Statement of Retraction: Alkannin reverses lipopolysaccharides-induced inflammatory responses by suppressing mitogen-activated protein kinase and nuclear factor kappa-B signalling

Statement of Retraction We, the Editors and Publisher of the journal Bioengineered, have retracted the following article from publication. Yang, J., Li, J., Yang, L., & Guo, R. (2022). Alkannin reverses lipopolysaccharides-induced inflammatory responses by suppressing mitogen-activated protein kinase and nuclear factor kappa-B signalling. Bioengineered, 13(7–12), 14936–14946. https://doi.org/10.1080/21655979.2023.2184455 Since publication, significant concerns have been raised about the integrity of the data and reported results in the article. When approached for an explanation, the authors provided their original data and answered our queries, but these do not sufficiently address the concerns. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The authors have been informed of this decision. The authors agree with the retraction. We have been informed in our decision-making by our policy on publishing ethics and integrity and COPE guidelines. The retracted article will remain online to maintain the scholarly record and will be digitally watermarked on each page as ‘Retracted’.

Myeloid differentiation protein 2 (MD2), a co-receptor of toll-like receptor 4 (TLR4) in the innate immune system, has emerged as a promising target for anti-inflammatory therapies. Rheumatoid arthritis (RA), a chronic autoimmune disorder characterized by persistent synovial inflammation and progressive joint destruction, remains a therapeutic challenge due to the lack of effective treatment options. In this study, we investigated the role of MD2 in the pathogenesis and progression of RA. Our findings show that MD2 is overexpressed in both the whole blood and synovial tissues of RA patients. Furthermore, MD2 expression was upregulated in collagen-induced RA mouse models. MD2 knockout significantly alleviated key symptoms of RA, including improved body weight, reduced paw swelling, and decreased bone destruction and cartilage erosion. Additionally, MD2 deficiency led to a significant reduction in serum levels of inflammatory cytokines and a decrease in the expression of inflammatory protein within synovial tissue. Notably, animal models revealed that genetic ablation of MD2 exerts potent anti-ferroptosis effects in arthritic pathophysiology. This protective effect was recapitulated at the cellular level through pharmacological interventions, where MD2-targeting inhibitors effectively attenuated lipopolysaccharide-induced ferroptotic cell death in murine macrophages, as evidenced by characteristic biomarkers including glutathione depletion and lipid peroxidation. Mechanistically, the reduction in ferroptosis and inflammation following MD2 knockout was associated with the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in the synovial tissue. These results suggest that MD2 plays a critical role in both the inflammatory response and ferroptosis, in the context of RA. Consequently, MD2 represents a key mediator of RA pathogenesis and an innovative therapeutic target for the treatment of this debilitating disease. KEY MESSAGES: MD2 expression is upregulated in synovial tissue following the onset of rheumatoid arthritis. MD2 knockout alleviates bone destruction, cartilage erosion, and inflammation in rheumatoid arthritis mice. MD2 deficiency mitigates rheumatoid arthritis in mice by inhibiting ferroptosis induced by the MAPK and NF-κB signaling pathways. MD2 may serve as a potential therapeutic target for rheumatoid arthritis.

Ultraviolet-B radiation (285–320 nm) elicits a number of cellular signaling elements. We investigated the preventive effect of linalool, a natural monoterpene, against UVB-induced oxidative imbalance, activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling in HDFa cells. We observed that linalool treatment (30 μM) prevented acute UVB-irradiation (20 mJ/cm2) mediated loss of activities of antioxidant enzymes in HDFa cells. The comet assay results illustrate that linalool significantly prevents UVB-mediated 8-deoxy guanosine formation (oxidative DNA damage) rather than UVB-induced cyclobutane pyrimidine (CPD) formation. This might be due to its ability to prevent UVB-induced ROS formation and to restore the oxidative imbalance of cells. This has been reflected in UVB-induced overexpression of MAPK and NF-κB signaling. We observed that linalool inhibited UVB-induced phosphorylation of ERK1, JNK and p38 proteins of MAPK family. Linalool inhibited UVB-induced activation of NF-κB/p65 by activating IκBa. We further observed that UVB-induced expression of TNF-α, IL6, IL-10, MMP-2 and MMP-9 was modulated by linalool treatment in HDFa cells. Thus, linalool protects the human skin cells from the oxidative damages of UVB radiation and modulates MAPK and NF-κB signaling in HDFa cells. The present findings substantiate that linalool may act as a photoprotective agent against UVB-induced skin damages.

