Activation Of Nuclear Factor Kappa Research Articles

Effect of turmeric extract on bone healing in an experimental model of femoral bone fracture.

Objective:Following bone trauma, several factors participate in making a balance between the activity of osteoblasts and osteoclasts. The receptor activator of nuclear factor kappa B ligand (RANKL), receptor activator of nuclear factor kappa B (RANK), and osteoprotegerin (OPG) molecules play critical roles in the healing process via regulation of osteoclasts function. Turmeric is suggested to have an anti-osteogenic potential; however, its effect on accelerating bone healing has not been adequately studied. Here, we used a rat model of femur fracture to explore the effect of treatment with turmeric extract on the bone repair and the expression of RANK, RANKL, and OPG molecules.Materials and Methods:Eight rats were subjected to surgery, randomly divided into two groups, and treated orally with turmeric (200 mg/kg), or olive oil. Four oil-treated rats without bone fracture were used as control group. After six weeks of treatment, the femurs of animals were examined for radiological, histological, and gene expression analysis. Results:X-ray radiography showed thicker callus and a more obscure fracture line in the turmeric group. Furthermore, higher osteoblast percentages but no osteoclasts were observed in turmeric-treated animals, representing better repair of bone in the fracture site. Also, real-time analyses showed that treatment with turmeric reduced RANK and RANKL expression (p<0.0001) and lowered RANKL/OPG ratio (p=0.01) in femoral bone tissue.Conclusion:Our findings indicated the turmeric ability to facilitate bone hemostasis and optimize the expression of key markers involved in the bone metabolism.

Bone Turnover Markers and Osteokines in Adolescent Female Athletes of High- and Low-Impact Sports Compared With Nonathletic Controls.

This study examined differences in resting concentrations of markers of bone formation and resorption, and osteokines between female adolescent (12-16y) swimmers, soccer players, and nonathletic controls. Resting, morning blood samples were obtained after an overnight fast from 20 swimmers, 20 soccer players, and 20 nonathletic controls, matched for age. carboxyl-terminal cross-linking telopeptide of type I collagen (CTX), amino-terminal propeptide of type I collagen (P1NP), total osteocalcin (OC), sclerostin, osteoprotegerin (OPG), and receptor activator of nuclear factor kappa B ligand(RANKL) were analyzed in serum. After controlling for percent body fat, there were no significant differences between swimmers and nonathletic controls in any of the measured markers. In contrast, soccer players had significantly higher P1NP (89.5 [25.6]ng·mL-1), OC (57.6 [22.9]ng·mL-1), and OPG (1052.5 [612.6]pg·mL-1) compared with both swimmers (P1NP: 66.5 [20.9]ng·mL-1; OC: 24.9 [12.5]ng·mL-1; OPG: 275.2 [83.8]pg·mL-1) and controls (P1NP: 58.5 [16.2]ng·mL-1; OC: 23.2 [11.9]ng·mL-1; OPG: 265.4 [97.6]pg·mL-1), with no differences in CTX, sclerostin, and RANKL. These results suggest that bone formation is higher in adolescent females engaged in high-impact sports like soccer compared with swimmers and controls.

Steroid Receptor Coactivator-1 (SRC-1) Promoted Cell Metastasis of Gastric Cancer via VEGFC Activator by NF-κB.

The regulatory mechanism and function of steroid receptor coactivator-1 (SRC-1) was determined in vitro and the role played in gastric cancer was investigated. The study collected 64 patients with gastric cancer tissue and paracancerous tissue to investigate the clinical patterns of SRC-1 expression in gastric cancer. Quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, and immunofluorescence staining were used in this study. In patients with gastric cancer, SRC-1 serum expression levels were up-regulated. Over-expression of SRC-1 promoted cell growth and cell metastasis in vitro model of gastric cancer. However, down-regulation of SRC-1 reduced cell growth and cell metastasis in vitro model of gastric cancer. SRC-1 over-expression induced vascular endothelial growth factor C (VEGFC) protein expressions in vitro model by activation of nuclear factor-kappa B (NF-kB) expression. The inhibition of NF-κB reduced the pro-cancer effects of SRC-1 on cell growth and cell metastasis in vitro model of gastric cancer through inhibition of VEGFC expression. These results suggest that SRC-1 promoted cell metastasis of gastric cancer via VEGFC activator by NF-κB. These novel findings may shed further light on the pathogenesis of gastric cancer and on potential precursor markers.

