Expression Of Inflammatory Enzymes Research Articles

Anti-Inflammatory Effects of Idebenone Attenuate LPS-Induced Systemic Inflammatory Diseases by Suppressing NF-κB Activation.

Inflammation is a natural protective process through which the immune system responds to injury, infection, or irritation. However, hyperinflammation or long-term inflammatory responses can cause various inflammatory diseases. Although idebenone was initially developed for the treatment of cognitive impairment and dementia, it is currently used to treat various diseases. However, its anti-inflammatory effects and regulatory functions in inflammatory diseases are yet to be elucidated. Therefore, this study aimed to investigate the anti-inflammatory effects of idebenone in cecal ligation puncture-induced sepsis and lipopolysaccharide-induced systemic inflammation. Murine models of cecal ligation puncture-induced sepsis and lipopolysaccharide-induced systemic inflammation were generated, followed by treatment with various concentrations of idebenone. Additionally, lipopolysaccharide-stimulated macrophages were treated with idebenone to elucidate its anti-inflammatory effects at the cellular level. Idebenone treatment significantly improved survival rate, protected against tissue damage, and decreased the expression of inflammatory enzymes and cytokines in mice models of sepsis and systemic inflammation. Additionally, idebenone treatment suppressed inflammatory responses in macrophages, inhibited the NF-κB signaling pathway, reduced reactive oxygen species and lipid peroxidation, and normalized the activities of antioxidant enzyme. Idebenone possesses potential therapeutic application as a novel anti-inflammatory agent in systemic inflammatory diseases and sepsis.

Clinical outcome of early-stage knee osteoarthritis after intra-articular platelet rich plasma injection

<p><strong>Background:</strong> Osteoarthritis (OA) is a degenerative joint disease due to degradation of articular cartilage, proliferative reformation of subchondral bone and low degree of synovitis resulting in reduced quality of life (QOL), being the major cause of pain and disability in the elderly population. Platelet-rich plasma (PRP) is an autologous mixture of concentrated platelets and growth factors produced by centrifugation of whole blood, used to treat bone, tendon and ligament injuries. The growth factors released by PRP have been shown to promote cell recruitment, proliferation and angiogenesis resulting in a decrease in the expression of inflammatory enzymes. The aim was to study the effectiveness of intra-articular PRP injections in early-stage OA knee patients and to evaluate the clinical outcome and QOL at 6 months.</p><p><strong>Methods:</strong> We conducted an observational study of 100 patients with early OA knee changes with age group >50 years and injected their knees with PRP injections and serial follow up assessment was done.</p><p><strong>Results:</strong> We saw significant improvement in quality of lives evaluated as per world health organization quality of life (WHOQOL) questionnaire after PRP injections on their follow-up. Significant reduction in pain, reduction in joint stiffness and improvement in physical activities shown by significant reduction in Western Ontario and McMaster universities osteoarthritis index (WOMAC) scores.</p><p><strong>Conclusions: </strong>OA of knee is one of the commonest rheumatological problems after 50 years of age. It was commonly observed in females more than 60 years age with sedentary lifestyle. PRP therapy has given excellent results in pain relief, reduction of joint stiffness and improvement in physical activities and improvement in QOL.</p>

Zoletil promotes apoptosis in BV-2 microglial cells via induction of oxidative stress and neural inflammation.

Zoletil® (ZOL) is a combination drug of tiletamine, a dissociative anesthetic and zolazepam, a minor tranquilize, which has been used to induce short-term anesthesia in various animals. Depending on the administered dose, the effects of ZOL can range from sedation to anesthesia. Here, we aimed to determine the neurotoxicity of ZOL and elucidate its mechanism of action using BV-2 microglial cells. The results of MTT reduction assay and TUNEL staining revealed that ZOL induced neuronal toxicity and apoptosis in BV-2 cells. ZOL caused apoptosis via phosphorylation of c-Jun N-terminal kinase, increased ratio of Bax to Bcl-2, disruption of mitochondrial membrane potential, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase. Furthermore, reactive oxygen species were involved in ZOL-induced neuronal cell death as assessed by 2',7'-dichlorofluorescein diacetate staining. Moreover, BV-2 cells treated with ZOL exhibited increased expression of inflammatory enzymes, such as inducible nitric oxide synthase and cyclooxygenase-2, along with subsequent production of nitric oxide and prostaglandin E2. ZOL upregulated the expression of interleukin-1β, a proinflammatory cytokine. With respect to its molecular mechanism, ZOL increased the nuclear translocation and DNA binding of redox-sensitive transcription factor NF-κB, which seemed to be mediated by activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. These findings suggest that ZOL leads to apoptosis in BV-2 cells by inducing oxidative stress and inflammatory responses.

