Inhibition Of NF-κB Activation Research Articles

EXPRESS: AMPK Activation Mitigates Inflammatory Pain by Modulating STAT3 Phosphorylation in Inflamed Tissue Macrophages of Adult Male Mice.

Inflammatory pain presents a significant clinical challenge. AMP-activated protein kinase (AMPK) is recognized for its capacity to alleviate inflammation by inhibiting transcription factors such as nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription (STAT). Our prior research demonstrated that AMPK reduces inflammatory pain by inhibiting NF-κB activation and interleukin-1 beta (IL-1β) expression. However, the role of AMPK in regulating reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) by modulating STAT3 phosphorylation in inflammatory pain remains inadequately understood. A Complete Freund's Adjuvant (CFA)-induced inflammatory pain model was established by subcutaneous injection into the plantar surface of the left hindpaw of adult male mice. Behavioral tests of mechanical allodynia and thermal latency were used to determine nociceptive behavior. Immunoblotting quantified p-AMPK and iNOS expression levels. Nuclear translocation of p-STAT3(Ser727) and STAT3 in macrophages was assessed by western blot and immunofluorescence. ROS accumulation and mitochondrial damage in NR8383 macrophages were detected by flow cytometry. Lentivirus infection cells experiment was performed to transfect vectors encoding the STAT3 S727D mutants. Treatment with the AMPK activator AICAR alleviated CFA-induced inflammatory pain, enhanced AMPK phosphorylation, and reduced iNOS expression in inflamed skin tissues. AICAR effectively prevented STAT3 nuclear translocation while promoting the phosphorylation of STAT3 (Ser727) in the cytoplasm. In vitro studies with CFA-stimulated NR8383 macrophages revealed that AICAR increased STAT3(Ser727) phosphorylation, curtailed iNOS expression, and attenuated ROS accumulation and mitochondrial damage. Furthermore, the S727D mutation, which enhances STAT3 phosphorylation, replicated the protective effects of AICAR against CFA-induced oxidative stress and mitochondrial dysfunction. Our study shows that the AMPK acitvation downregulates iNOS expression by inhibiting the STAT3 nuclear translocation and promotes cytoplasmic STAT3(Ser727) phosphorylation, which reduces ROS expression and mitochondrial dysfunction, thereby alleviating inflammatory pain. These findings underscore the therapeutic potential of targeting AMPK and STAT3 pathways in inflammatory pain.

Gold(I) N-heterocyclic carbene complexes show strong proapoptotic, antioxidant and anti-inflammatory effects in A2780 and endothelial cells.

A series of eight gold(I) N-heterocyclic carbene (NHC) complexes [Au(IMes)(Ln)] based on 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene (IMes) and 7-azaindole derivatives (HLn), where n=1-8 for HL1=5-fluoro-7-azaindole, HL2=5-bromo-7-azaindole, HL3=3-chloro-7-azaindole, HL4=3-iodo-7-azaindole, HL5=5-bromo-3-chloro-7-azaindole, HL6=5-bromo-3-iodo-7-azaindole, HL7=4-chloro-2-methyl-7-azaindole and HL8=7-azaindole, was prepared, characterised and studied for their in vitro anti-cancer and anti-inflammatory effects. The complexes showed significant cytotoxicity on human ovarian cancer cell lines (A2780, IC50≈8-19μM and A2780R, IC50≈8-19μM) and lowered toxicity in normal HaCat and MRC-5cells. Cellular effects of the selected complexes 1 and 7 were evaluated in A2780cells using flow cytometry. Moreover, the time-dependent cellular uptake in A2780cells, a shotgun proteomic analysis, an ESI-MS study of hydrolysis and interactions with l-cysteine and reduced glutathione (GSH) were performed. Complexes 1 and 7 revealed remarkable anti-inflammatory effects via inhibition of NF-κB activity in human endothelial cells.

Discovery of novel XPO1 PROTAC degraders for the treatment of acute myeloid leukemia.

