Secoisolariciresinol Diglucoside Research Articles

Distribution, biosynthesis and therapeutic potential of lignans.

Lignans have long been known for their abundant therapeutic properties due to their polyphenolic structure. Linseed is the richest plant source of lignans and has been studied widely for their properties. The most prevalent lignan, secoisolariciresinol diglucoside (SDG), is consumed with linseed and converted into mammalian lignans, enterodiol (END) and enterolactone (ENL), by the gut microbiota. SDG can easily be assessed using HPLC and its deglycosylated form viz secoisolariciresinol can be asses using GC-MS techniques. Variety of extraction and analysis methods has been reported for plant lignans. SDG is known to have therapeutic properties including anti-oxidant, anti-cancerous, anti-inflammatory, modulation of gene expression, anti-diabetic, estrogenic and anti-estrogenic. Despite a large number of bioactivities, strong evidences for the underlying mechanisms for most of the properties are still unknown. SDG is most studied for its anti-cancerous properties. But the use of lignans as anti-carcinogenic agent is limited and commercially not reported due to challenges of purification at commercial level, rapid metabolism, untargeted delivery and toxic compounds associated with lignans. Exploration of more prominent and active derivatives of SDG and their targeted drug delivery should be an important research toward the use of bioactive lignans of linseed.

Feeding Fiber-Bound Polyphenol Ingredients at Different Levels Modulates Colonic Postbiotics to Improve Gut Health in Cats

Simple SummaryFood eaten by humans or companion animals is broken down by enzymes produced by the host and also by bacteria present in the large intestine of the host. Many of the compounds produced can have beneficial effects on the host’s health. Previous studies in dogs evaluated changes after they ate food containing a fiber bundle made of pecan shells, flax seed, and powders from cranberry, citrus, and beet. These studies showed that bacteria in the large intestine switched from digesting mainly protein to digesting mainly carbohydrates resulting in production of compounds with beneficial properties. The study presented here tested this fiber bundle in cats to see which compounds and/or bacteria in the feces changed. After cats consumed food containing the fiber bundle, several compounds associated with beneficial health effects increased, and some compounds that indicate the breakdown of protein decreased. In contrast, little change in fecal bacteria was observed following consumption of food with the fiber bundle. Overall, these findings indicate that, similar to the dog studies, bacteria in the large intestine of cats were able to digest the fiber bundle to make compounds that may contribute to host health and also shifted to digestion of carbohydrates instead of protein.Consumption of fiber in its different forms can result in positive health effects. Prior studies in dogs found that addition of a fiber bundle (composed of pecan shells, flax seed, and powders of cranberry, citrus, and beet) to food resulted in a shift in fecal bacterial metabolism from proteolysis to saccharolysis. The present study evaluated the changes in fecal metabolites and microbiota in healthy cats following the consumption of this fiber bundle. Following a 28-day pre-feed period, 56 healthy adult cats received food with none or one of three concentrations (0%, 1%, 2%, and 4%) of the fiber bundle for a 31-day period. In cats that consumed the 4% fiber bundle, levels of ammonium and fecal branched-chain fatty acids (BCFAs) decreased from baseline and compared with the other groups. Addition of any level of the fiber bundle resulted in increases in beneficial metabolites: polyphenols hesperidin, hesperetin, ponciretin, secoisolariciresinol diglucoside, secoisolariciresinol, and enterodiol. Little change in fecal microbiota was observed. Since higher levels of ammonia and BCFAs indicate putrefactive metabolism, the decreases in these with the 4% fiber bundle indicate a shift toward saccharolytic metabolism despite little change in the microbiota composition.

Personalized Nutrition Using Microbial Metabolite Phenotype to Stratify Participants and Non-Invasive Host Exfoliomics Reveal the Effects of Flaxseed Lignan Supplementation in a Placebo-Controlled Crossover Trial