Treatment of fibrous dysplasia: focus on denosumab

ABSTRACT Introduction Fibrous dysplasia (FD) is a rare bone disease that is associated with various endocrine conditions, such as McCune Albright syndrome. It manifests as abnormal osteolysis, multiple fractures, or deformities that are reported during disease course. The receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) pathway is upregulated in FD and can be targeted with denosumab, a blocking monoclonal antibody. Areas covered Preclinical and clinical data on the scientific rationale for using denosumab in FD and on the efficacy and safety of this therapy for this condition have been reviewed, in addition to other therapies. Expert opinion Denosumab is a potential therapeutic agent against FD. A combined synergic approach involving theranostics might increase its therapeutic potential.

Development of chimeric receptor activator of nuclear factor-kappa B with glutathione S-transferase in the extracellular domain: Artificial switch in a membrane receptor.

Various chimeric receptors have been developed and used for biological experiments. In the present study, we constructed three types of chimeric receptor activator of nuclear factor-kappa B (RANK) with the glutathione S-transferase (GST) protein in the extracellular domain, and stimulated them using newly synthesized chemical trimerizers with three glutathiones. Although this stimulation did not activate these proteins, we unexpectedly found that the chimera named RANK-GST-SC, in which GST replaced a major part of the RANK extracellular domain, activated nuclear factor-kappa B (NF-κB) signaling approximately sixfold more strongly than wild-type RANK without the ligand. The dimerization of extracellular GST is considered to function as a switch outside the cell, and signal transduction then occurs. GST has been widely employed as a tag for protein purification; GST-fusion protein can be conveniently captured by glutathione-conjugated beads and easily purified from impurity. The present study is a pioneering example of the novel utility of GST and provides information for the development of new chemical biology systems.

Effects of Alendronate and Dexamethasone on Osteoclast Gene Expression and Bone Resorption in Mouse Marrow Cultures.

Osteoclasts are cells whose main function is the resorption of bone matrix. However, several factors, including medications, can interfere with the resorption process. Alendronate (ALN), a nitrogen-containing type of bisphosphonate, and dexamethasone (DEX), a glucocorticoid, are drugs that may affect the resorption activity. The aim of this study is to investigate the effects of ALN, and/or DEX on osteoclast gene expression and resorption activity in primary mouse marrow cultures stimulated with 1,25-dihydroxyvitamin D3, a model for the bone microenvironment. Cultures were treated only with ALN (10-5 M), DEX (10-6 M), and with a combination of both agents. Viability assays performed at days 5, 7, and 9 showed the highest number of viable cells at day 7. All the following assays were then performed at day 7 of cell culture: tartrate resistant acid phosphatase (TRAP) histochemistry, receptor activator of nuclear factor kappa B ligand (RANKL) immunofluorescence, osteoprotegerin (OPG), and RANKL gene expression by qPCR and resorption analysis by scanning electron microscopy. Treatment with ALN, DEX, and the combination of both did not promote significant changes in the number of TRAP+ cells, although larger giant cells were detected in groups treated with DEX. DEX treatment increased the gene expression of RANKL and reduced OPG. The treatment with ALN reduced the depth of the resorption pits, but their inhibitory effect was less effective when administered with DEX.

VF-4 and DR-8 Derived from Salted Egg White Inhibit Inflammatory Activity via NF-κB/PI3K-Akt/MAPK Signal Transduction Pathways in HT-29 Cells Induced by TNF-α.

