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The inhibitory-kappaB kinases (IKKs) IKKα and IKKβ play central roles in regulating the non-canonical and canonical NF-κB signalling pathways. Whilst the proteins that transduce the signals of each pathway have been extensively characterised, the clear dissection of the functional roles of IKKα-mediated non-canonical NF-κB signalling versus IKKβ-driven canonical signalling remains to be fully elucidated. Progress has relied upon complementary molecular and pharmacological tools; however, the lack of highly potent and selective IKKα inhibitors has limited advances. Herein, we report the development of an aminoindazole-pyrrolo[2,3-b]pyridine scaffold into a novel series of IKKα inhibitors. We demonstrate high potency and selectivity against IKKα over IKKβ in vitro and explain the structure–activity relationships using structure-based molecular modelling. We show selective target engagement with IKKα in the non-canonical NF-κB pathway for both U2OS osteosarcoma and PC-3M prostate cancer cells by employing isoform-related pharmacodynamic markers from both pathways. Two compounds (SU1261 [IKKα Ki = 10 nM; IKKβ Ki = 680 nM] and SU1349 [IKKα Ki = 16 nM; IKKβ Ki = 3352 nM]) represent the first selective and potent pharmacological tools that can be used to interrogate the different signalling functions of IKKα and IKKβ in cells. Our understanding of the regulatory role of IKKα in various inflammatory-based conditions will be advanced using these pharmacological agents. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic autoimmune disease featured by patches on the skin. It is caused by malfunction of immune cells and keratinocytes with inflammation as one of its key features. Apigenin (API) is a natural flavonoid with anti-inflammatory and immunoregulatory properties. Therefore, we speculated that API can ameliorate psoriasis, and determined its effect on the development of psoriasis by using imiquimod (IMQ)-induced psoriasis mouse model. Our results showed that API attenuated IMQ-induced phenotypic changes, such as erythema, scaling and epidermal thickening, and improved splenic hyperplasia. Abnormal differentiation of immune cells was restored in API-treated mice. Mechanistically, we revealed that API is a key regulator of signal transducer activator of transcription 3 (STAT3). API regulated immune responses by reducing interleukin-23 (IL-23)/STAT3/IL-17A axis. Moreover, it suppressed IMQ-caused cell hyperproliferation by inactivating STAT3 through regulation of extracellular signal-regulated kinase 1/2 and nuclear factor-κB (NF-κB) pathway. Furthermore, API reduced expression of inflammatory cytokines through inactivation of NF-κB. Taken together, our study demonstrates that API can ameliorate psoriasis and may be considered as a strategy for psoriasis treatment.

This study evaluated the anti-inflammation effect of the three main short-chain fatty acids (SCFAs) on Acinetobacter baumannii-induced THP-1 cells. The three main SCFAs could inhibit A. baumannii-stimulated THP-1 cell NF-κB pathway activity and the expressions of NLRP3 inflamma-some and GSDMD, and increase autophagy. The three main SCFAs, especially the sodium butyrate (NaB), had the effect of down-regulation of ROS and TLR-2 expression in THP-1 cells. NaB and sodium propionate (NaPc), but not sodium acetate (NaAc), dramatically suppressed IL-1β and IFN-γ expression. The results indicated that NaB and NaPc could significantly inhibit the inflammation of THP-1 cells induced by A. baumannii, and the inhibitory effect was in the order of NaB > NaPc > NaAC. NaB and NaPc may inhibit inflammation through TLR-2/NF-κB/ROS/NLRP3 signaling pathway.

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A myogenetic oligodeoxynucleotide, iSN04, is the 18-base single-stranded DNA that acts as an anti-nucleolin aptamer. iSN04 has been reported to restore myogenic differentiation by suppressing inflammatory responses in myoblasts isolated from patients with diabetes or healthy myoblasts exposed to cancer-releasing factors. Thus, iSN04 is expected to be a nucleic acid drug for the muscle wasting associated with chronic diseases. The present study investigated the anti-inflammatory mechanism of iSN04 in the murine myoblast cell line C2C12. Tumor necrosis factor-α (TNF-α) or Toll-like receptor (TLR) ligands (Pam 3 CSK 4 and FSL-1) induced nuclear translocation and transcriptional activity of nuclear factor-κB (NF-κB), resulting in upregulated expression of TNF-α and interleukin-6. Pre-treatment with iSN04 significantly suppressed these inflammatory responses by inhibiting the nuclear accumulation of β-catenin induced by TNF-α or TLR ligands. These results demonstrate that antagonizing nucleolin with iSN04 downregulates the inflammatory effect mediated by the β-catenin/NF-κB signaling pathway in C2C12 cells. In addition, the anti-inflammatory effects of iSN04 were also observed in the rat smooth muscle cell line A10 and the murine adipocyte-like fibroblast cell line 3T3-L1, suggesting that iSN04 may be useful in preventing inflammation induced by metabolic disorders. • Anti-nucleolin aptamer iSN04 impairs inflammatory responses in myoblast cell line. • iSN04 suppresses nuclear translocation and transcriptional activity of NF-κB. • iSN04 inhibits nuclear accumulation of β-catenin upon inflammatory stimuli. • iSN04 impairs inflammatory responses in smooth muscle and adipocyte-like cell lines. [ABSTRACT FROM AUTHOR]

Geniposide (GEN), a medical herb, is known for its therapeutic applications in cardiovascular diseases, though its efficacy in treating myocardial ischemia/reperfusion injury (MI/RI) is yet to be fully elucidated. This study is an endeavor to explore the potential protective mechanism of GEN against MI/RI. To simulate the MI/RI condition, the left anterior descending artery was occluded for 30 min, followed by a reperfusion period of 120 min in a rat model. Three dosages (50, 100, or 150 mg/kg) of GEN were intraperitoneally injected to the Sprague-Dawley rats once a day, for seven days before the ligation of the artery. The rats were categorized into sham group, MI/RI group, and three different dosages GEN-treated groups. As the results showed, the pretreatment with GEN mitigated myocardial injury, reduced infarct volume, inhibited apoptosis, enhanced superoxide dismutase activity, and decreased malondialdehyde and myeloperoxidase activity, as well as serum creatine kinase-MB and lactate dehydrogenase levels. Moreover, GEN ameliorated MI/RI by downregulating protein expression of toll-like receptor 4, myeloid differentiation primary response 88, and p-nuclear factor-κB. In conclusion, the pretreatment of GEN may be considered as a potential therapeutic option for MI/RI.

