During the transformation of viral hepatitis into hepatocellular carcinoma (HCC), oxidative stress levels increase significantly, leading to tissue damage and chronic inflammation. HCC is characterized by spatiotemporal heterogeneity, which influences oxidative stress patterns, with reactive oxygen species (ROS) as the primary representative molecules. ROS serve not only as critical biomarkers of cancer but also as potential therapeutic targets for HCC, given that their increased levels can either promote or inhibit disease progression. In this review, we systematically examine the temporal heterogeneity of ROS, emphasizing its role in different stages of HCC progression caused by viral hepatitis and in influencing cell fate. We further explore ROS spatial heterogeneity at three levels: cellular, organelle, and biomolecular. Next, we comprehensively review clinical applications and potential therapies designed to selectively modulate ROS on the basis of its spatiotemporal heterogeneity. Finally, we discuss potential future applications of novel therapies that target ROS spatiotemporal heterogeneity to prevent and manage HCC onset and progression. In conclusion, this review enhances understanding of ROS in the progression of viral hepatitis to HCC and offers insights into developing new therapeutic targets and strategies centered on ROS heterogeneity.

Although immunotherapy has been predominant for advanced gastric cancer treatment, it still has limitations. Polyunsaturated fatty acids (PUFAs) are associated with inflammation while their roles in tumor immune microenvironment (TIME) are unclear. This study explores PUFAs' impacts on gastric cancer immunity and immunotherapy efficacy. Bioinformatics analysis was conducted to identify differential expressions of PUFAs metabolic genes and their immune correlations. Clinical data of advanced gastric cancer patients receiving immunotherapy at Zhongda Hospital (2020-2024), whose serum PUFAs were measured by mass spectrometry (MS), were collected and analyzed. Bioinformatics analysis revealed differential expression of half of PUFAs metabolic genes in gastric cancer. PUFAs metabolism towards Omega-3 (ω-3) tended to increase infiltration of active anti-tumor cells and up-regulate multiple immune checkpoints expressions, while metabolism towards Omega-6 (ω-6) led to opposite TIME outcomes. The clinical study demonstrated that lower serum ω-6/ω-3 ratio, arachidonic acid/eicosapentaenoic acid (AA/EPA) ratio, linoleic acid/alpha-linolenic acid (LA/ALA) ratio and higher EPA were associated with better six-month progression-free survival rate (6-month PFS) and one-year overall survival rate (1-year OS). This study deepens our understandings of TIME in gastric cancer. It clearly demonstrates that maintaining appropriate PUFAs ratios or values is promising in improving prognosis.

The liver is a central metabolic organ, but is also hosting a unique immune microenvironment to sustain homeostasis and proper defense measures against injury threats in healthy individuals. Liver macrophages, mostly represented by the tissue-resident Kupffer cells and bone marrow- or monocyte-derived macrophages, are intricately involved in various aspects of liver homeostasis and disease, including tissue injury, inflammation, fibrogenesis and repair mechanisms.

We review recent findings on defining the liver macrophage landscape and their functions in liver diseases with the aim of highlighting potential targets for therapeutic interventions. A comprehensive literature search in PubMed and Google Scholar was conducted to identify relevant literature up to date.

Liver macrophages orchestrate key homeostatic and pathogenic processes in the liver. Thus, targeting liver macrophages represents an attractive strategy for drug development, e.g. to ameliorate liver inflammation, steatohepatitis or fibrosis. However, translation from fundamental research to therapies remains challenging due to the versatile nature of the liver macrophage compartment. Recent and major technical advances such as single-cell and spatially-resolved omics approaches deepened our understanding of macrophage biology at a molecular level. Yet, further studies are needed to identify suitable, etiology- and stage-dependent strategies for the treatment of liver diseases.

The change of plasma lipid species has close contacts with gastric cancer (GC). However, the specific mechanism still needs to be explored further. We aim to utilize plasma proteins to decipher the association between lipid species and GC, and seek possible drug targets for GC. We performed a two-step Mendelian randomization (MR) analysis to investigate causal relationships among 179 lipid species, 4907 plasma proteins, and GC. Using summary-data-based MR and colocalization, we first examined protein-GC associations in discovery (N = 35,559) and validation (N = 54,219) cohorts. Subsequent MR analyses assessed lipid-GC and lipid-protein relationships, followed by mediation analysis using error propagation methods. Finally, macromolecular docking of prioritized proteins identified potential therapeutic ligands. Our MR analysis revealed causal relationships between 12 lipid species and GC, as well as 3 plasma proteins and GC. Importantly, mediation analysis demonstrated that CCDC80 protein mediates 2.90% (95% CI: 0.30-5.5%) of the protective effect of diacylglycerol (16:1_18:1) against GC. Based on these findings, we identified valproic acid as a promising therapeutic candidate targeting CCDC80 for GC treatment. Our study demonstrates that reduced CCDC80 expression mediates the tumor-promoting effects of diacylglycerol (16:1_18:1) in GC pathogenesis. Molecular docking confirms valproic acid binds stably to CCDC80, suggesting its therapeutic potential. These findings advance GC etiology understanding and provide a new drug development direction.

Gastric adenocarcinoma is one of the most common cancers in the world. The purpose of this study was to investigate the role of non-smooth muscle cell aggregation protein II complex G2 subunit (NCAPG2) in gastric cancer cells. Cell growth, proliferation, migration, invasion and albumin-bound paclitaxel resistance were detected by cell counting kit-8, flow cytometry, Transwell chamber and nude mouse xenograft model. Western blot was used to detect the expression of NCAPG2, STAT3 and NF-κB signaling pathways. The expression of NCAPG2 was significantly up-regulated in gastric adenocarcinoma cells. Knockdown of NCAPG2 inhibited cell proliferation, migration and invasion, and inhibited tumor growth. In addition, knockdown of NCAPG2 reduced the resistance of gastric adenocarcinoma cells to albumin-bound paclitaxel and down-regulated STAT3 and NF-κB signaling pathways. In summary, NCAPG2 plays an important role in the malignant progression of gastric adenocarcinoma and is involved in the resistance to albumin-bound paclitaxel.

Our aim was to identify crucial RNA-binding proteins (RBP) genes associated with Ewing sarcoma (EwS) in order to provide valuable insights into its mechanisms of tumorigenesis and to enhance therapeutic intervention.

Differential gene expression analysis identified candidate genes. Next, hub genes were generated by the results of protein-protein interaction (PPI) network, and univariate COX regression analysis. CIBERSORT was applied to analyze immune landscape. Furthermore, both in vitro and in vivo experiments were conducted to investigate the function of NOP58 in EwS.

