secoisolariciresinol-diglucoside and Inflammation

Osteoarthritis (OA) is an age-related joint disease in which inflammation and extracellular matrix (ECM) degradation play a crucial role in the destruction of articular cartilage. Secoisolariciresinol diglucoside (SDG), the main lignan in wholegrain flaxseed, which has been reported to remarkably suppress inflammation and oxidative stress, may have potential therapeutic value in OA. In this study, the effect and mechanism of SDG against cartilage degeneration were verified in the destabilization of the medial meniscus (DMM) and collagen-induced (CIA) arthritis models and interleukin-1β (IL-1β)-stimulated osteoarthritis chondrocyte models. From our experiments, SDG treatment downregulated the expression of pro-inflammatory factors induced by IL-1β in vitro, including inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX2), tumor necrosis factor (TNF-α), and interleukin 6 (IL-6). Additionally, SDG promoted the expression of collagen II (COL2A1) and SRY-related high-mobility-group-box gene 9(SOX9), while suppressing the expression of a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5) and matrix metalloproteinases 13(MMP13), which leads to catabolism. Consistently, in vivo, SDG has been identified to have chondroprotective effects in DMM-induced and collagen-induced arthritis models. Mechanistically, SDG exerted its anti-inflammation and anti-ECM degradation effects by activating the Nrf2/HO-1 pathway and inhibiting the nuclear factor kappa B (NF-κB) pathway. In conclusion, SDG ameliorates the progression of OA via the Nrf2/NF-κB pathway, which indicates that SDG may have therapeutic potential for OA.

Topics: Chondrocytes; Cyclooxygenase 2; Humans; Inflammation; Interleukin-1beta; Interleukin-6; NF-E2-Related Factor 2; NF-kappa B; Osteoarthritis; Signal Transduction

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.

Topics: Animals; Anti-Inflammatory Agents; Butylene Glycols; Colitis; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Microbiome; Glucosides; Inflammation; Male; Mice; Mice, Inbred C57BL

Although alveolar macrophages play a critical role in malignant transformation of mesothelial cells following asbestos exposure, inflammatory and oxidative processes continue to occur in the mesothelial cells lining the pleura that may contribute to the carcinogenic process. Malignant transformation of mesothelial cells following asbestos exposure occurs over several decades; however, amelioration of DNA damage, inflammation, and cell injury may impede the carcinogenic process. We have shown in an in vitro model of asbestos-induced macrophage activation that synthetic secoisolariciresinol diglucoside (LGM2605), given preventively, reduced inflammatory cascades and oxidative/nitrosative cell damage. Therefore, it was hypothesized that LGM2605 could also be effective in reducing asbestos-induced activation and the damage of pleural mesothelial cells. LGM2605 treatment (50 µM) of huma n pleural mesothelial cells was initiated 4 h prior to exposure to asbestos (crocidolite, 20 µg/cm2). Supernatant and cells were evaluated at 0, 2, 4, and 8 h post asbestos exposure for reactive oxygen species (ROS) generation, DNA damage (oxidized guanine), inflammasome activation (caspase-1 activity) and associated pro-inflammatory cytokine release (IL-1β, IL-18, IL-6, TNFα, and HMGB1), and markers of oxidative stress (malondialdehyde (MDA) and 8-iso-prostaglandin F2a (8-iso-PGF2α). Asbestos induced a time-dependent ROS increase that was significantly (p < 0.0001) reduced (29.4%) by LGM2605 treatment. LGM2605 pretreatment also reduced levels of asbestos-induced DNA damage by 73.6% ± 1.0%. Although levels of inflammasome-activated cytokines, IL-1β and IL-18, reached 29.2 pg/mL ± 0.7 pg/mL and 43.9 pg/mL ± 0.8 pg/mL, respectively, LGM2605 treatment significantly (p < 0.0001) reduced cytokine levels comparable to baseline (non-asbestos exposed) values (3.8 pg/mL ± 0.2 pg/mL and 5.4 pg/mL ± 0.2 pg/mL, respectively). Furthermore, levels of IL-6 and TNFα in asbestos-exposed mesothelial cells were high (289.1 pg/mL ± 2.9 pg/mL and 511.3 pg/mL ± 10.2 pg/mL, respectively), while remaining undetectable with LGM2605 pretreatment. HMGB1 (a key inflammatory mediator and initiator of malignant transformation) release was reduced 75.3% ± 0.4% by LGM2605. Levels of MDA and 8-iso-PGF2α, markers of oxidative cell injury, were significantly (p < 0.001) reduced by 80.5% ± 0.1% and 76.6% ± 0.3%, respectively. LGM2605, given preventively, reduced ROS generation, DNA damage, and inflammasome-activa

Topics: Asbestos; Butylene Glycols; Cytokines; DNA Damage; Glucosides; HMGB1 Protein; Humans; Inflammasomes; Inflammation; Interleukin-18; Interleukin-6; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

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.