High-fiber plant foods contain lignans that are converted to bioactive enterolignans, enterolactone (ENL) and enterodiol (END) by gut bacteria. Previously, we conducted an intervention study to gain mechanistic insight into the potential chemoprotective effects of flaxseed lignan supplementation (secoisolariciresinol diglucoside; SDG) compared to a placebo in 42 men and women. Here, we expand on these analyses to further probe the impact of the microbial metabolite phenotype on host gene expression in response to lignan exposure. We defined metabolic phenotypes as high- or low-ENL excretion based on the microbial metabolism of SDG. RNA-seq was used to assess host gene expression in fecal exfoliated cells. Stratified by microbial ENL excretion, differentially expressed (DE) genes in high- and low-ENL excreter groups were compared. Linear discriminant analysis using the ENL phenotypes identified putative biomarker combinations of genes capable of discriminating the lignan treatment from the placebo. Following lignan intervention, a total of 165 DE genes in high-ENL excreters and 1450 DE genes in low-ENL excreters were detected. Functional analysis identified four common upstream regulators (master genes): CD3, IFNG, IGF1 and TNFRSF1A. Our findings suggest that the enhanced conversion of flaxseed lignan to ENL is associated with a suppressed inflammatory status.

Flaxseed Alters Gut Microbiota-Mammary Gland MicroRNA Relationships Differently Than its Oil and Lignan Components

ObjectivesConsumption of flaxseed (FS) and its oil (FSO) and lignan (secoisolariciresinol diglucoside, SDG) components have been associated with changes during mammary gland (MG) development which then lead to reduced breast cancer risk in adulthood. FS components are metabolized by the gut microbiota and MG microRNA (miRNA) response to FS may be an underlying mechanism. We aimed to determine if there is an association between the cecal microbiota and MG miRNome, if it is affected by FS or its components, and to identify altered pathways. MethodsWe used MG miRNome (NanoString nCounterâ system) and cecal microbiota (16S rRNA gene sequencing) data from our previous study where 4–5 week old female C57BL/6 mice were randomized to receive one of four isocaloric diets (n = 5–6/group): basal AIN-93G diet (BD), 10% FS, 3.67% FSO, and 0.15% SDG for 3 weeks. Within-group Spearman correlations between paired (by mouse) miRNA and bacterial genera were compared across the 4 conditions by Differential Correlation Analysis (DGCA v1.0.2 R Package). Genes targeted by miRNA in significantly (q < 0.15) altered correlations were identified with miRDB v6.0 and used for pathway analysis (pathDIP 4, Bonferroni adjusted p-value < 0.05). Results619,541, 811, and 768 significant miRNA-genera correlations were found in the BD, FS, FSO, and SDG groups, respectively. FS reversed 24 of the BD within-group correlations, but FSO or SDG did not. SDG reversed 24 of the FS within-group correlations, but FSO did not. Of correlations reversed by FS when compared to BD, enriched pathways of miRNA gene targets included cadherin and Wnt signalling, processes vital to MG development, tumour formation and metastasis. When comparing SDG correlations to FS, involved pathways were related to MG development, tumour initiation and progression. ConclusionsThere is a relationship between gut microbial taxa and MG miRNAs, which is modified by FS. This suggests that the microbiota is a mediator of FS miRNA-dependent effects in the MG. SDG, but not FSO, may participate in FS effects but it does not influence microbial genera-miRNA relationships alone. This suggests that whole FS consumption is necessary for benefits in MG development and breast cancer risk via cecal microbiota-MG miRNA mechanisms. Funding SourcesNatural Sciences and Engineering Research Council of Canada.

Secoisolariciresinol diglucoside induces pyroptosis by activating caspase-1 to cleave GSDMD in colorectal cancer cells.

Secoisolariciresinol diglucoside (SDG) is the main component of lignans with various biological activities, including anticancer activity. However, whether SDG has obvious anticancer effects on colorectal cancer (CRC) is unclear. Pyroptosis, a form of programmed cell death, has received increasing attention in cancer‐related research. In this study, we aimed to test the anticancer properties and relatecd functional mechanisms of SDG. we found that SDG not only inhibited the cell viability of HCT116 cells, but also induced HCT116 cells to swell with apparent large bubbles, which are typical signs of pyroptosis. Furthermore, SDG induced cell pyroptosis by enhancing cleavage of the N‐terminal fragment of gasdermin D (GSDMD) in CRC cells, accompanied by increased caspase‐1 cleavage. Consistent with this, SDG‐induced GSDMD‐N‐terminal fragment cleavage and pyroptosis were reduced by siRNA‐mediated silencing of caspase‐1 or treatment with the specific caspase‐1 inhibitor VX‐765 treatment, suggesting that active caspase‐1 further induces pyroptosis. A mechanistic study showed that SDG induced reactive oxygen species (ROS) accumulation and inhibits phosphatidylinositol 3‐kinase (PI3K) phosphorylation and increases pyroptosis, while increasing GSDMD and caspase‐1 cleavage and enhancing expression of BCL2‐associated X (BAX), which could be rescued by the ROS scavenger (NAC), suggesting that SDG‐induced GSDME‐dependent pyroptosis is related to the ROS/PI3K/AKT/BAX‐mitochondrial apoptotic pathway. In vivo results showed that SDG significantly inhibited tumor growth and induced pyroptosis in the HCT116‐CRC nude mouse model. In conclusion, our findings suggest that the anticancer activity of SDG in CRC is associated with the induction of GSDMD‐dependent pyroptosis by SDG through the generation of ROS/P13K/AKT/BAK‐mitochondrail apoptosis pathway, providing insights into SDG in its potential new application in cancer treatment.

