Cervical cancer is a leading cause of cancer-related deaths, with cervical squamous cell carcinoma (CSCC) accounting for a majority of cases. Circular RNAs (circRNAs) have been repeatedly suggested as crucial effectors in modulating the development of multiple malignancies. The expression of circ_0002762 was predicted to be high in CSCC tissues in GEO dataset, but the functional role and underlying regulatory mechanism of circ_0002762 in CSCC was unclear. By series of functional assays and mechanism assays, supported by bioinformatics analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis and western blot assays, we identified that circ_0002762 aberrantly up-regulated in CSCC, promoting CSCC cell migration and invasion. Mechanically, circ_0002762 was transcriptionally activated by Fork head box A1 (FOXA1). Moreover, the involvement of nuclear factor kappa B (NF-kB) signalling in circ_0002762 regulation mechanism in CSCC cells was ascertained. Additionally, circ_0002762, predominantly accumulated in cell cytoplasm, was proved to recruit Mov10 RISC complex RNA helicase (MOV10) to enhance RelA mRNA stability, thus affecting CSCC cell migration and invasion. In summary, FOXA1-mediated circ_0002762 up-regulation could enhance the migratory and invasive abilities of CSCC cells via the MOV10/RelA/NF-kB pathway.

From tumorigenesis to the establishment of local or metastatic high-grade tumours, an integral part of the cellular lifespan relies on various signalling pathways. Particular pathways that allow cells to proliferate by creating a network of new blood vessels have been documented, whereas other pathways are primarily involved with a migration to distant body parts, partially through the process of epithelial-mesenchymal transition (EMT). This review will discuss the different signalling pathways, such as TGF-β, Cripto-1, Wnt pathways, Hedgehog, Notch and NF-κB pathways, and how they promote tumour initiation and progression by influencing diverse cellular processes and EMT in general and in benign and malignant prostate tumours. This review will discuss only the critical pathways. Therefore, many other types of signalling pathways which are related to prostate cancer will not be discussed. Possibilities for further investigation will be mentioned, as many underlying mechanisms involved in these pathways have potential as targets in future tumour therapy. This review will also introduce some novel clinical trials relating to the inhibition of signalling pathways and their clinical outcomes.

Mechanical stress is a pivotal factor in the development of knee osteoarthritis (KOA). Piezo1, an innovative mechanosensitive ion channel, plays a key role in detecting variations in mechanical stress and transforming them into electrical signals. This research focuses on examining how Piezo1 influences synovial inflammation and fibrosis induced by mechanical stress in KOA, as well as delving into the potential underlying mechanisms. In vivo, pathological changes and immunohistochemical staining were conducted on both normal and overexercise rat synovial tissues to analyze the expression of Piezo1 and the NF-κB/NLRP3 pathways. In vitro utilized a cell stretcher to replicate the mechanical conditions seen in KOA. Levels of pro-inflammatory cytokines and fibrosis-related markers were assessed to investigate the impact of Piezo1 on mechanical stress in fibroblast-like synoviocytes (FLS). Subsequently, following cell stretching interventions, the effects on synovial inflammation and fibrosis were observed with the use of the Piezo1 inhibitor GsMTx4 or the NLRP3 inhibitor MCC950. Mechanical stress significantly promoted the activation of Piezo1, increased the phosphorylation ratio of p65, and elevated the levels of NLRP3, caspase-1, ASC, GSDMD, IL-1β, IL-18, IL-6, and TNF-α. Both in vitro and in vivo, mechanical stress also promoted the occurrence and development of synovial fibrosis, with significant increases in the expression levels of fibrosis-related markers. Under mechanical stress overload, upregulation of Piezo1 can promote the secretion of pro-inflammatory cytokines and the fibrotic process in synovium through the NF-κB/NLRP3 signaling pathway.

Acute kidney injury (AKI) is a critical condition marked by a sudden decline in kidney function, frequently resulting in high morbidity and mortality. Renal ischemia-reperfusion injury (IRI) is a leading cause of AKI, characterized by reactive oxygen species (ROS) release, cell death, and inflammation. Alpha-lipoamide (ALM), a neutral derivative of lipoic acid, is recognized for its antioxidant and organ-protective properties. Prior research indicates that ALM mitigates diabetic nephropathy by decreasing ROS. This study examines ALM's protective role in a mouse model of IRI-induced AKI and its mechanisms using mouse renal tubular epithelial cells (mRTECs). Mice were subjected to IRI by renal artery occlusion for 30 min, followed by reperfusion, and treated with ALM (100 or 200 mg/kg) for three days before surgery. In vitro, mRTECs were exposed to hypoxia/reoxygenation injury, with ALM (200 μM) applied to assess oxidative stress. ALM significantly decreased serum creatinine levels, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury marker-1 (KIM-1), mitigated kidney injury, and reduced both ROS and Malondialdehyde(MDA) content. ALM increased glutathione (GSH) levels and upregulated SIRT1 expression. This resulted in the deacetylation of the NF-κB p65 subunit, facilitating its nuclear export, suppressing NF-κB signaling, and reducing the expression of the inflammatory marker NLRP3. ALM decreased the levels of pyroptosis-related proteins (Caspase-1, GSDMD, and IL-1β), which in turn suppressed IL-6 secretion and macrophage infiltration. These findings suggest that ALM reduces inflammation and pyroptosis-associated proteins by promoting the upregulation of SIRT1, ultimately preventing IRI-mediated renal tubular epithelial cell damage and inflammation.

Bacterial infections are a major cause of death worldwide. However, it is difficult to track the in vivo dynamics of pathogenic bacteria and the expression of inflammatory factors in infected animals throughout the infection process. This work used Pseudomonas aeruginosa as an infection model and utilised genetically bioluminescence-labeled P. aeruginosa and hydrodynamic transfection technology to construct a liver-visual NF-κB, IL-6, TNF-α inflammation model, thereby enabling the tracking of the dynamic spread of P. aeruginosa in infected animals and the transient activation of the liver inflammation response. The results showed that P. aeruginosa introduced via the tail vein initially accumulates in the liver and gradually activates NF-κB, IL-6, and TNF-α. Subsequently, the P. aeruginosa infection gradually spreads to the lungs and small intestine, and final proliferation leads to septic death in mice. During the infection process, we observed a strictly negative correlation between platelet activation and bacterial proliferation; the higher the degree of platelet activation, the stronger the inhibitory effect on bacterial proliferation and liver inflammation. In conclusion, this bioluminescence-based in vivo imaging technique offers new opportunities to investigate the innate immune response in controlling pathogenic infections.