Dietary Barley Leaf Mitigates Tumorigenesis in Experimental Colitis-Associated Colorectal Cancer.

Dietary barley (Hordeum vulgare L.) leaf (BL) is a popular functional food known to have potential health benefits; however, the effect of BL in colorectal cancer prevention has not been examined. Here, we examined the role of BL on the prevention of colorectal carcinogenesis and defined the mechanism involved. BL supplementation could protect against weight loss, mitigate tumor formation, and diminish histologic damage in mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS). Moreover, BL suppressed colonic expression of inflammatory enzymes, while improving the mucosal barrier dysfunctions. The elevated levels of cell proliferation markers and the increased expression of genes involved in β-catenin signaling were also reduced by BL. In addition, analyses of microbiota revealed that BL prevented AOM/DSS-induced gut microbiota dysbiosis by promoting the enrichment of Bifidobacterium. Overall, these data suggest that BL is a promising dietary agent for preventing colitis-associated colorectal cancer.

Curcumin Loaded Ethosomal Gel for Improved Topical Delivery: Formulation, Characterization and Ex-vivo Studies.

Curcumin is a curcuminoid, which is an active constituent of turmeric and is obtained from the rhizomes of Curcuma longa, family Zingiberaceae. Curcumin modulates the activity of various transcription factors and regulates the expression of inflammatory enzymes, cell survival proteins, adhesion molecules and cytokines by binding to a variety of proteins and inhibiting the activity of various kinases. Curcumin falls in the BCS class IV drug, with poor solubility and poor permeability which makes it very challenging to utilize the maximum therapeutic potential of this moiety Objective: The major aim of the study was to enhance transdermal penetration of curcumin via ethosomal gel and to overcome the barriers of poor permeability of transdermal drug delivery. Curcumin loaded ethosomes were prepared with varying quantities of ethanol and soya lecithin by the cold method and were optimised based on entrapment efficiency, vesicular size and Ex-vivo studies. Optimised ethosomal formulation was further incorporated into a gel and was evaluated. Ex-vivo studies were performed with the ethosomal gel of curcumin and was compared with simple drug solution. Prepared ethosomal system showed a vesicle size ranging from 211 to 320 nm with spherical, smooth surface and entrapment efficiency of 87 to 91%. Optimised ethosomal system (ET3) was incorporated into gel and was further evaluated. The findings of the research work suggested that the ethosomal gel holds excellent potential for transdermal delivery of curcumin.

Abstract 2447: TLR4 expression as a determinant of EMT and stress response gene expression in UV exposed human keratinocytes

Abstract Toll-like receptor 4 (TLR4) is gaining attention for its role in several cancer-associated signaling pathways, including the regulation of inflammation, DNA repair and epithelial-mesenchymal transition (EMT). There is evidence that TLR4 contributes to ultraviolet (UV) radiation-induced stress signaling in skin cells, including keratinocytes. Blockade of TLR4 activity using the pharmacological antagonist resatorvid (TAK-242) inhibits not only acute UV-induced signaling in vitro and in vivo, but blocks UV-induced skin carcinogenesis in mouse models. In order to genetically explore the role of TLR4 in keratinocyte responses to UV-induced stress, we recently utilized CRISPR/Cas9 techniques to delete TLR4 from the genome of human HaCaT keratinocyte cells in culture. First, using differential gene expression analysis (employing the EMTRT2 Profiler PCR array technology) it was observed that TLR4 KO status is associated with pronounced downregulation of EMT-related gene expression (MMP9, VIM, FN1, SNAI1, TWIST1) confirmed by independent RT-qPCR analysis. TLR4 was also a determinant of UV-induced inflammatory enzyme expression including PTGS2. Phenotypically, TLR4 KO cells displayed an attenuation of Matrigel transwell migration. TLR4 KO cells demonstrated increased sensitivity to UV-induced apoptosis as detected by flow cytometry of annexin V/propidium iodide stained cells, and by immunodetection of increased PARP cleavage. Moreover, NanoString nCounter expression analysis of murine skin chronically exposed to tumorigenic UV indicated that topical resatorvid treatment was associated with MMP9 downregulation. Future studies will employ this novel TLR4 KO keratinocyte cell line as a mechanistic tool to dissect the role of TLR4 in inflammatory signaling and EMT response in the context of skin photodamage and carcinogenesis. Supported by NIH grants ES029579, R03CA230830, P01CA229112. Citation Format: Viktoria Kirschnerova, Prajakta Vaishampayan, Maria Khawam, Clara Curiel-Lewandrowski, Georg T. Wondrak, Sally E. Dickinson. TLR4 expression as a determinant of EMT and stress response gene expression in UV exposed human keratinocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2447.

