Inhibition Of NF-κB Activation Research Articles

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 MESSAGES: I3A 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.

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.

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

Poria cocos polysaccharides alleviate dextran sulphate sodium-induced ulcerative colitis in mice by modulating intestinal inflammatory responses and microbial dysbiosis

Poria cocos polysaccharide (PCP), one of the main active components of P. cocos, is extensively used worldwide and exhibits strong pharmacological effects. However, whether PCP can attenuate inflammatory bowel disease remains unclear. In this study, we assessed the effects of PCP supplementation on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in mice. We found that PCP supplementation mitigated UC symptoms in DSS-treated mice, as evidenced by reductions in body weight loss, colon length shortening and disease activity index score. Importantly, PCP supplementation enhanced colonic barrier integrity by increasing tight junction protein abundance and exerted anti-inflammatory effects by suppressing nuclear factor-κB (NF-κB) activation in DSS-treated mice. Furthermore, PCP supplementation reversed DSS-induced dysbiosis in colonic microbiota by increasing the colonic abundance of beneficial bacteria (e.g. Akkermansiaceae) and decreasing the colonic abundance of harmful bacteria (e.g. Erysipelotrichaceae) in DSS-treated mice. Although PCP supplementation failed to ameliorate DSS-induced UC in antibiotic-treated mice, faecal microbiota transplantation from PCP-administered mice ameliorated DSS-induced UC in antibiotic-treated mice. In summary, PCP alleviates UC in mice by attenuating intestinal inflammation via the inhibition of NF-κB activation and modulating the intestinal microbiota.

Mollugin Derivatives as Anti-Inflammatory Agents: Design, Synthesis, and NF-κB Inhibition.

Nuclear factor κB (NF-κB) is a key inducible transcription factor that controls a large number of genes involved in inflammatory and immune processes. The entire inflammation-mediated process uses NF-κB as a hub, and inflammatory gene transcription and expression can be decreased by blocking the NF-κB signaling pathway, thereby reducing inflammatory damage. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation. Here, we designed and synthesized 27 mollugin derivatives and evaluated the anti-inflammatory activity against NF-κB transcription. Most of the compounds exhibited potent anti-inflammatory activity, and compound 5k was the most potent with 81.77% inhibition after intraperitoneal administration, which was significantly more potent than mollugin (49.72%), ibuprofen (47.51%), and mesalazine (47.24%). Investigation of the mechanism of action indicated that 5k down-regulated NF-κB expression, possibly by suppressing LPS-induced expression of the p65 protein. ADMET prediction analysis indicated that compounds 5h and 5k showed good pharmacokinetic properties. The relationship between the structures of the synthesized compounds and the NF-κB inhibitory activity was rationalized using molecular docking simulation experiments. Overall, these results provide an initial basis for the development of 5h and 5k as potential anti-inflammatory agents.

Cinnamaldehyde-Mediated Suppression of MMP-13, COX-2, and IL-6 Through MAPK and NF-κB Signaling Inhibition in Chondrocytes and Synoviocytes Under Inflammatory Conditions.

Inflammatory disorders encompass a range of conditions, including osteoarthritis (OA), characterized by the body's heightened immune response to diverse stimuli. OA is a prevalent degenerative joint disease characterized by the progressive deterioration of joint cartilage and subchondral bone, leading to pain, limited mobility, and physical disability. Synovitis, the inflammation of the synovial membrane, is increasingly recognized as a critical factor in OA pathogenesis and progression. This study evaluates the therapeutic potential of cinnamaldehyde (CA), a bioactive compound derived from cinnamon, on synovial and articular inflammation in OA. Given CA's established anti-inflammatory, antioxidant, and antibacterial properties, this research explores its specific impact on OA and synovitis. The cytotoxicity of CA was assessed using a CCK-8 assay in human IL-1β pretreated chondrocytes and synoviocytes, which serve as in vitro models of OA and synovitis. The study further examined the effects of CA on the expression of proinflammatory cytokines, including IL-6, COX-2, and TNF-α, utilizing multiple analytical techniques. Additionally, the production of matrix metalloproteinases (MMP-3 and MMP-13) and the activation of the NF-κB signaling pathway, particularly the phosphorylation of p65 (pp65), were investigated. The role of the NF-κB inhibitor 5HPP-33 and its downstream effects on gene expression, including COX-2 and IL-6, as well as the MAPK pathway components (p38, ERK, and JNK), were also explored. An MEK inhibitor (U0126) was employed to assess its downstream impact on COX-2 and IL-6 expressions. The results demonstrated that CA significantly inhibited the expression of proinflammatory cytokines and suppressed NF-κB activation in IL-1β pretreated chondrocytes and synoviocytes. These findings suggest that CA, in a dose-dependent manner, may serve as an effective therapeutic agent for preventing OA and synovitis, offering valuable insights into its potential role in managing synovial inflammation and OA.