Targeting XPO1 inhibition has emerged as a promising therapeutic strategy in cancer treatment. Despite the numerous XPO1 inhibitors reported to date, no XPO1 degraders have been disclosed. In this study, we reported the design, synthesis and biological characterization of small-molecule XPO1 degraders based upon the proteolysis targeting chimera (PROTAC), marking the first public disclosure of XPO1 degraders. The potent PROTAC compound 2c was identified, demonstrating effective degradation of XPO1 protein in MV4-11 acute myeloid leukemia (AML) cells, with a DC50 of 23.67nM. Treatment with 2c resulted in significant antiproliferative effects, with IC50 values of 0.142±0.029μM in MV4-11cells and 0.186±0.024μM in MOLM-13cells. Additionally, 2c induced apoptosis, inhibited NF-κB activity, and caused G1 phase cell cycle arrest. The study highlights the therapeutic potential of targeting XPO1 degradation in AML treatment and emphasizes the advantages of PROTAC technology in developing novel anticancer strategies. These findings provide a foundation for further exploration of XPO1 degraders in cancer therapy, offering new hope for effective treatment options in hematological malignancies.

The natural product-derived JM-9 alleviates high-fat diet-induced fatty liver in mice by targeting MD2.

Metabolic dysfunction-associated steatotic liver disease (MASLD), is gradually emerging as one of the most prevalent liver diseases worldwide. Previous research demonstrated the involvement of myeloid differentiation factor 2 (MD2), a co-receptor of TLR4, as a key mediator in MASLD pathogenesis. The current study identifies JM-9 as a novel MD2 inhibitor, and focuses on evaluating its potential therapeutic effects in mitigating MASLD progression. Drug affinity responsive target stability (DARTS) assay and surface plasmon resonance assay were utilized to evaluate the MD2-targeting specificity of JM-9. In vitro, hepatocytes and macrophages were stimulated with palmitic acid (PA) followed by JM-9 treatment. In vivo, a high-fat diet (HFD)-induced MASLD model was established and subjected to JM-9 administration during the last 2months. JM-9 directly bound the Phe76 residue of MD2 to disrupt the PA-induced MD2/TLR4 complex formation, thus further restoring AMPK phosphorylation and inhibiting NF-κB activation to reducing lipid accumulation and inflammation, respectively. In the HFD-mediated MASLD mouse model, JM-9 alleviated the binding between MD2 and TLR4 in the liver and counteracted hepatic TBK1 and p65 activation and AMPK suppression, thereby mitigating liver inflammation, steatosis, and fibrosis. JM-9, as a novel MD2 inhibitor, holds potential as a viable treatment option for MASLD by playing a dual role in regulating both lipid metabolism and inflammation response.

HHV-6B ribonucleotide reductase sequesters NF-κB subunit p65 to inhibit innate immune responses.

Human herpesvirus 6B (HHV-6B) belongs to the genus Roseolovirus of the betaherpesvirus subfamily, causing exanthema subitum and encephalitis. Although viral ribonucleotide reductase (RNR) is conserved in betaherpesviruses, it has lost its enzymatic activity. Human cytomegalovirus (HCMV) belongs to the other betaherpesvirus genus, Cytomegalovirus; its RNR inhibits nuclear factor-kappa B (NF-κB) signaling via interaction with the adaptor molecule RIPK1. However, the significance of enzymatically inactive RNR in roseoviruses is unclear. Here, we show that the RNRs from all three human roseoloviruses inhibit NF-κB activation. HHV-6B RNR sequesters NF-κB subunit p65 in the cytoplasm and inhibits its translocation into the nucleus. Silencing HHV-6B RNR increased the expression of inflammatory molecules in infected cells. This study reveals that inhibiting NF-κB is a conserved role of the RNR in betaherpesviruses but that the precise mechanisms responsible for these effects are different.

