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Therapeutic benefits of a component of coffee in a rat model of Alzheimer's disease

A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT), provides protection in a rat model for Alzheimers disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I2(PP2A), or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic amyloid-β protein. Dietary supplementation with EHT for 6-12 months resulted in substantial amelioration of all these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiologic studies indicating that coffee drinkers have substantially lowered risk of developing AD.

SIG1273: a new cosmetic functional ingredient to reduce blemishes and Propionibacterium acnes in acne prone skin.

Propionibacterium acnes is a major contributing factor to the inflammatory component of acne. The interaction of P. acnes with keratinocytes leads to an innate immune response via activation of toll‐like receptors (TLR2, TLR4) resulting in the production and secretion of pro‐inflammatory mediators. SIG1273, an isoprenylcysteine small molecule modulates inflammatory signaling pathways and kills P. acnes. SIG1273 represents a novel cosmetic functional ingredient that provides relief from blemishes in acne prone skin.

Anti-inflammatory and anti-bacterial properties of tetramethylhexadecenyl succinyl cysteine (TSC): a skin-protecting cosmetic functional ingredient

The skin is the first line of defence against exposure to microbial, physical, environmental and chemical insults. In mobilizing a protective response, several different cell types located in our skin release and respond to pro‐inflammatory cytokines ensuring skin homeostasis and health. However, chronic activation of this response eventually causes damage resulting in premature ageing. Diosodium tetramethylhexadecenyl succinyl cysteine (TSC or SIG1273), an isoprenylcysteine small molecule, down modulates these inflammatory signalling pathways in various cell types (keratinocytes, peripheral blood mononuclear cells (PBMCs) and endothelial cells) and possesses anti‐bacterial properties. Thus, TSC represents a novel cosmetic functional ingredient that provides a broad spectrum of benefits for the skin.

N-acetyl-S-farnesyl-l-cysteine suppresses chemokine production by human dermal microvascular endothelial cells.

Isoprenylcysteine (IPC) molecules modulate G‐protein‐coupled receptor signalling. The archetype of this class is N‐acetyl‐S‐farnesyl‐l‐cysteine (AFC). Topical application of AFC locally inhibits skin inflammation and elicitation of contact hypersensitivity in vivo. However, the mechanism of these anti‐inflammatory effects is not well understood. Dermal microvascular endothelial cells (ECs) are involved in inflammation, in part, by secreting cytokines that recruit inflammatory cells. We have previously shown that the sympathetic nerve cotransmitter adenosine‐5′‐triphosphate (ATP) and adenosine‐5′‐O‐(3‐thio) triphosphate (ATPγS), an ATP analogue that is resistant to hydrolysis, increase secretion of the chemokines CXCL8 (interleukin‐8), CCL2 (monocyte chemotactic protein‐1) and CXCL1 (growth‐regulated oncogene α) by dermal microvascular ECs. Production of these chemokines can also be induced by the exposure to the proinflammatory cytokine TNFα. We have now demonstrated that AFC dose‐dependently inhibits ATP‐, ATPγS‐ and TNFα‐induced production of CXCL1, CXCL8 and CCL2 by a human dermal microvascular EC line (HMEC‐1) in vitro under conditions that do not affect cell viability. Inhibition of ATPγS‐ or TNFα‐stimulated release of these chemokines was associated with reduced mRNA levels. N‐acetyl‐S‐geranyl‐l‐cysteine, an IPC analogue that is inactive in inhibiting G‐protein‐coupled signalling, had greatly reduced ability to suppress stimulated chemokine production. AFC may exert its anti‐inflammatory effects through the inhibition of chemokine production by stimulated ECs.

Eicosanoyl-5-hydroxytryptamide (EHT) prevents Alzheimer’s disease-related cognitive and electrophysiological impairments in mice exposed to elevated concentrations of oligomeric beta-amyloid

Soluble forms of oligomeric beta-amyloid (Aβ) are thought to play a central role in Alzheimer’s disease (AD). Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aβ. In addition, eicosanoyl-5-hydroxytryptamide (EHT), a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson’s disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aβ. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aβ-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aβ-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aβ-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.

In vitro and clinical evaluation of SIG1273: a cosmetic functional ingredient with a broad spectrum of anti-aging and antioxidant activities

Isoprenylcysteine (IPC) small molecules were identified as a new class of anti‐inflammatory compounds over 20 years ago. Since then, they have been developed as novel cosmetic functional ingredients (CFI) and topical drug candidates. SIG1273 is a second generation CFI that has previously been shown to provide a broad spectrum of benefits for the skin through its anti‐inflammatory and antimicrobial properties.

SIG1459: A novel phytyl‐cysteine derived TLR2 modulator with in vitro and clinical anti‐acne activity

Cutibacterium (formerly Propionibacterium acnes) is a major contributor to the pathogenesis of acne. C. acnes initiates an innate immune response in keratinocytes via recognition and activation of toll‐like receptor‐2 (TLR2), a key step in comedogenesis. Tetramethyl‐hexadecenyl‐cysteine‐formylprolinate (SIG1459), a novel anti‐acne isoprenylcysteine (IPC) small molecule, is shown in this study to have direct antibacterial activity and inhibit TLR2 inflammatory signalling. In vitro antibacterial activity of SIG1459 against C. acnes was established demonstrating minimal inhibitory concentration (MIC = 8.5 μmol\L), minimal bactericidal concentration (MBC = 16.1 μmol\L) and minimal biofilm eradication concentration (MBEC = 12.5 μmol\L). To assess SIG1459s anti‐inflammatory activity, human keratinocytes were exposed to C. acnes and different TLR2 ligands (peptidoglycan, FSL‐1, Pam3CSK4) that induce pro‐inflammatory cytokine IL‐8 and IL‐1α production. Results demonstrate SIG1459 inhibits TLR2‐induced IL‐8 release from TLR2/TLR2 (IC50 = 0.086 μmol\L), TLR2/6 (IC50 = 0.209 μmol\L) and IL‐1α from TLR2/TLR2 (IC50 = 0.050 μmol\L). To assess the safety and in vivo anti‐acne activity of SIG1459, a vehicle controlled clinical study was conducted applying 1% SIG1459 topically (n = 35 subjects) in a head‐to‐head comparison against 3% BPO (n = 15 subjects). Utilizing the Investigator Global Assessment scale for acne as primary endpoint, results demonstrate 1% SIG1459 significantly outperformed 3% BPO over 8 weeks, resulting in 79% improvement as compared to 56% for BPO. Additionally, 1% SIG1459 was well tolerated. Thus, SIG1459 and phytyl IPC compounds represent a novel anti‐acne technology that provides a safe dual modulating benefit by killing C. acnes and reducing the inflammation it triggers via TLR2 signalling.