Therapeutic comparison of flex seed and black seed supplementation for treatment of type II diabetic patients

Diabetes is one of the most prevailing global health issues. Genetic factors, obesity, environmental factors, poor dietary habits and sedentary life style are the main causes of its occurrence that leads to hyperglycemia and insulin resistance. In recent years therapeutic effects of dietary flaxseed and blackseed in management of diabetes has been studied. Both possess anti-oxidant, anti-hyperglycemic and anti-inflammatory properties. Secoisolariciresinol diglucoside (SDG) is a lignan present in flaxseed that lower the blood glucose level and fiber control insulin secretion and its mechanism of action. Thymoquinone (TQ) is a bioactive component present in flaxseed that control blood glucose level, insulin secretion and maintain glucose hemostasis. Both seeds are considered as highly acceptable with the great safety profile in management of type II diabetes. Therefore, this article highlights the therapeutic effects of flaxseed and blackseed supplementation in management of type II diabetes.

Feeding Fiber-Bound Polyphenol Ingredients at Different Levels Modulates Colonic Postbiotics to Improve Gut Health in Dogs.

Simple SummaryMicrobes present in the large intestine of humans and companion animals produce bioactive metabolites from host-ingested food. These bioactive metabolites can influence host health. A prior study in dogs that were healthy or had chronic enteritis/gastroenteritis showed that stool quality improved when they ate food containing a fiber bundle made from fibers of pecan shells, flax seed, cranberry, citrus, and beet. In addition, eating food containing the fiber bundle resulted in the gut bacteria shifting from digesting mainly protein to digesting mainly carbohydrates. The present study tested the impact of the fiber bundle at a lower range of concentrations in dogs. Fecal levels of several bioactive metabolites with beneficial antioxidant or anti-inflammatory properties increased after dogs consumed food with the fiber bundle, though no changes in the bacteria or their functional pathways were observed. Stool quality remained in the acceptable range. These results suggest that the gut bacteria were able to digest the fiber bundle to produce beneficial bioactive metabolites to improve host health.This study assessed changes in canine fecal metabolites and microbiota with the consumption of foods with increasing concentrations of a fiber bundle including pecan shells, flax seed, and powders of cranberry, citrus, and beet that was previously shown (at 14% w/w) to improve stool quality, shift fecal bacterial metabolism from proteolysis to saccharolysis, increase abundance of saccharolytic bacteria, and decrease abundance of proteolytic bacteria. In this study, 48 healthy adult dogs were split evenly to consume different inclusion levels (0%, 1%, 2%, and 4%) of the fiber bundle for a 31-day period following a 28-day pre-feed period. Increases from baseline in the fecal short-chain fatty acids butyric acid, valeric acid, and hexanoic acid were observed only in the dogs that consumed the food with the 4% fiber bundle. With addition of any level of the fiber bundle, increases were seen in the polyphenols hesperidin, hesperetin, ponciretin, secoisolariciresinol diglucoside, secoisolariciresinol, and enterodiol. However, fecal microbiota and their metabolism, and stool scores were largely unaffected by the fiber bundle. Overall, addition of the fiber bundle appeared to increase bioactive metabolites of increased antioxidant and anti-inflammatory potency for beneficial to health and, at levels ≥4%, shifted gut bacterial metabolism toward saccharolysis.

Secoisolariciresinol Diglucoside Improves Ovarian Reserve in Aging Mouse by Inhibiting Oxidative Stress.