The Anti-inflammatory Potential of Tricyclic Antidepressants (TCAs): A Novel Therapeutic Approach to Atherosclerosis Pathophysiology

Atherosclerosis, a chronic inflammatory disease, is driven by complex molecular mechanisms involving inflammatory cytokines and immune pathways. According to recent research, tricyclic antidepressants (TCAs), which are typically prescribed to treat depressive disorders, have strong anti-inflammatory effects. TCAs, including imipramine and amitriptyline, alter inflammatory signaling cascades, which include lowering the levels pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 and inhibiting NF-κB activation. By inhibiting the NLRP3 inflammasome and suppressing pathways including JAK/STAT, MAPK, and PI3K, these effects are produced, improving endothelial function and reducing oxidative stress. The intricacy of TCAs’ anti-inflammatory actions has demonstrated by the existence of contradictory findings about how they alter IL-6 levels. The dependence of the heterogeneity of the reaction on the use of particular TCAs and experimental settings is shown by the fact that some studies show reduced IL-6 production, while others indicate increases or no changes. This review explores the multifaceted mechanisms through which TCAs modulate inflammatory pathways. TCAs inhibit NF-κB activation, reduce oxidative stress, and suppress the production of key inflammatory mediators, including IL-6 and TNF-α. They also regulate Toll-like receptor (TLR) signaling and NOD-, LRR-, and NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome activation, reducing the release of IL-1β and IL-18, critical drivers of endothelial dysfunction and plaque instability. Given their capacity to target critical inflammatory molecules and pathways, TCAs provide great potential in the therapy of atherosclerosis, particularly for individuals with associated depression and cardiovascular risk factors. Nevertheless, further research is essential to clarify the precise molecular mechanisms, resolve inconsistencies in current findings, and establish the clinical applicability of TCAs as anti-inflammatory agents in atherosclerosis management.

Zinc regulates microglial polarization and inflammation through IKBα after spinal cord injury and promotes neuronal repair and motor function recovery in mice

IntroductionSpinal cord injury (SCI) leads to severe inflammation and neuronal damage, resulting in permanent loss of motor and sensory functions. Zinc ions have shown potential in modulating inflammation and cellular survival, making them a promising therapeutic approach for SCI. This study investigates the mechanisms of zinc ion treatment in SCI, focusing on its effects on inflammation.MethodsWe used transcriptomic analysis to identify key pathways and genes involved in the inflammatory response in a mouse model of SCI. In vitro studies assessed the impact of zinc ions on inflammation, cell polarization, and apoptosis. IKBα expression was evaluated as a potential target of zinc ions, both in cultured cells and in vivo.ResultsTranscriptomic analysis revealed that zinc ions modulate inflammatory pathways through IKBα, which inhibits NF-κB activity. In vitro, zinc treatment upregulated IKBα expression, reducing inflammation, polarization, and apoptosis. These results were confirmed in the SCI mouse model, where zinc ions also reduced inflammation and cell death.DiscussionOur findings highlight a novel mechanism by which zinc ions regulate inflammation in SCI by upregulating IKBα and inhibiting NF-κB activation. This suggests potential therapeutic applications of zinc ions in SCI and other inflammatory conditions, warranting further investigation into their clinical benefits.

The Chikungunya Virus nsP3 Macro Domain Inhibits Activation of the NF-κB Pathway

The role of the chikungunya virus (CHIKV) non-structural protein 3 (nsP3) in the virus lifecycle is poorly understood. The protein comprises three domains. At the N-terminus is a macro domain, biochemically characterised to bind both RNA and ADP-ribose and to possess ADP-ribosyl hydrolase activity—an enzymatic activity that removes ADP-ribose from mono-ADP-ribosylated proteins. As ADP-ribosylation is important in the signalling pathway, leading to activation of the transcription factor NF-κB, we sought to determine whether the macro domain might perturb NF-κB signalling. We first showed that CHIKV infection did not induce NF-κB activation and could not block exogenous activation of the pathway via TNFα, although TNFα treatment did result in a modest reduction in virus titre. In contrast, ectopic expression of nsP3 was able to inhibit both basal and TNFα-mediated NF-κB activation, and this was dependent on the macro domain, as a mutation previously shown to disrupt ADP-ribose binding and hydrolase activity (D10A) eliminated the ability to inhibit NF-κB activation. The macro domain D10A mutant also resulted in a dramatic reduction in virus infectivity, consistent with the notion that the ability of the macro domain to inhibit NF-κB activation plays a role in the virus lifecycle.

NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons in the anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1−/− and wild-type (WT) EAE mice and found increased RGC loss and axonal injury in Nlrx1−/− mice compared to WT mice in both active immunization EAE and spontaneous opticospinal encephalomyelitis (OSE) models. To minimize the effects of Nlrx1−/− on peripheral lymphocyte priming during EAE, we performed adoptive transfer experiments, in which activated myelin-specific T cells were transferred into lymphocyte-deficient Rag−/− or Nlrx1−/−Rag−/− mice. In this model, we found more severe microgliosis and astrogliosis in the optic nerve of Nlrx1−/−Rag−/− mice compared to Rag−/− mice, suggesting a regulatory role of NLRX1 in innate immune cells. Transcriptome analysis in primary astrocytes activated with LPS and IFNγ demonstrated that NLRX1 suppresses NF-κB activation and regulates mitochondrial oxidative phosphorylation in inflammatory reactive astrocytes. The novel pharmacologic NLRX1 activators NX-13 and LABP-66 decreased LPS-mediated gene expression of inflammatory cytokines and chemokines in mixed glial cultures. Moreover, treating EAE mice with oral LABP-66, compared to vehicle, after the onset of paralysis resulted in less anterior visual pathway neurodegeneration. These data suggest that pharmacologic NLRX1 activators have the potential to limit inflammatory neurodegeneration. This study highlights that NLRX1 could serve as a promising target for neuroprotection in progressive MS and other neurodegenerative diseases. Further studies are needed to better understand the cell-specific mechanisms underlying the neuroprotective role of NLRX1 in response to inflammation in the CNS.

RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis factor (TNF) associated with MPN disease severity and transformation. We further evaluate a therapeutic approach utilizing a first-in-class RSK inhibitor, PMD-026, currently in Phase 2 development for breast cancer, for use in myeloid malignancies. Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML.

Gedunin Mitigates Cutibacterium acnes-Induced Skin Inflammation by Inhibiting the NF-κB Pathway.

Background/Objectives: Cutibacterium acnes (C. acnes), a bacterium residing in hair follicles, triggers acne by inducing monocyte-mediated inflammatory cytokine production. Gedunin, a limonoid derived from Azadirachta indica (commonly known as neem), is renowned for its antifungal, antimalarial, anticancer, anti-inflammatory, and neuroprotective effects. However, its role in mitigating C. acnes-induced skin inflammation remains unexplored. This study investigates the anti-inflammatory effects of gedunin on C. acnes-induced skin inflammation and elucidates the underlying mechanisms. Methods: The anti-inflammatory activity of gedunin was assessed using RAW 264.7 mouse macrophage cells and mouse bone-marrow-derived macrophages (BMDMs). Key inflammatory mediators, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6), were evaluated. Mechanistic studies focused on the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, along with the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. An in vivo acne model was employed to examine gedunin's therapeutic efficacy. Results: Gedunin significantly reduced the expression of IL-1β, TNF-α, iNOS, COX-2, and IL-6 in RAW 264.7 cells. It inhibited NF-κB activation without affecting the MAPK pathways, including JNK/SAPK, ERK, and p38 MAPK. Gedunin also suppressed the activation of the NLRP3 inflammasome in BMDMs. In the mouse acne model, gedunin effectively alleviated C. acnes-induced inflammation, primarily by targeting NF-κB signaling. Conclusions: Gedunin demonstrates potential as a therapeutic agent for acne treatment by targeting key inflammatory pathways, particularly NF-κB signaling. This study highlights gedunin's promise as an alternative approach to managing C. acnes-induced skin inflammation.