ABSTRACT: Ceramide-containing phospholipids improve skin hydration and barrier function and are ideal for use in skin care products. In this study, we evaluated the photoprotective effect of milk phospholipids on the skin condition of UVB-irradiated hairless mice. Skin parameters were assessed following oral administration of milk phospholipids. The UVB irradiation induced photoaging in mice. The animals were divided into 5 groups: a control group (oral administration of saline with no UBV irradiation), UVB group (oral administration of saline with UVB irradiation), and 3 UVB irradiation groups receiving the milk phospholipids at 3 different concentrations of oral administration, 50 mg/kg (ML group), 100 mg/kg (MM group), and 150 mg/kg (MH group), for 8 wk. An increase in skin hydration and transepidermal water loss were improved in the 150 mg/kg of milk phospholipid–administered group. Hematoxylin and eosin staining revealed a decrease in epidermal thickness in the milk phospholipid–administered groups (50, 100, and 150 mg/kg of body weight). In particular, the 100 and 150 mg/kg groups showed significant changes in the area, length, and depth of the wrinkles compared with the UVB group. Moreover, the gene expression of matrix metalloproteins was attenuated, and that of proinflammatory cytokines, especially tumor necrosis factor-α, was significantly reduced in the milk phospholipid–administered groups than in the UVB group. The reduced ceramide and increased sphingosine-1-phosphate levels in the skin tissue due to UVB exposure were restored to levels similar to those of the control group following milk phospholipid administration. These results were confirmed to be due to the downregulation of protein expression of nuclear factor kappa-B (NF-κB) and phosphorylated IκB-α (inhibitor of κB α). Collectively, oral administration of milk phospholipids improves skin health through a synergistic effect on photoprotective activity.

F1012-2, a novel sesquiterpene lactone isolated from the Chinese herbal medicine Eupatorium lindleyanum DC, exhibits an antitumor effect. In this study, we investigated the anticancer activities of F1012-2 on ten human breast cancer lines and demonstrated significantly lower IC50 values for triple-negative breast cancer (TNBC) than for non-TNBC cell lines. The transcription factors p53 and nuclear factor-κB (NF-κB) are important regulators of tumorigenesis. F1012-2 not only depleted mutant p53, but also activated wild-type p53. F1012-2 reduced the expression of phosphorylated p65 and p105 NF-κB family members and coregulated p53, NF-κB members and their dependent targets. To further clarify the key role of p53, lentivirus small hairpin RNA (shRNA) infection was used to knockdown p53 in MDA-MB-231 cells. F1012-2 significantly reduced the inhibitory effect on cell proliferation and apoptosis, while the levels of p53, NF-κB family members and their dependent genes were not significantly different. F1012-2 exhibited a significant antitumor effect and reduced the expression of p53 in MDA-MB-231 xenografts. Taken together, our results show that F1012-2 exhibited an inhibitory effect on TNBC and affected the regulation of p53/NF-κB signaling pathways.

Steroid Receptor Coactivators (SRCs) are essential regulators of transcription with a wide range of impact on human physiology and pathology. In immunology, SRCs play multiple roles; they are involved in the regulation of nuclear factor-κB (NF-κB), macrophage (MΦ) activity, lymphoid cells proliferation, development and function, to name just a few. The three SRC family members, SRC-1, SRC-2 and SRC-3, can exert their immunological function either in an independent manner or act in synergy with each other. In certain biological contexts, one SRC family member can compensate for lack of activity of another member, while in other cases one SRC can exert a biological function that competes against the function of another family counterpart. In this review we illustrate the diverse biological functionality of the SRCs with regard to their role in immunity. In the light of recent development of SRC small molecule inhibitors and stimulators, we discuss their potential relevance as modulators of the immunological activity of the SRCs for therapeutic purposes.

Alcoholic liver disease (ALD) regarding to liver damage caused by alcohol abuse is characterized by chronic liver inflammation, with dysregulations of the gut microbiota and its metabolites. Accumulating studies has demonstrated that butyrate exhibits pleitropic benefits in chronic metabolic diseases. The present study was designed to investigate the effects and mechanisms of butyrate on ALD. In vivo, C57BL/6J mice were fed with isocaloric modified Lieber-DeCarli liquid diets with or without ethanol which supplemented with sodium butyrate (NaB, 0.6 g/kg) for 6 weeks. In vitro, murine macrophage RAW264.7 were pretreated with NaB or G protein coupled receptor (GPR) 43 antagonist to verify the specific mechanism of NaB effectiveness in LPS-induced inflammatory response. Finally, the routine indexes indicated that NaB treatment significantly alleviated liver injury and lipid deposition, as well as inflammation in ALD mice. On the other hand, M2 macrophage (Mψ) along with its representative enzyme Arg-1, were significantly elevated, whereas M1 Mψ coupled with its marker enzyme iNOS, showed decreased after NaB intervention. Moverover, the expressions of Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), nod-like receptor protein 3 (NLRP3) and caspase-1 were notably decreased with NaB intervention. Intriguingly, the inhibition of GPR43 signals impaired the anti-inflammation effects of NaB. And our further research found that NaB supplementation not only increased the expressions of GPR43 and β-arrstine2 (ARRB2), but also strengthened the interactions between ARRB2 and NLRP3/TAK1 binding protein 1 (TAB1). These results indicated that butyrate may ameliorate ALD by means of modulating Mψ polarization and suppressing LPS-TLR4-NF-κB/NLRP3 axis via mediating GPR43-ARRB2 signaling pathway.

Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It is of great significance to identify their shared key regulatory molecules and thus explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model in mice, we reported an elevated expression of PDCD4 both in injured neurons and activated microglia of the inflamed brain. A similar change in PDCD4 expression was observed in vitro in the microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear translocation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPK/NF-κB signaling activation to boost PDCD4 expression in microglia, indicating the presence of a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic proteins BAX and Cleaved-PARP, suggesting the proapoptotic activity of PDCD4 in neurons. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4–MAPK–NF-κB positive feedback loop may act as pivotal signaling for neuroinflammation which subsequently exaggerates neuronal injury, and thus may become a potential therapeutic target for neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is one of the widely used anti-tumor drugs. However, DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) are among the side effects that limited its therapeutic efficiency and clinical applicability. This study aimed to investigate the cardioprotective and hepatoprotective potentials of curcumin (CMN)—a bioactive polyphenolic compound—in alleviating DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) in male rats. A single intraperitoneal (i.p.) dose of DOX (20 mg/kg) was used to induce DIC and DIH. DOX-intoxicated rats were co-treated with CMN (100 mg/kg, oral) for 10 days before and 5 days after a single dose of DOX. We studied the anti-inflammatory and anti-oxidative activities of CMN on biochemical and immunohistochemical aspects. DOX disrupted cardiac and hepatic functions and stimulated oxidative stress and inflammation in both tissues that was confirmed biochemically and immunohistochemically. DOX enhanced inflammatory interferon-gamma (IFN-γ) and upregulated immunoexpression of nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNF-α). DOX induced structural alterations in both cardiac and hepatic tissues. CMN demonstrated cardioprotective potential through reducing cardiac troponin I (cTn1) and aspartate amino transaminase (AST). In addition, CMN significantly ameliorated liver function through decreasing alanine amino transaminase (ALT) and, gamma-glutamyl transferase (GGT), total cholesterol (TC), and triglycerides (TG). CMN demonstrated anti-inflammatory potential through decreasing IFN-γ levels and immunoexpression of iNOS, NF-κB, and TNF-α. Histopathologically, CMN restored DOX-associated cardiac and liver structural alterations. CMN showed anti-oxidative and anti-inflammatory potentials in both the cardiac and hepatic tissues. In addition, cTn1, IFN-γ, and AST could be used as blood-based biomarkers. [ABSTRACT FROM AUTHOR]

Objective·To explore the expression characteristics of silent information regulator transcript 1 (SIRT1) in intestinal tissues of necrotizing enterocolitis (NEC), and preliminarily discuss the effect and possible mechanisms of SIRT1 in NEC. Methods·From June 2018 to October 2020, 80 children with NEC who were treated by neonatal surgery in the Children's Hospital, Zhejiang University School of Medicine were divided into observation group and control group. The tissue samples of the observation group were inflammatory necrotic intestinal tubes, while those of the control group were incised intestinal tubes. The NEC children in the control group were with intestinal strictures after conservative treatment, and then were treated by surgery again. The clinical data of the two groups were collected 24 h before surgery, including procalcitonin (PCT), hypersensitive C reactive protein (hs-CRP), cytokines [interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)] in the serum, gender, gestational age and so on. The expression characteristics of SIRT1, nuclear factor-κB (NF-κB), transforming growth factor β1 (TGF-β1) and Smad3 proteins of the tissues in the two groups were detected by immunohistochemistry. IEC-6 cells of small intestinal epithelium of SD female rats were cultured in vitro. After SIRT1 expression in IEC-6 cells was inhibited by small interfering RNA (siRNA) technology, the protein expression of NF-κB was detected by Western blotting and the effects of SIRT1 on IEC-6 cells were detected by Cell Counting Kit-8 (CCK8) and Transwell migration assay. Results·There was no significant difference in gender, gestational age, birth weight and delivery mode between the two groups. Compared with the control group, the levels of hs-CRP, PCT, IL-6 and IL-10 in the serum in the observation group increased within 24 h before surgery (all P=0.000). Compared with the margin tissues of narrow intestines in the control group, the positive expression of SIRT1 in NEC necrotic intestinal tissues in the observation group showed low expression, and the positive expression of NF-κB was overexpressed (both P=0.000). There was no significant difference in the expression of Smad3 and TGF-β1 between the two groups. The expression of SIRT1 in NEC necrotic intestinal tissue was negatively correlated with the expression of NF-κB (r=-0.592, P=0.000). After inhibiting the mRNA and protein expression of SIRT1, the relative expression of NF-κB in IEC-6 cells was increased, and the proliferation and migration ability of the cells was significantly decreased. Conclusion·The mechanism for the SIRT1 reducing progression of NEC may be that SIRT1 can inhibit the expression of NF-κB to reduce the expression of inflammatory factors in NEC, and another possible mechanism may be that SIRT1 can protect intestinal epithelial cells by promoting cell proliferation and migration. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a major age-related disease, which may be caused by the accumulation of advanced glycation end-products (AGEs). Excessive degradation of type II collagen and aggrecan by matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS) induced by AGEs is a pivotal event in the pathogenesis of osteoarthritis. In addition, activation of the nuclear factor-κB (NF-κB) pathway induces the expression of a cascade of proinflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). In the present study, we investigated the effects of salicin, one of the main constituents of aspirin and a derivative of Alangium chinense, on AGE-induced degradation of the articular extracellular matrix in SW1353 human chondrocytes. Our findings reveal a novel beneficial role of salicin in rescuing degradation of type II collagen and aggrecan, reducing oxidative stress, attenuating expression of proinflammatory cytokines, and inhibiting activation of the NF-κB proinflammatory signaling pathway in chondrocytes stimulated with AGEs. Salicin may thus have potential as a safe and effective therapy against the development and progression of OA.

Periodontitis is the sixth most prevalent diseases around the globe, which is closely related to many systemic diseases and affects general health. As the leading cause of tooth loss, periodontitis is characterized by irreversible alveolar bone loss and activated osteoclastogenic process, which might be closely related to the activated intracellular reactive oxygen species (ROS) in osteoclasts. Here, we demonstrated triggering receptor expressed on myeloid cells 2 (Trem2) as a key regulator of osteoclastogenesis with the regulation of intracellular ROS signals in periodontitis. In the present study, the expression of Trem2 was significantly upregulated in human alveolar bones diagnosed with chronic periodontitis, as assessed by RNA-seq. In the mice model of periodontitis, the alveolar bone resorption was impeded in the presence of the conditional knockout of Trem2 in osteoclasts. Furthermore, we identified Trem2/DAP12/Syk-dependent cascade as a vital intracellular signaling for the amplification of reactive oxygen species (ROS) signals in osteoclastogenesis, while the accumulation of soluble Aβ42 oligomers (Aβo) in periodontitis microenvironment further strengthened the signals and enhanced osteoclastogenesis through direct interactions with Trem2. Collectively, Trem2 mediated ROS signal amplification cascade was crucial in the process of osteoclastogenesis in periodontitis, suggesting the potential of Trem2 as a target for the prevention and treatment of bone destruction in periodontitis.

