cellular and mechanistic level are unknown. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) is a bi-organellar protein responsible for optimal mitochondrial function to achieve energy and redox homeostasis. In addition, MNRR1 also is required for optimal induction of cellular stress-responsive signaling pathways such as the mitochondrial unfolded protein response (UPRmt). Here, in a lipopolysaccharide-induced model of placental inflammation, we show that MNRR1 levels are reduced in placental tissues and cell lines. Reduction in MNRR1 is associated with mitochondrial dysfunction and enhanced oxidative stress along with activation of pro-inflammatory signaling. Mechanistically, we uncover a non-conventional pathway independent of Toll-like receptor 4 (TLR4) that results in a specific ATM kinase-dependent threonine phosphorylation and activation of a mitochondrial protease, YME1L1, degrading MNRR1. Furthermore, enhancing MNRR1 levels in placental cells either genetically or with specific activators abrogates the bioenergetic defect and induces an anti-inflammatory phenotype, suggesting that MNRR1 is upstream of the mitochondrial dysfunction observed in our model. Reduction in MNRR1 levels is a generalized phenomenon observed in cells under an inflammatory stimulus. We therefore propose MNRR1 as a novel anti-inflammatory therapeutic target in pathologies associated with placental inflammation.

scholarly journals Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

2021 ◽  
Vol 22 (14) ◽  
pp. 7711
Author(s):  
Maddalena Grieco ◽  
Maria Giovanna De Caris ◽  
Elisa Maggi ◽  
Federica Armeli ◽  
Roberto Coccurello ◽  
...  
Keyword(s):  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Protein Activation ◽  
Cytoskeleton Reorganization ◽  
Microglia Polarization ◽  
Inflammatory Phenotype ◽  
Faah Inhibition ◽  
Anti Inflammatory ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer’s disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-β peptide (Aβ). The morphological evaluation showed that Aβ treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aβ. Moreover, URB597 reduced both the increase of Rho protein activation in Aβ-treated BV-2 cells and the Aβ-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.

Emerging Promise of Immunotherapy for Alzheimer’s Disease: A New Hope for the Development of Alzheimer’s Vaccine

2020 ◽  
Vol 20 (13) ◽  
pp. 1214-1234 ◽  
Author(s):  
Md. Tanvir Kabir ◽  
Md. Sahab Uddin ◽  
Bijo Mathew ◽  
Pankoj Kumar Das ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Neutralizing Antibodies ◽  
Neurodegenerative Disorder ◽  
Symptomatic Relief ◽  
Aβ Oligomers ◽  
Th2 Immune Response ◽  
Age Related ◽  
Anti Inflammatory

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language. Objective: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine. Summary: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aβ) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aβ conformers. The induction of an effective vaccine’s immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aβ oligomers (AβOs) and also anti-inflammatory cytokines, thus preventing the AD-related inflammation. Conclusion: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective and convenient approach to avoid the treatment-related huge expense.

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