Polypyrrole/Ni(II) metal-organic frameworks nanocomposites: Fabrication, characterization, and biocompatibility investigations

Over the past few years, possible applications of nickel nanocompounds have attracted more interest in biomedicine. This study reports the fabrication and biocompatibility of some nickel-based metal-organic frameworks (MOFs) with polypyrrole (PPy) nanocomposites, PPy/x%Ni-MOFs nanocomposites (PPy/x%Ni-MOFs, x = 20, 50, and 80), via the solution mixing procedure. The structures and chemical composition of the as-fabricated nanocomposites were investigated by FT-IR, PXRD, SEM, and TEM techniques. PPy exhibited an amorphous structure, as confirmed by the PXRD study. The spherical morphology of the pure PPy and its nanocomposites was confirmed by SEM and TEM analyses. In vitro and in vivo toxicity of the PPy/x%Ni-MOFs were assessed by MTT and hemolysis assay. The expression of inflammatory enzymes in macrophages was also evaluated by measuring the serum level of two liver transaminases. The pure PPy and Ni-MOFs were nontoxic for 3T3 fibroblasts, J774. A1 macrophages, and breast tumor MCF-7 cells. In contrast, the as-fabricated PPy/x%Ni-MOFs, especially the PPy/80%Ni-MOFs, were toxic in tumor cells (MCF-7) to a greater extent than that in the normal cells (3T3 fibroblasts, J774. A1macrophages, and human red blood cells). The PPy/80%Ni-MOFs activated macrophages to produce inflammatory enzymes COX-2 at the concentration of 75 μg mL−1. Serum level of ALT and AST, which refers to liver damage did not change significantly at 20 days post intravenous injection of PPy/x%Ni-MOFs. The as-fabricated PPy/50%Ni-MOFs demonstrated a proper degree of biocompatibility among the PPy/x%Ni-MOFs. Collectively, the as-obtained PPy/x%Ni-MOFs could be a turning point in the field of biomedicine.

Turmeric for knee pain

Turmeric may be an effective analgesic in treating chronic knee pain, according to a randomized, clinical study published on September 15 in the Annals of Internal Medicine. Turmeric is already well known for its anti-inflammatory properties and is a common spice traditionally and widely used in India. Turmeric contains the phytochemical curcumin, which not only gives curry and mustard that unmistakable golden color but also has caused turmeric to score as the most anti-inflammatory food on the Dietary Inflammatory Index. Available as a dietary supplement, turmeric's antioxidant and anti-inflammatory properties may address numerous health conditions, including arthritis. Turmeric's therapeutic potential originates from curcumin's mediation of inflammatory enzyme expression. Curcumin regulates numerous signaling molecules, including pro-inflammatory cytokines, apoptotic proteins, NF–κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. Curcumin also downregulates cyclin D1, cyclin E, and MDM2. According to the National Institutes of Health, turmeric and curcumin have a variety of interesting biological activities, but they’re challenging to study because curcumin is unstable and has low bioavailability when it's taken orally. In addition, curcumin products may differ in composition or contain more substances than expected, which makes the results of research on these products difficult to understand and compare. The most common type of arthritis, osteoarthritis (OA), has no cure, and treatments such as exercise, weight loss, and pain relievers are not always effective. Often, patients with OA look for dietary or natural alternatives to anti-inflammatory drugs. Several studies have evaluated turmeric (Curcuma longa) and curcumin for treatment of arthritis. In one recent study, the researchers randomly assigned 70 patients with painful knee OA and knee effusion or synovitis to receive placebo or 1,000 mg of C. longa capsules daily for 12 weeks. Primary outcomes of knee pain changes were measured on a visual analogue scale, and effusion–synovitis volume was measured by MRI. While the C. longa group showed a statistically significant, but modest, reduction in pain over the placebo group, there was no significant difference between groups for change in effusion–synovitis volume or cartilage composition on MRI. In addition, no differences were reported in the incidence of adverse events. This study indicates that while C. longa may not impact joint effusion, it may help reduce knee pain. While these results are promising, limitations to the study include small sample size and short duration. The authors noted that larger, longer-term studies are needed to assess clinical significance of C. longa in inflammatory knee OA. Clinical trials have established the safety and tolerability of turmeric at high doses and indicate that 500 mg to 2,000 mg per day may be effective. The average Indian diet provides around 2,000 mg of turmeric per day, and WHO recommends an acceptable daily intake of 1.4 mg per pound of body weight. Turmeric can be added to the diet as a supplement, as tea, or in meals. NIH warns that turmeric supplements have low bioavailability and need fat or heat to enhance absorption. Combining turmeric with black pepper or ginger, or coconut milk or other fats, enhances bioavailability. Most turmeric supplements contain 1,000 mg of the spice along with 5 mg of black pepper. Advise patients that turmeric and curcumin are safe in recommended amounts when taken orally or applied to the skin. While there are no reported adverse effects and many potential health benefits, turmeric should not replace conventional therapy for OA. Caution pregnant or breastfeeding women as well as patients who have gallstones or are susceptible to kidney stones to moderate their turmeric consumption and not to exceed amounts commonly found in food.