A total of 179 RBP-related genes were significantly different in EwS tissues and normal controls. Among these, NOP58 ribonucleoprotein (NOP58) was considered as the hub gene, demonstrating significant prognostic value. Significantly, high NOP58 expression correlated with poor prognosis of EwS patients. Additionally, the levels of NOP58 were significantly up-regulated in EwS cells compared with human mesenchymal stem cells. Furthermore, knockdown of NOP58 notably inhibited the proliferation and migration of EwS cells. Moreover, NOP58 deficiency remarkably induced apoptosis and cell cycle arrest in EwS cells. In vivo studies on tumor-bearing mice demonstrated that NOP58 downregulation significantly inhibited tumor growth in EwS.

Collectively, downregulation of NOP58 could inhibit the proliferation and migration of EwS cells in vitro and reduce murine xenograft tumor growth in vivo. These findings identified NOP58 as a promising regulator of EwS tumorigenesis, suggesting it may serve as a potential therapeutic target for EwS treatment.

This study aimed to analyze the association between the Dietary Inflammatory Index (DII) and the risk of gynecological cancers using data collected from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2018.

The data for this study were obtained from NHANES, conducted between 2011 and 2018, and included a total of 8,380 women. To examine the association between the Dietary Inflammatory Index and gynecological cancers, weighted multivariable logistic regression analyses were performed, using DII both as a continuous variable and as a categorical variable divided into tertiles. Subgroup analyses stratified by DII and gynecological cancer characteristics were conducted to further explore this association. Additionally, restricted cubic spline (RCS) analysis was applied to evaluate potential non-linear relationships between DII and gynecological cancer risk.

Among the 8,380 women included in the analysis, the mean age was 47.02 (SD: 16.91) years, and 196 participants self-reported a diagnosis of gynecological cancer. In fully adjusted models, DII was significantly positively associated with the prevalence of gynecological cancer, whether analyzed as a continuous variable (OR = 1.15, 95% CI: 1.00-1.33, p = 0.046) or as a categorical variable (highest tertile compared to the lowest tertile: OR = 2.14, 95% CI: 1.14-4.04, p = 0.021, p for trend = 0.021). Restricted cubic spline analysis confirmed a linear relationship between DII and gynecological cancer risk (p for non-linear association = 0.1984). Subgroup analyses revealed a significant interaction effect with smoking status (p for interaction = 0.037).

Our findings suggest that higher DII scores are positively associated with an increased risk of gynecological cancer. These results contribute to the existing literature and underscore the need for further validation through larger prospective cohort studies.

To explore the bioinformatics characteristics and potential mechanisms of signal transducer and activator of transcription (STAT3) in chronic myelogenous leukemia (CML).

Through the cancerSEA and CCLE databases, the expression of STAT3 in CML was verified and analyzed. Subsequently, K562 cells were treated with the STAT3 inhibitor Stattic. Western blotting, cell counting, and flow cytometry were utilized to observe its impact on the functions of K562 cells. Then, Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were applied to deeply explore the regulatory mechanism of STAT3. The "LIMMA" software package was used to calculate STAT3-related differentially expressed genes (DEGs). Machine-earning methods were utilized to screen the STAT3-related hub genes. The "pROC" software package was employed to perform Receiver Operating Characteristic (ROC) curve analysis on the hub genes. The "corrplot" software package was used to conduct a correlation analysis of the hub genes. The "RMS" software package was applied to construct a nomogram of the hub genes. Based on the DisGENET database, a disease network of the hub genes was constructed, and the DGIdb database was used to construct a drug network of the hub genes.

In CML, the expression of STAT3 is upregulated compared to housekeeping genes. Among the 14 cell lines related to CML, STAT3 has the highest expression level in K562 cells. Stattic at a concentration of 5 μM can inhibit the proliferation of K562 cells, promote their apoptosis, and block the cell cycle at the S phase (P < 0.05). GSEA and GSVA indicates that amino acid metabolism, NOD-like receptor of STAT3. LASSO and SVM-RFE show that NCF4, PLAS1, IL7R, and TAGLN2 are hub differentially expressed genes (DEGs) related to STAT3. ROC and Nomogram indicate that the hub DEGs have high clinical diagnostic value. Correlation analysis shows that PLAS1 and NCF4 are negatively correlated, while PLAS1 and TAGLN2 are positively correlated. The construction of gene-disease networks reveals that these genes not only participate in the occurrence and development of CML but also jointly participate in multiple disease processes. The gene-drug network obtained 38 drugs targeting genes.

STAT3 might serve as a potential target for the treatment of CML. In CML, NCF4, PLAS1, IL7R, and TAGLN2 are hub genes associated with STAT3. These findings offer a fundamental theory for comprehending the pathogenesis of CML.

Recent studies have demonstrated that PLEKHA4 promotes tumor growth in some cancers, such as small-cell lung cancer, melanoma, and hepatic carcinomas; however, the underlying mechanism in glioblastoma remains ambiguous. Bioinformatic was used to analysis PLEKHA4 expression. In vitro and in vivo experiments were conducted to detect the effect of PLEKHA4 on glioblastoma cell glycolytic reprogramming and progression. GSEA was used to analyze the signal pathways related to PLEKHA4. Pharmacological methods further validated the role of activation pathways. We evaluated the effects of PLEKHA4 knockdown combined with temozolomide (TMZ) on glioblastoma cell proliferation and apoptosis in vitro and in vivo. We observed an overexpression of PLEKHA4 in GBM cell lines, resulting in enhanced cell proliferation, inhibited apoptosis, and promoted glycolysis. Mechanistically, our study demonstrated that PLEKHA4 mediates cell proliferation, apoptosis, and glycolysis via the STAT3/SOCS1 signaling pathway. Additionally, HOXD9 was predicted using Jasper, which is a transcription factor that binds to the PLEKHA4 promoter region. Knocking down PLEKHA4 combined with TMZ inhibited cell proliferation and promoted cell apoptosis in vitro and in vivo. Our results indicated that HOXD9-medicated PLEKHA4 regulates glioblastoma cell proliferation and glycolysis via activation of the STAT3/SOCS1 pathway.

Microglia-mediated neuroinflammation is crucial for obstructive sleep apnea (OSA)-induced cognitive impairment. We aimed to investigate roles of acetate (ACE) and SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) in neuroinflammation of OSA.