Triptolide induces apoptosis of glioma cells by inhibiting NF-κB activation during oxidative stress

Glioma is a common and fatal malignant primary brain tumor. Radiotherapy and first-line chemotherapy have little effect on the survival rate of patients, requiring alternative therapies. The main active ingredient of Tripterygium wilfordii Hook. F. triptolide (TP) has been shown to have anti-inflammatory and anti-proliferative properties, along with a wide range of anticancer activities. This study aimed to investigate the molecular mechanisms of triptolide in glioma treatment through network pharmacology and experimental validation. Cell viability was first assessed using Cell Counting Kit-8 (CCK8), followed by cell scratch assay and cell migration ability. Apoptosis-related markers, including TUNEL staining, Bcl-2-associated X protein (Bax), and B-cell lymphoma-2 (Bcl-2), were detected. Network pharmacology was used to predict the key targets of glioma, detect its signal pathways, screen the key components and targets for molecular docking, and explore the signaling pathways of TP. Lastly, immunofluorescence assays and ELISA were performed to elucidate the underlying mechanistic pathways. The network pharmacology data suggested that TP may inhibit glioma proliferation by regulating the signaling pathway of the nuclear factor kappa-B (NF-κB). The results showed that the underlying mechanism involved the regulation of the NF-κB signaling pathway to promote the generation of reactive oxygen species, thereby enhancing oxidative stress response and promoting cell apoptosis.

Anti-Inflammatory Effects of Apostichopus japonicus Extract in Porphyromonas gingivalis-Stimulated RAW 264.7 Cells.

Apostichopus japonicus has been used both as a food and in traditional medicine. However, its anti-inflammatory effects in periodontal diseases have not been studied. We examined the anti-inflammatory properties of Apostichopus japonicus extract in RAW 264.7 cells stimulated by Porphyromonas gingivalis. The cytotoxicity of Apostichopus japonicus extract was evaluated using the MTS assay. Its effect on NO production was then measured using the NO assay. The mRNA expression of inducible nitric oxide synthase (iNOS) and the pro-inflammatory cytokines IL-1β and IL-6 were assessed using quantitative real-time PCR (qRT-PCR). Western blotting was performed to investigate the expression of regulatory proteins involved in the NF-κB and MAPK signaling pathways. Apostichopus japonicus extract significantly inhibited NO production without cytotoxicity in RAW 264.7 cells. Following Porphyromonas gingivalis stimulation, treatment with the extract decreased iNOS mRNA expression and protein levels, which are responsible for NO production. The extract also suppressed the mRNA expression of pro-inflammatory cytokines. Additionally, Apostichopus japonicus extract inhibited NF-κB activation by regulating signaling molecules such as IKK and IκBα, while also preventing the phosphorylation of MAPK, including ERK, p38, and JNK, showing anti-inflammatory potential. Therefore, it may be a promising natural candidate for the development of new preventive and therapeutic strategies for periodontitis.

Panduratin A mitigates inflammation and oxidative stress in DSS-induced colitis mice model.

This study explored Panduratin A's protective effects against DSS-induced colitis in mice, focusing on reducing inflammation and oxidative stress in the colon. Mice were treated with dextran sodium sulfate (DSS) and Panduratin A (3, 6, 18 mg/kg), and changes in body weight, colon length, Disease Activity Index (DAI), histopathology, inflammation markers including tumor necrosis factor- α (TNF-α), Interleukin-1 β (IL-1β), Myeloperoxidase (MPO), and oxidative stress, Malondialdehyde (MDA) were evaluated. Panduratin A significantly reversed DSS-induced symptoms, including body weight loss, colonic length shortening, and DAI increase, while reducing histopathological damage. It lowered inflammatory markers and oxidative stress, suppressed NF-κB activation, and enhanced Nrf2 and HO-1 expression. Panduratin A shows promise as a colitis treatment, warranting further research for broader clinical application.

Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote colonization.

Gonorrhea, caused by the human-restricted pathogen Neisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women's cervixes without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both pro- (IL-1β and TNF-α) and anti-inflammatory (IL-10) cytokines during the first 24-h. Cytokine induction required GC expression of Opa isoforms that bind the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-κB activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-κB activation, which reduced GC-induced IL-1β and TNF-α, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, decreased GC-induced IL-10 secretion. These results show that GC induce local secretion of IL-10, a potent anti-inflammatory cytokine, at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding, providing a potential mechanism for GC asymptomatic colonization in women.

The Therapeutic Potential of Agarwood as an Antimicrobial and Anti-Inflammatory Agent: A Scoping Review.

