Search Results (8)

Inorganic polyphosphate (PolyP) is a high-molecular-weight polymer that plays multiple roles in regulating immune responses. However, the specific anti-inflammatory mechanisms of bacteria-derived PolyP are unclear. In the present study, PolyP was extracted from Lactobacillus plantarum (L. plantarum), and the chain length was estimated to be approximately 250 Pi residues. The immune regulatory functions of PolyP were investigated using a lipopolysaccharide (LPS)-induced RAW264.7 cell oxidative stress model, and dexamethasone was used as a positive control. The result revealed that both dexamethasone and PolyP were protective against oxidative stress by inhibiting macrophage M1 polarization and the production of several markers, such as nitric oxide (NO), reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2. In addition, PolyP suppressed inflammation progression by regulating the production of several cytokines, such as interleukin (IL)-1β, interferon (INF)-γ, tumor necrosis factor (TNF)-α, and IL-6, and inhibited the expressions of inhibitory κB kinase (IKK) α, IKKβ, and extracellular regulated protein kinases 2 (ERK2). Conclusively, PolyP derived from L. plantarum has the ability to protect cells from oxidative stress damage by inhibiting M1 polarization in macrophages. These findings provide insights into the function of PolyP and offer support for the potential application of PolyP in immune-related diseases. Full article

(+)-Aeroplysinin-1 (Apl-1) is a brominated compound isolated from the marine sponge Aplysina aerophoba that exhibits pleiotropic bioactive effects, impairing cell growth in cancer cells, inhibiting angiogenesis in vitro and in vivo and modulating the redox status of different cell types, among other reported activities. In addition to the aforementioned effects, the anti-inflammatory potential of this natural compound was explored in previous work of our laboratory, but the mechanism of action underlying this effect was not described. In this work, we delve into the anti-inflammatory effect of Apl-1 in the context of vascular endothelial cells in vitro, providing new data regarding the molecular mechanism underlying this activity. The characterization of the mechanism of action points to an inhibitory effect of Apl-1 on the NF-κB pathway, one of the main axes involved in endothelial response during inflammatory events. Our results show that Apl-1 can inhibit the expression of pro-inflammatory genes in tumor necrosis factor alpha (TNF-α)- and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), targeting the nuclear factor kappa B subunit (NF-κB) pathway through a mechanism of action involving the inhibition of I kappa B kinase (IKK) complex phosphorylation and RelA/p65 nuclear import. In addition, Apl-1 prevented the phosphorylation of Akt induced by TNF-α in HUVECs, probably supporting the inhibitory effect of this compound in the NF-κB pathway. Experimental evidence reported in this work opens the door to the potential pharmacological use of this compound as an anti-inflammatory agent in diseases that course with a pathological endothelial response to inflammation, such as atherosclerosis. Full article

Streptococcus agalactiae is common pathogenic bacteria in aquaculture and can cause mass mortality after fish infection. This study aimed to investigate the effects of S. agalactiae infection on the immune and antioxidant regulatory mechanisms of golden pompano (Trachinotus ovatus). Serum and liver samples were obtained at 0, 6, 12, 24, 48, 96, and 120 h after golden pompano infection with S. agalactiae for enzyme activity and gene expression analyses. After infection with S. agalactiae, the content of reactive oxygen species (ROS) in serum was significantly increased (p < 0.05). Serum levels of glucose (GLU), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA) increased and then decreased (p < 0.05), reaching a maximum at 6 h. Serum antioxidant enzyme (LZM) activity increased significantly (p < 0.05) and reached a maximum at 120 h. In addition, the mRNA expression levels of antioxidant genes (SOD, CAT, and GPx) in the liver increased and then decreased, reaching the maximum at 24 h, 48 h, and 24 h, respectively. During the experimental period, the mRNA expression levels of NF-κB-related genes of the inflammatory signaling pathway inhibitory κB (IκB) showed an overall decreasing trend (p < 0.05) and the lowest expression at 120 h, whereas the mRNA expression levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), IκB kinase (IKK), and nuclear factor NF-κB increased significantly (p < 0.05) and the highest expression was at 120 h. In conclusion, these results showed that S. agalactiae could activate internal regulatory signaling in the liver of golden pompano to induce defense and immune responses. This study is expected to lay a foundation to develop the healthy aquaculture of golden pompano and promote a more comprehensive understanding of its disease resistance mechanisms. Full article