Neferine is a bisbenzylisoquinoline alkaloid derived from the seed embryo of Nelumbo nucifera, a traditional Chinese medicine. It has been extensively studied for its therapeutic potential in various disease models. Extensive research has highlighted its diverse pharmacological activities, including antitumor, anti‑inflammatory, anti‑fibrosis, anti‑oxidative stress, anti‑platelet aggregation and anti‑arrhythmic effects. The present review, however, focuses on the anti‑inflammatory properties of neferine, emphasizing its fundamental mechanisms as demonstrated in both in vivo and in vitro studies. By critically evaluating its effect on inflammation and the underlying pathways, this review aims to provide a comprehensive understanding of the potential of neferine in the management of inflammatory diseases. Furthermore, it seeks to establish a foundational framework for the future development of neferine as a novel therapeutic agent for inflammatory conditions.

Acute pancreatitis (AP) is an acute inflammation of the pancreas, which is considered a prevalent gastrointestinal emergency characterized by rapid progression and significant mortality. Currently available medications primarily serve as adjunctive therapies, yielding suboptimal therapeutic outcomes. Consequently, there remains a dearth of specific and efficient treatment modalities for AP. In recent years, nanomedicine-based treatment strategies have exhibited significant potential as drug therapy approaches for pancreatitis. The distinctive features of the AP microenvironment encompass aberrant activation of pancreatic enzymes, oxidative stress induced by elevated reactive oxygen species levels, and excessive production of pro-inflammatory cytokines; these factors offer promising targeted sites for early diagnosis and treatment using nanomedicine. This article comprehensively delineates the pathological microenvironmental characteristics associated with AP while highlighting the application of microenvironment-responsive strategies in nanodrug delivery systems for its treatment, thereby providing insights into future prospects.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical player in cancer pathogenesis. Concurrently, inflammation, a key biological response to tissue injury or infection, significantly influences cancer development and progression. The interplay between ferroptosis and inflammation represents a promising yet underexplored area of research. This review synthesizes recent advances in understanding the molecular mechanisms governing their interaction, emphasizing how ferroptosis triggers inflammatory responses and how inflammatory mediators, such as TNF-α, regulate ferroptosis through iron metabolism and lipid peroxidation pathways. Key molecular targets within the ferroptosis-inflammation axis, including GPX4, ACSL4, and the NF-κB signaling pathway, offer therapeutic potential for cancer treatment. By modulating these targets, it may be possible to enhance ferroptosis and fine-tune inflammatory responses, thereby improving therapeutic outcomes. Additionally, this review explores the broader implications of targeting the ferroptosis-inflammation interplay in disease treatment, highlighting opportunities for developing innovative strategies to combat cancer. By bridging the gap in current knowledge, this review provides a comprehensive resource for researchers and clinicians, offering insights into the therapeutic potential of this intricate biological relationship.

Oxidative stress (OS) is a key pathophysiological mechanism in multiple sclerosis (MS). However, the underlying mechanisms by which OS triggered MS remain unknown. To identify potential causal targets of 1216 OS-related genes for MS, a summary-data-based Mendelian randomization (SMR) method was applied. Given that genes can exert their biological functions through different omics levels, the multi-omics SMR integrating expression, methylation, and protein quantitative trait loci (eQTL, mQTL, and pQTL) of OS-related genes from blood and brain tissues was utilized. Bayesian colocalization test was conducted to examine potential regulatory mechanisms of QTL risk variation in MS. To verify the robustness of our results, we validated these findings in FinnGen cohort. Furthermore, the QTL evidence levels, colocalization findings, and replication cohort results were integrated and potential target genes were categorized into three levels. Consequently, three genes (BACH2, TRAF3, and MAPK3) were identified as potential contributors to MS in blood, and four genes (HMGCL, TSFM, TRAF3 and HLA-B) were identified as potential contributors to MS in brain tissue. Additionally, HMGCL and TSFM from brain tissue were supported by first-level evidence related to MS and were validated via in vitro experiments. This research not only contributed to fundamental research of OS in MS but also supported the identification of potential targets for clinical interventions in MS.