After C57BL/6J mice were exposed to OSA-associated intermittent hypoxia (IH) or normoxia for four weeks, the composition of the gut microbiota (GM) and the levels of serum short-chain fatty acids (SCFAs) were measured by 16S rRNA and GC-MS methods, respectively. To assess the effect of ACE on IH mice, glyceryl triacetate (GTA) was gavaged in IH-exposed mice and the cognitive function, microglial activation, and hippocampal neuronal death were examined. Moreover, ACE-treated BV2 microglia cells were also utilized for further mechanistic studies.

IH disrupts the gut microbiome, reduces microbiota-SCFAs, and impairs cognitive function. Gavage with GTA significantly mitigated these cognitive deficits. Following IH exposure, we observed substantial increases in SETDB1 both in vivo and in vitro, along with elevated levels of histone H3 lysine 9 trimethylation (H3K9me3). Genetic or pharmacological inhibition of SETDB1 in microglia led to decreased induction of proinflammatory factors, as well as reduced reactive oxygen species (ROS) generation. Mechanistically, SETDB1 was found to upregulate the transcription factors p-signal transducer and activator of transcription 3 (p-STAT3) and p-NF-κB. In vitro, ACE supplementation effectively repressed high SETDB1 and H3K9me3 levels, thereby inhibiting microglial pro-inflammatory responses induced by IH. In vivo, ACE supplementation significantly reduced hippocampal levels of p-STAT3, p-NF-κB, and pro-inflammatory cytokines while also protecting neuronal integrity.

This study provides the first evidence that H3K9 methyltransferase SETDB1 promotes microglial pro-inflammatory response distinct from its previously shown role in macrophages. Our findings also identify ACE supplementation as a promising dietary intervention for OSA-related cognitive impairment with SETDB1 serving as both a mechanistic biomarker and potential therapeutic target.

Intervertebral disc degeneration (IVDD) and its attendant lower back pain are a major medical challenge. Ferroptosis has become a new target for the treatment of IVDD. Mesenchymal stem cells (MSCs) are a promising regenerative therapy for IVDD. Hydrogel is usually used as a delivery carrier for MSCs. This study investigated the effect of bone mesenchymal stem cells (BMSCs) in IVDD by magnetic resonance imaging (MRI) and hematoxylin and eosin (HE) staining analysis using a rat-punctured IVDD model. A vitro model of tert-butyl hydroperoxide (TBHP)-induced oxidative stress injury in annulus fibrosus cells (AFCs) was used to explore the underlying molecular mechanisms. Cell viability was detected by cell counting kit-8 assay. Ferroptosis was assessed by measuring the levels of LDH, Fe2+, glutathione, lipid reactive oxygen species, and malondialdehyde. The underlying mechanism was investigated by western blot and phosphor-kinase array. Results suggested that BMSCs inhibited TBHP-induced ferroptosis and the phosphorylated levels of STAT3 in AFCs. The activation of STAT3 (colivelin, a specific agonist for STAT3) reversed the effects on the ferroptosis of BMSCs. Additionally, BMSCs alleviated IVDD progression based on matrix hydrogels, while colivelin abolished the protective effects of BMSCs-encapsulated hydrogels on IVDD. In short, BMSCs inhibited oxidative stress-induced AFCs ferroptosis, thereby alleviating IVDD, which is associated with inhibited STAT3 activation. This study demonstrated the possible underlying mechanism by which BMSCs mitigate IVDD and may provide a new therapeutic idea for IVDD.

Triple-negative breast cancer (TNBC), is a highly aggressive tumor. Formosanin C (FC) is a diosgenin with immunomodulatory and antitumor properties, the precise mechanism through which it is against TNBC remains uncertain.

Clarifying the mechanism of FC against TNBC.

The impact of FC on two TNBC cell lines for 24 h was investigated through various techniques including the CCK8 assay, flow cytometry, transwell assay, scratch tests, immunoblot assay, and immunofluorescence. To elucidate the mechanism behind the anti-TNBC effect of FC, MDA-MB-231 cells were subjected to STAT3 overexpression. Moreover, the in vivo efficacy of FC was examined using a xenograft nude mice (BALB/C). Mice were divided into the control group (equal amount of PBS), the napabucasin group (5 mg/kg) and the FC groups (1 mg/kg, 2 mg/kg). The study duration was 30 days.

FC exhibited inhibitory effects against MDA-MB-231 and Hs578T cells. FC can decrease the migratory capacity of TNBC cells by inhibiting epithelial-mesenchymal transition (EMT). Meanwhile, we demonstrated that the inhibition of phosphorylation of STAT3 (Y705) is the crucial mechanism of FC against TNBC. Moreover, FC also hindered the polarization of macrophage M2.

This study is the first to show that FC restrains the EMT of TNBC cells by obstructing the STAT3 pathway and hinders the M2 polarization of macrophages and immune evasion. Therefore, FC holds the possibility of being utilized as a therapeutic remedy for TNBC.

Inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis depend on the pathology of the nuclear factor kappa B (NF-κB) signalling pathway and M1 macrophage polarization. This review discusses the intimate molecular interactions and processes that modulate NF-κB's promotion of M1 macrophages and chronic inflammation/tissue damage within the confines of this review. NF-κB activation in macrophages produces pro-inflammatory mediators (cytokines - TNFα, IL6, IL1β, and reactive oxygen species (ROS), further increasing airway remodeling and fibrosis. MAPK, JAK-STAT, and PI3K-Akt signalling systems cross-talked with the pathway, amplifying its effect on lung disease progression. Therapeutic strategies focused on inhibiting this axis, including inhibition of NF-κB and small molecule/modulation of macrophage polarization, represent potential ways to attenuate inflammation and promote tissue repair. The potential of precision medicine is illustrated by natural compounds such as curcumin and resveratrol and innovative RNA-based and nanoparticle delivery systems. Despite these challenges, specificity, minimizing systemic side effects, and optimized delivery methods remain difficult. To develop targeted therapies, more research must be conducted to refine targeted approaches, including immune profiling and single-cell analysis. This review aims to advance the management of hard-to-treat inflammatory lung diseases by addressing these complexities.