Delayed administration of high dose human immunoglobulin G enhances recovery after traumatic cervical spinal cord injury by modulation of neuroinflammation and protection of the blood spinal cord barrier

Background/introductionThe neuroinflammatory response plays a major role in the secondary injury cascade after traumatic spinal cord injury (SCI). To date, systemic anti-inflammatory medications such as methylprednisolone sodium succinate (MPSS) have shown promise in SCI. However, systemic immunosuppression can have detrimental side effects. Therefore, immunomodulatory approaches including the use of human immunoglobulin G (hIgG) could represent an attractive alternative. While emerging preclinical data suggests that hIgG is neuroprotective after SCI, the optimal time window of administration and the mechanism of action remain incompletely understood. These knowledge gaps were the focus of this research study. MethodsFemale adult Wistar rats received a clip compression-contusion SCI at the C7/T1 level of the spinal cord. Injured rats were randomized, in a blinded manner, to receive a single intravenous bolus of hIgG (2 g/kg) or control buffer at 15 minutes (min), 1 hour (h) or 4 h post-SCI. At 24 h and 8 weeks post-SCI, molecular, histological and neurobehavioral analyses were undertaken. ResultsAt all 3 administration time points, hIgG (2 g/kg) resulted in significantly better short-term and long-term outcomes as compared to control buffer. No significant differences were observed when comparing outcomes between the different time points of administration. At 24 h post-injury, hIgG (2 g/kg) administration enhanced the integrity of the blood spinal cord barrier (BSCB) by increasing expression of tight junction proteins and reducing inflammatory enzyme expression. Improvements in BSCB integrity were associated with reduced immune cell infiltration, lower amounts of albumin and Evans Blue in the injured spinal cord and greater expression of anti-inflammatory cytokines. Furthermore, hIgG (2 g/kg) increased expression of neutrophil chemoattractants in the spleen and sera. After hIgG (2 g/kg) treatment, there were more neutrophils in the spleen and fewer neutrophils in the blood. hIgG also co-localized with endothelial cell ligands that mediate neutrophil extravasation into the injured spinal cord. Importantly, short-term effects of delayed hIgG (2 g/kg) administration were associated with enhanced tissue and neuron preservation, as well as neurobehavioral and sensory recovery at 8 weeks post-SCI. Discussion and conclusionhIgG (2 g/kg) shows promise as a therapeutic approach for SCI. The anti-inflammatory effects mediated by hIgG (2 g/kg) in the injured spinal cord might be explained in twofold. First, hIgG might antagonize neutrophil infiltration into the spinal cord by co-localizing with endothelial cell ligands that mediate various steps in neutrophil extravasation. Second, hIgG could traffic neutrophils towards the spleen by increasing expression of neutrophil chemoattractants in the spleen and sera. Overall, we demonstrate that delayed administration of hIgG (2 g/kg) at 1 and 4-h post-injury enhances short-term and long-term benefits after SCI by modulating local and systemic neuroinflammatory cascades.