A new series of xanthine-based derivatives were designed, synthesized, and investigated to achieve promising antifibrotic and antioxidant agents for management of liver injury. Structure-based optimizations of the methylxanthine-based KMUP-1 (IX) were performed for inhibiting NF-κB activation pathway. All the newly designed xanthine derivatives 3, 4, 5, 6a-d, 7a-d, and 9a-d were in vitro screened for the antioxidant activity using the DPPH method. Compounds 4 and 5 showed the highest antioxidant activity with an IC50 of 28.02 and 36.02 μM, respectively. Compounds 9c and 9d retained a promising interception of the NF-κB activation pathway in molecular docking simulations within I-κB kinase α (IKKα) crystal structure (PDB ID: 5EBZ). Subsequently, compounds 9c and 9d were evaluated for their in vivo antifibrotic and chemoprotective activity using CCl4-induced hepatic fibrosis rat model. Compounds 9c and 9d successfully ameliorated liver fibrosis, as evidenced by the improved liver histopathological examination and liver enzyme activity levels. Compounds 9c and 9d were evaluated for their effects on mRNA expression levels of key genes involved in liver fibrosis via real-time PCR assays. Compound 9c exhibited a greater inhibitory effect on the expression levels of NF-κB and HIF-1α and a more pronounced stimulation of Nrf2 than compound 9d. Moreover, all the new xanthine derivatives were screened for the cytotoxic activity against the NCI tumor cell lines. Compounds 9c and 9d revealed a non-significant cytotoxic activity against all the assayed tumor cell lines, which indicate their selectivity for the antifibrotic activity. While compounds 6a and 6c displayed promising selective activity against melanoma SK-MEL-5 cell line (GI = 125.6, 90.3 %, respectively), and breast T-47D cell line (GI =87.8, 80.6 %, respectively). The utilized design approach unveiled the versatility of xanthine scaffold to deliver potential antioxidant, liver antifibrotic and chemoprotective agents, along with anticancer candidates via structure modification and optimization.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Despite advances in targeted therapies and immunotherapy, which have improved survival rates, drug resistance and immune-related side effects continue to necessitate the development of new treatments. S-adenosylmethionine (SAM), a key metabolite in the methionine cycle, has indicated potential for cancer therapy and enhancing chemotherapy sensitivity. However, its effects on NSCLC remain undetermined. In our study, SAM inhibits NSCLC growth and enhances chemosensitivity both in vitro and in vivo. Mechanistic investigations revealed that SAM plays a significant regulatory role in autophagy and oxidative stress within NSCLC. Furthermore, we identified P62 as a critical target of SAM by constructing biotin-labeled SAM for immunocoprecipitation-mass spectrometry. Both in vitro and in vivo studies confirmed that P62 mediates SAM regulatory effects on NSCLC. Furthermore, by constructing truncated P62 expression plasmids for immunocoprecipitation experiments, we discovered that SAM inhibits the NF-κB signaling pathway by directly targeting the ZZ and TB domains of the P62 protein, thereby blocking autophagy and activating oxidative stress. These findings highlight SAM as a novel inhibitor of the P62/NF-κB axis and suggest that SAM could be a potential therapeutic agent for NSCLC.

The traditional action of Rabdosia rubescens (Hemsl.) H. Hara is heat-clearing and detoxifying, relieve sore throat, dissipate binds and disperse swelling. DLC, as an extract prepared from Rabdosiae Rubescentis Herba, could regulate the polarization of tumor associated macrophages (TAMs). For TAMs play an important role in the tumor microenvironment. It is worthy to further explore the mechanism of DLC on the polarized function of macrophages.

The aim of this study is to investigate the activity and molecular mechanisms of DLC on dissipating binds and dispersing swelling by modulating the gastric cancer microenvironment and macrophage polarization.

We conducted comprehensive qualitative and quantitative chromatographic analyses to characterize the main components of DLC. To evaluate its anti-tumor effects, immunofluorescence, MTT assay, plate cloning, transcriptomics analysis, western blotting, and siRNA knockdown experiments were performed to assess DLC's action on gastric cancer cell proliferation. Additionally, we utilized Trypan blue staining, a THP-1 and MGC-803 co-culture model, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and a mouse xenograft model with five distinct dosage groups to systematically investigate DLC's effects on macrophage polarization.

Key compounds in DLC were identified. The vivo tests demonstrated the tumor inhibition rate of the 5 g/kg DLC group reached 66.99 %, surpassing that of the 5-fluorouracil group (59.94 %). Mechanistically, DLC upregulated SIRT1 expression and suppressed NF-κB pathway, thereby preventing p65 from translocating into nuclear and modulating downstream p53/MDM2/USP7 signaling. Moreover, DLC enhanced M1 macrophage factors such as TNF-α, IL-6 while inhibiting M2 marker TGF-β, effectively repolarizing M2 TAMs toward an M1 phenotype. This effect was associated with suppressed protein expression of HIF-1α, p-p65, and p-PI3K.

This study provides insights into DLC's mechanisms in regulating tumor microenvironment remodeling and promoting macrophage polarization toward an anti-tumor phenotype. These results provide a solid basis for DLC's potential clinical treament in gastric cancer, highlighting its promise as a natural therapeutic agent.

Klebsiella pneumoniae (Kp) is a significant pathogen responsible for various clinical bacterial infections, including pneumonia, sepsis, and even death. However, effective treatment options remain limited due to the rising prevalence of antimicrobial resistance. Traditional Chinese medicine (TCM) has shown potential in the treatment of bacterial pneumonia. Qingfei Litan decoction (QFLT) has been reported to alleviate symptoms in patients with bacterial pneumonia, though its precise mechanisms in regulating pulmonary inflammation remain unclear.

This study aimed to investigate the therapeutic potential of QFLT in Kp-induced pneumonia and to elucidate its underlying molecular mechanisms.

In vivo, a murine pneumonia model was established through intratracheal instillation of Kp, and QFLT was administered by oral gavage. miR-146a-5p expression was downregulated by tail vein injection of an antagomir. The therapeutic effects of QFLT on pulmonary pathology, inflammatory factors, and miR-146a-5p expression were evaluated using qRT-PCR, flow cytometry, and other methods. Bioinformatics tools were employed to predict miR-146a-5p targets and associated inflammatory pathways. In vitro, an alveolar macrophage inflammation model was established by stimulating MH-S cells with heat-inactivated Klebsiella pneumoniae (iKp), followed by QFLT treatment. Inhibition of miR-146a-5p was achieved through transfection with specific inhibitors. The effects of QFLT on inflammatory responses, miR-146a-5p expression, and TLR4/MyD88/NF-κB signaling were assessed using qRT-PCR, Western blotting (WB) and other methods.

Kp infection significantly exacerbated pulmonary inflammation and downregulated miR-146a-5p expression in both lung tissues and MH-S cells. QFLT treatment alleviated inflammatory responses and upregulated miR-146a-5p expression. Bioinformatics analysis demonstrated that miR-146a-5p targeted TRAF6, a key mediator of the TLR4/MyD88/NF-κB pathway. Western blot analysis further confirmed that QFLT reduced Kp-induced upregulation of the TLR4/MyD88/NF-κB pathway in MH-S cells. Moreover, inhibition of miR-146a-5p exacerbated inflammatory responses in both lung tissues and MH-S cells, whereas QFLT treatment effectively attenuated these inflammatory effects. Furthermore, miR-146a-5p suppression resulted in elevated expression of proteins in the TLR4/MyD88/NF-κB signaling pathway in MH-S cells, while QFLT administration significantly reduced the expression levels of these signaling components.