Distraction spinal cord injury (DSCI) is a severe complication following scoliosis correction surgery, for which there are currently no effective clinical treatments. This study aims to evaluate the inhibitory effects of rutin, a natural product, on inflammation in DSCI and to investigate the underlying mechanisms. In vitro, microglial cells were exposed directly to rutin to assess its ability to inhibit lipopolysaccharide (LPS)-induced inflammation. In rats with DSCI, the inhibitory effect of rutin on DSCI was evaluated using behavioral tests. mRNA sequencing was performed on spinal cord tissues to elucidate the mechanism of rutin's action. Rutin significantly suppressed the LPS-induced increase in inflammatory factors in microglial cells. In DSCI rats treated with rutin, scores in the Basso-Beattie-Bresnahan (BBB) were significantly improved. The mechanism of rutin's action was found to be related to its ability to reduce inflammatory infiltration in spinal cord tissue, protecting neurons from apoptosis and microstructural demyelination. Through assays of transcriptomic differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and RT-qPCR validation of the top DEGs, MAPK13 (also known as P38 MAPK) was finally identified as the key target gene in promoting DSCI development. Further molecular docking analysis indicated an interaction between rutin and P38 MAPK, supporting the rutin's action and the underlying mechanism in anti-inflammation. In conclusion, rutin effectively inhibited the development of DSCI in rats. The mechanism of rutin's action was associated with its activity in blocking the P38 MAPK/NF-κB/STAT3 pathway in the microglial cells of spinal cord. Rutin could be developed as a potential anti-DSCI drug for clinical applications.

The cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) executes anti-microbial and pro-apoptotic functions, and loss-of-function mutations are associated with increased susceptibility to various infections and the development of tumors. A targeted mutation in mice expressing an N-terminally truncated STAT1 protein (STAT1-ΔN) typically develops splenomegaly in animals older than 6 months due to the formation of splenic non-Hodgkin lymphomas. The expression of the STAT1-ΔN variant resulted in the disruption of normal spleen architecture by malignant CD3- and CD20-negative tumor cells, which stained positively for both tyrosine-phosphorylated STAT1 and STAT3. Immunoblotting of lysates from isolated tumor cells revealed the cytokine-independent hyperphosphorylation of both STAT proteins, whereas the expression level of NF-κB was significantly reduced. Gel-shift assays showed that the DNA-binding activity of STAT1-ΔN was increased compared to the wild-type protein. This elevated level of tyrosine-phosphorylated STAT1-ΔN did not further increase upon stimulation of isolated tumor cells with either interferon-γ (IFNγ), lipopolysaccharide (LPS), or the combination of both. Since the truncation mutant was unable to accumulate in the nucleus upon cytokine stimulation, real-time PCR data from tumor tissue as well as from isolated, IFNγ/LPS-treated lymphoma cells demonstrated significantly reduced STAT1-regulated target gene expression despite its observed hyperphosphorylation. The nuclear import defect of tyrosine-phosphorylated STAT1-ΔN was associated with an elevated tyrosine-phosphorylation level of its antagonistic homolog STAT3, which is a known oncogene. These data demonstrate that the lack of STAT1 nuclear accumulation interferes with the functional balance between the two STAT proteins and, thereby, promotes the formation of phospho-STAT3-expressing CD3-/- CD20-/- non-Hodgkin lymphomas in the spleens of the diseased animals.

This study investigates the phytoconstituents of the less explored leaf of Piper nigrum, a common ethnomedicinal plant as an alternate source for multiple bioactivities.

Hydro-ethanolic (1:4) extract of Piper nigrum leaves (PNLE) prepared and profiled using liquid chromatography and mass spectrometry for identification of phytomolecules. Anti-oxidant activity, intracellular reactive oxygen species (ROS) expression, phagocytosis activity, and cytokine expression were estimated using cell-free and cell-based assays. Anti-cancer activity was determined with cancer cell viability, migration inhibition and colony-formation assay. Apoptosis and membrane depolarization assay were done using fluorescent microscopic staining methods while network pharmacology, and molecular docking analysis were done using open source and online tools.

Major phytomolecules identified in PNLE were pentanamide N,N-didecyl, piperettine, curcumin, myristicin, pipernonaline, sesamin, and lupenone. PNLE exhibited anti-bacterial activity with higher activity against Gram-positive bacteria, Staphylococcus aureus. PNLE also showed anti-oxidant and anti-inflammatory activity through neutralization of free radicals; inhibition of intracellular ROS generation; inhibition of phagocytosis and reduction of cytokine (IL-6 and TNF-α) levels. PNLE showed anti-proliferative activity against human breast cancer cells (MDA-MB-231), rat mammary tumor cells (LA7), and mouse melanoma cells (B16-F10) with highest activity against MDA-MB-231 cells. The extract did not inhibit human kidney cells (HEK-293). Further, PNLE treatment significantly inhibited cell migration and colony formation of MDA-MB-231 cells. Fluorescent staining techniques confirmed induction of apoptosis in cancer cells by PNLE. Further, network pharmacology and molecular docking studies revealed that the identified PNLE phytomolecules share 97 targets of out of potential breast cancer and inflammation-related target genes with four best common target proteins among the top hub genes and sesamin showed the highest binding affinity with these important cellular targets.

Overall, the phytochemical profile of PNLE showed clear presence of important phytomolecules and their association with critical human cellular mechanistic pathways responsible for exhibited bioactivities. This study further establishes the leaf of P. nigrum as an additional anatomical plant part with potent medicinal properties and  as a potential renewable source for bioactive phyomolecules.

Cell senescence-associated endothelia dysfunction is a vital point in the pathological progression of atherosclerosis (AS). G-protein coupled receptor 4 (GPR4) is a proton-sensing receptor involved in developing endothelial dysfunction.

In this study, we investigated the protective role of NE 52-QQ57, a GPR4 inhibitor in endothelial cell senescence induced using an oxidized low-density lipoprotein (ox-LDL). We also unravel the underlying molecular mechanism of NE 52-QQ57 as a therapeutic agent.

Endothelial cell senescence model was established using human aortic endothelial cells (HAECs) stimulated with ox-LDL. The expression levels of GPR4, p53, p16, and sirtuin1 (SIRT1) were evaluated using real-time PCR and western blot assays. ROS production was determined using dihydroethidium (DHE) staining. Further, interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) secretion and expression were determined using ELISA and real-time PCR analysis, respectively. Finally, β-galactosidase (SA-β-Gal) staining associated with cell senescence, telomerase activity, and cell cycle assay were used to determine the state of cell senescence.

Firstly, GPR4 was found to be upregulated in the ox-LDL-stimulated HAECs. We also identified elevated ROS, IL-6, and MCP-1 levels induced by ox-LDL and significantly abrogated by NE 52-QQ57 treatment. Second, a reversal in SA-β-Gal activity, telomerase activity, and G0/G1 proportion, with an upregulation in p53 and p16 expressions was observed on NE 52-QQ57 treatment in the ox-LDL induced model. Lastly, the decreased expression level of SIRT1 was extremely elevated by NE 52-QQ57. Notably, the inhibitory effect of NE 52-QQ57 against ox-LDL-induced cell senescence was abolished by the SIRT1 inhibitor EX-527.