Ovarian reserve is a key factor in the reproductive function of the ovaries. Ovarian aging is characterized by a gradual decline in the quantity and quality of follicles. The underlying mechanism of ovarian aging is complex and age-related oxidative stress is considered one of the most likely factors. Secoisolariciresinol diglucoside (SDG) has been shown to have good scavenging ability against reactive oxygen species (ROS) which slowly accumulates in ovarian tissues. However, it is unknown whether SDG had beneficial effects on aging ovaries. In this study, we used 37-week-old female C57BL/6J mouse as a natural reproductive aging model to evaluate the role of SDG in ovarian aging. SDG (7 and 70 mg/kg) intragastric administration was performed in the mice daily. After 8 weeks, the effects of SDG on aging ovaries were evaluated by counting the number of follicles and the expression of follicle-stimulating hormone receptors (FSHR) in the ovary. The mechanism of SDG on the aging ovaries was further explored through ovarian metabolomics. It was found that SDG can effectively increase the number of growing follicles and increase the expression of the FSHR protein. The metabolomics results showed that the ovaries in the SDG intervention group achieved better uptake and transport of nutrients, including amino acids and glucose that are necessary for the development of oocytes. At the same time, the ovaries of the SDG intervention group showed that the drug reduced ROS generation. Additionally, we found that ovarian telomere length and ovarian mitochondrial DNA copy number that are highly susceptible to ROS damage and are also related to aging. The results showed that SDG can significantly increase mitochondrial DNA copy number and slow down the process of telomere shortening. These data indicate that SDG improves ovarian reserve by inhibiting oxidative stress.

Secoisolariciresinol diglucoside ameliorates high fat diet-induced colon inflammation and regulates gut microbiota in mice.

Secoisolariciresinol diglucoside (SDG) has a strong anti-inflammatory effect, which depends partly on the participation of gut microbiota. We studied the effect of SDG on colonic inflammation caused by a common poor diet, high-fat diet (HFD), and the regulation of gut microbiota as well as its metabolites. Considering the difference of sources, prices, and possible bioactivity, we compared the effects of a single compound and the extract of SDG on colon inflammation. The results displayed that both the single compound and the extract ameliorated morphologic damage of the colon and improved intestinal barrier integrity. In addition, SDG suppressed the mRNA expressions of inflammatory cytokines in the colon, and the inhibitory effect of a single compound was stronger than that of the extract. The results of 16S rRNA sequencing showed that SDG altered the diversity and composition of gut microbiota, particularly the abundance of inflammation-related bacteria, and the effect of the extract was greater than that of a single compound. The analysis of short-chain fatty acids (SCFAs) manifested the improved concentration with the intervention of SDG. These results confirmed that SDG, including a single compound and extract, exerted protective effects against colon inflammation, which might be partly explained by the gut microbiome. Our research could provide a positive nutritional intervention for chronic intestinal inflammation.

High-yield production of secoisolariciresinol diglucoside from flaxseed hull by extraction with alcoholic ammonium hydroxide and chromatography on microporous resin

This study used alcoholic ammonium hydroxide to directly hydrolyze and extract secoisolariciresinol diglucoside (SDG) from flaxseed hull in a one pot reaction. The optimal extraction conditions, including the concentration of ammonium hydroxide, extraction time, and temperature, were examined in single factor experiments, followed by response surface methodology (RSM) with 3-level, 3-factor Box-Behnken experiments. As a result, the optimal extraction conditions were determined as follows: material-liquid ratio 1:20, percentage of reagent ammonium hydroxide (25–28% of NH3 in water) in ethanol 33.7% (pH = 12.9), extraction time 4.9 h, and extraction temperature 75.3 °C. Under these conditions, the yield of SDG, as measured by ultra-high-performance liquid chromatography-mass spectrometry, was 23.3 mg/g, consistent with the predicted content of SDG in flaxseed hull (23.0 mg/g). Further, 30.0 g of pulverized flaxseed hull was extracted under the optimal conditions, and the extract was subjected to a single run of macroporous resin chromatography to obtain 772.1 mg of a fraction with an SDG content exceeding 76.1%. Subsequent chromatography on Sephadex LH20, yielded 602.8 mg SDG of 98.0% purity, and the yield was 20.1 mg/g (2.0%) from flaxseed hulls. Thus, one-pot hydrolysis and extraction of SDG using alcoholic ammonium hydroxide is simple, and of high-yield.Graphical abstract

Water stress intensified the relation of seed color with lignan content and seed yield components in flax (Linum usitatissimum L.)