These findings demonstrated that QFLT ameliorated Kp-induced pneumonia by modulating the TLR4/MyD88/NF-κB axis via miR-146a-5p.

Andrographolide, a labdane diterpenoid isolated from Andrographis paniculata, putatively functions through covalent inhibition of NF-κB, a transcription factor that modulates tumor survival and metastasis. Previous studies have found that functionalization of the C-19 hydroxyl alters the primary mode of action from inhibition of NF-κB to the modulation of the Wnt1/β-catenin signaling pathway. Here, we synthesized a series of twelve C-19 trityl and silyl ether analogs, including three novel substituted trityl analogs and four novel substituted silyl analogs of andrographolide. MTT assays revealed cell line selectivity between colorectal and breast cancer cells, which is consistent with known mechanisms of β-catenin-driven cell proliferation in colorectal cancer cell lines. Most compounds exhibited cell line specific antiproliferative activity in HCT-116 and HT-29 colorectal cancer cell lines. Specifically, within 24 h, C-19 analogs of andrographolide exhibit far more limited antiproliferative activity in MCF-7 breast cancer cells compared to HCT-116, HT-29, and MDA-MB-231 cells. Through in vitro TNF-α-dependent NF-κB reporter and Wnt1-dependent luciferase reporter assays, we observed that several analogs generally exhibit greater inhibitory activity compared to andrographolide. Fluorescence imaging demonstrated that cells treated with andrographolide and its C-19 analogs retained similar distributions of active β-catenin, but notable differences in antiproliferative potency upon co-delivery with GSK-3β inhibitor CHIR99021 indicate that several lead compounds exhibit attenuated biological activity selectively in HT-29 cells. Collectively, this work indicates that modest structural modifications at C-19 of andrographolide can have profound implications for its biological activity in mechanisms connected to its anticancer activity.

Malignant melanoma is the most lethal form of skin cancer, characterised by a poor survival rate. One of the key factors driving the aggressive growth of melanoma cells is the elevated expression of the proto-oncogene Bcl-3. This study aims to optimise, evaluate and characterise a second-generation Bcl-3 inhibitor, using melanoma as a model to demonstrate its potential therapeutic efficacy.

We synthesised and screened a series of structural analogues and selected A27, the most promising candidate for further investigation. We assessed whether A27 disrupted the interaction between Bcl-3 and its binding partner, p50, and examined the subsequent effects on cyclin D1 expression. Additionally, we evaluated the impact of A27 on melanoma cell proliferation and migration in vitro, as well as its therapeutic efficacy in various in vivo melanoma models.

Nuclear magnetic resonance (NMR) confirmed that A27 directly binds to Bcl-3, effectively inhibiting its function. By disrupting the Bcl-3/p50 interaction, A27 led to a significant down-regulation of cyclin D1 expression. In cellular assays, A27 markedly reduced proliferation and migration of melanoma cells. In vivo, treatment with A27 resulted in a substantial reduction in melanoma tumour growth, with no observed toxicity in treated animals.

At present, no other Bcl-3 inhibitors exist for clinical application in the field of oncology, and as a result, our novel findings provide a unique opportunity to develop a highly specific drug against malignant melanoma to meet an urgent clinical need.

Acute myeloid leukemia (AML) is a lethal hematologic malignancy caused by leukemic blasts that fail to mature normally. AML has a high relapse rate, primarily due to a small subset known as leukemic stem cells (LSCs). In this work, we investigated the ability of a Ru(II)-thymine complex (RTC) with the formula [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh3 = triphenylphosphine, Thy = thymine, and bipy = 2,2'-bipyridine) to suppress AML LSCs. RTC exhibited potent cytotoxicity toward both solid and hematologic malignancies and suppressed primary AML LSCs, as observed by the reduction in the CD34 +CD38- cell population. In the AML cell line KG-1a, which has an LSC-like population, RTC reduced the number of CD34 + and CD123 + cells. A reduction in leukemic blasts was detected in the bone marrow of RTC-treated NSG mice bearing KG-1a xenografts. Increased DNA fragmentation, YO-PRO-1 staining, active caspase-3 and cleaved PARP (Asp 214) levels, and mitochondrial superoxide levels were detected in RTC-treated KG-1a cells. The pancaspase inhibitor Z-VAD-(OMe)-FMK, but not the antioxidant N-acetylcysteine, partially prevented RTC-induced cell death in KG-1a cells, indicating that RTC induces caspase-mediated apoptosis in KG-1a cells via an oxidative stress-independent pathway. In molecular mechanism studies, transcripts of the NF-κB inhibitor NFKBIA were upregulated, and the level of NF-κB p65 phosphorylated at the Ser529 residue was reduced in RTC-treated KG-1a cells, indicating that RTC may inhibit NF-κB signaling. Overall, these results indicate the anti-AML potential of RTC in AML LSCs via the suppression of NF-κB signaling.

Sea buckthorn is a fruit rich in many bioactive compounds and shows the benefits of antioxidant, anti-inflammatory, anti-obesity, hepatoprotective, anti-tumor, and immunomodulatory properties, etc. The main bioactive compounds extracted and characterized in sea buckthorn are polyphenols, carotenoids, and functional lipids, which could provide health benefits by scavenging free radicals, regulating enzyme activities, and modulating signaling pathways, etc. Although there are many studies focused on the values of sea buckthorn, a comprehensive review on its chemical composition, functional mechanism and food application are still lacking. Thus, this paper aims to review the bioactive compounds in sea buckthorn, their underlying mechanisms for health benefits, as well as the applications in health food development. Particularly, the potential value of sea buckthorn and the novel technologies applied in previous studies are also discussed to improve its use for human health.

Metabolic reprogramming, particularly the Warburg effect, plays a crucial role in the onset and progression of tumors. The ubiquitin-conjugating enzyme E2 Q2 (UBE2Q2) has been identified overexpressed in hepatocellular carcinoma (HCC). Our aim was to determine if UBE2Q2 plays a role in regulating glycolysis, contributing to the carcinogenesis of HCC.