Inflammation is the pathological basis of many chronic diseases, and persistent intestinal inflammation is a key factor in the further development of colon cancer. Egg-derived peptides have been proven to have anti-intestinal inflammation activity. Egg white treated with salt contains a lot of rich protein, whether its peptides have anti-inflammatory activity and how their mechanism of action is still unclear. In this study, ELISA is used to determine the anti-inflammatory activity of the peptides (VF-4 and DR-8 from salted egg white), and then RNA-seq is used to explore the mechanism of their anti-inflammatory activity, and then verified by western blotting and inhibitors. The results show that VF-4 and DR-8 significantly inhibit TNF-α-induced IL-8 secretion in HT-29 cells in a concentration-dependent manner, and VF-4 show a more significant anti-inflammatory effect than DR-8. The anti-inflammatory mechanism of VF-4 and DR-8 is through inhibiting the activation of Nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3' -kinase(PI3K)-Akt pathways, reducing the production of inflammatory mediators. VF-4 and DR-8 have obvious anti-inflammatory activity, which can reduce intestinal inflammation and inhibit its further development into colon cancer.

By-Products of the Black Soybean Sauce Manufacturing Process as Potential Antioxidant and Anti-Inflammatory Materials for Use as Functional Foods.

To assess the potential of by-products of the black bean fermented soybean sauce manufacturing process as new functional food materials, we prepared black bean steamed liquid lyophilized product (BBSLP) and analysed its antioxidant effects in vitro. RAW264.7 macrophages were cultured and treated with BBSLP for 24 h, and 1 μg/mL lipopolysaccharide (LPS) was then used for another 24 h to induce inflammation. The cellular antioxidant capacity and inflammatory response were then analysed. Activation of nuclear factor kappa B (NF-κB) signaling in RAW264.7 macrophages was also analysed. Results showed BBSLP had 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium (ABTS+) radical-scavenging abilities and reducing power in vitro. The levels of both reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) were reduced after RAW264.7 macrophages were treated with BBSLP after LPS induction. After RAW264.7 macrophage treatment with BBSLP and induction by LPS, the levels of inflammatory molecules, including nitric oxide (NO), prostaglandin E2 (PGE2), IL-1α, IL-6 and TNF-α, decreased. NF-κB signaling activity was inhibited by reductions in IκB phosphorylation and NF-κB DNA-binding activity after RAW264.7 macrophages were treated with BBSLP after LPS induction. In conclusion, BBSLP has antioxidant and anti-inflammatory capabilities and can be a supplement material for functional food.

N-3 PUFA ameliorated bone loss induced by postmenopausal depression following exposure to chronic mild stress and maternal separation by regulating neuronal processes

Depression induced by chronic mild stress (CMS) reduced bone mass in ovariectomized (OVX) rats, and maternal separation (MS) during early life aggravated depression-induced bone mass destruction. N-3 polyunsaturated fatty acids (PUFA) have been shown to improve bone mass and depression, but the bone-protecting effects of n-3 PUFA were unclear in CMS+MS-induced depression models. The purpose of this study was to determine whether n-3 PUFA improved CMS+MS-induced postmenopausal bone loss via its antidepressant-like action. Rats were fed diets containing 0% of total energy intake (en %) of n-3 PUFA during lifetime or 1 en % n-3 PUFA during pre-weaning or post-weaning periods, or their entire lifetimes and were allocated to CMS or CMS+MS groups after OVX. Lifetime supply of n-3 PUFA enhanced bone mass and microarchitecture, and expression of runt-related transcription factor 2, while decreasing blood levels of amino-terminal cross-linked telopeptide of type 1 collagen and the expression of receptor activator of nuclear factor kappa Β ligand/osteoprotegerin, activating transcription factor 4, and adrenergic receptor β2. Lifetime supply of n-3 PUFA decreased levels of adrenocorticotropic hormone and corticosterone and the expression of corticotropin-releasing factor in the brain but increased expression of the glucocorticoid receptor, serotonin-2C receptor, cAMP response element-binding protein (CREB), and calmodulin kinase IV and serotonin levels. Supply of n-3 PUFA during the pre-and post-weaning periods had beneficial effects on the brain but not on the bones. Lifetime supply of n-3 PUFA ameliorated bone loss induced by chronic stress by regulating hypothalamic-pituitary-adrenal axis activity and serotonin-CREB signaling.