The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson’s disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

Abstract Background Our previous studies demonstrated that eyes absent homolog 4 (EYA4), a member of the eye development-related EYA family in Drosophila, is frequently methylated and silenced in hepatocellular carcinoma (HCC) specimens and associated with shorter survival. The current work aimed to explore the mechanisms through which EYA4 functions as a tumor suppressor in HCC. Methods Stable EYA4-expressing plasmid (pEYA4) transfectants of the human HCC cell lines Huh-7 and PLC/PRF/5 (PLC) were established. Xenografts tumors were established via subcutaneous injection of the stable transfectants into BALB/c nude mice. Tissue samples were obtained from 75 pathologically diagnosed HCC patients. Quantitative real-time polymerase chain reaction, Western blotting and immunohistochemistry were performed to determine the expression of EYA4 in cell lines, xenografts and clinical specimens. The cell proliferation, colony formation, invasiveness and tumor formation of stable transfectants were studied. A gene expression microarray was utilized to screen genes regulated by EYA4 expression. The effect of EYA4 on nuclear factor-κB (NF-κB)/RAS-related protein 1 (RAP1) signaling was demonstrated through the co-transfection of pEYA4 and Flag-tagged RAS-related protein 1A gene-expressing plasmid (Flag-RAP1A), functional studies, chromatin immunoprecipitation, immunofluorescence staining and cellular ubiquitination assay. Results The restoration of EYA4 expression in HCC cell lines suppressed cell proliferation, inhibited clonogenic outgrowth, reduced cell invasion and restrained xenograft tumor growth, and Flag-RAP1A reversed the suppressive effects of pEYA4 in vitro. Activation of NF-κB with tumor necrosis factor-α (TNF-α) increased the binding of p65 to the RAP1A gene promoter and up-regulated RAP1 protein expression. The inhibition of NF-κB with BAY 11-7085 and p65 siRNA successfully blocked TNF-α-induced RAP1 up-regulation. EYA4 antagonized the TNF-α-induced phosphorylation and ubiquitination of inhibitor of NF-κBα (IκBα) as well as the nuclear translocation and transactivation of p65, resulting in repressed NF-κB activity and RAP1 expression. Blocking the serine/threonine phosphatase activity of EYA4 with calyculin A notably abrogated its suppressive effect on NF-κB activity. In addition, EYA4 expression was inversely correlated with IκBα/RAP1 activity in clinical HCC specimens. Conclusion Our findings provide a functional and mechanistic basis for identifying EYA4 as a bona fide tumor suppressor that disrupts aberrant activation of the NF-κB/RAP1 signaling pathway and thus orchestrates a physiological impediment to HCC growth and invasion.

Background: The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor is a key regulator of cell survival, proliferation, and gene expression. Although activation of NF-κB signaling in thyroid follicular cells after thyrotropin (TSH) receptor (TSHR) engagement has been reported, the downstream signaling leading to NF-κB activation remains unexplored. Here, we sought to elucidate the mechanisms that regulate NF-κB signaling activation in response to TSH stimulation. Methods: Fisher rat-derived thyroid cell lines and primary cultures of NF-κB essential modulator (NEMO)-deficient mice thyrocytes were used as models. Signaling pathways leading to the activation of NF-κB were investigated by using chemical inhibitors and phospho-specific antibodies. Luciferase reporter gene assays and site-directed mutagenesis were used to monitor NF-κB-dependent gene transcriptional activity and the expression of thyroid differentiation markers was assessed by reverse transcription quantitative polymerase chain reaction and Western blot, respectively. Chromatin immunoprecipitation (ChIP) was carried out to investigate NF-κB subunit p65 DNA binding, and small interfering RNA (siRNA)-mediated gene knockdown approaches were used for studying gene function. Results: Using thyroid cell lines, we observed that TSH treatment leads to protein kinase C (PKC)-mediated canonical NF-κB p65 subunit nuclear expression. Moreover, TSH stimulation phosphorylated the kinase TAK-1, and its knockdown abolished TSH-induced NF-κB transcriptional activity. TSH induced the transcriptional activity of the NF-κB subunit p65 in a protein kinase A (PKA)-dependent phosphorylation at Ser-276. In addition, p65 phosphorylation at Ser-276 induced acetyl transferase p300 recruitment, leading to its acetylation on Lys-310 and thereby enhancing its transcriptional activity. Evaluation of the role played by NF-κB in thyroid physiology demonstrated that the canonical NF-κB inhibitor BAY 11-7082 reduced TSH-induced expression of thyroid differentiation markers. The involvement of NF-κB signaling in thyroid physiology was confirmed by assessing the TSH-induced gene expression in primary cultures of NEMO-deficient mice thyrocytes. ChIP and the knockdown experiments revealed that p65 is a nuclear effector of TSH actions, inducing the transcripcional expression of thyroid differentiation markers. Conclusions: Taken together, our results point to NF-κB being a pivotal mediator in the TSH-induced thyroid follicular cell differentiation, a relevant finding with potential physiological and pathophysiological implications. [ABSTRACT FROM AUTHOR]

Objectives: Interferons (IFNs) play multifunctional roles in host defense against infectious diseases by inducing IFN-stimulated genes (ISGs). However, little is known about how ISGs regulate host immune response to Mycobacterium tuberculosis (Mtb) infection, the major cause of tuberculosis (TB).Methods: We thus profiled the potential effects and mechanisms of eight Mtb-induced ISGs on Mtb infection by RNA interference in human macrophages (Mφs) derived from peripheral blood monocytes (hMDMs) and THP-1 cell line derived Mφs (THP-1-Mφs).Results: MxA silencing significantly decreased intracellular Mtb infection in Mφs. Mechanistically, MxA silencing promoted inflammatory cytokines IL-1β, IL-6 and TNF-α production, and induced NF-κB p65 activation. Pharmacological inhibition of NF-κB p65 activation or gene silencing of NF-κB p65 blocked the increased production of IL-1β, IL-6 and TNF-α and restored Mtb infection by MxA silencing. Furthermore, pharmacological inhibition of TAK1 and IKKα/β blocked NF-κB p65 activation and subsequent production of pro-inflammatory cytokines by MxA silencing. Isoniazid (INH) treatment and MxA silencing could promote TAK1-IKKα/β-NF-κB signaling pathway activation and combat Mtb infection independently.Conclusions: Our results reveal a novel role of MxA in regulating TAK1-IKKα/β-NF-κB signaling activation and production of antimicrobial inflammatory cytokines upon Mtb infection, providing a potential target for clinical treatment of TB. [ABSTRACT FROM AUTHOR]