The GPR4 antagonist NE 52-QQ57 might prevent cellular senescence by promoting the expression of SIRT1.

Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.

Taraxacum mongolicum Hand.-Mazz., generally known as dandelion, is a herb renowned for its pharmacological properties, including detoxifying and anti-inflammatory effects. Historically, this herb has been extensively utilized in the treatment of breast diseases. Recent studies have demonstrated that dandelion exhibits inhibitory properties against triple-negative breast cancer (TNBC) and modulates the tumor-associated macrophages (TAMs) microenvironment. However, the primary pharmacological mechanisms remain to be completely revealed.

This study is focused on examining the mechanism by which dandelion extract regulates the communication between TNBC and TAMs through an integrative approach of network-based pharmacology and experimental verification.

A three-dimensional (3D) co-culture cell model was employed to visualize the impact of dandelion extract on the crosstalk between TAMs and TNBC. To shed light on the crucial mechanisms of dandelion inhibitory effects on TNBC, a network pharmacology analysis was undertaken. Transwell assays were utilized to assess cell capabilities to migrate and infiltrate. Small interfering RNA (siRNA) and an overexpression plasmid targeting Ras-related C3 botulinum toxin substrate 2 (RAC2) were applied to knock down or upregulate the expression levels of RAC2. The altered expression levels of associated molecules were evaluated using quantitative real-time PCR, Western blotting, and immunohistochemistry.

The results from 3D co-culture model demonstrated that dandelion extract significantly hindered the consolidating strength between TNBC cells and TAMs. The extract effectively suppressed TAM-induced epithelial-mesenchymal transition (EMT) in TNBC cells and inhibited the recruitment of TAMs and M2 polarization mediated by TNBC cells. Network pharmacology analysis predicted that dandelion extract attenuates the inflammatory response in TNBC through NF-κB p65/p38 MAPK. Notably, dandelion extract reduced the levels of NF-κB p65/p38 MAPK-related cytokines, including TNF-α, IL-1β, and IL-6 in TNBC cells, while increasing them in TAMs. Overexpression of RAC2 in TNBC cells not only augmented their proliferation, migration, invasion, and EMT processes but also facilitated increased recruitment and M2 polarization of TAMs. TAMs were observed to promote lung metastasis, whereas dandelion extract significantly inhibited lung metastasis and EMT in 231 xenografts. Mechanically, dandelion extract significantly mitigated the RAC2/NF-κB p65/p38 MAPK-mediated inflammatory response both in TNBC cells and 231 xenografts, thereby disrupting the crosstalk between TNBC cells and TAMs.

Dandelion extract inhibits the crosstalk between TNBC and TAMs through RAC2/NF-κB p65/p38 MAPK inflammatory pathway, thereby suppressing lung metastasis in TNBC. This study revealed dandelion extract exerts a bidirectional regulatory effect on inflammation in modulating the interaction between TNBC and TAMs, offering a promising therapeutic insight for TNBC treatment.

Solar radiation is essential for life on Earth but is also a major contributor to skin carcinogenesis. Solar radiation, particularly ultraviolet (UV) B (280-320 nm) and UVA (320-400 nm), induces photocarcinogenesis via various pathways. UV light can directly cause DNA damage, resulting in genetic mutations if not repaired correctly. UV light can also induce photocarcinogenesis by generating reactive oxygen species, inducing immunosuppression and inflammation. Recently, visible light (400-760 nm) has been shown to contribute to photocarcinogenesis by activating oxidative pathways. In addition to the irradiation dose (fluence, J/m2), UVB irradiance (W/m2) is also considered a factor influencing photocarcinogenesis. In this review, we summarize the mechanisms of photocarcinogenesis and provide strategies to prevent skin cancer.

Jasminum humile is widely used in traditional medicines to treat hard lumps, mouth inflammation, ringworms, and other infections. Leaf decoction of the plant is known to be effective in treating various skin conditions. In addition, root juice is traditionally utilized as a remedy for ringworm infections. Studies have reported that J. humile contains various antioxidant metabolites with analgesic and anti-inflammatory properties. In this study, J. humile chloroform extract (JHC) was investigated for anti-inflammatory effects against carrageenan-induced paw oedema in rat models.

High-performance liquid chromatography was used to examine phenolic compounds present in JHC. The in-vivo anti-inflammatory activities were investigated using carrageenan-induced paw oedema rat models, while indomethacin was referred to as positive control. Therapeutic properties of JHC were examined by assessing paw volumes, motility score, and inflammatory proteins in serum. The anti-inflammatory nature of JHC was further investigated by biochemical and hematological profiles along with genetic expression of inflammatory and antioxidant genes through qRT-PCR analysis.

Indomethacin at 10 mg/kg and JHC at 100, 200, and 300 mg/kg doses decreased the concentration of C-reactive protein (CRP) while upregulating the concentration of albumin and myeloperoxidase (MPO). Moreover, JHC administration reduced the expression levels of inflammatory markers, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) compared to the Carr-treated control. However, a significant rise was induced in nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) levels after JHC treatment as compared to Carr-treated rats.

These results showed significant anti-inflammatory potential of J. humile by increasing the activity levels of enzymatic antioxidants and lowering inflammatory markers. These results confirm the beneficial use of natural plants in the development of new anti-inflammatory drugs.

