Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro.

OBJECTIVES: Urolithins, ellagitannin-gut microbial-derived metabolites, have been reported to mediate pomegranate's neuroprotective effects against Alzheimer's disease (AD), but there are limited data on their effects against neuroinflammation. Herein, we: (1) evaluated whether urolithins (urolithins A and B and their methylated derivatives) attenuate neuroinflammation in murine BV-2 microglia and human SH-SY5Y neurons, and (2) evaluated hippocampus of transgenic AD (R1.40) mice administered a pomegranate extract (PE; 100 or 200 mg/kg/day for 3 weeks) for inflammatory biomarkers. METHODS: Effects of urolithins (10 µM) on inflammatory biomarkers were evaluated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. In a non-contact co-culture cell model, SH-SY5Y cell viability was assessed after exposure to media collected from LPS-BV-2 cells treated with or without urolithins. Effects of urolithins on apoptosis and caspase 3/7 and 9 release from H2O2-induced oxidative stress of BV-2 and SH-SY5Y cells were assessed. Hippocampal tissues of vehicle and PE-treated transgenic R1.40 mice were evaluated for gene expression of inflammatory biomarkers by qRT-PCR. RESULTS: Urolithins decreased media levels of nitric oxide, interleukin 6 (IL-6), prostaglandin E2, and tumor necrosis factor alpha from LPS-BV-2 microglia. In the co-culture cell model, media from LPS-BV-2 cells treated with urolithins preserved SH-SY5Y cell viability greater than media from cells treated without urolithins. Urolithins mitigated apoptosis and caspase 3/7 and 9 release from H2O2-induced oxidative stress of BV-2 and SH-SY5Y cells. While not statistically significant, inflammatory biomarkers (TNF-α, COX-2, IL-1, and IL-6) appeared to follow a decreasing trend in the hippocampus of high-dose PE-treated animals compared to controls. DISCUSSION: The attenuation of neuroinflammation by urolithins may contribute, in part, toward pomegranate's neuroprotective effects against AD.

Effects of a Standardized Phenolic-Enriched Maple Syrup Extract on ß-Amyloid Aggregation, Neuroinflammation in Microglial and Neuronal Cells, and ß-Amyloid Induced Neurotoxicity in Caenorhabditis elegans.

Published data supports the neuroprotective effects of several phenolic-containing natural products, including certain fruit, berries, spices, nuts, green tea, and olive oil. However, limited data are available for phenolic-containing plant-derived natural sweeteners including maple syrup. Herein, we investigated the neuroprotective effects of a chemically standardized phenolic-enriched maple syrup extract (MSX) using a combination of biophysical, in vitro, and in vivo studies. Based on biophysical data (Thioflavin T assay, transmission electron microscopy, circular dichroism, dynamic light scattering, and zeta potential), MSX reduced amyloid ß1-42 peptide (Aß1-42) fibrillation in a concentration-dependent manner (50-500 µg/mL) with similar effects as the neuroprotective polyphenol, resveratrol, at its highest test concentration (63.5 % at 500 µg/mL vs. 77.3 % at 50 µg/mL, respectively). MSX (100 µg/mL) decreased H2O2-induced oxidative stress (16.1 % decrease in ROS levels compared to control), and down-regulated the production of lipopolysaccharide (LPS)-stimulated inflammatory markers (22.1, 19.9, 74.8, and 87.6 % decrease in NOS, IL-6, PGE2, and TNFα levels, respectively, compared to control) in murine BV-2 microglial cells. Moreover, in a non-contact co-culture cell model, differentiated human SH-SY5Y neuronal cells were exposed to conditioned media from BV-2 cells treated with MSX (100 µg/mL) and LPS or LPS alone. MSX-BV-2 media increased SH-SY5Y cell viability by 13.8 % compared to media collected from LPS-BV-2 treated cells. Also, MSX (10 µg/mL) showed protective effects against Aß1-42 induced neurotoxicity and paralysis in Caenorhabditis elegans in vivo. These data support the potential neuroprotective effects of MSX warranting further studies on this natural product.

Indazole-type alkaloids from Nigella sativa seeds exhibit antihyperglycemic effects via AMPK activation in vitro.

Six rare naturally occurring indazole-type alkaloids including two new compounds, 17-O-(ß-d-glucopyranosyl)-4-O-methylnigellidine (1) and nigelanoid (2), and four known compounds (3-6) were isolated from a defatted extract of Nigella sativa (black cumin) seeds. 17-O-(ß-d-Glucopyranosyl)-4-O-methylnigellidine (1) increased glucose consumption by liver hepatocytes (HepG2 cells) through activation of AMP-activated protein kinase (AMPK). Also, this is the first report of compounds 4 and 6 from a natural source.

Efficacy of Adjunctives in Periodontal Surgeries: An Evidenced-Based Summary.