The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder. [ABSTRACT FROM AUTHOR]

Cimicifugae Rhizoma has been used as a medicinal herb for fever, pain, and inflammation in East Asia. We conducted this study because the effect of Cimicifugae Rhizoma extract (CRE) on allergic asthma has not yet been evaluated. To induce allergic airway inflammation, we intraperitoneally injected ovalbumin (OVA) mixed with aluminum hydroxide into mice twice at intervals of 2 weeks (Days 0 and 14) and then inhaled them thrice with 1% OVA solution using a nebulizer (Days 21 to 23). CRE (30 and 100 mg/kg) was administered orally daily for 6 days (Days 18 to 23). The mice showed remarkable reduction in allergic inflammation at 100 mg/kg of CRE, as evidenced by decreased inflammatory cell counts, pro-inflammatory cytokine levels, OVA-specific immunoglobulin E level, airway hyperresponsiveness, and production of mucus. Additionally, these effects were involved with the enhancement of heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase (NQO1), and nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduction of nuclear factor-κB (NF-κB) phosphorylation and matrix metalloproteinase-9 expression. Our findings indicated that CRE effectively protected against OVA-induced inflammation and oxidative stress via upregulation of the Nrf2/HO-1/NQO1 signaling and downregulation of NF-κB phosphorylation in asthma caused by OVA.

Osteoarthritis (OA) is a common joint disease for which a safe and reliable treatment has yet to be developed. Here, we demonstrated the potential benefit of treatment with paeonol, a derivative of Paeonia suffruticosa, in the treatment and prevention of OA. Chondrogenic cell line ATDC5 cells were cultured with IL-1β and the effects of paeonol were assessed through qRT-PCR, western blot analysis, MTT, ELISA, and NF-κB luciferase reporter gene assay. Our findings demonstrate a novel ability of paeonol to inhibit numerous factors of OA, including expressions of IL-6, TNF-α, NOX2, PTGS2, NUCB2/nesfatin-1, ICAM-1, VCAM-1, MMP-3/13, degradation of type II collagen, and NF-κB activation through the rescue of IκBα. Additionally, we assessed the effects of paeonol on cell viability to confirm its safety. These findings implicate a valuable potential role of paeonol in the treatment and prevention of OA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: MicroRNA-16 (miR- 16) expression has been proved to take part in the initiation and development of several cancers, including hepatocellular carcinoma (HCC). However, its role and its molecular mechanism in HCC cells remain unclear. Our study aimed to elucidate miR-16 probable role and potential mechanism in HCC cells. PATIENTS AND METHODS: MiR-16 expression in HCC was measured by Real Time-Polymerase Chain Reaction (RT-PCR). MiR-16 mimic or inhibitor was applied to increase or decrease miR-16 expression in Huh7 cells separately. The cell viability was measured by MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide). The invaded cells and migrated cells were detected by the transwell assay. The epithelial- mesenchymal transition (EMT) and the nuclear factor-κB (NF-κB) were performed using Western blot. The tumor growth was measured via xenograft tumor formation assay. Moreover, bioinformatical methods and luciferase reporter assay were carried out to confirm the miR-16 target gene. RESULTS: MiR-16 expression was downregulated in HCC tissues and cells. Furthermore, the increasing miR-16 expression was suppressed, whereas the decreasing miR-16 expression promoted cell proliferation, invasion, and migration in Huh7 cells. Moreover, miR-16 targeted FEAT in regulating HCC progression. FEAT was associated with a poor prognosis of HCC patients. Especially, miR-16 suppressed EMT and NF-κB pathway in HCC and inhibited the tumor growth in vivo. CONCLUSIONS: We stated that miR-16 suppressed HCC cell progression by targeting FEAT and inhibiting EMT and NF-κB pathway. MiR-16 may be clinically utilized as a factor for the clinical diagnosis and prognosis of HCC. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a major age-related disease, which may be caused by the accumulation of advanced glycation end-products (AGEs). Excessive degradation of type II collagen and aggrecan by matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS) induced by AGEs is a pivotal event in the pathogenesis of osteoarthritis. In addition, activation of the nuclear factor-κB (NF-κB) pathway induces the expression of a cascade of proinflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). In the present study, we investigated the effects of salicin, one of the main constituents of aspirin and a derivative of Alangium chinense, on AGE-induced degradation of the articular extracellular matrix in SW1353 human chondrocytes. Our findings reveal a novel beneficial role of salicin in rescuing degradation of type II collagen and aggrecan, reducing oxidative stress, attenuating expression of proinflammatory cytokines, and inhibiting activation of the NF-κB proinflammatory signaling pathway in chondrocytes stimulated with AGEs. Salicin may thus have potential as a safe and effective therapy against the development and progression of OA. [ABSTRACT FROM AUTHOR]

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Mangiterpenes A–C and 2′,3′- seco -manginoid C, four undescribed sesquiterpene/monoterpene–shikimate–conjugated meroterpenoids with spiro ring systems, were isolated from Guignardia mangiferae. The structures and absolute configurations of these compounds were established by comprehensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Mangiterpenes A–C represent the first examples of sesquiterpene–shikimate-conjugated spirocyclic meroterpenoids, and 2′,3′- seco -manginoid C features an unexpected 2′,3′- seco -manginoids skeleton. Mangiterpene C strongly inhibited the production of NO inducted by LPS, with an IC 50 value of 5.97 μ M. It showed an anti-inflammatory effect by means of blocking in the NF-κB signaling pathway and decreasing the expression of inflammatory mediators. Four undescribed sesquiterpene/monoterpene–shikimate–conjugated meroterpenoids with spiro ring systems were isolated from Guignardia mangiferae. Image 1 • Four undescribed meroterpenoids were isolated from Guignardia mangiferae. • Mangiterpenes A–C are sesquiterpene–shikimate-conjugated spirocyclic meroterpenoids. • Mangiterpene C strongly inhibited the production of NO inducted by LPS (IC 50 = 5.97 μ M). [ABSTRACT FROM AUTHOR]