Microorganisms such as bacteria, viruses, and fungi are frequently the cause of infections. Antimicrobial agents, such as antibiotics, antivirals, and antifungals, are used to target and eliminate these infectious agents. On the other hand, inflammation is a natural response of the immune system to injury, infection, or irritation. Although herbal remedies have been used to treat these conditions for centuries and can be effective in certain situations, it is crucial to use them with caution. Not all herbal remedies are supported by scientific evidence, and their safety and efficacy can vary. Thus, we conducted this review to determine the potential health benefits of agarwood as an antimicrobial and anti-inflammatory agent. Three databases (PubMed, Scopus, and Google Scholar) were used to search for original papers submitted between 2013 and 2023, using the Medical Subject Heading (MeSH) terms "agar-wood" crossed with the terms "antimicrobial" and/or "anti-inflammatory". Synonyms and relevant search terms were also searched. The most-studied agarwood for antimicrobial and anti-inflammatory agents is Aquilaria sinensis. Some studies have shown its potential application as a potent inhibitor of fungi, including Lasiodiplodia theobromae, Fusarium oxysporum, and Candida albicans. Moreover, it is capable of inhibiting Bacillus subtilis and Staphylococcus aureus activities. Several chromones detected in agarwood have been shown to inhibit NF-κB activation, LPS-induced NO production, and superoxide anion generation. In conclusion, more research is needed, particularly regarding future intervention studies, to enhance our knowledge and understanding of agarwood and its isolates. This review reveals that despite the absence of clinical trials, agarwood exhibits antimicrobial and anti-inflammatory properties.

CTNI-44. NCT03643549 PHASE IB/II TRIAL: EFFICACY, SAFETY, AND BIOLOGICAL MECHANISMS OF OBJECTIVE RESPONSES IN RECURRENT GBM PATIENTS WITH UNMETHYLATED MGMT PROMOTER TREATED WITH SEQUENTIAL BORTEZOMIB AND TEMOZOLOMIDE

Abstract BACKGROUND Glioblastoma (GBM) is amongst the deadliest malignancies in adults, but especially for patients with unmethylated MGMT promoter (uMGMT) who gain limited benefit from the standard treatment. We previously demonstrated that proteosome inhibitor bortezomib (BTZ), inhibited NFkB activation,depleted MGMT protein and sensitized uMGMT GBM cells to Temozolomide (TMZ). Thus, a phase I/II trial testing sequential combination BTZ+TMZ was launched to investigate safety and clinical benefit. METHODS Recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, KPS≥70 and radiologically measurable lesions were enrolled. The trial was powered for n=63 patients compared with n=102 historical controls. Patients received BTZ 1.3mg/m² IV on days 1, 4, and 7 of each 4-week cycle, starting on day 3 with oral 200mg/m² TMZ for 5 days/week. Whole exome sequencing (WES) of tumor DNA was conducted to identify genetic changes and LC-MS/MS used to asses proteomic changes in plasma collected during treatment. RESULTS As of January 2024, 54 patients (median 55y (25-70); 38 males, 16 females) were treated. The median KPS 90 (range 70-100) and NANO score was 1 (range 0-7). QoL was preserved, with mild /moderate adverse events. Adjusted analyses showed overall survival (OS) of 16.2 months compared to 8.4 months for uMGMT control patients, HR0.48, 95%CI[1.057-2.74],P=0.028. Objective radiological responses stable disease or better were observed in 22% (12/54) patients. Survival from recruitment was 10.5 months for responders vs. 4.8 months for rest of cohort, P=0.054 HR2.55, 95%CI[0.984-5.94]. Preliminary data indicate 78% (7/9) of responders harboured amplified EGFR vs. 38% in rest-of-the patients. The responders differentially expressed proteins critical for cellular processes, including ADAMTSL4, NCAM1, AZGP1, MMP2, CD163, and IL6ST. CONCLUSION Sequential BTZ+TMZ therapy is safe, effective and showed clinical benefit. EGFR amplification may be a predictive biomarker for response through NFκB activation, that is targeted by BTZ thereby depleting MGMT protein and enhancing treatment efficacy. Sequential BTZ+TMZ treamtment may represent additional treatment option at recurrence.

Repurposing Tolfenamic Acid to Anchor the Uncharacterized Pocket of the PUB Domain for Proteolysis of the Atypical E3 Ligase HOIP.