Bioinformatics analysis, western blot and qPCR were used to detect the expression of UBE2Q2. Functional experiments, proteomics analysis and subcutaneous tumors were constructed to find the biological function of UBE2Q2 in HCC. Co-immunoprecipitation, western blot and ubiquitination assays were used to identify the mechanisms involved.

We found a significant association between high UBE2Q2 expression and poor prognosis in HCC patients. Functionally, UBE2Q2 was shown to advance tumor progression in HCC through both in vitro assays and in vivo assessments. Proteomics analysis and glycolysis stress tests corroborated an increase in glycolytic activity due to UBE2Q2. Our findings reveal that UBE2Q2 augments glycolysis by boosting the transcription levels of hypoxia-inducible factor 1α (HIF1α), primarily through the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. At the molecular level, UBE2Q2 interaction with baculoviral IAP repeat-containing 2 (cIAP1) orchestrates the K63-linked ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1), which in turn, activates the NF-κB signaling pathway.

Our investigation reveals that UBE2Q2 regulates the glycolysis in HCC through modulation of the NF-κB/HIF1α signaling pathway, pinpointing UBE2Q2 as a promising therapeutic target for the disease.

Breast cancer (BC) is the most prevalent form of cancer in women worldwide and the main cause of cancer-related fatalities in females. BC can be classified into various types based on where cancer has begun to grow or spread, specific characteristics that influence how cancer behaves, and treatment choices. BC is multifaceted, and due to its diverse nature, the mechanisms involved are complex and have not yet been understood. Overexpression and expression of various factors involved in the functioning of mechanisms lead to abnormal changes, providing an environment supporting cancer cell growth. Understanding BC risk factors and early diagnosis through screening techniques like mammography and diagnostic techniques such as imaging and biopsies has advanced significantly. A wide range of treatment options, including surgery, radiation, chemotherapy, targeted treatments, and hormonal therapies, are now available. Daily advancements are being made in the clinical treatment of BC. Still, BC drug resistance cases remain highly prevalent and are currently one of the biggest problems faced by medical science. To increase response rates and possibly lengthen survival, there is a critical requirement for novel medicines with minimal sensitivity to overcome drug resistance. This review classifies different mechanisms that are involved in the development of BC and workable pharmacological targets and explains how they relate to the development of BC drug resistance. By concentrating on the mechanisms covered in this review, we can have a deep understanding of different mechanisms and learn innovative ways to develop novel therapeutics for the disease to combat medication resistance.

Acute lung injury (ALI) represents a complicated and debilitating pulmonary disorder for which therapeutic options are currently limited. Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis, and has demonstrated beneficial effects in ALI. The objective of this study was to investigate the protective effect of Gen-17, a beta-methyl derivative of genipin, against ALI in vitro and in vivo, and explore its mechanism of action.

In this study, we prepared a beta-methyl derivative of genipin, Gen-17, and assessed the antioxidative and anti-inflammatory effects of Gen-17 in LPS-induced murine macrophages and ALI in mice, and explored the mechanism of action of Gen-17. In an in vivo model, the impact of Gen-17 on lipopolysaccharide (LPS)-induced ALI in mice was investigated by assessing pro-inflammatory cytokine levels, lung histology, edema, and vascular and alveolar barrier integrity, and in an in vitro model, murine macrophages-Raw 264.7 cells were used to establish a cell model of inflammation and oxidative stress by incubating with LPS. Keap1-Nrf2/HO-1, NF-κB and MAPK signaling pathways related factors were tested in vitro and in vivo to explore the possible mechanism of Gen-17.

The study showed that administration of Gen-17 conferred protection against LPS-induced ALI in mice, characterized by the mitigation of histological lung tissue alterations, reduction in lung edema, diminished protein content in bronchoalveolar lavage fluid, attenuation of inflammatory cell infiltration, and a decrease in cytokine secretion. Furthermore, Gen-17 exhibited the capacity to inhibit the nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) in the context of LPS-induced lung injury. In vitro, research findings revealed that Gen-17 demonstrated notable efficacy in reducing oxidative stress and inflammation in RAW 264.7 cells induced by LPS. Its central mechanism of action revolved around enhancing the antioxidant defense pathway, mediated through nuclear factor erythroid 2-related factor 2 (Nrf2). Consequently, this intervention repressed the release of pro-inflammatory mediators initiated by LPS, along with the modulation of the mitogen-activated protein kinase (MAPK) signaling pathway.

Gen-17 demonstrates the ability to mitigate oxidative stress and inflammation in the context of LPS-induced ALI via modulation of the MAPK, NF-κBp65, and Keap1/Nrf2/heme oxygenase-1 (HO-1) pathways. As such, it emerges as a promising and novel therapeutic candidate for treating ALI.

Natural compounds have garnered significant attention as potential therapeutic agents due to their inherent properties. Their notable qualities, including safety, efficacy, favorable pharmacokinetic properties, and heightened effectiveness against certain diseases, particularly inflammatory conditions, make them particularly appealing. Among these compounds, curcumin has attracted considerable interest for its unique therapeutic properties and has therefore been extensively studied as a potential therapeutic agent for treating various diseases. Curcumin exhibits diverse anti-inflammatory, antioxidant, and antimicrobial effects. Curcumin's immune system regulatory ability has made it a promising compound for treatment of various inflammatory diseases, such as psoriasis, atherosclerosis, asthma, colitis, IBD, and arthritis. Among the signaling pathways implicated in these conditions, the CD40 receptor together with its ligand, CD40L, are recognized as central players. Studies have demonstrated that the interaction between CD40 and CD40L interaction acts as the primary mediator of the immune response in inflammatory diseases. Numerous studies have explored the impact of curcumin on the CD40:CD40L pathway, highlighting its regulatory effects on this inflammatory pathway and its potential therapeutic use in related inflammatory conditions. In this review, we will consider the evidence concerning curcumin's modulatory effects in inflammatory disease and its potential therapeutic role in regulating the CD40:CD40L pathway.