Topics: Animals; Bronchoalveolar Lavage Fluid; Butylene Glycols; Chlorine; Copper; DNA Damage; Female; Glucosides; Inflammasomes; Inflammation; Lung; Metal Nanoparticles; Mice; Mice, Inbred C57BL; Oxidative Stress; Oxides; Peroxidase; Reactive Oxygen Species

Exposure to Libby amphibole (LA) asbestos-like fibers is associated with increased risk of asbestosis, mesothelioma, pulmonary disease, and systemic autoimmune disease. LGM2605 is a small molecule antioxidant and free radical scavenger, with anti-inflammatory effects in various disease models. The current study aimed to determine whether the protective effects of LGM2605 persist during the late inflammatory phase post-LA exposure. Male and female C57BL/6 mice were administered daily LGM2605 (100 mg/kg) via gel cups for 3 days before and 14 days after a 200 µg LA given via intraperitoneal (i.p.) injection. Control mice were given unsupplemented gel cups and an equivalent dose of i.p. saline. On day 14 post-LA treatment, peritoneal lavage was assessed for immune cell influx, cytokine concentrations, oxidative stress biomarkers, and immunoglobulins. During the late inflammatory phase post-LA exposure, we noted an alteration in trafficking of both innate and adaptive immune cells, increased pro-inflammatory cytokine concentrations, induction of immunoglobulin isotype switching, and increased oxidized guanine species. LGM2605 countered these changes similarly among male and female mice, ameliorating late inflammation and altering immune responses in late post-LA exposure. These data support possible efficacy of LGM2605 in the prolonged treatment of LA-associated disease and other inflammatory conditions.

Topics: Adaptive Immunity; Animals; Asbestos, Amphibole; B-Lymphocytes; Butylene Glycols; Chemokine CCL2; Female; Glucosides; Immunity, Innate; Immunoglobulin Isotypes; Immunoglobulins; Inflammation; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; T-Lymphocytes

Visual function depends on the intimate structural, functional and metabolic interactions between the retinal pigment epithelium (RPE) and the neural retina. The daily phagocytosis of the photoreceptor outer segment tips by the overlaying RPE provides essential nutrients for the RPE itself and photoreceptors through intricate metabolic synergy. Age-related retinal changes are often characterized by metabolic dysregulation contributing to increased lipid accumulation and peroxidation as well as the release of proinflammatory cytokines. LGM2605 is a synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant and anti-inflammatory properties demonstrated in diverse in vitro and in vivo inflammatory disease models. In these studies, we tested the hypothesis that LGM2605 may be an attractive small-scale therapeutic that protects RPE against inflammation and restores its metabolic capacity under lipid overload. Using an in vitro model in which loss of the autophagy protein, LC3B, results in defective phagosome degradation and metabolic dysregulation, we show that lipid overload results in increased gasdermin cleavage, IL-1 β release, lipid accumulation and decreased oxidative capacity. The addition of LGM2605 resulted in enhanced mitochondrial capacity, decreased lipid accumulation and amelioration of IL-1 β release in a model of defective lipid homeostasis. Collectively, these studies suggest that lipid overload decreases mitochondrial function and increases the inflammatory response, with LGM2605 acting as a protective agent.

Topics: Antioxidants; Autophagy; Butylene Glycols; Cell Line; Cytokines; Gene Expression; Glucosides; Humans; Inflammation; Lignans; Lipid Metabolism; Lipids; Mitochondria; Oxidation-Reduction; Oxidative Stress; Phagocytosis; Phagosomes; Retinal Pigment Epithelium; Retinal Pigments

Updated measurements of charged particle fluxes during the transit from Earth to Mars as well as on site measurements by Curiosity of Martian surface radiation fluxes identified potential health hazards associated with radiation exposure for human space missions. Designing mitigation strategies of radiation risks to astronauts is critical. We investigated radiation-induced endothelial cell damage and its mitigation by LGM2605, a radioprotector with antioxidant and free radical scavenging properties. We used an in vitro model of lung vascular networks (flow-adapted endothelial cells; FAECs), exposed to gamma rays, low/higher linear energy transfer (LET) protons (3⁻4 or 8⁻10 keV/µm, respectively), and mixed field radiation sources (gamma and protons), given at mission-relevant doses (0.25 gray (Gy)⁻1 Gy). We evaluated endothelial inflammatory phenotype, NLRP3 inflammasome activation, and oxidative cell injury. LGM2605 (100 µM) was added 30 min post radiation exposure and gene expression changes evaluated 24 h later. Radiation induced a robust increase in mRNA levels of antioxidant enzymes post 0.25 Gy and 0.5 Gy gamma radiation, which was significantly decreased by LGM2605. Intercellular cell adhesion molecule-1 (ICAM-1) and NOD-like receptor protein 3 (NLRP3) induction by individual or mixed-field exposures were also significantly blunted by LGM2605. We conclude that LGM2605 is a likely candidate to reduce tissue damage from space-relevant radiation exposure.