Colorectal cancer (CRC) remains a principal contributor to oncological mortality worldwide, with chronic inflammation serving as a fundamental driver of its pathogenesis. Protease-activated receptor-2 (PAR-2), a G-protein-coupled receptor, orchestrates inflammation-driven tumorigenesis by potentiating NF-κB and Wnt/β-catenin signaling, thereby fostering epithelial-mesenchymal transition (EMT), immune evasion, and therapeutic resistance. Despite its pathological significance, targeted modulation of PAR-2 remains an underexplored avenue in CRC therapeutics. Oleocanthal (OC), a phenolic constituent of extra virgin olive oil, is recognized for its potent anti-inflammatory and anti-cancer properties; however, its regulatory influence on PAR-2 signaling in CRC is yet to be elucidated. This study interrogates the impact of OC on PAR-2-mediated inflammatory cascades using HT-29 and Caco-2 CRC cell lines subjected to lipopolysaccharide (LPS)-induced activation of PAR-2. Expression levels of PAR-2 and TNF-α were quantified through Western blotting and RT-PCR, while ELISA assessed TNF-α secretion. Intracellular calcium flux, a pivotal modulator of PAR-2-driven oncogenic inflammation, was evaluated via Fluo-4 calcium assays. LPS markedly elevated PAR-2 expression at both mRNA and protein levels in CRC cells (p < 0.01, one-way ANOVA). OC administration (20-150 μg/mL) elicited a dose-dependent suppression of PAR-2, with maximal inhibition at 100-150 μg/mL (p < 0.001, Tukey's post hoc test). Concomitant reductions in TNF-α transcription (p < 0.01) and secretion (p < 0.001) were observed, corroborating the anti-inflammatory efficacy of OC. Additionally, OC ameliorated LPS-induced calcium dysregulation, restoring intracellular calcium homeostasis in a concentration-dependent manner (p < 0.01). Crucially, OC exhibited selectivity for PAR-2, leaving PAR-1 expression unaltered (p > 0.05), underscoring its precision as a therapeutic agent. These findings position OC as a selective modulator of PAR-2-driven inflammation in CRC, disrupting the pro-tumorigenic microenvironment through attenuation of TNF-α secretion, calcium dysregulation, and oncogenic signaling pathways. This study furnishes mechanistic insights into OC's potential as a nutraceutical intervention in inflammation-associated CRC. Given the variability in OC bioavailability and content in commercial olive oil, future investigations should delineate optimal dosing strategies and in vivo efficacy to advance its translational potential in CRC therapy.

MYD88 (myeloid differentiation primary response 88) is a key adaptor protein mediate immune responses, primarily through Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) signaling. The TLR/MYD88 pathway plays a critical role in dendritic cells (DC) maturation and function, contributing to the body's innate immunity. Recent studies have further highlighted MYD88's pivotal role in intrinsic immunity and its regulatory influence on the tumor microenvironment (TME) in hepatocellular carcinoma (HCC). The expression of MYD88 in DCs and its regulatory role in the TME have gained increasing attention.

RNA-sequencing data retrieved from the TCGA and GEO databases were utilized for both the training and validation of our signature. Single-cell RNA transcriptome data from GEO were analyzed to investigate the correlation among subclusters of T cells, myeloid cells, and dendritic cells (DCs) within the HCC tumor microenvironment (TME). A combination of bioinformatics and machine learning approaches was employed to perform statistical analyses.Additionally, flow cytometry was conducted to quantify T cell subtypes and assess biomarker expression in DCs. A BALB/c-derived xenograft mouse model was established to evaluate the functional role of MyD88 in tumor progression and immunotherapy response. Furthermore, immunohistochemical (IHC) staining was performed to reassess the biological effects of MyD88 in HCC patients undergoing immune checkpoint inhibitor (ICI) therapy.

Our pan-cancer data analysis further highlights the significant impact of MYD88 on clinical outcomes in HCC. Analysis of TCGA and GEO databases confirms that MYD88 serves as a key signaling molecule in DCs, reinforcing its critical role in immune regulation. Our in vitro experiments demonstrates that MyD88 modulates T cell function through DCs. In vivo, H22 tumor cells exhibited accelerated growth in MyD88 knockout mice and a reduced response to anti-PD-1 treatment, whereas wild-type mice showed the opposite trend.

These findings underscore the critical role of MYD88 in DC function, suggesting its potential as a biomarker for immunoregulation in HCC. By shaping the TME, MYD88 not only regulates the immune response in HCC but also influences patient clinical outcomes. Both ex vivo and in vivo experiments further validate that MYD88 impacts DC functionality, contributing to variations in HCC progression.

Chronic inflammation, immune cell infiltration, and metabolic reprogramming play a crucial role in the development of head and neck squamous cell carcinoma (HNSCC). Based on the summary-level data from a genome-wide association study (GWAS), this study used Mendelian randomization (MR) analysis to investigate the causal relationship between immune cell phenotype and HNSCC. Two-step MR was employed to quantify the proportion of the effect of metabolite-mediated immunophenotypes on HNSCC. 16 immune phenotypes exhibited a causal relationship with HNSCC. HLA DR + CD4 + AC (OR: 1.31, 95% CI 1.07-1.59, P < 0.01) and EM CD8br AC cells (OR: 1.36, 95% CI 1.14-1.62, P < 0.01) showed the most significant P values. 13 metabolites have a causal relationship with HNSCC (P < 0.05). The proportion of the effect of Bilirubin degradation product, C16H18N2O5 (3) levels-mediated HLA DR + CD4 + AC on HNSCC was 7.17% (95% CI 1.04%-13.3%), while the proportion of the effect of Glutamine to alanine ratio-mediated EM CD8br AC on HNSCC was 8.88% (95% CI 2.2%-15.6%). Moreover, single-cell RNA-sequencing analysis confirmed that HLA DR + CD4 + AC and EM CD8br AC cells were commonly present in the HNSCC tumor microenvironment (TME). High expression of two immune phenotypes indicated a poorer prognosis. The results of differentially expressed genes (DEGs) analysis and functional enrichment indicated that Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)/Follicular dendritic cell secreted protein (FDCSP) and Keratin 19 type I (KRT19)/Kallikrein-related peptidase 5 (KLK5) may be responsible genes for two immune phenotypes, respectively. The results of quantitative real-time polymerase chain reaction (qRT-PCR) and survival analysis showed that FDCSP was significantly downregulated in HNSCC and could exert a protective effect. Collectively, our study clarified the causal relationship between immune cells, metabolites, and HNSCC, providing new insight for clinical diagnosis and treatment of HNSCC.

Background: ATRTs and DIPGs are deadly pediatric brain tumors with poor prognosis. These tumors can develop resistance to chemotherapies, which may be significantly influenced by their microenvironment. Since astrocytes are the most abundant glial cell type in the brain microenvironment and may support tumor growth and chemoresistance, this study investigated the effects of induced pluripotent stem cell-derived astrocytes (iPSC-astrocytes) on cisplatin sensitivity in CHLA-05-ATRT and SF8628 (DIPG) cells. iPSCs provide an unlimited and standardized source of nascent astrocytes, which enables modeling the interaction between childhood brain tumor cells and iPSC-astrocytes within a controlled coculture system. Methods: To study the effects on tumor growth, the iPSC-astrocytes were cocultured with tumor cells. Additionally, the tumor cells were exposed to various concentrations of cisplatin to evaluate their chemosensitivity in the presence of astrocytes. Results: The paracrine interaction of iPSC-astrocytes with tumor cells upregulated astrocyte activation markers GFAP and STAT3 and promoted tumor cell proliferation. Moreover, the cisplatin treatment significantly decreased the viability of CHLA-05-ATRT and SF8628 cells. However, tumor cells exhibited reduced sensitivity to cisplatin in the coculture with iPSC-astrocytes. During cisplatin treatment, DIPG cells in particular showed upregulation of resistance markers, ERK1, STAT3, and MTDH, which are associated with enhanced proliferation and invasion. They also had increased expression of APEX1, which is involved in the base excision repair pathway following cisplatin-induced DNA damage. Conclusion: These findings underscore the significance of the tumor microenvironment in modulating tumor cell survival and chemosensitivity.