Neuroinflammation is the cornerstone of most neuronal disorders, particularly neurodegenerative diseases. During the inflammatory process, various pro-inflammatory cytokines, chemokines, and enzymes—such as interleukin 1-β (IL1-β), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthases (iNOS), inhibitory kappa kinase (IKK), and inducible nitric oxide (NO)—are over-expressed in response to every stimulus. Methods: In the present study, we focused on the anti-neuroinflammatory efficacy of (2E,4E)-N,5-bis(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamide, encoded D5. We investigated the efficacy of D5 on the upstream and downstream products of inflammatory pathways in CHME3 and SVG cell lines corresponding to human microglia and astrocytes, respectively, using various in silico, in vitro, and in situ techniques. Results: The results showed that D5 significantly reduced the level of pro-inflammatory cytokines by up-regulating PPAR-γ expression and suppressing IKK-β, iNOS, NO production, and NF-κB activation in inflamed astrocytes (SVG) and microglia (CHME3) after 24 h of incubation. The data demonstrated remarkably higher efficacy of D5 compared to ASA (Aspirin) in reducing NF-κB-dependent neuroinflammation. Conclusions: We observed that the functional-group alteration had an extreme influence on the levels of druggability and the immunomodulatory properties of two analogs of piperamide, D5, and D4 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(4-(hydroxymethyl)phenyl)penta-2,4-dienamide)). The present study suggested D5 as a potential anti-neuroinflammatory agent for further in vitro, in vivo, and clinical investigations. Full article

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1). Full article

The cellular kinases inhibitory-κB kinase (IKK) α and Nuclear Factor-κB (NF-κB)-inducing kinase (NIK) are well recognised as key central regulators and drivers of the non-canonical NF-κB cascade and as such dictate the initiation and development of defined transcriptional responses associated with the liberation of p52-RelB and p52-p52 NF-κB dimer complexes. Whilst these kinases and downstream NF-κB complexes transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes, they also play a key role in the pathogenesis of a number of inflammatory-based conditions and diverse cancer types, which for the latter may be a result of background mutational status. IKKα and NIK, therefore, represent attractive targets for pharmacological intervention. Here, specifically in the cancer setting, we reflect on the potential pathophysiological role(s) of each of these kinases, their associated downstream signalling outcomes and the stimulatory and mutational mechanisms leading to their increased activation. We also consider the downstream coordination of transcriptional events and phenotypic outcomes illustrative of key cancer ‘Hallmarks’ that are now increasingly perceived to be due to the coordinated recruitment of both NF-κB-dependent as well as NF-κB–independent signalling. Furthermore, as these kinases regulate the transition from hormone-dependent to hormone-independent growth in defined tumour subsets, potential tumour reactivation and major cytokine and chemokine species that may have significant bearing upon tumour-stromal communication and tumour microenvironment it reiterates their potential to be drug targets. Therefore, with the emergence of small molecule kinase inhibitors targeting each of these kinases, we consider medicinal chemistry efforts to date and those evolving that may contribute to the development of viable pharmacological intervention strategies to target a variety of tumour types. Full article

Twenty-three new berberine (BBR) analogues defined on substituents of ring D were synthesized and evaluated for their activity for suppression of tumor necrosis factor (TNF)-α-induced nuclear factor (NF)-κB activation. Structure–activity relationship (SAR) analysis indicated that suitable tertiary/quaternary carbon substitutions at the 9-position or rigid fragment at position 10 might be beneficial for enhancing their anti-inflammatory potency. Among them, compounds 2d, 2e, 2i and 2j exhibited satisfactory inhibitory potency against NF-κB activation, with an inhibitory rate of around 90% (5 μM), much better than BBR. A preliminary mechanism study revealed that all of them could inhibit TNF-α-induced NF-κB activation via impairing IκB kinase (IKK) phosphorylation as well as cytokines interleukin (IL)-6 and IL-8 induced by TNF-α. Therefore, the results provided powerful information on further structural modifications and development of BBR derivatives into a new class of anti-inflammatory candidates for the treatment of inflammatory diseases. Full article

Amyloid-β peptides (Aβ) exist in several forms and are known as key modulators of Alzheimer’s disease (AD). Fibrillary Aβ (fAβ) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAβ_1–40. We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAβ_1–40-damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAβ_1–40, luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAβ_1–40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAβ_1–40. Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAβ_1–40-induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAβ_1–40-induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAβ_1–40-induced injury. Full article