Topics: Animals; Antioxidants; Butylene Glycols; Gamma Rays; Glucosides; Humans; Inflammasomes; Inflammation; Intercellular Adhesion Molecule-1; Linear Energy Transfer; Lung; NLR Family, Pyrin Domain-Containing 3 Protein; Phenotype; Protons; Radiation-Protective Agents

Exposure to the Libby amphibole (LA) asbestos-like fibers found in Libby, Montana, is associated with inflammatory responses in mice and humans, and an increased risk of developing mesothelioma, asbestosis, pleural disease, and systemic autoimmune disease. Flaxseed-derived secoisolariciresinol diglucoside (SDG) has anti-inflammatory, anti-fibrotic, and antioxidant properties. We have previously identified potent protective properties of SDG against crocidolite asbestos exposure modeled in mice. The current studies aimed to extend those findings by evaluating the immunomodulatory effects of synthetic SDG (LGM2605) on LA-exposed mice.. Male and female C57BL/6 mice were given LGM2605 via gavage initiated 3 days prior to and continued for 3 days after a single intraperitoneal dose of LA fibers (200 μg) and evaluated on day 3 for inflammatory cell influx in the peritoneal cavity using flow cytometry.. LA exposure induced a significant increase (p < 0.0001) in spleen weight and peritoneal influx of white blood cells, all of which were reduced with LGM2605 with similar trends among males and females. Levels of peritoneal PMN cells were significantly (p < 0.0001) elevated post LA exposure, and were significantly (p < 0.0001) blunted by LGM2605. Importantly, LGM2605 significantly ameliorated the LA-induced mobilization of peritoneal B1a B cells.. LGM2605 reduced LA-induced acute inflammation and WBC trafficking supporting its possible use in mitigating downstream LA fiber-associated diseases.. Following acute exposure to Libby amphibole (LA) asbestos-like fibers, synthetic SDG (LGM2605), a small synthetic molecule, significantly reduced the LA-induced increase in spleen weight and peritoneal inflammation in C57BL/6 male and female mice. Our findings highlight that LGM2605 has immunomodulatory properties and may, thus, likely be a chemopreventive agent for LA-induced diseases.

Topics: Animals; Asbestos, Amphibole; Butylene Glycols; Female; Glucosides; Inflammation; Male; Mice; Mice, Inbred C57BL; Organ Size; Peritoneum; Spleen

Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2(+/mu) mice. Mice (n = 16-17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM.

Topics: Animals; Antioxidants; Asbestos, Crocidolite; Butylene Glycols; Chromatography, Liquid; Diet; Dietary Supplements; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flax; Glucosides; Inflammation; Lignans; Mesothelioma; Mice; Mice, Mutant Strains; Oxidative Stress; Peritoneal Lavage; Peritoneum; Precancerous Conditions; Reverse Transcriptase Polymerase Chain Reaction; Seeds; Tandem Mass Spectrometry; Transcriptome

While dietary wholegrain Flaxseed (FS) has potent anti-inflammatory, anti-fibrotic and antioxidant properties in murine models of acute and chronic lung injury, the main bioactive ingredient that contributes to these protective effects remains unknown. This study evaluated the lignan complex of FS (FLC) enriched in secoisolariciresinol diglucoside with respect to lung radioprotective and tumor radiosensitizing efficacy using a mouse model of thoracic radiation-induced pneumonopathy. C57/Bl6 mice were fed 0% FS, 10% FS, 10% FLC or 20% FLC for 3 weeks, then irradiated with a single fraction (13.5 Gy) of X-ray radiation treatment (XRT). Mouse survival was monitored for 4 months after irradiation and inflammatory lung parameters were evaluated in bronchoalveolar lavage (BAL) fluid. Gene and protein levels of protective antioxidant and phase II enzymes were evaluated in lung tissue using qPCR and protein levels were verified by immunoblotting. Prolonged administration of the FLC diet was well tolerated and was not associated with any toxicity. Importantly, comparable to the whole grain 10% FS diet, irradiated mice fed 10% and 20% FLC diets displayed improved survival. Improved hemodynamic measurements were also recorded in irradiated mice fed 10% FS or 10% FLC diet compared to irradiated 0% FS fed mice. Flaxseed lignan complex diet also attenuated polymorphonuclear infiltration and overall lung inflammation to levels comparable to those in nonirradiated mice. Flaxseed lignan complex, similarly to FS, up-regulated gene expression as well as protein levels of protective antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Dietary FLC induced radiosensitizing effects in our murine model of metastatic lung cancer. Importantly, protection of normal tissue does not thwart tumor cell death by radiation treatment. The dietary lignan complex of FS, mainly consisting of the phenolic secoisolariciresinol, is protective against radiation pneumonopathy in vivo while not hindering the tumoricidal effects of radiotherapy.

Topics: Animals; Antioxidants; Butylene Glycols; Dietary Carbohydrates; Eating; Female; Flax; Glucosides; Inflammation; Lignans; Lung; Mice; Mice, Inbred C57BL; Phenols; Radiation Pneumonitis; Radiation-Protective Agents; Survival Analysis; Thorax; Weight Loss