Our previous work has shown that the membrane microdomain-associated flotillin proteins are potentially involved in epidermal growth factor (EGF) receptor signaling. Here we show that knockdown of flotillin-1/reggie-2 results in reduced EGF-induced phosphorylation of specific tyrosines in the EGF receptor (EGFR) and in inefficient activation of the downstream mitogen-activated protein (MAP) kinase and Akt signaling. Although flotillin-1 has been implicated in endocytosis, its depletion affects neither the endocytosis nor the ubiquitination of the EGFR. However, EGF-induced clustering of EGFR at the cell surface is altered in cells lacking flotillin-1. Furthermore, we show that flotillins form molecular complexes with EGFR in an EGF/EGFR kinase-independent manner. However, knockdown of flotillin-1 appears to affect the activation of the downstream MAP kinase signaling more directly. We here show that flotillin-1 forms a complex with CRAF, MEK1, ERK, and KSR1 (kinase suppressor of RAS) and that flotillin-1 knockdown leads to a direct inactivation of ERK1/2. Thus, flotillin-1 plays a direct role during both the early phase (activation of the receptor) and late (activation of MAP kinases) phase of growth factor signaling. Our results here unveil a novel role for flotillin-1 as a scaffolding factor in the regulation of classical MAP kinase signaling. Furthermore, our results imply that other receptor-tyrosine kinases may also rely on flotillin-1 upon activation, thus suggesting a general role for flotillin-1 as a novel factor in receptor-tyrosine kinase/MAP kinase signaling.

Nitric oxide (NO*) expression by inducible nitric oxide synthase (iNOS) is an important host defense mechanism against Mycobacterium tuberculosis in mononuclear phagocytes. The objective of this investigation was to examine the role of mitogen-activated protein (MAP) kinase (MAPK) and nuclear factor kappaB (NF-kappaB) signaling pathways in the regulation of iNOS and NO* by a mycobacterial cell wall lipoglycan known as mannose-capped lipoarabinomannan (ManLAM). Specific pharmacologic inhibition of the extracellular-signal-regulated kinase (ERK) or NF-kappaB pathway revealed that both these signaling cascades were required in gamma interferon (IFN-gamma)-ManLAM-induced iNOS protein and NO2- expression in mouse macrophages. Transient cotransfection of dominant-negative protein mutants of the c-Jun NH2-terminal kinase (JNK) pathway revealed that the MAP kinase kinase 7 (MKK7)-JNK cascade also mediated IFN-gamma-ManLAM induction of iNOS promoter activity whereas MKK4 did not. Overexpression of null mutant IkappaBalpha, a potent inhibitor of NF-kappaB activation, confirmed that the IkappaBalpha kinase (IKK)-NF-kappaB signaling pathway enhanced IFN-gamma-ManLAM-induced iNOS promoter activity. By contrast, activated p38mapk inhibited iNOS induction. These results indicate that combined IFN-gamma and ManLAM stimulation induced iNOS and NO. expression and that MEK1-ERK, MKK7-JNK, IKK-NF-kappaB, and p38mapk signaling pathways play important regulatory roles.

Salvia miltiorrhiza polysaccharide activates T Lymphocytes of cancer patients through activation of TLRs mediated -MAPK and -NF-κB signaling pathways

As a kind of chronic inflammatory diseases, Rheumatoid arthritis (RA) has alowcurerateandeasyrecurrence. It has widely reported that abnormal activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways are associated with the development of RA inflammation. Blocking the inflammatory signaling pathways of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) can delay the development of RA. Ononin is a natural isoflavone glycoside and plays a key role in modulating inflammation related signaling pathways. However, whether Ononin exerts anti-inflammatory effects on RA inflammation remains unknown. In this study, we evaluated the therapeutic effect of Ononin on RA by establishing a tumor necrosis factor α (TNF-α)-induced RA-FLS cell model. Our data confirmed that Ononin could alleviate TNF-α-induced RA-FLS and MH7A cells viability, increase cell apoptosis, decrease the production of pro-inflammatory cytokines like interleukin-1β (IL-1β) and interleukin 6 (IL-6), and further inhibit the abnormal activation of NF-κB and MAPK pathways. Our results suggested that Ononin could be a potential therapeutic agent for RA.