Osteoclasts (OCs) are multinuclear giant cells responsible for bone resorption, and an excessive bone resorption by OCs plays an important role in osteoporosis. Commonly used drugs for the treatment of osteoporosis have severe side effects. As such, identification of alternative treatments is essential. Garcinol, a polyisoprenylated benzophenone extracted from the fruit of Garcinia indica, has shown a strong antitumor effect through the nuclear factor‐κB (NF‐κB) and mitogen‐associated protein kinases (MAPK) signaling pathways. However, the role of garcinol in the osteoclastogenesis is still unclear. Here, we demonstrated that garcinol can inhibit the receptor activator of NF‐κB ligand (RANKL)‐induced osteoclastogenesis, osteoclastogenesis‐related gene expression, the f‐actin ring, and resorption pit formation. In addition, garcinol abrogated RANKL‐induced osteoclastogenesis by attenuating the degradation of the MAPK, NF‐κB, and PI3K‐AKT signaling pathway as well as downstream factors c‐jun, c‐fos, and NFATC1. In vivo, suppression of osteoclastogenesis by garcinol was evidenced by marked inhibition of lipopolysaccharide‐induced bone resorption. In conclusion, our data demonstrated that garcinol inhibited the RANKL‐induced osteoclastogenesis by suppressing the MAPK, NF‐κB, and PI3K‐AKT signaling pathways and thus has potential as a novel therapeutic option for osteolytic bone diseases. Garcinol suppresses osteoclast (OCs) formation and function in vitro. Garcinol impairs the receptor activator for the nuclear factor‐κB ligand (RANKL)‐induced mitogen‐associated protein kinases (MAPK), nuclear factor‐κB (NF‐κB), and AKT signaling pathway. Garcinol suppresses osteolysis in vivo. Garcinol may be a new therapeutic option for osteolytic bone diseases [ABSTRACT FROM AUTHOR]

Excessive bone resorption by osteoclasts (OCs) plays an important role in lytic bone diseases, such as osteoporosis. Although the pharmacological treatment of osteoporosis has been extensively developed, alternative treatments are still needed. Deguelin, a rotenoid isolated from several plant species, is a strong antitumor agent; however, its effect on OCs remains unclear. To the best of our knowledge, this is the first study to report that deguelin inhibits the receptor activator of nuclear factor‐κB (NF‐κB) ligand (RANKL)‐induced osteoclastogenesis, messenger RNA expression of osteoclastic‐specific genes, and osteoclastic bone resorption, in primary bone marrow‐derived macrophages. At the molecular level, deguelin markedly blocked RANKL‐induced osteoclastogenesis by attenuating the phosphorylation of NF‐κB p65 and inhibiting p65 nuclear translocation. In addition, deguelin suppressed the downstream expression of nuclear factor of activated T‐cell cytoplasmic 1, which is a crucial transcription factor in OC differentiation. Consistent with the in vitro results, deguelin inhibited lipopolysaccharide‐induced bone resorption by suppressing osteoclastogenesis. Taken together, our findings reveal that deguelin has antiosteoclastic effects in vitro and in vivo and possesses potential as a new therapeutic option for osteolytic bone diseases. Deguelin suppresses osteoclast formation and function in vitro. Deguelin impairs the receptor activator of nuclear factor‐κB (NF‐κB) ligand (RANKL)‐induced NF‐κB signaling pathway. Deguelin suppresses osteolysis in vivo. Deguelin may be used for treating osteoclast‐related diseases. [ABSTRACT FROM AUTHOR]

Excessive release of inflammatory cytokines and oxidative stress (OS) are triggering factors in the onset of chronic diseases. One of the factors that can ensure health in humans is regular physical activity. This type of activity can enhance immune function and dramatically prevent the spread of the cytokine response and OS. However, if physical activity is done intensely at irregular intervals, it is not only unhealthy but can also lead to muscle damage, OS, and inflammation. In this review, the response of cytokines and OS to exercise is described. In addition, it is focused predominantly on the role of reactive oxygen and nitrogen species (RONS) generated from muscle metabolism and damage during exercise and on the modulatory effects of antioxidant supplements. Furthermore, the influence of factors such as age, sex, and type of exercise protocol (volume, duration, and intensity of training) is analyzed. The effect of antioxidant supplements on improving OS and inflammatory cytokines is somewhat ambiguous. More research is needed to understand this issue, considering in greater detail factors such as level of training, health status, age, sex, disease, and type of exercise protocol.

The activation of the nuclear factor-κB (NF-κB) pathway plays a central role in the initiation and progression of inflammation, which contributes to the pathogenesis and progression of various human diseases including kidney, brain, and other diseases. Tissue plasminogen activator (tPA), a serine protease regulating homeostasis of blood coagulation, fibrinolysis, and matrix degradation, has been shown to act as a cytokine to trigger profound receptor-mediated intracellular events, modulate the NF-κB pathway, and mediate organ dysfunction and injury. In this review, we focus on the current understanding of NF-κB and tPA signaling in the development and progression of kidney disease. Their roles in the nervous and cardiovascular system are also briefly discussed.

Cardiovascular diseases (CVDs) are closely linked to cellular oxidative stress and inflammation. This may be resulted from the imbalance generation of reactive oxygen species and its role in promoting inflammation, thereby contributing to endothelial dysfunction and cardiovascular complications. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a significant role in regulating expression of antioxidant and cytoprotective enzymes in response to oxidative stress. Natural products have emerged as a potential source of bioactive compounds which have shown to protect against atherogenesis development by activating Nrf2 signaling. This review aims to provide a comprehensive summary of the published data on the function, regulation and activation of Nrf2 as well as the molecular mechanisms of natural products in regulating Nrf2 signaling. The beneficial effects of using natural bioactive compounds as a promising therapeutic approach for the prevention and treatment of CVDs are reviewed.