Amelioration of Neuropathic Pain and Attenuation of Neuroinflammation Responses by Tetrahydropalmatine Through the p38MAPK/NF-\u03baB/iNOS Signaling Pathways in Animal and Cellular Models

—Neuropathic pain (NP) treatment remains a challenge because the pathomechanism is not yet fully understood. Because of low treatment efficacy, there is an important unmet need in neuropathic pain patients, and the development of a more effective pharmacotherapy is urgently required. Neuroinflammation induced by oxidative stress-mediated activation of nuclear factor-kappa B (NF-κB) plays an important role in NP. In this study, we aimed to investigate the protective properties of tetrahydropalmatine (THP) on a spared nerve injury (SNI) model of neuropathic pain in mice in in vivo and also in in vitro experiments. THP decreased mechanical hyperalgesia and cold allodynia compared with the SNI group. A microarray was applied to analyze differentially expressed of mRNA among different groups, and THP noticeably changed the expression of MAPK-related proteins compared with the SNI groups. H&E staining showed that the THP changed the inflammation after the spared nerve injury, with decreased NO expression in the THP group as compared to the SNI group. In addition, SNI-induced pain was reversed by intraperitoneal administration of THP, and further results indicated that THP suppressed inducible nitric oxide synthase (iNOS, pro-nociceptive mediators), phosphorylated MAPKs, and p65 in the dorsal root ganglions and sciatic nerve, while the serum levels of the pro-inflammatory cytokines IL-1β were significantly higher in the SNI group as compared to the THP group. To identify the molecular mechanism of the antineuropathic activity of THP, sodium nitroprusside (SNP)-induced neuro-2a (N2a) cells, LPS-induced BV2 cells, and LTA-induced astrocytes were further investigated in signaling pathways. In vitro experiments indicated that THP suppressed the expression of IL-1β, iNOS, phosphorylated MAPKs, and p65, which were assayed using western blotting, and immunofluorescence.

Dendrobine attenuates osteoclast differentiation through modulating ROS/NFATc1/ MMP9 pathway and prevents inflammatory bone destruction

Osteolytic diseases share symptoms such as bone loss, fracture and pain, which are caused by over-activated osteoclasts. Targeting osteoclast differentiation has emerged as a therapeutic strategy clinically. Dendrobine is an alkaloid isolated from Chinese herb Dendrobium nobile, with knowing effects of analgesia and anti-inflammation. The roles of dendrobine on osteoclasts and osteolysis remain unclear. Herein, the possible roles of dendrobine in osteoclastogenesis, inflammatory osteolysis and the underlying mechanism were explored. Bone marrow-derived macrophages (BMMs) and RAW264.7 cells were employed to evaluate the roles of dendrobine on osteoclastogenesis, bone absorption and the underlying mechanism in vitro. LPS injection was used to cause inflammatory osteolysis in vivo. Dendrobine repressed osteoclastogenesis, bone resorption induced by receptor activator of nuclear factor kappa B ligand (RANKL) in vitro. Mechanistically, dendrobine inhibited RANKL-upregulated intracellular (ROS), p-p38, c-Fos expression and nuclear factor of activated T cells (NFATc1) nucleartranslocation. Osteoclastic genes were reduced, and among them matrix metalloproteinase 9 (MMP9) mRNA was dramatically blocked by dendrobine. Moreover, it substantially suppressed MMP9 protein expression during osteoclastogenesis in vitro. Accordingly, oral 20mg/kg/day dendrobine was capableof preventing LPS-induced osteolysis with decreased osteoclasts in vivo. Taken together, dendrobine suppresses osteoclastogenesis through restraining ROS, p38-c-Fos and NFATc1-MMP9 in vitro, thus attenuates inflammatory osteolysis in vivo. This finding supports the discover of dendrobine as a novel osteoclast inhibitor for impeding bone erosion in the future.