Indole-3-Aldehyde alleviates lung inflammation in COPD through activating Aryl Hydrocarbon Receptor to inhibit HDACs/NF-κB/NLRP3 signaling pathways

Indole-3-aldehyde (I3A) is an intestinal microbial metabolite that regulates inflammation in various inflammatory diseases; however, its role in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the anti-inflammatory effects and molecular mechanisms of I3A in COPD. We constructed in vivo models using cigarette smoke (CS)-stimulated mice and in vitro models using cigarette smoke extract (CSE)-stimulated MH-S cells. The results demonstrated that I3A significantly alleviated bronchial obstruction in mice with COPD and reduced the expression of inflammatory factors such as TNF-α, IL-1β, and IL-6. Additionally, I3A decreased the levels of matrix metalloproteinases MMP2, MMP12, and inhibited the NF-κB p65/NLRP3 pathways. Further investigation revealed that I3A inhibited NF-κB activity by suppressing p65 phosphorylation and nuclear translocation in CSE-stimulated MH-S cells. The activation of the NF-κB and NLRP3 signaling pathways is mediated by histone deacetylase 5 (HDAC5) and HDAC6, both of which are inhibited by I3A. Subsequent experiments indicated that aryl hydrocarbon receptor (AHR) knockdown attenuated the inhibitory effect of I3A on pro-inflammatory cytokines and the HDACs/NF-κB/NLRP3 signaling pathways, highlighting the dependence of I3A's anti-inflammatory effects on the AHR receptor.Key messagesI3A effectively reduced lung inflammation in COPD mice by inhibiting the NF-κB pathway.In CSE-stimulated MH-S cells, I3A suppressed p65 phosphorylation and nuclear translocation, thereby inhibiting NF-κB activity.The activation of the NF-κB/NLRP3 pathways by HDAC5 and HDAC6 was diminished by I3A.Through the activation of the AHR receptor, I3A suppressed the activities of HDAC5/6, leading to a decrease in inflammatory factor levels.Graphical abstract

The therapeutic effect of different cumin essential oil fractions against gastric ulcer in rats.

Cumin, a popular spice, is widely used to treat stomach ailments in Central Asia and Xinjiang, China. Cumin essential oil has been found to effectively treat gastric ulcers, but its pharmacodynamic basis remains unclear. In this study, cumin essential oil was directly separated using column chromatography, and its components were identified through multi-dimensional gas chromatography-mass spectrometry. Finally, the cumin essential oil was fractionated into E1, E2, and E3. The effects of these fractions on gastric ulcers were studied using an anhydrous ethanol-induced rat model. The results indicated that the three fractions decreased ulcer index, gastric fluid pH, and pepsin activity to different extents. They lowered the levels of prostaglandin E2, gastrin, and epidermal growth factor in rat serum. According to an analysis of the above indices, E3 fraction had the best anti-ulcer effect. The detection results of the oxidative stress and inflammatory factors showed that all three fractions relieved the ethanol-induced oxidative stress and reduced the release of inflammatory factors to varying degrees. The E3 fraction played the most significant role. The E3 fraction was selected to explore the relevant mechanism, and the results showed that E3 fraction significantly prevented the cleaved caspase-3 and Bax protein levels that were ethanol-induced and resisted apoptosis induced by ethanol injury. The western blot results for detecting the NF-κB-related pathway protein showed that E3 fraction significantly inhibited the activation of p-p65, p-IKKβ, and p-IκBα. The study found that the E3 fraction of cumin essential oil had the most effective anti-ulcer effect by inhibiting NF-κB activation and apoptosis, thus reducing inflammation.