The heterogeneity and complex extracellular matrix (ECM) characteristics of non-small cell lung cancer (NSCLC) present significant challenges for understanding its pathological mechanisms and advancing precise treatment strategies. This study characterized the physicochemical properties of native NSCLC ECM to inform the biomimetic design of 3D models utilizing biomaterials and light-based 3D bioprinting technologies. A tunable 3D model was constructed that replicates the interfacial structures and matrix stiffness of both lung cancer tissue and adjacent normal tissue. This model elucidates the impact of matrix stiffness on cellular behaviors, including proliferation, invasion, and drug sensitivity, and delineates the role of the CCN1 gene under different mechanical conditions. Specifically, it demonstrates that a reduction in CCN1 expression within soft matrices can attenuate the migratory and proliferative capabilities of tumor cells. Furthermore, primary NSCLC patient-derived bioprinted tissues validated the model fidelity to clinical samples and its predictive potential for responses to combined chemotherapy and immunotherapy. This study establishes a versatile platform for NSCLC modeling and research, advancing biomaterial and bioprinting strategies to replicate the tumor microenvironment and optimize therapeutic approaches.

Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD.

Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N6-methyladenosine (m6A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF.

Stimulation with Aβ1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m6A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα.

Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.

HNSCC includes nasopharyngeal, laryngeal and oral cancers, and its pathogenesis is influenced by various factors. As an essential part of the ubiquitin (Ub)-proteasome system (UPS), deubiquitinating enzymes (DUBs) maintain the homeostasis of Ub molecules and influence the physiological functions of cells and disease processes by removing ubiquitinated proteins. Accumulating evidence has confirmed that the aberrant expression of DUBs is involved in cell proliferation, metastasis, and apoptosis during the development of HNSCC, with some acting as oncogenes and others as tumor-suppressor genes. In this review, the DUBs implicated in HNSCC were summarized and the mechanisms underlying abnormal DUBs expression in signaling pathways were discussed. In addition, given the important role of DUBs in tumorigenesis, recent studies were reviewed and agonists and inhibitors of DUBs were summarized to identify more effective therapeutic strategies.

Septic acute lung injury (Septic-ALI, SA) is a severe complication of sepsis with limited clinical treatment options. Ethyl Caffeate (EC) is a phenolic compound isolated from Ilex latifolia Thunb (I. latifolia) of the Aquifoliaceae family.

This study aimed to investigate the potential mechanisms of EC in treating SA by integrating network pharmacology and transcriptomics.

We used network pharmacology to predict the potential pathways and targets of EC and validated these predictions using the GEO database, molecular docking and MDS. Subsequently, LPS-induced inflammation models in RAW cells and a mouse model of SA were established to evaluate the therapeutic effects of EC. Cell transcriptomic sequencing, along with ELISA, qRT-PCR, and Western blot analyses, were performed on both cellular and animal models to validate the key pathways and targets.

EC targeted TNF-α and MMP9, significantly alleviating LPS-induced SA through the TNF-α/NF-κB/MMP9 axis. Specifically, network pharmacology and molecular docking suggested that EC may target TNF, MMP9, EGFR, PRKACA, and MAPK3. Transcriptomic analyses, MDS and in vitro and in vivo experiments showed that EC primarily reduced the expression of p-p65 and p-IκBα in the TNF pathway by inhibiting TNF-α, thereby downregulating the expression of downstream effector molecules MMP9 and MMP14, and improving lung tissue damage, cell apoptosis, and inflammation levels in mice.

This study was the first to integrate network pharmacology and transcriptomic results, revealing the mechanism by which EC ameliorated SA through the TNF-α/NF-κB/MMP9 axis. Furthermore, experimental validation identified TNF-α and MMP9 as two core targets of EC, providing a valuable reference for the clinical treatment of SA.

Delicate external mechanosensing, efficient intracellular mechanotransduction and effective alveolar bone remodeling lay the foundation of orthodontic tooth movement (OTM). Periodontal ligament stem cells (PDLSCs) are thought to be the primary cells that withstand mechanical stimuli and respond to biomechanical signals during orthodontic treatment. Nevertheless, the cellular and molecular mechanisms of orthodontic force-induced mechanosignaling and osteogenesis in PDLSCs still remain unclear. In the present study, we hypothesize that the ageing suppressor, Klotho, is correlated with orthodontic force-triggered mechanical signaling cascades, further contributing to alveolar bone remodeling. This study reveals that Klotho expression is notably upregulated via cytoskeletal-nuclei-mediated epigenetic modifications, consistent with osteogenic differentiation on the tension side during OTM. Additionally, Klotho deficiency undermines tensile force-induced new bone formation in NFκB- and PI3K/Akt-dependent manners. Notably, RNA sequencing (RNA-seq) results and targeted force application experiments unveil that Klotho not only functions as a downstream effector of external stress but also acts as an upstream regulator in mechanical signaling for the first time. In summary, we identify the indispensable role of Klotho in mechanotransduction and alveolar bone formation, which provide a latent target of linking cell senescence to mechanical force in future studies and offer novel insights into orthodontic force-induced tooth movement and bone remodeling.

The study aimed to investigate the effect and mechanism of monotropein on renal cell carcinoma (RCC).

After monotropein and NF-κB receptor activator (RANKL) treatment, cell proliferation, invasion, and apoptosis were evaluated using CCK-8, Transwell, and flow cytometry. Primary macrophages co-cultured with monotropein-treated RCC cells were analyzed to evaluate macrophage polarization using qRT-PCR, western blot, and ELISA assays by detecting the expression of M2 markers (CD206, CD168) and cytokines (IL-10, TGF-β). Additionally, the therapeutic efficacy of monotropein was examined using an RCC mouse xenograft model.