Four weeks exercise training enhanced the hepatic insulin sensitivity in high fat- and high carbohydrate-diet fed hyperinsulinemic rats.

Hyperinsulinemia is considered the primary defect underlying the development of type 2 diabetes. The liver is essential for the regular glucose homeostasis. In this study, we examined the effect of physical training on the insulin signaling, oxidative stress enzymes and Glucose-6-phosphatase(G6Pase) activity in the liver of Wistar rats. Adult male Wistar rats were divided into Control diet group(C), High carbohydrate diet(HCD), High fat diet(HFD), HCD and HFD with training(HCD Ex & HFD Ex). HFD Ex and HCD Ex were trained on a small animal treadmill running at 20m/min for 30min, 5 days/wk. The present work investigated the effect of training on hepatic insulin receptor(InsR) signaling events, oxidative stress marker expressions and G6Pase activity in hyperinsulinemic rats. High carbohydrate and fat feeding led to hyperinsulinemic status with increased hepatic G6Pase activity and impaired phosphorylation of insulin receptor substrate 1(IRS1) and reduced expression of antioxidant enzymes.Training significantly reduced hepatic G6Pase activity, upregulated phosphoinositide 3 kinase(PI3K) docking site phosphorylation and downregulated the negative IRS1 phosphorylations thereby increasing the glucose transporter(GLUT) expressions (aa(P < 0.001) when compared to HFD, b(P < 0.01),bb (P < 0.001 when compared to HCD). Anti oxidant enzymes like CAT, SOD, eNOS expression were increased with reduction in the expression of inflammatory enzymes like TNF-α and COX-2 (*(P < 0.05),**(P < 0.01),***(P < 0.001) when compared to control, †(P < 0.05),††(P < 0.01),†††(P < 0.001) when compared to HFD and HCD). Thus, our study shows that four weeks training enhanced the hepatic insulin sensitivity in high fat and high carbohydrate-diet fed hyperinsulinemic rats. The online version contains supplementary material available at 10.1007/s40200-020-00694-y.

Hippocampal Cholinergic Neurostimulating Peptide Suppresses LPS-Induced Expression of Inflammatory Enzymes in Human Macrophages.

Hippocampal cholinergic neurostimulating peptide (HCNP) is a secreted undecapeptide produced through proteolytic cleavage of its precursor protein, HCNPpp. Within hippocampal neurons, HCNP increases gene expression of choline acetyltransferase (ChAT), which catalyzes acetylcholine (ACh) synthesis, thereby modulating neural activity. HCNPpp also appears to be expressed in various immune cells. In the present study, we observed that HCNPpp is expressed in U937 human macrophage-like cells and that HCNP exposure suppresses lipopolysaccharide (LPS)-induced gene expression of ChAT. The opposite action is also seen in T lymphocytes, which suggest that HCNP appear to suppress cholinergic system in immune cells. In addition, HCNP suppresses LPS-induced gene expression of inflammatory enzymes including cyclooxygenase 2 (COX2) and inducible nitric oxide (NO) synthase (iNOS). The suppressive effect of HCNP may reflect suppression of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling activated by LPS. Thus, HCNP may have therapeutic potential as an anti-inflammatory drug.

Arachidonic Acid as an Early Indicator of Inflammation during Non-Alcoholic Fatty Liver Disease Development.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by excessive lipid deposition. Lipid metabolism disturbances are possibly associated with hepatocyte inflammation development and oxidative balance impairment. The aim of our experiment was to examine the first moment when changes in plasma and liver arachidonic acid (AA) levels as a pro-inflammatory precursor may occur during high-fat diet (HFD)-induced NAFLD development. Wistar rats were fed a diet rich in fat for five weeks, and after each week, inflammation and redox balance parameters were evaluated in the liver. The AA contents in lipid fractions were assessed by gas–liquid chromatography (GLC). Protein expression relevant to inflammatory and lipogenesis pathways was determined by immunoblotting. The oxidative system indicators were determined with assay kits. Our results revealed that a high-fat diet promoted an increase in AA levels, especially in the phospholipid (PL) fraction. Importantly, rapid inflammation development via increased inflammatory enzyme expression, elevated lipid peroxidation product content and oxidative system impairment was caused by the HFD as early as the first week of the experiment. Based on these results, we may postulate that changes in AA content may be an early indicator of inflammation and irreversible changes in NAFLD progression.