SARS-CoV-2 specific adaptations in N protein inhibit NF-κB activation and alter pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severe acute respiratory syndrome coronavirus (SARS-CoV) exhibit differences in their inflammatory responses and pulmonary damage, yet the specific mechanisms remain unclear. Here, we discovered that the SARS-CoV-2 nucleocapsid (N) protein inhibits the activation of the nuclear factor-κB (NF-κB) pathway and downstream signal transduction by impeding the assembly of the transforming growth factor β-activated kinase1 (TAK1)-TAK1 binding protein 2/3 (TAB2/3) complex. In contrast, the SARS-CoV N protein does not impact the NF-κB pathway. By comparing the amino acid sequences of the SARS-CoV-2 and SARS-CoV N proteins, we identified Glu-290 and Gln-349 as critical residues in the C-terminal domain (CTD) of the SARS-CoV-2 N protein, essential for its antagonistic function. These findings were further validated in a SARS-CoV-2 trans-complementation system using cellular and animal models. Our results reveal the distinctions in inflammatory responses triggered by SARS-CoV-2 and SARS-CoV, highlighting the significance of specific amino acid alterations in influencing viral pathogenicity.

Editorial Expression of Concern: DCAF12 promotes apoptosis and inhibits NF-κB activation by acting as an endogenous antagonist of IAPs.

Editorial Expression of Concern: DCAF12 promotes apoptosis and inhibits NF-κB activation by acting as an endogenous antagonist of IAPs.

Inhibition of AhR disrupts intestinal epithelial barrier and induces intestinal injury by activating NF-κB in COPD.

Chronic obstructive pulmonary disease (COPD) is frequently associated with intestinal comorbidities. Damage to the intestinal barrier plays a crucial role in these disorders, leading to increased intestinal and systemic inflammation, and thereby promoting the progression of COPD. This study aims to investigate the mechanism of intestinal epithelial barrier damage, focusing on the roles of the Aryl hydrocarbon Receptor (AhR) and NF-κB in COPD-related intestinal damage. A COPD rat model was induced by cigarette smoke and bacterial infection, while Caco-2/HT29 intestinal epithelial cells were treated with TNF-α or IL-1β to assess intestinal disorder and the underlying mechanisms of barrier damage. COPD rats exhibited significant lung function decline, pathological damage, and inflammatory response in lung tissues. Additionally, significant intestinal injury was observed, accompanied by pronounced colonic pathological damage, an enhanced inflammatory response, and intestinal barrier disruption. This was evidenced by decreased expression of apical junction proteins and elevated serum diamine oxidase levels. Pro-inflammatory cytokines TNF-α or IL-1β significantly downregulated the expression of apical junction proteins in Caco-2/HT29 cells, reduced transepithelial electrical resistance of Caco-2 cells, and increased FD-4 permeability. Moreover, TNF-α or IL-1β induction activated NF-κB in Caco-2/HT29 cells, with a similar activation observed in the colonic tissues of COPD rats. The NF-κB inhibitor PDTC suppressed this activation and protected against intestinal epithelial barrier damage. Furthermore, AhR inhibition was observed both invitro and invivo. The AhR activator FICZ inhibited NF-κB activation and mitigated intestinal epithelial barrier damage, whereas the AhR inhibitor CH223191 inhibited AhR and exacerbated intestinal epithelial barrier damage by facilitating NF-κB activation. However, the NF-κB inhibitor PDTC did not significantly affect AhR. Additionally, TNF-α/IL-1β inhibited the binding of AhR and p-NF-κB. Consequently, AhR inhibition can downregulate the expression of apical junction proteins, probably through activation of NF-κB signaling leading to intestinal epithelial barrier damage. This study confirmed the presence of lesions in the lungs and intestines of COPD rats, as well as the associated damage to the intestinal epithelial barrier. The inhibition of AhR followed by the activation of NF-κB has been identified as a critical mechanism underlying the injury to the intestinal epithelial barrier.

Chloroform Extract from Fermented Viola mandshurica Regulates LPS-Induced Inflammation Response in RAW 264.7 Cells by Inhibiting iNOS and COX-2.