Acute lung injury (ALI) is one of the most common high-risk diseases associated with a high mortality rate and is still a challenge to treat effectively. Netrin-1 (NT-1) is a novel peptide with a wide range of biological functions, however, its effects on ALI have not been reported before. In this study, an ALI model was constructed using lipopolysaccharide (LPS) and treated with NT-1. Pulmonary function and lung wet to dry weight ratio (W/D) were detected. The expressions of pro-inflammatory cytokines and chemokines interleukin-8 (IL-8), interleukin-1β (IL-1β), and chemokine (C-X-C motif) ligand 2 (CXCL2) were measured using real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We found that the levels of NT-1 were reduced in the LPS-induced ALI mice model. Administration of NT-1 improved histopathological changes of lung tissues and lung function in LPS-challenged ALI mice. We also report that NT-1 decreased Myeloperoxidase (MPO) activity and ameliorated pulmonary edema. Additionally, treatment with NT-1 reduced the levels of pro-inflammatory cytokines and chemokines such as IL-8, IL-1β, and CXCL2 in lung tissues of LPS-challenged ALI mice. Importantly, NT-1 reduced cell count in BALF and mitigated oxidative stress (OS) by reducing the levels of MDA and increasing the levels of GSH. Mechanistically, it is shown that NT-1 reduced the levels of Toll-like receptor 4 (TLR4) and prevented nuclear translocation of nuclear factor-κB (NF-κB) p65. Our findings indicate that NT-1 is a promising agent for the treatment of ALI through inhibiting TLR4/NF-κB signaling.

Spinal cord injury (SCI), a public health problem caused by mechanical injury, leads to secondary excessive inflammatory reactions and long-term damage to neurological function. ACY1215 is a highly selective histone deacetylase 6 (HDAC6) inhibitor and reportedly has anti-inflammatory effects; however, its regulatory role in SCI has not been studied. The purpose of this study was to explore the role of ACY1215 in preventing inflammation, inhibiting astrogliosis, enhancing remyelination and preserving axons after spinal cord injury and further exploring the possible cellular signaling pathways involved. First, lipopolysaccharide (LPS) was utilized to stimulate rat astrocytes in vitro. Quantitative RT (qRT)-PCR and Western blotting showed that ACY1215 inhibited the expression of glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) in LPS-activated astrocytes. In addition, Western blotting results showed that ACY1215 could inhibit the signal transduction pathway of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3). In vivo, ACY1215 could exert anti-inflammatory effects by inhibiting the expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Moreover, ACY1215 repaired spinal cord injury by reducing the formation of glial scars and promoting remyelination and nerve recovery. In summary, ACY1215 can inhibit the NF-κB and STAT3 signaling pathways in astrocytes, reduce inflammation and ameliorate SCI. Our results provide a novel strategy for the treatment of SCI.

Siweixizangmaoru decoction (SXD) is widely used as an anti-rheumatoid arthritis (RA) in Tibet, however, the specific anti-inflammatory mechanism of SXD is still unclear. This research attempts to examine the efficacy and possible mechanisms of SXD in treating RA. The primary chemical components of SXD were identified using UHPLC-Q-Exactive Orbitrap MS. We established a lipopolysaccharide (LPS)-induced RAW264.7 macrophage inflammatory injury model to explore the anti-inflammatory mechanism of SXD and validated it through in vivo experiments. According to our research in vitro as well as in vivo, SXD exhibits anti-inflammatory qualities. SXD can suppress nitric oxide (NO) and pro-inflammatory factor production in RAW264.7 cells activated by LPS. The mechanism underlying this effect might be connected to the janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2/STAT3) and nuclear factor-κB (NF-κB) signaling pathways. In vivo, SXD alleviates joint swelling, decreases the generation of inflammatory factors in the serum, lowers oxidative stress, and improves joint damage. In short, SXD improves joint degeneration and lowers symptoms associated with RA by regulating inflammation via the suppression of NF-κB and JAK2/STAT3 signaling pathway activation.

Abstract Evidence indicates that inflammation plays a crucial role in depression. Therefore, new antidepressants might be identified by screening drugs for their anti-inflammatory actions. Sertraline hydrochloride (SERT), a widely used antidepressant, has anti-inflammatory effects in clinical studies, but the mechanism involved is unclear. In this study, we used cell and molecular biology to determine the possible anti-inflammatory mechanism of SERT in vivo and in vitro. Experimental data from the in vivo study showed that mice exposed to chronic unpredictable mild stress (CUMS) had significantly higher levels of major inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β] and inducible nitric oxide synthase [iNOS]) in peripheral and central tissues compared with the control group. Treatment of CUMS mice with SERT significantly reduced the levels of these inflammatory cytokines and inhibited the phosphorylation of nuclear factor-κB (NF-κB) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). Moreover, SERT reduced serum levels of transaminase in CUMS mice. Our in vitro study revealed that SERT suppressed TNF-α-induced NF-κB activation in a dose-dependent manner. SERT also inhibited the TNF-α-induced nuclear translocation of NF-κB by inhibiting IκB-α phosphorylation. Furthermore, SERT inhibited TNF-α-induced inflammatory cytokines in BV2 microglia cells. SERT directly bound to TNF-α and TNF-α receptor 1 (TNFR1) to potently block TNF-α/TNFR1-triggered signaling. These results indicate that SERT might treat depression by inhibiting the activation of microglia via the NF-κB signaling pathway. This study provides a basis for the research and development of antidepressants that act to reduce inflammation and the expression of inflammatory mediators. Highlights • Sertraline ameliorated microglia cell activation. • Sertraline has anti-inflammatory effects by blocking TNF-α induced NF-κB signaling. • Sertraline ameliorated CUMS-induced the liver-brain inflammation axis. • Sertraline directly binds to TNF-α and TNFR1. [ABSTRACT FROM AUTHOR]

A new benzofuran, methyl (2S,2″S,3′E)-[2-(1″-acetoxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl]acrylate (1), and 13 known compounds (2-14) were isolated from an ethanol extract of Artemisia halodendron Turcz. ex Bess. The chemical structures of these compounds were determined by 1D and 2D NMR (1H-1H COSY, HMBC, HMQC and NOESY) and HR-ESI-MS spectra, and results were compared with data from the literature. The effects of compounds 1-14 were measured on NF-κB activation, with compounds 2 and 3 exhibiting inhibitory activities against TNF-α-induced NF-κB reporter gene expression in HeLa cells from 10 to 100 μM. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are closely linked to cellular oxidative stress and inflammation. This may be resulted from the imbalance generation of reactive oxygen species and its role in promoting inflammation, thereby contributing to endothelial dysfunction and cardiovascular complications. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a significant role in regulating expression of antioxidant and cytoprotective enzymes in response to oxidative stress. Natural products have emerged as a potential source of bioactive compounds which have shown to protect against atherogenesis development by activating Nrf2 signaling. This review aims to provide a comprehensive summary of the published data on the function, regulation and activation of Nrf2 as well as the molecular mechanisms of natural products in regulating Nrf2 signaling. The beneficial effects of using natural bioactive compounds as a promising therapeutic approach for the prevention and treatment of CVDs are reviewed. [ABSTRACT FROM AUTHOR]