This study aimed to investigate the effect of yellow and brown seed coat color of flax on lignan content, seed yield, and yield components under two contrasting environments of non-stress and water stress conditions. The water stress environment intensified the discrimination between the two seed color groups as the yellow seeded families had lower values for seed yield components under the water stress. Heritability and the genetic advance for seed yield were significantly higher in brown-seeded families than those of yellow-seeded ones at water stress conditions. Secoisolariciresinol diglucoside (SDG) as the chief lignan in flaxseed was more abundant in yellow-seeded families under the non-stress environment but under water stress conditions, it increased in brown seeded families and exceeded from yellow ones. Considering that the brown and yellow seed color families were full sibs and shared a similar genetic background but differed in seed color, it is concluded that a considerable interaction exists between the flax seed color and moisture stress concerning its effect on seed yield and yield components and also the seed SDG content. Brown-seeded genotypes are probably preferred for cultivation under water stress conditions for better exploitation of flax agronomic and nutritional potentials.

Secoisolariciresinol diglucoside mitigates benzo[a]pyrene-induced liver and kidney toxicity in mice via miR-101a/MKP-1-mediated p38 and ERK pathway

Benzo[a]pyrene (BaP) can cause hepatorenal toxicity. Secoisolariciresinol diglucoside (SDG), a polyphenolic compound present in flaxseed, has shown a variety of biological activities including antioxidant, anti-inflammatory, anti-apoptotic effects. This study aimed to investigate the protective effects and working mechanisms of SDG against BaP-induced hepatorenal injury. Forty male mice were administrated daily (via gastric gavage; 4 weeks) with 0.9% saline (control), BaP (75 mg/kg body weight (b.w.)), SDG (100 mg/kg b.w.), SDG (100 mg/kg b.w.)+BaP (75 mg/kg b.w.). Results showed that the mice treated with SDG + BaP had significantly (P < 0.05) higher body weight, lower organ-to-body weight ratio, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) activities, and less levels of serum creatinine (CRE) and blood urea nitrogen (BUN) than those treated with BaP alone. SDG administration alleviated BaP-induced oxidative damages, inflammation and apoptosis. Furthermore, it significantly (P < 0.05) downregulated phosphor-p38 (p-p38) and phosphor-extracellular regulated protein kinases (p-ERK) levels, upregulated mitogen-activated protein kinase phosphatase-1 (MKP-1) level, and suppressed miR-101a expression compared with BaP alone group. Taken together, these results showed for the first time that SDG has protective effects against BaP-induced liver and kidney toxicity in mice through regulating oxidative stress, inflammation and apoptosis via miR-101a/MKP-1-mediated p38 and ERK pathway.

Hypocholesterolemic Efficacy of Secoisolariciresinol Diglucoside and Its Polymer in Rat.

Hypercholesterolemia is a risk factor for cardiovascular disease. Conventional treatment methods include lifestyle changes and pharmaceutical interventions, but recently Health Canada approved a health claim for whole ground flaxseed as an alternative treatment for hypercholesterolemia. The literature suggests flaxseed lignans are responsible for the cholesterol-reducing effects of flaxseed. In this study, 96.1% secoisolariciresinol diglucoside (SDG) and a 50% SDG enriched polymer (SDG polymer) were investigated as treatments for hypercholesterolemia in rats. Wistar female rats were fed a 1% high-cholesterol diet for a one-week acclimatization prior to a 23-day intervention with enriched SDG or SDG polymer. A reduction in body weight normalized liver weight was observed in rats treated with enriched SDG when compared to the controls. Both enriched SDG (96.1%) and SDG polymer reduced serum triacylglycerol (19% and 15%, respectively) and increased high-density lipoprotein cholesterol (15% and 24%, respectively). Histopathologic analyses revealed lipid-lowering effects of either enriched SDG or SDG polymer along with lower steatosis scores and nonalcoholic fatty liver disease activity. Furthermore, the lack of statistical significance between SDG and SDG polymer treatment groups suggests that SDG polymer may be a potential alternative to enriched SDG for hypercholesterolemia with similar efficacy but lower cost.