Infectious bronchitis (IB) poses a major challenge to global poultry production, causing substantial economic burdens and underscoring the necessity for novel therapeutic interventions given the limitations of current vaccines and conventional antiviral agents. The purpose of this study is to comprehensively explore the active components in Shuanghuanglian and their interaction with the key pathological targets of IBV (Infectious bronchitis virus) infection. By using advanced computational methods, this study aims not only to identify the therapeutic potential of active ingredients, but also to reveal their mechanism of action against IBV.

Through integrative systems pharmacology approaches, we systematically investigated Shuanghuanglian and its phytochemical constituents against IB, employing multi-omics analysis, ensemble machine learning, and all-atom molecular dynamics (MD) simulations. Network pharmacology revealed 65 target genes associated with Shuanghuanglian's primary bioactive components (quercetin, kaempferol, wogonin, and luteolin), exhibiting high network centrality.

Using the TCMSP database, we found 65 target genes associated with key active components, such as quercetin and kaempferol, which exhibited strong connectivity in our network analysis. The GeneCards database also identified 40 common target genes shared by Shuanghuanglian and IB. Importantly, BCL2 and IL6 were recognized as key targets in the protein-protein interaction (PPI) network analysis, highlighting their roles in apoptosis and inflammation. Furthermore, analyses using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed significant roles in regulating the cell cycle and inflammatory responses. Machine learning techniques identified BCL2 and IL6 as critical genes for therapeutic intervention, supported by molecular docking results that showed strong binding energies. Furthermore, molecular dynamics simulations confirm the stability of the complexes, underscoring the importance of these interactions for treatment efficacy.

We used a variety of analytical methods, and finally identified the potential active ingredients of Shuanghuanglian as kaempferol, quercetin, wogonin, and luteolin. The active ingredients target BCL2 and IL6 and play a therapeutic role in avian infectious bronchitis by inhibiting apoptosis and reducing inflammatory response.

Background and Objectives: Platinum-resistant ovarian cancer (PROC) is associated with limited treatment options and poor outcomes, with median progression-free survival (PFS) and overall survival (OS) remaining suboptimal. Neutropenia, a common chemotherapy-related toxicity, has shown potential as a predictive biomarker for treatment efficacy in several malignancies, including ovarian cancer. However, its role as a prognostic marker, particularly baseline neutropenia, remains underexplored. This study aimed to evaluate the prognostic and predictive value of initial neutropenia and neutrophil dynamics in PROC patients undergoing chemotherapy. Materials and Methods: A retrospective cohort study was conducted on 250 PROC patients treated between 2018 and 2022 at the OncoHelp Medical Center, Timișoara, Romania. Patients were stratified into two groups based on baseline absolute neutrophil count (ANC), as those with initial neutropenia (ANC < 2000/mm3) and without initial neutropenia (ANC ≥ 2000/mm3). Clinical outcomes, including tumor response, PFS, and OS, were assessed using RECIST 1.1 criteria. Hematological toxicities and neutrophil dynamics across three chemotherapy cycles were analyzed. Results: Patients with baseline neutropenia demonstrated significantly higher tumor response rates (47.05% vs. 27.27%; p = 0.002), longer median PFS (8.2 vs. 6.3 months; p = 0.008), and extended median OS (14.5 vs. 11.2 months; p = 0.002). Hematological toxicities, including Grade ≥3 neutropenia and febrile neutropenia, were more frequent in the neutropenic group (p < 0.001). Baseline ANC thresholds effectively predicted clinical outcomes, with an AUC of 0.79 for OS. Conclusions: Baseline neutropenia is a significant prognostic marker in PROC, correlating with improved tumor response and survival outcomes despite increased hematological toxicities. These findings support incorporating baseline ANC into treatment personalization strategies for PROC.

Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic and epigenetic alterations. Enhancer reprogramming has emerged as a pivotal driver of carcinogenesis, with cancer cells often relying on aberrant transcriptional programs. The advent of high-throughput sequencing technologies has provided critical insights into enhancer reprogramming events and their role in malignancy. While targeting enhancers presents a promising therapeutic strategy, significant challenges remain. These include the off-target effects of enhancer-targeting technologies, the complexity and redundancy of enhancer networks, and the dynamic nature of enhancer reprogramming, which may contribute to therapeutic resistance. This review comprehensively encapsulates the structural attributes of enhancers, delineates the mechanisms underlying their dysregulation in malignant transformation, and evaluates the therapeutic opportunities and limitations associated with targeting enhancers in cancer.

The pathogenesis of psoriasis involves hyperproliferation of epidermal keratinocytes and abnormal interactions between activated keratinocytes and infiltrating immune cells. Emerging evidence has shown that keratinocytes play essential roles in both the initiation and maintenance of psoriasis, suggesting that exposing keratinocytes to agents with antiproliferative and anti-inflammatory effects may be effective for psoriasis treatment. Guggulsterone (GS), a plant sterol derived from the gum resin of Commiphora wightii, possesses a variety of pharmacological activities. However, the effects of GS on psoriasis and the underlying mechanism have not been elucidated. In this study, we evaluated the therapeutic effect of GS on psoriasis using an imiquimod-induced psoriasis mouse model and investigated the effect of GS on human keratinocytes and the underlying mechanism. We found that GS effectively alleviated psoriasis-like skin lesions in imiquimod-induced psoriasis model mice and that GS suppressed the proliferation, migration, and production of proinflammatory cytokines, chemokines and antimicrobial peptides in keratinocytes. Transcriptome analysis by RNA-seq revealed that the differentially expressed genes (DEGs) induced by GS in keratinocytes were intricately linked to the pathogenesis of psoriasis. Furthermore, STAT3, a key player in the development and pathogenesis of psoriasis, was identified as a critical downstream mediator of GS in keratinocytes. Mechanistically, GS upregulated the expression of miR-17-5p, which directly binds to the 3'-untranslated regions (3'UTRs) of JAK1 and STAT3, leading to the downregulation of JAK1 and STAT3 expression. Collectively, these findings suggest that GS may serve as an effective natural compound for the treatment of psoriasis.