In neuronal precursor cells, the magnitude and longevity of mitogen-activated protein (MAP) kinase cascade activation contribute to the nature of the cellular response, differentiation, or proliferation. However, the mechanisms by which neurotrophins promote prolonged MAP kinase signaling are not well understood. Here we defined the Rin GTPase as a novel component of the regulatory machinery contributing to the selective integration of MAP kinase signaling and neuronal development. Rin is expressed exclusively in neurons and is activated by neurotrophin signaling, and loss-of-function analysis demonstrates that Rin makes an essential contribution to nerve growth factor (NGF)-mediated neuronal differentiation. Most surprisingly, although Rin was unable to stimulate MAP kinase activity in NIH 3T3 cells, it potently activated isoform-specific p38alpha MAP kinase signaling and weakly stimulated ERK signaling in pheochromocytoma (PC6) cells. This cell-type specificity is explained in part by the finding that Rin binds and stimulates b-Raf but does not activate c-Raf. Accordingly, selective down-regulation of Rin in PC6 cells suppressed neurotrophin-elicited activation of b-Raf and p38, without obvious effects on NGF-induced ERK activation. Moreover, the ability of NGF to promote neurite outgrowth was inhibited by Rin knockdown. Together, these observations establish Rin as a neuronal specific regulator of neurotrophin signaling, required to couple NGF stimulation to sustain activation of p38 MAP kinase and b-Raf signaling cascades required for neuronal development.

Acute lung injury (ALI) is an inflammatory lung disease that is caused by bacterial infection. Lipopolysaccharide (LPS), a prototype pathogen-associated molecular pattern (PAMP) from Gram-negative bacteria such as Escherichia coli (E. coli), is an essential risk factor for ALI. LPS and E. coli induced the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-κB) signaling pathways, which led to the increasing immune molecule transcription, including pro-inflammatory cytokine and chemokine secretion. Codonopsis pilosula polysaccharides (CPPS) exhibit various biological activities and pharmacological effects. However, the effect of CPPS on ALI caused by LPS stimulation or E. coli infection remains unclear. Our results showed that CPPS (6.25, 12.5, 25, or 50 μg mL-1) could attenuate the secretion of TNF-α and IL-1β and impair the phosphorylation of ERK, p38 and p65 in E. coli-infected macrophages without causing toxic reactions. In addition to regulating the secretion of pro-inflammatory cytokines and the activation of MAPK and NF-κB signaling pathways, CPPS could enhance bacterial phagocytosis and intracellular killing in macrophages, and inhibit the bacterial growth of E. coli. In vivo experiments showed that CPPS attenuated LPS- and E. coli-induced lung damage in mice, which was characterized by decreased pro-inflammatory cytokine (TNF-α, IL-1β and IL-6) and chemokine (RANTES) production and production of the biomarkers of tissue damage (HABP2 and HMGB1) in the lungs. Altogether, this study demonstrated that CPPS have a protective effect on the lungs in LPS- and E. coli-induced ALI mouse models, suggesting that CPPS could be a potential drug for the treatment of ALI.

Finger Citron (Citrus medica L. var. sarcodactylis Swingle) holds significant potential as both a culinary ingredient and a traditional medicinal remedy; however, its precise molecular mechanisms of action remain largely unexplored. This study investigates the anti-inflammatory properties of Finger Citron extract (FCE) in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). Using UPLC-ESI-QTF-MS, we analyzed the extract's composition, revealing a rich presence of polyphenols and polysaccharides, with hesperidin, melitidin, and hesperetin as the predominant polyphenolic compounds. Additionally, the study elucidated the monosaccharide composition profile of polysaccharides in the extract. Furthermore, Finger Citron extract markedly suppressed the production of key inflammatory mediators, including TNF-α, IL-6, and NO. The inhibition of protein phosphorylation levels of inhibiting the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling was also observed, indicating that the anti-inflammatory effects of Finger Citron extract may involve the NF-κB and MAPK signaling pathway. Given these findings, Finger Citron extract has the potential to act as a natural product with anti-inflammatory activity.

