This review offers a systematic understanding about how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. It provides a clear understanding of the molecular mechanisms of action of phenolic compounds. Polyphenols regulate immunity by interfering with immune cell regulation, proinflammatory cytokines’ synthesis, and gene expression. They inactivate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and modulate mitogen-activated protein Kinase (MAPk) and arachidonic acids pathways. Polyphenolic compounds inhibit phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT), inhibitor of kappa kinase/c-Jun amino-terminal kinases (IKK/JNK), mammalian target of rapamycin complex 1 (mTORC1) which is a protein complex that controls protein synthesis, and JAK/STAT. They can suppress toll-like receptor (TLR) and pro-inflammatory genes’ expression. Their antioxidant activity and ability to inhibit enzymes involved in the production of eicosanoids contribute as well to their anti-inflammation properties. They inhibit certain enzymes involved in reactive oxygen species ROS production like xanthine oxidase and NADPH oxidase (NOX) while they upregulate other endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px). Furthermore, they inhibit phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) leading to a reduction in the production of prostaglandins (PGs) and leukotrienes (LTs) and inflammation antagonism. The effects of these biologically active compounds on the immune system are associated with extended health benefits for different chronic inflammatory diseases. Studies of plant extracts and compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation such as diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions.

/pdf/the-immunomodulatory-and-anti-inflammatory-role-of-3entgum03f.pdf

The Immunomodulatory and Anti-Inflammatory Role of Polyphenols.

Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1.

/pdf/are-sirtuins-viable-targets-for-improving-healthspan-and-1940vio95c.pdf

Are sirtuins viable targets for improving healthspan and lifespan

Aging leads to numerous transitions in brain physiology including synaptic dysfunction and disturbances in cognition and memory. With a few clinically relevant drugs, a substantial portion of aging population at risk for age-related neurodegenerative disorders require nutritional intervention. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as Alzheimer's disease (AD), stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Huntington's disease (HD). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once. Firstly, we review the advances in the therapeutic role of polyphenols in cell and animal models of AD, PD, MS, and HD and activation of drug targets for controlling pathological manifestations. Secondly, we present principle pathways in which polyphenol intake translates into therapeutic outcomes. In particular, signaling pathways like PPAR, Nrf2, STAT, HIF, and MAPK along with modulation of immune response by polyphenols are discussed. Although current polyphenol researches have limited impact on clinical practice, they have strong evidence and testable hypothesis to contribute clinical advances and drug discovery towards age-related neurological disorders.

/pdf/polyphenols-multipotent-therapeutic-agents-in-3g8dfd4lin.pdf

Polyphenols: multipotent therapeutic agents in neurodegenerative diseases.

Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation.

Resveratrol is the most well-known polyphenolic stilbenoid, present in grapes, mulberries, peanuts, rhubarb, and in several other plants. Resveratrol can play a beneficial role in the prevention and in the progression of chronic diseases related to inflammation such as diabetes, obesity, cardiovascular diseases, neurodegeneration, and cancers among other conditions. Moreover, resveratrol regulates immunity by interfering with immune cell regulation, proinflammatory cytokines’ synthesis, and gene expression. At the molecular level, it targets sirtuin, adenosine monophosphate kinase, nuclear factor-κB, inflammatory cytokines, anti-oxidant enzymes along with cellular processes such as gluconeogenesis, lipid metabolism, mitochondrial biogenesis, angiogenesis, and apoptosis. Resveratrol can suppress the toll-like receptor (TLR) and pro-inflammatory genes’ expression. The antioxidant activity of resveratrol and the ability to inhibit enzymes involved in the production of eicosanoids contribute to its anti-inflammation properties. The effects of this biologically active compound on the immune system are associated with widespread health benefits for different autoimmune and chronic inflammatory diseases. This review offers a systematic understanding of how resveratrol targets multiple inflammatory components and exerts immune-regulatory effects on immune cells.