The Crosstalk Between Regulatory Non-Coding RNAs and Nuclear Factor Kappa B in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly lethal type of malignancies that possesses great loss of life safety to human beings worldwide. However, few effective means of curing HCC exist and its specific molecular basis is still far from being fully elucidated. Activation of nuclear factor kappa B (NF-κB), which is often observed in HCC, is considered to play a significant part in hepatocarcinogenesis and development. The emergence of regulatory non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is a defining advance in cancer biology, and related research in this branch has yielded many diagnostic and therapeutic opportunities. Recent studies have suggested that regulatory ncRNAs act as inhibitors or activators in the initiation and progression of HCC by targeting components of NF-κB signaling or regulating NF-κB activity. In this review, we attach importance to the role and function of regulatory ncRNAs in NF-κB signaling of HCC and NF-κB-associated chemoresistance in HCC, then propose future research directions and challenges of regulatory ncRNAs mediated-regulation of NF-κB pathway in HCC.

The anti-inflammatory and protective role of interleukin-38 in inflammatory bowel disease.

Interleukin (IL)-38 exerts an anti-inflammatory function by binding to several cytokine receptors, including the IL-36 receptor. In this study, we evaluated IL-38 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and investigated its functions. IL-38 mRNA expression in endoscopic biopsy samples was evaluated using quantitative PCR. IL-38 protein expression was analyzed using immunohistochemical technique. Dextran sulfate sodium-induced colitis was induced in C57BL/6 background IL-38KO mice. The IL-38 mRNA and protein expression were enhanced in the active mucosa of ulcerative colitis, but not in Crohn’s disease. The ratio of IL-36γ to IL-38 mRNA expression was significantly elevated in the active mucosa of UC patients. Immunofluorescence staining revealed that B cells are the major cellular source of IL-38 in the colonic mucosa. IL-38 dose-dependently suppressed the IL-36γ-induced mRNA expression of CXC chemokines (CXCL1, CXCL2, and CXCL8) in HT-29 and T84 cells. IL-38 inhibited the IL-36γ-induced activation of nuclear-factor kappa B (NF-κB) and mitogen-activated protein kinases in HT-29 cells. DSS-colitis was significantly exacerbated in IL-38KO mice compared to wild type mice. In conclusion, IL-38 may play an anti-inflammatory and protective role in the pathophysiology of IBD, in particular ulcerative colitis, through the suppression of IL-36-induced inflammatory responses.

Stress-induced phosphoprotein 1 restrains spinal cord ischaemia-reperfusion injury by modulating NF-κB signalling.

Spinal cord injury (SCI), a major cause of disability, causes high global disease and economic burdens. Stress‐induced phosphoprotein 1 (STIP1) has been identified to be involved in spinal cord ischaemia‐reperfusion injury (SCII); however, the effect of STIP1 on SCII remains unclear until now. This study aimed to examine the role of STIP1 in SCII and unravel the possible mechanisms. Western blotting and immunohistochemical staining showed that STIP1 expression rapidly increased and then decreased in rat spinal cord following SCII treatment. Neurological function scoring, HE staining, immunohistochemical staining and Western blotting revealed that STIP1 overexpression alleviated SCII‐induced motor dysfunction of hind limbs, neuronal loss and inflammation in spinal cord, and inhibited activity of nuclear factor kappa B (NF‐κB) signalling in rats. Immunoprecipitation identified that STIP1 was co‐located with Iba‐1. In addition, STIP1 was found to ameliorate oxygen and glucose deprivation (OGD)‐induced inflammation and activation of NF‐κB signalling in mouse microglia BV2 cells, and STIP1 resulted in decrease of heat shock protein family A member 8 (HSPA8), increase of IκBβ expression and reduced binding of IκBβ to HSPA8 in BV2 cells. The results of the present study demonstrate that STIP1 alleviates ischaemia/reperfusion‐induced neuronal injury and inflammation in rat spinal cord and mouse microglial cells by deactivating NF‐κB signalling. These findings may provide novel insights for the clinical diagnosis and treatment of SCI.

QiangGuYin Modulates the OPG/RANKL/RANK Pathway by Increasing Secretin Levels during Treatment of Primary Type I Osteoporosis.