Antimicrobial peptides like human beta-defensin-2 (HBD-2) play an important role in the innate immune system protecting the intestinal mucosa against bacterial invasion. The dietary histone deacetylase (HDAC) inhibitors sulforaphane (SFN) and butyrate have received a great deal of attention because of their ability to simultaneously modulate multiple cellular targets involved in cellular protection. In this study the influence of SFN and butyrate on HBD-2 expression as well as the molecular pathways involved in SFN-mediated induction of HBD-2 were scrutinized. Treatment of Caco-2, HT-29 and SW480 cells with SFN led to a time- and dose-dependent upregulation of HBD-2 mRNA expression as determined by semi-quantitative reverse transcription-polymerase chain reaction. Moreover, HBD-2 protein production increased in response to SFN, measured by enzyme-linked immunosorbent assay. Induction of HBD-2 was also observed in response to butyrate. Immunofluorescence analysis revealed that the protein was localized in the cytosol. Coincubation of SFN with a vitamin D receptor (VDR), or an extracellular-regulated kinase 1/2 or a nuclear factor-kappaB inhibitor all reduced HBD-2 mRNA upregulation. In contrast, transfection of cells with a dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutant vector to inhibit PPARgamma wild-type action and inhibition of p38 mitogen-activated protein kinase (MAPK) signalling did not affect SFN-mediated upregulation of HBD-2 mRNA. Moreover, SFN induced the expression of VDR, PPARgamma and phosphorylated ERK1/2 but did not affect p38 MAPK activation. The data clearly demonstrate for the first time that the dietary HDAC inhibitor SFN is able to induce antimicrobial peptides in colonocytes. In this process HBD-2 expression is regulated via VDR, mitogen-activated protein kinase kinase/extracellular-regulated kinase and nuclear factor-kappaB signalling.

Novel bioactive peptides targeting Keap1-Nrf2 interaction for combating UVA-induced skin aging: Computational discovery and experimental validation.

Mating in Ustilago maydis requires cross-talk between cAMP and mitogen-activated protein kinase (MAPK) signalling. During this process, pheromone response factor 1 (Prf1) activates transcription of a and b mating type genes by binding to pheromone response elements (PREs) located in regulatory regions of these genes. Here, we show that PREs are also necessary and sufficient to mediate cAMP-induced gene expression. Prf1 interacts with cAMP-dependent protein kinase A (PKA) Adr1 as well as MAPK Kpp2 in vivo, and its central phosphorylation sites that are functionally important are modified by the respective kinases in vitro. PKA sites in Prf1 are essential for induced expression of a and b mating type genes. In contrast, MAPK sites are not required for pheromone-induced expression of a genes but are crucial for pheromone-responsive b gene expression. This illustrates how a single transcription factor can integrate signals from two pathways and how its phosphorylation status can determine different transcriptional responses.

FNF-12, a novel benzylidene-chromanone derivative, attenuates inflammatory response in in vitro and in vivo asthma models mediated by M2-related Th2 cytokines via MAPK and NF-kB signaling.

BackgroundOsteoarthritis (OA) treatment aims to improve inflammation and delay cartilage degeneration. However, there is no effective strategy presently available. Ononin, a representative isoflavone glycoside component extracted from natural Chinese herbs, exerts anti-inflammatory and proliferative effects. However, the therapeutic effect of ononin on chondrocyte inflammation remains unclear.MethodsIn this study, we explored the therapeutic effect and potential mechanism of ononin in OA by establishing an interleukin-1 beta (IL-1β)-induced chondrocyte inflammation model.ResultsOur results verified that ononin alleviated the IL-1β-induced decrease in chondrocyte viability, attenuated the overexpression of the inflammatory factors tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6), and simultaneously inhibited the expression of cartilage extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteinase-13 (MMP-13). Furthermore, the decomposition of Collagen II protein could be alleviated in the OA model by ononin. Finally, ononin improved chondrocyte inflammation by downregulating the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signalling pathways.ConclusionOur findings suggested that ononin could inhibit the IL-1β-induced proinflammatory response and ECM degradation in chondrocytes by interfering with the abnormal activation of the MAPK and NF-κB pathways, indicating its protective effect against OA.