Therapeutic Effects of Anti-Inflammatory N-Acylhydrazones in the Resolution of Experimental Colitis.

Inflammatory bowel diseases are caused by inflammation of the gastrointestinal tract, which may or may not have a specific cause or pathogen. They affect millions of people around the world and there are still few effective treatments. The aim of this work is to investigate the anti-inflammatory effect of the IKK-β inhibitor LASSBio-1524 and its three analogs, LASSBio-1760, LASSBio-1763, and LASSBio-1764, on mediator production and expression of inflammatory enzymes using experimental animal models of intestinal inflammatory diseases. Colitis was performed using two different models, which mimic Crohn disease (induced by dinitrobenzene acid) and ulcerative colitis (induced by sodium dextran sulfate) in mice. In both models, a therapeutic protocol with a daily dose of 1, 3, or 30 μmol/kg was performed. LASSBio-1524 and its three analogs reduced the secretion of tumor necrosis factor-α, IL-1β, IL-6, IL-12, and IFN-γ and increased secretion of IL-10, protecting gastrointestinal homeostasis. All compounds reduced macro- and microscopic colonic damage caused by experimental colitis and p38 mitogen-activated protein kinase expression in the colon, as well as leukocytosis and anemia resulting from the disease. Our data may suggest LASSBio-1524 and its analogs (LASSBio-1760, LASSBio-1763, and LASSBio-1764) as promising candidates for new prototypes designed to treat inflammatory bowel diseases. SIGNIFICANCE STATEMENT: Three new N-acylhydrazones were synthetized as analogs of LASSBio-1524. All new substances were evaluated in dextran sulfate- and dinitrobenzene acid-induced colitis, with LASSBio-1760, LASSBio-1762, and LASSBio-1763 presenting a significant effect in both models of colitis without toxic effects. The new substances could be considered as a new prototype for the development of new anti-inflammatory treatments of colitis.

Effects of [6]‐Gingerol on β‐amyloid‐induced Cognitive Impairment in Mice

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by disruption of cholinergic neurons and it is likely that promoted inflammation and oxidation is involved in pathogenesis of AD. Consequently, it is worthwhile developing effective phytochemical agents which can reinforce the cholinergic transmission and anti‐inflammatory defense capacity for the prevention and/or treatment of AD. In this study, we tested whether [6]‐gingerol, an active constituent of ginger could reduce β‐amyloid (Aβ)‐induced cognitive impairment in mice. Administration of [6]‐gingerol p.o. (25 mg/kg) significantly alleviated Aβ‐induced cognitive dysfunction as evaluated by Y‐maze and passive avoidance tests. To further elucidate the mechanisms underlying the effects of [6]‐gingerol, the possible involvement of inflammatory mediators were examined. Treatment of [6]‐gingerol reduced the expression of inflammatory enzymes and pro‐inflammatory cytokines such as COX2, IL‐1β, TNFα and iNOS. In addition, [6]‐gingerol decreased the phosphorylation of p66‐Shc which had been increased by Aβ. Taken together these findings suggest that [6]‐gingerol might potentiate anti‐inflammatory cellular defense system and have therapeutic potentials in the management of cognitive impairment in AD.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NFR) grant funded by the Korea government (MSIT)

Meroterpenoid-Rich Fraction of the Ethanol Extract of Sargassum Serratifolium Suppresses Collagen-Induced Rheumatoid Arthritis in DBA/1J Mice Via Inhibition of Nuclear Factor κB Activation.

Rheumatoid arthritis (RA) is an autoimmune disorder related to the inflammation of cartilage due to the infiltration of inflammatory cells. Sargassum serratifolium, a brown alga, possesses strong anti-inflammatory activities. The effect of meroterpenoid-rich fraction from the ethanol extract of S. serratifolium (MES) on RA and its underlying mechanisms on the inhibition of RA using a collagen-induced arthritis (CIA) mouse model are examined. The results show that MES ameliorates paw swelling and reduces the arthritis score. MES considerably decreases the secretion of pro-inflammatory cytokines in the serum and joint tissue of mice. Histopathological analysis demonstrates that MES strongly inhibited bone damage and inflammatory cell intrusion in the joint tissue. The expression of inflammatory enzymes and adhesion molecules is significantly inhibited in the serum and joint tissue of MES-fed mice. In addition, MES downregulates the nuclear factor κB (NF-κB) signaling pathway by suppressing the phosphorylation of protein kinase B, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases. MES supplementation remarkably reduces inflammatory response in CIA mouse model. These results indicate that MES can be used as a pharmaceutical agent against RA.