The E3 ligase HOIP is vital for the NF-κB pathway and is implicated in cancer and immunity. However, it remains challenging to achieve high selectivity by directly targeting the conserved catalytic RBR domain of HOIP. Herein, we identified four low-molecular-weight compounds that bind to an uncharacterized pocket of the HOIP PUB domain (HOIPPUB). The complex structure facilitated the discovery of the first single-digit micromolar ligand of HOIPPUB, tolfenamic acid, which exhibited over 30-fold selectivity due to the low sequence identity of the uncharacterized pocket of HOIPPUB. Although tolfenamic acid did not block the substrate recognition and linear ubiquitination activity of HOIP, a ligand of the uncharacterized PUB pocket of HOIP (LUPH), by chemical linking pomalidomide with tolfenamic acid, degraded HOIP, reduced NEMO ubiquitination and p65 phosphorylation, and eventually inhibited NF-κB activation and breast cancer cell proliferation. Our work proposes an alternative strategy to target the nonfunctional pocket of the PUB domain with high sequence diversity to promote HOIP degradation, rather than targeting the conserved RBR domain to block the catalytic function of HOIP.

Potential Strategies for Overcoming Drug Resistance Pathways Using Propolis and Its Polyphenolic/Flavonoid Compounds in Combination with Chemotherapy and Radiotherapy.

Conventional cancer treatments include surgical resection, chemotherapy, hyperthermia, immunotherapy, hormone therapy, and locally targeted therapies such as radiation therapy. Standard cancer therapies often require the use of multiple agents, which can activate nuclear factor kappa B (NF-κB) in tumor cells, leading to reduced cell death and increased drug resistance. Moreover, the use of multiple agents also contributes to added toxicity, resulting in poor treatment outcomes. Cancer cells gradually develop resistance to almost all chemotherapeutics through various mechanisms, such as drug efflux, alterations in drug metabolism and transport, changes in signal transduction pathways, enhanced DNA repair capacity, evasion of apoptosis, increased mutations, reactivation of drug targets, interaction with the cancer microenvironment, cancer cell-stroma interactions, epithelial-mesenchymal transition (EMT)-mediated chemoresistance, epigenetic modifications, metabolic alterations, and the effect of cancer stem cells (CSCs). Developing new strategies to improve chemotherapy sensitivity while minimizing side effects is essential for achieving better therapeutic outcomes and enhancing patients' quality of life. One promising approach involves combining conventional cancer treatments with propolis and its flavonoids. These natural compounds may enhance tumor response to treatment while reducing toxicity. Propolis and its components can sensitize cancer cells to chemotherapeutic agents, likely by inhibiting NF-κB activation, reprogramming tumor-associated macrophages (TAMs; an M2-like phenotype), and thereby reducing the release of matrix metalloproteinase (MMP)-9, cytokines, chemokines, and the vascular endothelial growth factor (VEGF). By reducing TAMs, propolis and its components may also overcome EMT-mediated chemoresistance, disrupt the crosstalk between macrophages and CSCs, inhibit the maintenance of stemness, and reverse acquired immunosuppression, thus promoting an antitumor response mediated by cytotoxic T-cells. This review highlights the potential of flavonoids to modulate the responsiveness of cancer to conventional treatment modalities. The evidence suggests that novel therapeutic strategies incorporating flavonoids could be developed to improve treatment outcomes. The positive effects of combining propolis with chemotherapeutics include reduced cytotoxicity to peripheral blood leukocytes, liver, and kidney cells. Therefore, polyphenolic/flavonoid components may hold potential for use in combination with chemotherapeutic agents in the clinical treatment of various types of cancers.

Translating molecular insights into clinical success: alkaloid-based therapies for leukemia.

Alkaloids, a diverse class of naturally occurring compounds, have shown significant potential in the treatment of leukemia by targeting key molecular pathways and cellular mechanisms. This review discusses several potent alkaloids, such as homoharringtonine, chaetominine, matrine, and jerantinine B, which induce apoptosis, cell cycle arrest, and autophagy and inhibit signaling pathways including PI3K/Akt/mTOR, MAPK, and NF-κB. For instance, homoharringtonine induces apoptosis in acute myeloid leukemia (AML) cells via the SP1/TET1/5hmC/FLT3/MYC axis, while chaetominine enhances chemosensitivity by inhibiting the PI3K/Akt/Nrf2 pathway. In addition, targeting leukemia stem cells (LSCs) with alkaloids such as zalypsis offers promise due to its ability to induce apoptosis without significantly affecting normal hematopoietic stem cells. The modulation of the immune response, such as the inhibition of NF-κB activation by noscapine, further underscores the potential of alkaloids in overcoming treatment resistance. Various studies have demonstrated the efficacy of alkaloids across different leukemia types. For example, jerantinine B targets AML cells, while vincristine has shown success in lymphocytic leukemia. Clinical trials have also highlighted the benefits of alkaloids, including homoharringtonine, which achieved a 79.9% complete remission rate in AML patients. However, adverse effects such as neutropenia and hepatotoxicity necessitate careful management. Collectively, these findings emphasize the need for further research into alkaloid-based combination therapies to enhance efficacy and minimize toxicity, providing a promising avenue for innovative leukemia treatments.