Usage of Flaxseed Lignan in Menaposal Complaınts in Perımenaposal Women Patıents

Lignans are phenylpropanoid dimers widely distributed in the plant kingdom. Flaxseed (Linum usitatissimum) is one of the richest sourcase of dietary lignans. Plant lignans comprise one of the two main groups of phytoestrogens the other group beigng the isoflavonoids. The major flax lignan is secoisolariciresinol diglucoside (SDG).Flaxseed is the richest food sourcase of SDG.Flaxseed also contains much smaller amounts of matairesinol, lariciresinol, and pineresinol. The plant lignans are converted by the intestinal microflora in the proximal or upper part of the large intestine to enterodiol (END) and enterolactone (ENL). Between 2017 and 2019, 26 female patients who applied for getat polk, obesity and perimenopausal complaints were included in the study. Demographic data of the patients were recorded. Age, weight, height, BMI and bloodT3,4, TSH, B12, Na, K levels were measured. Statistically average measurements were taken. Flaxseed was recommended for patients whose cholesterol levels were above the reference value. SDG has antioksidant activity.It also may have hypoglycemic, hypocholesterolemic, estrogenic,anti-estrogenic, anticancer, antiproliferative and renoprotective properties.

FLAXSEED MEAL FEEDING TO DAIRY COWS AS A STRATEGY TO IMPROVE MILK ENTEROLACTONE CONCENTRATION: A LITERATURE REVIEW

ABSTRACT: Flaxseed (Linum usitatissimum) is the richest source of the plant lignan secoisolariciresinol diglucoside (SDG). In mammals, including bovine, SDG is converted to the mammalian lignans enterolactone (EL) and enterodiol (ED) by the action of gastrointestinal microbes. There is a great deal of interest in promoting increased intakes of lignans in humans’ diet due to the potential health benefits of mammalian lignans, especially in the prevention of cardiovascular diseases, hypercholesterolaemia, breast and prostate cancers, and osteoporosis. Consumption of milk and dairy products enriched in EL could be an excellent strategy to increase the intake of lignans by humans. This literature review will focus on presenting feeding strategies capable to improve milk enterolactone concentration. Research has demonstrated the potential of flaxseed meal (FM) feeding to dairy cows as a strategy to improve milk EL concentration, therefore enhancing milk nutraceutical proprieties. A considerable number of studies have demonstrated that feeding vegetable lignans-rich sources, such as FM, to dairy cows improves EL in milk. Additionally, it has been reported that changes in the carbohydrate profile of FM-based diets fed to dairy cows can alter the output of milk EL. The application of animal nutrition as a tool to increase nutraceutical properties of milk (i.e. increased EL concentration) is a valuable strategy for promoting the association of milk with humans’ health benefits and is of great interest in contemporary society.&#x0D; Keywords: nutraceutical proprieties, bioactive compounds, lignans, dairy cows, disease risk reduction

Effect of ultrasonic pretreatment for lignan accumulation in flax sprouts (Linum usitatissimum L.)

This study evaluated different ultrasonic treatments for lignan biosynthesis in two varieties of flax sprouts. Results showed that lignans in flax sprouts significantly raised with ultrasonic pretreatment. Secoisolariciresinol diglucoside dramatically increased by about 6-fold at the flax sprouts. Ultrasonic pretreatment could also affect the accumulation of caffeic acid and p-coumaric acid in flax sprouts. Moreover, it is suggested that fiber flax sprout was more sensitive to ultrasonic pretreatment. The expression levels of genes involved in the biosynthesis of lignan were analyzed and the results could partly explain the accumulation of these compounds. The contents of secoisolariciresinol diglucoside were clustered with ferulic acid, which indicated that the accumulation of ferulic acid might be the key factor during flax sprout maturation for lignan accumulation. Present study could be useful guidance for ultrasonic pretreatment in the promotion of lignan accumulation and the fortification of nutritional values in flax sprouts as a functional vegetable.

Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605)

Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.

Emulgel Loaded with Flaxseed Extracts as New Therapeutic Approach in Wound Treatment.