Effects of Black Vinegar and Niacinamide on LPS-Induced Inflammation on Human Keratinocytes

In this study, the effects of black vinegar (BA) and niacinamide on lipopolysaccharide (LPS)-treated human keratinocytes, HaCaT cells, were investigated. First of all, BA and niacinamide have no cytotoxicity in HaCaT cells even at high concentrations. LPS treatment triggers the phosphorylation of p38 mitogen-activated protein kinases (MAPK) and the expression of inflammatory enzymes, iNOS and COX-2. In contrast, BA and niacinamide weakened the expression of LPS-induced COX-2 and iNOS. Based on the results, we concluded that BA and niacinamide have effective anti-inflammatory properties in HaCaT cells. Therefore, BA and niacinamide may be used as new alternative treatments for inflammatory skin diseases. Keywords: Black vinegar, HaCaT cell, Inflammation, Keratinocytes, Liposaccharides, Niacinamide

Humulus japonicus extract ameliorates collagen‑induced arthritis in mice through regulation of overall articular inflammation.

Humulus japonicus (HJ) is a widely used herbal medicine in Asia with anti-oxidative, anti-microbial, and anti-inflammatory effects. We investigated the potential therapeutic effects of HJ in rheumatoid arthritis (RA) using a mouse model of collagen-induced arthritis (CIA) and a lipopolysaccharide-stimulated murine macrophage cell line (RAW 264.7). The CIA mice were administered 300 mg/kg HJ orally starting 3 days prior to second immunization. The clinical and histopathological findings were assessed in the paw of CIA mice. The levels of autoantibodies and inflammatory markers were determined in the plasma and cell culture supernatant, respectively. The expression at mRNA and protein levels was analyzed by reverse transcription quantitative-PCR and western blot analysis, respectively. HJ significantly decreased the gross arthritic scores and paw swelling in CIA mice. Furthermore, synovial inflammation, cartilage destruction, and bone erosion were markedly reduced by HJ. It also decreased the expression of inflammatory enzymes in both the paw of mice and RAW 264.7 cells. Moreover, the expression of genes related to all macrophages and pro-inflammatory M1 macrophage were significantly decreased, whereas the expression of anti-inflammatory M2 macrophage marker was markedly increased in the paw of HJ-treated CIA mice. In addition, HJ suppressed the levels of plasma anti-type II collagen antibody following the decreased expression of T helper type 1 (Th1) and Th2 cell-associated surface markers and cytokines in the paw. HJ also significantly inhibited the expression of IL-6 both in vitro and in vivo, followed by reduced STAT3 phosphorylation and expression in the paw of CIA mice. Finally, the expression of osteoclast-related genes was decreased in the paw of HJ-treated CIA mice. These findings suggest that HJ can play a role in suppressing the development of CIA by overall regulation of articular inflammation. This study should provide new insights into the use of HJ as a therapeutically effective natural product against RA.

Identification of potential inflammatory inhibitors from Aster tataricus

Aster tataricus L.f. is a traditional Eastern Asian herbal medicine used for the relief of cough-related illnesses. In this study, 32 known compounds and two novel monoterpene glycosides were isolated from the roots of A. tataricus. With the aid of reported data, elucidation of the root-extract components was carried out using a multitude of spectroscopic techniques. All isolates were investigated for their ability to inhibit nitric oxide (NO) secretion in lipopolysaccharide-activated RAW264.7 cells. Compound 7 remarkably suppressed NO production with an IC50 value of 8.5 µM. In addition, compound 7 exhibited significant inhibitory activity against the production of inflammatory cytokines (prostaglandin E2, interleukin-6, and interleukin-1 beta) and the expression of inflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) via inhibition of nuclear factor-kappa B activation. Moreover, compound 7 effectively prevented the downstream activation of the mitogen-activated protein kinase signaling pathway by inhibiting phosphorylation of c-Jun N-terminal kinases, extracellular signal-regulated kinases, and p38. These results outline compound 7 as a potential inhibitor for the broad treatment of inflammatory diseases, such as atopic dermatitis, asthma, and various allergies.

Viburnum pichinchense methanol extract exerts anti-inflammatory effects via targeting the NF-κB and caspase-11 non-canonical inflammasome pathways in macrophages.