Abstract Abnormal reduction of extracellular matrix (ECM), including type II collagen and aggrecan, caused by tumor necrosis factor-α (TNF-α) is an important pathological feature of osteoarthritis (OA). Shikimic acid (SA), derived from natural plants, has displayed effective pharmacological properties in diverse diseases. The biological roles of SA in OA have not been reported before. Here, we found that treatment with SA (1 mM, 10 mM) prevented TNF-α-induced degradation of type II collagen and aggrecan ECM in human primary chondrocytes culture in vitro. Importantly, we also reported that SA treatment reduced TNF-α-induced expression of matrix metalloproteinase‑1, ‑3, and ‑13 (MMP‑1, ‑3, and ‑13) and increased expression of tissue inhibitor of metalloproteinase‑1 and ‑2 (TIMP‑1, ‑2). Additionally, SA treatment attenuated TNF-α-induced expression of a disintegrin and metalloprotease‑4 and ‑5 (ADAMTS‑4, ‑5). Mechanistically, we found that SA prevented activation of the nuclear factor-κB (NF‑κB) pathway. Our findings suggest that SA might act as an important therapeutic agent in the treatment of OA. Highlights • SA ameliorated TNF-α-induced degradation of type II collagen and aggrecan. • SA reduced MMP‑1, ‑3, ‑13, ADAMTS‑4, ‑5 but increased TIMP‑1 and TIMP‑2. • SA attenuated TNF-α-induced activation of the IκBα/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

In this study we isolate a heptameric peptide from the marine microalga Pavlova lutheri and examine its inhibitory effect and mechanism of action on the matrix metalloproteinase-9 (MMP-9) protein in human fibrosarcoma HT1080 cells. Through consecutive rounds of purification we isolated a potent MMP-9 inhibitory peptide composed of seven amino acids: Leu-Leu-Ala-Pro-Pro-Glu-Arg (796.4 Da). We show that the mRNA and protein expression levels of MMP-9 are reduced in the presence of this purified peptide. Furthermore, we show that this peptide inhibits PMA-induced translocation of nuclear factor-κB (NF-κB) by suppressing IκB-α phosphorylation and that it suppresses the phosphorylation of the c-Jun N-terminal (JNK) and p38 mitogen-activated protein kinases (MAPKs). Our results indicate that this peptide, purified from P. lutheri, has the potential to be a valuable natural preventive agent against MMP-related diseases. [ABSTRACT FROM AUTHOR]

Porcine epidemic diarrhea virus (PEDV) is a highly infectious pathogen that can cause severe diseases in pigs and result in enormous economic losses in the worldwide swine industry. Previous studies revealed that PEDV exhibits an obvious capacity for modulating interferon (IFN) signaling or expression. The newly discovered type III IFN, which plays a crucial role in antiviral immunity, has strong antiviral activity against PEDV proliferation in IPEC-J2 cells. In this study, we aimed to investigate the effect of PEDV nucleocapsid (N) protein on type III IFN-λ. We found that the N proteins of ten PEDV strains isolated between 2013 and 2017 from different local farms shared high nucleotide identities, while the N protein of the CV777 vaccine strain formed a monophyletic branch in the phylogenetic tree. The N protein of the epidemic strain could antagonize type III IFN, but not type I or type II IFN expression induced by polyinosinic-polycytidylic acid (poly(I:C)) in IPEC-J2 cells. Subsequently, we demonstrated that the inhibition of poly(I:C)- induced IFN-λ3 production by PEDV N protein was dependent on the blocking of nuclear factor-κB (NF-κB) nuclear translocation. These findings might help increase understanding of the pathogenesis of PEDV and its mechanisms for evading the host immune response. [ABSTRACT FROM AUTHOR]

Sea tangle (Laminaria japonica Aresch), a brown alga, has been used for many years as a functional food ingredient in the Asia-Pacific region. In the present study, we investigated the effects of fermented sea tangle extract (FST) on receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-stimulated osteoclast differentiation, using RAW 264.7 mouse macrophage cells. FST was found to inhibit the RANKL-stimulated activation of tartrate-resistance acid phosphatase (TRAP) and F-actin ring structure formation. FST also down-regulated the expression of osteoclast marker genes like TRAP, matrix metalloproteinase-9, cathepsin K and osteoclast-associated receptor by blocking RANKL-induced activation of NF-κB and expression of nuclear factor of activated T cells c1 (NFATc1), a master transcription factor. In addition, FST significantly abolished RANKL-induced generation of reactive oxygen species (ROS) by activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and its transcriptional targets. Hence, it seems likely that FST may have anti-osteoclastogenic potential as a result of its ability to inactivate the NF-κB-mediated NFATc1 signaling pathway and by reducing ROS production through activation of the Nrf2 pathway. Although further studies are needed to inquire its efficacy in vivo, FST appears to have potential use as an adjunctive or as a prophylactic treatment for osteoclastic bone disease.

CNB-001, a pyrazole derivative of curcumin, has been found to exert neuroprotective and memory-enhancing effects that may be effective for the treatment of Alzheimer's disease. Since aberrant activation of microglia is involved in the pathogenesis of Alzheimer's disease, the present study was undertaken to investigate the effect of CNB-001 on microglia-mediated inflammatory responses. In primary cultured rat microglia, CNB-001 (1–10 µM) suppressed the lipopolysaccharide (LPS)-induced nitric oxide (NO) production and expression of inducible NO synthase (iNOS), and the potency of CNB-001 was stronger than curcumin. CNB-001 also suppressed the LPS-induced nuclear translocation of nuclear factor κB (NF-κB), which is essential for the expression of iNOS. LPS treatment promoted phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). CNB-001 significantly suppressed the LPS-induced phosphorylation of p38 MAPK, but not ERK and JNK. The suppressive effect of CNB-001 on NO production was mimicked by blockade of the p38 MAPK signaling pathway with SB203580. These results suggest that CNB-001 exerts anti-inflammatory effects through inhibition of NF-κB and p38 MAPK pathways in microglia. [ABSTRACT FROM AUTHOR]