QiangGuYin (QGY) is a common Traditional Chinese medicine prescription for the treatment of osteoporosis. Previous clinical studies have found that QGY effectively improves bone mineral density (BMD) in postmenopausal women, but its underlying mechanism remains unclear. The osteoprotegerin (OPG)/receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK) pathway is a classic pathway involved in osteoporosis. Secretin levels are a serum marker of osteoporosis, but their effect on the OPG/RANKL/RANK pathway has not been reported. Hence, we investigated the relationship between the OPG/RANKL/RANK pathway and secretin and further revealed the mechanism underlying the effect of QGY in the treatment of osteoporosis. Mice were divided into secretin knockdown, secretin overexpression, and corresponding control groups. Micro-computed tomography was used to detect BMD in different groups, and the results show that QGY significantly improved BMD in mice of the secretin knockdown group. To further verify this, the serum levels of OPG, RANKL, RANK, and secretin were measured by enzyme-linked immunosorbent assays, and femur levels of OPG, RANKL, RANK, and secretin were evaluated by real-time quantitative PCR and western blotting. The results show that the expression of OPG was inhibited and that of RANKL and RANK was increased in mice from the secretin knockdown group, whereas the expression of OPG was upregulated and that of RANKL and RANK was downregulated after QGY intervention. Therefore, QGY inhibited bone resorption by promoting the expression of secretin and modulating the OPG/RANKL/RANK pathway. In addition to the effect of QGY, we also revealed the general regulatory effect of secretin on the OPG/RANKL/RANK pathway. We conclude that QGY modulates the OPG/RANKL/RANK pathway by increasing secretin levels during treatment of primary type I osteoporosis. This work provides a theoretical basis for the clinical use of QGY in the treatment of osteoporosis.

Bone health in pediatric transfusion-dependent beta-thalassemia: Circulating osteoprotegerin and RANKL system.

While the mechanism of bone disease in thalassemia is multifactorial and still under investigation, the receptor activator of nuclear factor kappa B (RANK), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) have pivotal roles in regulating bone metabolism. This study aimed to measure RANKL and OPG serum levels, and to detect the incidence of RANKL rs9533156, OPG rs2073618, and OPG rs2073617 genotypes in pediatric β-thalassemia patients and to assess their relation to bone mineral density. Sixty patients with transfusion-dependent β-thalassemia (TBT) patients ages 5 to 14 years were included, and 60 healthy, age- and sex-matched volunteers contributed as a control group. The patients were scanned for bone mineral density. The mean of spine dual-energy X-ray absorptiometry (DXA) Z-score in patients was -1.66 ± 1.02 standard deviation (SD). Twenty-four of them had low spine DXA Z-scores. The patients showed significantly lower OPG levels and OPG/RANKLs ratios than the control group (3.28 ± 9.11ng/ml and 11.38 ± 14.93ng/ml, and 0.01 ± 0.03 and 0.07 ± 0.09, respectively). The RANKL SNP rs9533156 TC heterozygous genotype was detected more with statistical significance in patients than controls. The incidence of OPG rs2073618 and OPG rs2073617 genotypes were 2.3 times and 1.9 times more frequent in patients than controls, respectively. The RANK/RANKL/OPG system may have an important role in regulating bone metabolism in TBT patients, although further studies are needed to clarify its role.

Multivariate Analysis Reveals That Unsubstituted β-Ring and C8-Keto Structures Are Important Factors for Anti-Inflammatory Activity of Carotenoids.

Carotenoids are natural lipophilic pigments with substantial health benefits. Numerous studies have demonstrated the anti-inflammatory activities of carotenoids, especially toward lipopolysaccharide-induced inflammatory responses. As such, there are few reports on the evaluation and comparison of the anti-inflammatory activities of carotenoids against inflammation induced by other stimuli. In this study, we used pathogen-associated molecular patterns, proinflammatory cytokines, degenerated proteins, and chemical irritants as inflammatory inducers to evaluate the anti-inflammatory activities of eight different carotenoids. Each carotenoid showed characteristic anti-inflammatory activities; thus, we conducted a multivariate analysis to clarify the differences among them. Unsubstituted β-ring (i.e., provitamin A) and C8-keto structures of carotenoids were found to be crucial for their inhibitory effects on the activation of nuclear factor-kappa B and interferon regulatory factors, respectively. Furthermore, we found that β-carotene and echinenone treatment increased intracellular retinoid levels in monocytes and that the retinoids showed the similar activities to β-carotene and echinenone. Taken together, the intake of both provitamin A and C8-keto carotenoids (e.g., siphonaxanthin and fucoxanthin) might be effective in improving the inflammatory status of individuals. A multivariate analysis of anti-inflammatory activities is a useful method for characterizing anti-inflammatory compounds.