Monotropein could inhibit the proliferation, invasion, and M2 macrophage polarization and accelerate the apoptosis of RCC cells. Mechanistically, monotropein suppressed NF-κB pathway activation in RCC cells and reduced the expression of NF-κB downstream targets, including Bcl-2, c-Myc, and MMP9. RANKL could eliminate the effect of monotropein on RCC progression. In primary macrophages co-cultured with monotropein-treated RCC cells, monotropein downregulated M2 polarization markers and cytokines, further supporting its role in modulating the tumor microenvironment. In mouse models, monotropein reduced RCC tumor growth, induced apoptosis, and blocked NF-κB pathway.

Monotropein prevents RCC malignant progression and reduces M2 macrophage polarization by suppressing the NF-κB pathway, suggesting that monotropein may serve as a potential therapeutic agent for RCC by targeting both tumor cells and the tumor microenvironment.

Regulation of the nuclear factor-kappa B (NF-kB) signaling pathway is a major host homeostatic mechanism for controlling hyper-inflammation or chronic inflammation. Despite extensive research, the regulatory factors of NF-kB signaling required to preserve homeostasis and control inflammatory disorders are not fully understood. Moreover, the role of MARCH2 in chronic inflammation models and the regulation of MARCH2 activation remain to be elucidated.

We monitored disease severity and mortality in MARCH2-/- or MARCH2+/+ mice induced experimental colitis. Susceptibility to DSS-induced experimental colitis was determined by various methods, including Swiss roll assay and fluorescein isothiocyanate (FITC)-dextran treatment, respectively. RNA-sequencing was conducted to recognize the inflammatory response-related genes in the distal colon of colitis-induced mice. Enzyme-linked immunosorbent assay (ELISA) was used to measure the cytokines and chemokines with in vitro and in vivo samples. Affinity purification and LC-MS/MS analysis were used to identify the MARCH2 interacting proteins and posttranslational modifications. The underlying mechanism was elucidated using immunoblotting, co-immunoprecipitation, ubiquitination assay, and confocal microscopy.

Here, we report that MARCH2-/- mice were more susceptible to experimental inflammatory bowel disease (IBD) due to the massive production of cytokines. Stimulation by inflammatory cytokines such as TNF induces dimerization of MARCH2 at a later stage and dimerized MARCH2 undergoes K63-linked autoubiquitination at lysine 127 and 238, which promotes NEMO recognition, ubiquitination and proteasomal degradation. We also show an interaction between MARCH2 and MARCH8 in resting cells that inhibits MARCH2 activation. Taken together, these findings provide new insights into the molecular mechanism of MARCH2 and suggest a crucial role of MARCH2 in the modulation of inflammation and cellular homeostasis.

Our results indicate that MARCH2 plays a critical role in regulating NEMO/IKKγ under the inflammatory and resting conditions, thereby suppressing excessive or unexpected inflammatory responses. Our findings here not only demonstrate a biological role of MARCH2 in inflammatory signaling pathways but also provide a novel insight in the underlying mechanism.

The protein lysine methyltransferase 2 (SMYD2) can affect cell proliferation, differentiation, and survival through methylation of its histone and non-histone substrates. SMYD2 has been shown to act as an oncogene to promote disease progression in a variety of cancer diseases, but its role in chronic kidney diseases (CKD) pathogenesis has not been fully elucidated. This study aims to investigate the effect of SMYD2 on cisplatin-induced CKD and its underlying mechanisms. In this study, we found that cisplatin caused severe renal injury in mice, which was accompanied by the up-regulation of SMYD2 expression. AZ505 treatment significantly down-regulated cisplatin-induced renal injury and fibrosis. It also alleviated renal apoptosis and inhibited the phosphorylation level of NF-κB p65. Conditional knockdown of Smyd2 achieved similar effects as AZ505. In renal tubular epithelial cells, inhibition or silencing of SMYD2 down-regulated cisplatin-induced apoptotic response, while overexpression of SMYD2 induced apoptotic response and activated NF-κB in response to the up-regulation of SMYD2 expression. Up-regulation of SMYD2 induced interaction and phosphorylation of SMYD2 and NF-κB p65, and inhibition of NF-κB activation further suppressed cisplatin-induced NF-κB activation and apoptosis. The present study suggests that up-regulation of SMYD2 expression in cisplatin-induced CKD may promote apoptosis of renal tubular epithelial cells and accelerate the process of renal injury through NF-κB activation. SMYD2 may serve as a potential target for effective CKD treatment.

Rosacea is a chronic inflammatory skin disease and its pathogenesis remains unclear. Key genes were screened in the GSE155141 and GSE65914 datasets through a bioinformatics approach. To establish a rosacea-like mouse model with periostin (POSTN) knockdown, mice were subcutaneously injected with lentivirus-packaged Lv-shPOSTN, followed by LL37 treatment on the dorsal skin. Skin tissues were collected for the assessment of skin lesion area, skin thickness, redness score, as well as for hematoxylin and eosin (HE) staining, toluidine blue staining, and immunofluorescence staining. The inflammatory factors and chemokine levels were determined by enzyme-linked immunosorbent assay. Wound healing and Transwell assays were performed to assess cell migration and invasion. Phosphorylation levels of JAK2, STAT3, IKKβ, and p65 were evaluated via western blotting. Hub genes, including COL1A2, POSTN, LOX, BGN, COL3A1, DCN, and COL1A1 were screened. POSTN was highly expressed in rosacea and POSTN silencing ameliorated pathological changes and suppressed inflammation, immune infiltration, and angiogenesis. The levels of inflammatory factors (TNF-α, IL-1β, and IL-6) and chemokines (CCL2, CXCL10, and CXCL2), as well as the KLK5, CAMP, TLR2, and VEGF expression levels were reduced after POSTN knockdown. POSTN silencing inhibited migration and invasion of LL37-induced human umbilical vein endothelial cells (HUVEC). Importantly, POSTN silencing suppressed the JAK2/STAT3 and NF-κB pathways both in vivo and in vitro. POSTN knockdown suppresses inflammation and angiogenesis in rosacea possibly by obstructing the JAK2/STAT3 and NF-κB pathways, which offers a potential therapeutic strategy for rosacea.