Viburnum pichinchense Benth. Mainly found in Ecuador and Colombia has been ethnopharmacologically utilized as a remedy for various female disorders with kidney inflammation and uterine relaxant. The pharmacological activity of Viburnum pichinchense has never been studied, therefore, this study explored anti-inflammatory activity of Viburnum pichinchense methanol extract (Vp-ME). Anti-inflammatory activities of Vp-ME were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and HCl/EtOH-induced gastritis mice by MTT assay, nitric oxide (NO) production assay, semi-quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR), luciferase reporter assay, Western blotting, and enzyme-linked immunosorbent assays (ELISA). Anti-inflammatory compounds in Vp-ME were identified by high performance liquid chromatography (HPLC). Vp-ME inhibited NO production in RAW264.7 cells stimulated with pam3CSK4, poly I:C or LPS and in LPS-stimulated peritoneal macrophages without cytotoxicity and downregulated mRNA expression of inflammatory enzymes, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6. The anti-inflammatory activity was accomplished by inhibiting nuclear factor-kappa B (NF-κB) transcriptional activation, upstream signaling molecules in the NF-κB pathway, and caspase-11 non-canonical inflammasome in RAW264.7 cells. Moreover, Vp-ME exhibited in vivo anti-inflammatory activity by ameliorating gastritis symptoms, inhibiting iNOS and IL-6 mRNA expression and IκBα activation in mice. HPLC analysis identified resveratrol, quercetin, luteolin, and kaempferol as the anti-inflammatory components in Vp-ME. This study demonstrated Vp-ME has the anti-inflammatory activity via targeting NF-κB and caspase-11 non-canonical inflammasome pathways in macrophage-mediated inflammatory responses, suggesting Vp-ME could be developed as anti-inflammatory ethnopharmacological remedies to prevent and treat inflammatory diseases.

The effects of human immunoglobulin G on enhancing tissue protection and neurobehavioral recovery after traumatic cervical spinal cord injury are mediated through the neurovascular unit

BackgroundSpinal cord injury (SCI) is a condition with few effective treatment options. The blood-spinal cord barrier consists of pericytes, astrocytes, and endothelial cells, which are collectively termed the neurovascular unit. These cells support spinal cord homeostasis by expressing tight junction proteins. Physical trauma to the spinal cord disrupts the barrier, which leads to neuroinflammation by facilitating immune cell migration to the damaged site in a process involving immune cell adhesion. Immunosuppressive strategies, including methylprednisolone (MPSS), have been investigated to treat SCI. However, despite some success, MPSS has the potential to increase a patient’s susceptibility to wound infection and impaired wound healing. Hence, immunomodulation may be a more attractive approach than immunosuppression. Approved for modulating neuroinflammation in certain disorders, including Guillain-Barre syndrome, intravenous administration of human immunoglobulin G (hIgG) has shown promise in the setting of experimental SCI, though the optimal dose and mechanism of action remain undetermined.MethodsFemale adult Wistar rats were subjected to moderate-severe clip compression injury (35 g) at the C7-T1 level and randomized to receive a single intravenous (IV) bolus of hIgG (0.02, 0.2, 0.4, 1, 2 g/kg), MPSS (0.03 g/kg), or control buffer at 15 min post-SCI. At 24 h and 6 weeks post-SCI, molecular, histological, and neurobehavioral effects of hIgG were analyzed.ResultsAt 24 h post-injury, human immunoglobulin G co-localized with spinal cord pericytes, astrocytes, and vessels. hIgG (2 g/kg) protected the spinal cord neurovasculature after SCI by increasing tight junction protein expression and reducing inflammatory enzyme expression. Improvements in vascular integrity were associated with changes in spinal cord inflammation. Interestingly, hIgG (2 g/kg) increased serum expression of inflammatory cytokines and co-localized (without decreasing protein expression) with spinal cord vascular cell adhesion molecule-1, a protein used by immune cells to enter into inflamed tissue. Acute molecular benefits of hIgG (2 g/kg) led to greater tissue preservation, functional blood flow, and neurobehavioral recovery at 6 weeks post-SCI. Importantly, the effects of hIgG (2 g/kg) were superior to control buffer and hIgG (0.4 g/kg), and comparable with MPSS (0.03 g/kg).ConclusionshIgG (2 g/kg) is a promising therapeutic approach to mitigate secondary pathology in SCI through antagonizing immune cell infiltration at the level of the neurovascular unit.