Influence of Resveratrol on the Immune Response

Activation of microglia, the resident macrophages of the brain, around the amyloid plaques is a key hallmark of Alzheimer's disease (AD). Recent evidence in mouse models indicates that microglia are required for the neurodegenerative process of AD. Amyloid-β (Aβ) peptides, the core components of the amyloid plaques, can trigger microglial activation by interacting with several Toll-like receptors (TLRs), including TLR4. In this study, we show that resveratrol, a natural polyphenol associated with anti-inflammatory effects and currently in clinical trials for AD, prevented the activation of murine RAW 264.7 macrophages and microglial BV-2 cells treated with the TLR4 ligand, lipopolysaccharide (LPS). Resveratrol preferentially inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation upon LPS stimulation by interfering with IKK and IκB phosphorylation, an effect that potently reduced the transcriptional stimulation of several NF-κB target genes, including tumor necrosis factor-α and interleukin-6. Consequently, downstream phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3 upon LPS stimulation was also inhibited by resveratrol. We found that resveratrol acted upstream in the activation cascade by interfering with TLR4 oligomerization upon receptor stimulation. Resveratrol treatment also prevented the pro-inflammatory effect of fibrillar Aβ on macrophages by potently inhibiting the effect of Aβ on IκB phosphorylation, activation of STAT1 and STAT3, and on tumor necrosis factor-α and interleukin-6 secretion. Importantly, orally administered resveratrol in a mouse model of cerebral amyloid deposition lowered microglial activation associated with cortical amyloid plaque formation. Together this work provides strong evidence that resveratrol has in vitro and in vivo anti-inflammatory effects against Aβ-triggered microglial activation. Further studies in cell culture systems showed that resveratrol acted via a mechanism involving the TLR4/NF-κB/STAT signaling cascade.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2011.07594.x

Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade.

Signal transducer and activator of transcription 3 (STAT3) is a key mediator of the inflammatory response of macrophages and other immune cell types. The naturally occurring polyphenol resveratrol is associated with anti-proliferative and anti-inflammatory properties via mechanisms implicating inhibition of STAT3 signaling. Here, we report that the small-molecule analogs of resveratrol, RSVA314 and RSVA405, are potent inhibitors of STAT3. RSVA314 and RSVA405 inhibited both constitutive and stimulated STAT3 activity in HEK293 cells and lipopolysaccharide-stimulated RAW 264.7 macrophages, respectively. The small-molecule analogs inhibited STAT3 nearly 50 times more potently than did resveratrol (apparent IC(50) ~0.5 μM). We further show that RSVA405 interfered with the inflammatory response by RAW 264.7 cells upon lipopolysaccharide stimulation by inhibiting IκB kinase and IκBα phosphorylation and by decreasing the expression of several cytokines, including the NF-κB target genes tumor necrosis factor α and interleukin-6. Downstream activation of STAT1 upon lipopolysaccharide stimulation was also inhibited by RSVA405. Consequently, RSVA405 significantly interfered with the phagocytotic activity and proliferation of lipopolysaccharide-activated RAW 264.7 macrophages. Finally, we found that the effect of the two small-molecule analogs on STAT3 phosphorylation could be prevented by inhibitors of protein tyrosine phosphatases, indicating that the small molecules acted by promoting dephosphorylation of STAT3 by protein tyrosine phosphatases.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2012.08739.x

Identification of potent small‐molecule inhibitors of STAT3 with anti‐inflammatory properties in RAW 264.7 macrophages

The amyloid-β protein precursor (AβPP) is a type I transmembrane protein that undergoes maturation during trafficking in the secretory pathway. Proper maturation and trafficking of AβPP are necessary prerequisites for AβPP processing to generate amyloid-β (Aβ), the core component of Alzheimer's disease senile plaques. Recently, we reported that the glycosylphosphatidylinositol (GPI)-anchored protein growth arrest-specific 1 (Gas1) binds to and interferes with the maturation and processing of AβPP. Gas1 expression led to a trafficking blockade of AβPP between the endoplasmic reticulum (ER) and the Golgi. GPI-anchored proteins can exit the ER by transiting through raft subdomains acting as specialized sorting platforms. Here, we show that Gas1 co-partitioned and formed a complex with AβPP in raft fractions, wherein Gas1 overexpression triggered immature AβPP accumulation. Pharmacological interference of ER to Golgi transport increased immature AβPP accumulation upon Gas1 expression in these raft fractions, which were found to be positive for the COPII protein complex component Sec31A, a specific marker for ER exit sites. Furthermore, a Gas1 mutant lacking the GPI anchor that could not transit through rafts was still able to form a complex with AβPP but did not lead to immature AβPP accumulation in rafts. Together these data show that Gas1 interfered with AβPP trafficking by interacting with AβPP to facilitate its translocation into specialized ER-associated rafts where immature AβPP accumulated.

/pdf/gas1-interferes-with-abpp-trafficking-by-facilitating-the-1945dzsz12.pdf

Hemachander Capiralla

Papers

Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade.

Identification of potent small‐molecule inhibitors of STAT3 with anti‐inflammatory properties in RAW 264.7 macrophages

Gas1 interferes with AβPP trafficking by facilitating the accumulation of immature AβPP in endoplasmic reticulum-associated raft subdomains.