Periodontal surgery is required to access the root surfaces in order to debride them of dental plaque and calculus, promote pocket reduction, create healthy bone architecture, and provide patients greater access to out-of-reach areas to maintain oral hygiene. The use of adjunctive agents and materials-enamel matrix derivatives, low-laser treatment, ozone, locally administered minocycline HCL, doxycycline gels, tetracycline fibers, chlorhexidine chips, granular beta-tricalcium phosphate, and hyaluronic acid, and the like-have been reported to improve pocket depth reduction, periodontal ligament healing, bone defect filling, and mechanical debridement during guided tissue regeneration/flap surgeries. However, the efficacy and benefits of these adjuvants compared to periodontal surgery alone is still widely debated. This evidence-based review critically evaluates and summarizes the efficacy of adjuvants used in periodontal surgery that have been reported in the literature.

Perfluorooctanesulfonic Acid (PFOS) Thwarts the Beneficial Effects of Calorie Restriction and Metformin.

A combination of calorie restriction (CR), dietary modification, and exercise is the recommended therapy to reverse obesity and nonalcoholic fatty liver disease. In the liver, CR shifts hepatic metabolism from lipid storage to lipid utilization pathways, such as AMP-activated protein kinase (AMPK). Perfluorooctanesulfonic acid (PFOS), a fluorosurfactant previously used in stain repellents and anti-stick materials, can increase hepatic lipids in mice following relatively low-dose exposures. To test the hypothesis that PFOS administration interferes with CR, adult male C57BL/6N mice were fed ad libitum or a 25% reduced calorie diet concomitant with either vehicle (water) or 100 µg PFOS/kg/day via oral gavage for 6 weeks. CR alone improved hepatic lipids and glucose tolerance. PFOS did not significantly alter CR-induced weight loss, white adipose tissue mass, or liver weight over 6 weeks. However, PFOS increased hepatic triglyceride accumulation, in both mice fed ad libitum and subjected to CR. This was associated with decreased phosphorylated AMPK expression in liver. Glucagon (100 nM) treatment induced glucose production in hepatocytes, which was further upregulated with PFOS (2.5 µM) co-treatment. Next, to explore whether the observed changes were related to AMPK signaling, HepG2 cells were treated with metformin or AICAR alone or in combination with PFOS (25 µM). PFOS interfered with glucose-lowering effects of metformin, and AICAR treatment partially impaired PFOS-induced increase in glucose production. In 3T3-L1 adipocytes, metformin was less effective with PFOS co-treatment. Overall, PFOS administration disrupted hepatic lipid and glucose homeostasis and interfered with beneficial glucose-lowering effects of CR and metformin.

Anti-Inflammatory Effects of Novel Standardized Solid Lipid Curcumin Formulations.

Inflammation and the presence of pro-inflammatory cytokines are associated with numerous chronic diseases such as type-2 diabetes mellitus, cardiovascular disease, Alzheimer's disease, and cancer. An overwhelming amount of data indicates that curcumin, a polyphenol obtained from the Indian spice turmeric, Curcuma longa, is a potential chemopreventive agent for treating certain cancers and other chronic inflammatory diseases. However, the low bioavailability of curcumin, partly due to its low solubility and stability in the digestive tract, limits its therapeutic applications. Recent studies have demonstrated increased bioavailability and health-promoting effects of a novel solid lipid particle formulation of curcumin (Curcumin SLCP, Longvida(®)). The goal of this study was to evaluate the aqueous solubility and in vitro anti-inflammatory effects of solid lipid curcumin particle (SLCP) formulations using lipopolysaccharide (LPS)-stimulated RAW 264.7 cultured murine macrophages. SLCPs treatment significantly decreased nitric oxide (NO) and prostaglandin-E2 (PGE2) levels at concentrations ranging from 10 to 50 µg/mL, and reduced interleukin-6 (IL-6) levels in a concentration-dependent manner. Transient transfection experiments using a nuclear factor-kappa B (NF-κB) reporter construct indicate that SLCPs significantly inhibit the transcriptional activity of NF-κB in macrophages. Taken together, these results show that in RAW 264.7 murine macrophages, SLCPs have improved solubility over unformulated curcumin, and significantly decrease the LPS-induced pro-inflammatory mediators NO, PGE2, and IL-6 by inhibiting the activation of NF-κB.

Chemical compositional, biological, and safety studies of a novel maple syrup derived extract for nutraceutical applications.

Maple syrup has nutraceutical potential given the macronutrients (carbohydrates, primarily sucrose), micronutrients (minerals and vitamins), and phytochemicals (primarily phenolics) found in this natural sweetener. We conducted compositional (ash, fiber, carbohydrates, minerals, amino acids, organic acids, vitamins, phytochemicals), in vitro biological, and in vivo safety (animal toxicity) studies on maple syrup extracts (MSX-1 and MSX-2) derived from two declassified maple syrup samples. Along with macronutrient and micronutrient quantification, thirty-three phytochemicals were identified (by HPLC-DAD), and nine phytochemicals, including two new compounds, were isolated and identified (by NMR) from MSX. At doses of up to 1000 mg/kg/day, MSX was well tolerated with no signs of overt toxicity in rats. MSX showed antioxidant (2,2-diphenyl-1-picrylhydrazyl (DPPH) assay) and anti-inflammatory (in RAW 264.7 macrophages) effects and inhibited glucose consumption (by HepG2 cells) in vitro. Thus, MSX should be further investigated for potential nutraceutical applications given its similarity in chemical composition to pure maple syrup.