Identifying genetic mutations contributing to solid tumors by altering the biological pathways related to tumor formation and development is essential for the development of targeted therapies. This study aimed to identify commonly mutated genes and altered pathways in canine solid tumors. Four dogs with different types of naturally occurring neoplasias (urothelial carcinoma, adenocarcinoma, rhabdomyosarcoma, and chondrosarcoma) were randomly selected and classified into carcinoma and sarcoma groups based on histopathological findings. Tumor tissues were analyzed using whole-genome sequencing, and significant variants shared within each tumor group were identified. Gene set enrichment analyses were conducted to compare the biological and functional pathways altered by the mutations in each carcinoma and sarcoma group. Forty-three and fifty-eight genes were identified in the carcinoma and sarcoma groups, respectively. Distinctions between the two tumor groups were noted for mutations related to tumor metastatic function. Mutations were identified in genes encoding cell adhesion molecules in the carcinoma group, whereas significant variations in extracellular matrix-related molecules were evident in the sarcoma group. This study revealed mutations and modified pathways associated with immune and tumor metastatic functions in canine carcinoma and sarcoma, indicating their significant relevance to the development and progression of each tumor group. Additionally, the distinctions indicated that different therapeutic approaches were required for each tumor group.

Benzo(a)pyrene (BaP), a carcinogen prevalent in high-temperature processed foods, activates the aryl hydrocarbon receptor (AhR) and induces liver pyroptotic injury. MicroRNAs regulate mRNA expression and are involved in BaP toxicity. In this study, we investigated the essential role of microRNA in BaP-induced pyroptosis. In vivo, BaP induces liver pyroptotic injury by activating AhR, which may be attributed to AhR's influence on microRNA expression. The miRNA-382-5p/Akt and miRNA-382-5p/IκB pairs were predicted to post-transcriptionally regulate pyroptosis. In vitro, miRNA-382-5p activates the classical NF-κB/NLRP3/Caspase-1 pyroptosis signaling pathway by targeting and inhibiting the IκB gene. Furthermore, AhR activation by BaP could promote the high expression of miRNA-382-5p, thereby upregulating the NF-κB/NLRP3/Caspase-1 pyroptosis signaling pathway. In summary, we established that the AhR-mediated miR-382-5p/NF-κB/NLRP3/Caspase-1 axis is a key driver of BaP-induced pyroptosis in hepatocytes and elucidated the underlying mechanisms. These findings provide a valuable theoretical basis for considering miRNA-382-5p as a potential target for preventing BaP toxicity.

Long-term exposure to arsenic (As), which is a ubiquitous environmental contaminant, significantly enhances the risk of multiple cancers, including bladder and lung cancers. In recent years, the important roles of circular RNAs (circRNAs) in tumorigenesis and development have attracted widespread attention. However, the specific molecular mechanisms by which circRNAs promote bladder cancer development following exposure to arsenic remain incompletely understood. This study is the first to demonstrate that circPDE3B is significantly upregulated in a cell model of transformation triggered by arsenic and that it promotes this transformation process. Our study elucidated the biological function of circPDE3B in vitro, in SV-HUC-1 cells, showing that it accelerates the malignant transformation from arsenic via increasing cell proliferation and inhibiting apoptosis. Furthermore, we delineated a novel molecular mechanism whereby circPDE3B directly binds to NF-κB and STAT3, inhibiting their ubiquitination and increasing their stability. This, in turn, affects downstream HIF-1α expression, promoting the malignant transformation of SV-HUC-1 cells and eventually resulting in bladder carcinogenesis. Our research reveals the critical regulatory role of circPDE3B in the arsenic-triggered malignant transformation within SV-HUC-1 cells. This study offers broader perspectives on the molecular mechanisms driving bladder cancer progression, while also identifying potential targets for early diagnosis and treatment of bladder tumour.

Biyuantong decoction (BYT), a traditional Chinese medicinal formulation, has been used for years to treat chronic rhinosinusitis (CRS) with good clinical results. However, the underlying mechanisms of its treatment for CRS remain to be fully elucidated.

This research investigates the molecular mechanism by which BYT ameliorates CRS and provide new perspectives for CRS treatment research.

Clinical research is conducted on CRS patients who underwent surgery, and post-operative treatments and observations were performed. The pathological alterations of CRS were inspected by H&E staining and nasal endoscopy. Flow cytometry and ELISA were employed to measure the levels of inflammatory cells and cytokines in the peripheral blood of CRS patients. The cytotoxic impacts of BYT were assessed by cell viability, cell cycle and apoptosis assays. The effects of BYT on the adhesion and invasion of inflammatory cells to endothelial cells were evaluated by hetero-adhesion and transwell assay. Flow cytometry was employed to analyze the expression of cell adhesion molecules (CAMs) on HUVECs. The effects of BYT on NF-κB signaling pathway was analyzed by Western blot and immunofluorescence staining. The chemical components of BYT was determined by UPLC-HRMS, and network pharmacology analysis was adopted to predict potential targets in the NF-κB pathway.

Clinical samples demonstrated that BYT treatment could effectively alleviate sinus mucosal edema and significantly decreased the recurrence rate after surgery. H&E staining disclosed obvious inflammatory cell infiltration in the sinus mucosa of CRS patients. Flow cytometry and ELISA results indicated that BYT treatment reduced the levels of eosinophils (median decrease 16.21 %) and cytokines in peripheral blood. Cell adhesion and transwell assays manifested that BYT inhibited the adhesion and invasion of U937 cells to TNF-α-induced HUVECs. Moreover, BYT counteracted the TNF-α-induced upregulation of CAMs on endothelial cells. Western blot and immunofluorescence analyses confirmed that BYT reduced the expression of NF-κB-related proteins and hindered the nuclear translocation of NF-κB. Network pharmacology analysis and component identification of BYT further supported the function of its compounds in synergistically modulating NF-κB signaling.

BYT enhances the clinical efficacy of CRS by suppressing inflammatory cell adhesion and infiltration into the nasal mucosa via NF-кB pathway regulation. These findings provide a robust foundation for the clinical application of BYT in CRS treatment and suggest interrupting inflammatory cell adhesion as a potential new approach.