Inflammatory is a crucial part of the immune system of body protect it from harmful invaders, such as bacteria, viruses, and other foreign substances. In this study, the effects of chloroform extract of fermented Viola mandshurica (CEFV) on lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 macrophages were investigated. The CEFV significantly inhibited NO production and reduced the expression of inducible nitric oxide synthase (iNOS) at both protein and mRNA levels in a dose-dependent manner. Also, CEFV decreased PGE2 production, suppressed COX-2 expression, and inhibited the activation of the ERK and JNK pathways but not the p38 pathway. Taken together, CEFV suppressed NF-κB activation, which is a key regulator in the inflammatory response. The main phenolic compounds identified in CEFV were tectoridin, luteolin, resveratrol, and hesperetin. Therefore, in this study, CEFC exhibits potent anti-inflammatory effects by downregulating the production of pro-inflammatory mediators and inhibiting key inflammatory pathway in RAW264.7 cells.

4-Aza Cyclopentenone Prostaglandin Analogues: Synthesis and NF-κB Inhibitory Activities.

Inspired by the cyclopentenone family of prostaglandins, a series of 4-aza, cross-conjugated cyclopentenones is described. Synthesised from N-protected (4R)-aza-cyclopentenone 5, the exocyclic alkene was installed using a modified Baylis-Hillman type aldol reaction, whereby carbon-carbon bond formation is accompanied by dehydration. In this manner octanal and octenal, for example, can be introduced to mimic the ω-group present in the natural prostaglandins. Similarly, a focused range of alternative substituents were introduced using different aldehydes and ketones. The presence of the tert-butyloxycarbonyl (Boc) group on the 4-amino-cyclopentenone substituent enabled subsequent derivatisation and various electrophiles were successfully incorporated. The ability of the family of 4-amino functionalised cross-conjugated cyclopentenones to block activation of nuclear factor-kappa B (NF-κB) was studied and compared with the natural prostanoid, Δ12,14-15-deoxy-PGJ2 (2). Thereafter, the synthesis of a series of thiol adducts from these compounds were prepared and similarly evaluated biologically. The adducts showed comparable and, on occasion, more potent inhibition of NF-κB than their cyclopentenone precursors and generally demonstrated diminished cytotoxicity. For example, cross-conjugated dieneone 12 inhibited the activation of NF-κB with an IC50 value of 6.2 μM, whereas its endocyclic N-Boc (27) and N-acetyl (28) cysteine adducts blocked NF-κB activity with values of 1.0 and 8.0 μM respectively.

Harnessing Nature's Arsenal: Phytoconstituents targeting mediators involved in pathogenesis of Asthma

Abstract: Asthma is a persistent respiratory disorder characterized by inflammation and con-striction of the air passages, resulting in recurrent symptoms, including difficulty breathing, wheezing, coughing, and a sensation of tightness in the chest. It requires ongoing management through medications and lifestyle adjustments. The use of natural bioactive compounds in asthma management is on the rise. Researchers are increasingly exploring the potential of compounds derived from plants and herbs, such as quercetin, resveratrol, and Boswellia ex-tracts, for their anti-inflammatory and bronchodilator properties. Compounds like quercetin and resveratrol are known to reduce inflammation by inhibiting enzymes like PDE4 and LOX-5, which play key roles in asthma-related inflammation. They can additionally regulate im-mune reactions by inhibiting the secretion of pro-inflammatory cytokines like “IL-6, IL-5, and IL-4”. Additionally, some compounds, like those found in Boswellia extracts, inhibit NF-κB activation, which further reduces the production of inflammatory mediators. These natural remedies offer a promising avenue for complementing traditional asthma treatments, potential-ly providing relief from symptoms and reducing the reliance on synthetic drugs. The aim of this review is to offer an outline of well-researched plant-derived phytoconstituents that influ-ence cellular activity to control inflammatory mediators associated with asthma. Nevertheless, additional high-quality research is essential to validate the clinical effectiveness of plant-based treatments for asthma.

Retraction notice to "Helenalin from Centipeda minima ameliorates acute hepatic injury by protecting mitochondria function, activating Nrf2 pathway and inhibiting NF-κB activation" [Biomed. Pharmacother.119 (2019) 109435

Retraction notice to "Helenalin from Centipeda minima ameliorates acute hepatic injury by protecting mitochondria function, activating Nrf2 pathway and inhibiting NF-κB activation" [Biomed. Pharmacother.119 (2019) 109435