Circular RNAs as potential regulators in bone remodeling: a narrative review.

ObjectiveIn this review, we focus on the recent progress of circular ribonucleic acids (circRNAs)-related molecular mechanisms in the processes of osteogenesis and osteoclastogenesis, and explore their roles in the development of bone-remodeling disorders.BackgroundThe well-coupled bone-formation and bone-resorption processes are vital in bone remodeling. Once the balance is disrupted, bone-remodeling disorders (e.g., osteoporosis and osteopetrosis) occur, severely affecting patients’ quality of life. CircRNAs, the newly discovered members of the non-coding RNA family, have been reported to act as key checkpoints of various signaling pathways that influence osteoblasts and osteoclasts functions, thus regulating the physiological and pathological processes of bone homeostasis.MethodsThree English and three Chinese databases [i.e., PubMed, Embase, MEDLINE (via Ovid), Chinese Biomedical Literature, China National Knowledge Infrastructure, and VIP databases] were searched to June 2021 without language restrictions. Studies exploring the roles of circRNAs in key bone remodeling mediators, such as Smad-dependent bone morphogenetic protein (BMP)/transforming growth factor beta (TGF-β), Wnts, runt-related transcription factor (RUNX), forkhead boxes (FOXs), colony-stimulating factor 1 (CSF-1), receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG), and circRNA-related bone-remodeling disorders, were included.ConclusionsMany circRNAs have been shown to promote osteogenesis and facilitate osteoclast differentiation via diverse mechanisms, and thus modulate the process of bone homeostasis. The imbalance or impairment of these two parts causes diseases, such as osteoporosis, and osteonecrosis of the femoral head, which are also closely correlated to the aberrant presence of circRNAs. Current evidence provides us with promising diagnosis and treatment methods for some bone homeostasis disorders.

IL-18 binding protein suppresses IL-17-induced osteoclastogenesis and rectifies type 17 helper T cell / regulatory T cell imbalance in rheumatoid arthritis

BackgroundPatients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro.MethodsSerum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed.ResultsIL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients’ PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of TRAP, NFATC1, CTSK, and TNFRSF11A (RANK) genes were lower in the IL-18BP treated cells.ConclusionWe showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment.

Ulmoidol, an unusual nortriterpenoid from Eucommia ulmoides Oliv. Leaves prevents neuroinflammation by targeting the PU.1 transcriptional signaling pathway

Chronic neuroinflammation is closely associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). In the current study, 13 anti-neuroinflammatory compounds were isolated from Eucommia ulmoides Oliv. leaves. Among these compounds, trans-sinapaldehyde (6), 3′,4′,5,7-tetrahydroxy-3-methylflavone (7), and amarusine A (13) were isolated from E. ulmoides leaves for the first time. The ursane-type C29-triterpenoid, ulmoidol (ULM, 9), significantly inhibited the production of proinflammatory mediators and reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, ULM inhibited the cluster of differentiation 14 (CD14)/Toll-like receptor 4 (TLR4) signaling pathway and consequently limited the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Notably, electrophoretic mobility shift assay (EMSA) and molecular docking analyses indicated that ULM could prevent PU box binding-1 (PU.1) from binding to DNA, suggesting that PU.1 might be a potential ULM target. In conclusion, ULM alleviates neuroinflammatory responses in microglia, which could be partly explained by its targeting of PU.1 and the resulting suppression of the TLR4/MAPK/NF-κB signaling pathways. These results suggested that ULM may have therapeutic potential as an agent for treating neuroinflammation-related neurodegenerative diseases.