Dry (D.E.) and liquid (L.E.) extracts were prepared from flaxseeds and their application in health field was evaluated. The chemical analysis showed that D.E. is rich in the lignan secoisolariciresinol diglucoside and L.E. in unsaturated triglycerides containing linolenic acid. Mainly, D.E. showed reducing (15.73 μmol Fe2+/g) and radical scavenging capacities (5.25 mg TE/g) and ability to down-regulate the expression of the pro-inflammatory cytokines NO (IC50 = 0.136 ± 0.009 mg/mL) and IL-6 (IC50 = 0.308 ± 0.103 mg/mL), suggesting its use in wound treatment. D.E. and L.E. were active against S. pyogenes and D.E. also against S. aureus. The two extracts were combined in a novel O/W emulgel in which the water phase was viscosized using a low molecular weight and highly deacetylated chitosan (1% wt./v). The presence of this polymer in the emulgel decreased the MIC values of the extracts. In fact, MIC shifted from 0.59 mg/mL to 0.052 mg/mL for D.E. and from 0.22 mg/mL to 0.036 mg/mL for L.E., concentrations safe both for keratinocytes and macrophages. Moreover, the emulgel demonstrated to inhibit S. aureus, P. aeruginosa, S. pyogenes, E. coli, and K. pneumoniae growth (inhibition halos 24–36 mm), strains often responsible for diabetic foot ulcer infection.

Discriminatory and cooperative effects within the mouse gut microbiota in response to flaxseed and its oil and lignan components

Gut microbial processing of dietary flaxseed (FS) contributes to its health benefits, but the relative effects of its bioactive components (lignans, omega-3 fatty acids, fiber) on the microbiota are unclear. We investigated the gut microbial compositional and functional responses to whole FS and its isolated components, FS oil (FSO) and secoisolariciresinol diglucoside (SDG) (precursor to microbial-derived enterolignans) to help understand their contribution to whole FS benefits.Cecum content and fecal samples were collected from C57BL/6 female mice fed a basal diet (AIN93G) or isocaloric diets containing 10% FS or 10% FS-equivalent amounts of FSO or SDG for 21 days. Cecal and fecal microbiota composition and predicted genomic functions, and their relationship with serum enterolignans were evaluated. Only FS modified the community structure. Shared- and diet-specific enriched taxa and functions were identified. Carbohydrate and protein processing functions were enriched in FS mice, and there was a positive correlation between select enriched taxa, encompassing fiber degraders and SDG metabolizers, and serum enterolignans. This was not observed in mice receiving isolated FSO and SDG, suggesting that FS fiber supports SDG microbial metabolism.In conclusion, the cooperative activities of a diverse microbiota are necessary to process FS components and, when administered at the amount present in FS, these components may act together to affect SDG-derived enterolignans production. This has implications for the use of FS, FSO and SDG in clinical practice.

A Network Pharmacology-Based Investigation to the Pharmacodynamic Material Basis and Mechanisms of the Anti-Inflammatory and Anti-Viral Effect of Isatis indigotica.

PurposeIsatis indigotica (Ii) is a cruciferous herb that is widely distributed in China, and its roots and leaves have been used in two renowned antipyretic detoxicate crude drugs in Chinese Pharmacopoeia, Radix (R) and Folium (F) Isatidis. However, the pharmacodynamic material basis and underlying mechanisms of the herbal efficacy remained to be elucidated.MethodsUltra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was adopted for the chemical profiling of R and F Isatidis. The active ingredients were screened out through the prediction of gastrointestinal absorption and druglikeness analysis using SwissADME. A herb-ingredient-target network was constructed through target prediction of the herbal active ingredients and anti-inflammation or anti-viral properties, followed by protein–protein interaction analysis. Then, the potential relevant signaling pathways were predicted by pathway enrichment. Finally, for verification, RAW 264.7 cell line was adopted to examine the anti-inflammatory and anti-viral activities of 6 representative ingredients in Ii.ResultsSeventy-three compounds have been identified from Ii through UPLC-Q-TOF-MS. A total of 17 potential active ingredients were screened through pharmacokinetics and drug-likeness evaluation using SwissADME. It was shown that key targets might include TNF, AKT1, SRC, IL2, CASP9, and CASP3 in our herb-ingredient-target network, and isovitexin, a flavonoid, tended to participate in the inflammatory response, indoles were more likely to affect the cell proliferation processes, and lignans might have a broader affinity to key targets than the other active ingredients, such as regulating immune system (targeting IL-2) and PI3K-Akt signaling pathway. In vitro, indigo and secoisolariciresinol diglucoside markedly reduced TNF-α expression in Poly (I: C)-incubated cells. Isovitexin significantly inhibited TNF-α expression, and isatin treatment markedly reduced IL-1β expression in LPS-incubated cells.ConclusionAs the pharmacodynamics material basis of Ii, indoles, lignans, and flavonoids are believed to confer beneficial properties through various cellular aspects with multiple signaling pathways involved.