Acute pancreatitis (AP) is a common digestive emergency with high morbidity and mortality. Over the past decade, significant progress has been made in understanding the mechanisms of AP, including oxidative stress, disruptions in calcium homeostasis, endoplasmic reticulum stress, inflammatory responses, and various forms of cell death. This review provides an overview of the typical signaling pathways involved and proposes the latest clinical translation prospects. These strategies are important for the early management of AP, preventing multi-organ injury, and improving the overall prognosis of the disease.

Pulsed electromagnetic field (PEMF) is a non-invasive treatment that utilizes electromagnetic fields to reduce inflammation and promote tissue repair. However, PEMFs' anti-inflammatory effect on osteoarthritis (OA) and the potential mechanism has not been fully elucidated.

Human chondrocytes (C28/I2) were stimulated with interleukin (IL)-1β with or without the treatment of PEMF. CCK-8 assay Kit was used to detect cell viability. RT-qPCR, ELISA, immunofluorescent staining and western blot was used to analyze relative markers of inflammatory response and extracellular matrix (ECM) under the treatment of PEMF and related mechanism. Besides, the significance role of Sirt1 was assessed by using the Sirt1 inhibitor (EX-527). Moreover, immunohistochemistry and immunofluorescence staining were carried out to evaluate the curative effect of PEMF on OA mice induced by the destabilization of the medial meniscus (DMM).

PEMF inhibited IL-1β-mediated the expression of pro-inflammatory factors. Besides, PEMF alleviated IL-1β-induced degradation of ECM by increasing the expression of Col2a1 and ACAN, while inhibiting the expression of MMP13 and ADAMTS5. At the mechanism level, PEMF increased the expression of Sirt1 and inhibited IL-1β-induced the activation of NF-κB pathway. Furthermore, blocking Sirt1 with EX-527 attenuated the effect of PEMF on the inhibition of NF-κB pathway and the expression of ECM in IL-1β-induced chondrocytes. In vivo, PEMF-treated OA mice showed low modified mankin scores, reduced the number of osteophytes and preserved joint structure.

Our results suggest that PEMF inhibits NF-κB pathway and blocks the expression of inflammatory factors by activating the expression of Sirt1, which may be a novel strategy for OA.

Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential-often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulation in vivo without noticeable cytotoxicity. Moreover, sequential cycles of albendazole and paclitaxel-a commonly used chemotherapeutic -displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations.

Network-based approaches, as shown in a study on metastatic breast cancer, can develop effective combinatorial therapies targeting complementary subpopulations. By analyzing scRNA-seq data and using clinically relevant drugs, researchers identified and depleted chemoresistant Cancer Stem-Like Cells, enhancing the efficacy of standard chemotherapies.

Yinxu Weitong Capsule (YXWTC) is a Chinese patent medicine used to treat chronic gastritis. However, its efficacy and mechanisms of action in treating precancerous lesions of gastric cancer (PLGC) remain unclear.

To evaluate the effects of YXWTC on PLGC and explore the underlying mechanisms.

YXWTC components were identified using ultra-high-performance liquid chromatography coupled with electrospray ionization quadrupole-exactive orbitrap mass spectrometry. A PLGC animal model was established and the protective effects of YXWTC on the gastric mucosa in PLGC rats were evaluated using hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff and Alcian blue-high iron diamine staining, and transmission electron microscopy (TEM). The vital organs of the rats were examined using H&E staining to evaluate biosafety. Network pharmacology identified potential targets and pathways of YXWTC in PLGC treatment, followed by molecular docking validation. Various techniques, including enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, Western blotting, immunohistochemistry, apoptosis detection, and reactive oxygen species fluorescence staining were employed to elucidate the underlying mechanisms.

In total, 340 YXWTC components were identified. YXWTC effectively improves gastric mucosal pathology in rats with PLGC. Network pharmacology identified 403 targets common to PLGC and YXWTC. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses identified 2,323 biological processes and 206 signaling pathways, respectively. Molecular docking revealed that the primary target proteins and major drug molecules exhibited strong binding affinities. Animal studies demonstrated that YXWTC inhibited the IL-6/STAT3 pathway, promoted mitochondrial apoptosis, and induced ROS release.

We verified the pharmacodynamic effects of YXWTC in PLGC. In summary, the effects are mediated by inhibition of the IL-6/STAT3 pathway, promotion of mitochondrial apoptosis, and induction of ROS release.

This study investigates the therapeutic effects of recombinant human IL-10 (rhIL-10) administered via aerosol inhalation in acute lung injury (ALI), with a particular focus on neutrophils. It explores how rhIL-10, in the presence of platelets, modulates neutrophil polarization to ameliorate acute lung injury. Initially, the ALI model established in mice demonstrated that aerosol inhalation of rhIL-10 significantly mitigated the cytokine storm in the lungs, reduced pulmonary edema, and alleviated histopathological damage to lung tissue. Additionally, rhIL-10 administration was found to decrease neutrophil infiltration and platelet activation in the lungs of mice, inhibiting the formation of platelet-neutrophil aggregates (PNAs) and promoting the differentiation of neutrophils toward an anti-inflammatory phenotype in the presence of platelets. Subsequently, primary neutrophils and platelets were isolated from mouse bone marrow and blood to explore the underlying mechanisms. The results indicated that rhIL-10 promotes the expression of the signal transducer and activator of transcription 3 (STAT3) and the suppressor of cytokine signaling 3 (SOCS3) in neutrophils while inhibiting the activation of the nuclear factor kappa B (NF-κB) and the NF-κB inhibitor (IκB), which in turn enhances CD40 expression. This interaction facilitates the formation of PNAs and influences neutrophil phenotype differentiation. Furthermore, the application of the STAT3 phosphorylation inhibitor Stattic and CD40 antibody in vivo provided further validation of this potential mechanism. In conclusion, these results indicate that aerosol inhalation of rhIL-10 effectively ameliorates ALI. The underlying mechanism may involve the modulation of the neutrophil STAT/SOCS-IκB/NF-κB-CD40 signaling pathway, promoting interactions between neutrophils and platelets that facilitate the differentiation of neutrophils toward an anti-inflammatory phenotype.

The skin represents the first barrier of defense, and its integrity is crucial for overall health. Skin wounds present a considerable risk seeing how their progression is rapid and sometimes they are caused by comorbidities like diabetes and venous diseases. Nutraceutical combinations like the ones between polyphenols and metal ions present considerable applications thanks to their increased bioavailability and their ability to modulate intrinsic molecular pathways.

The research findings presented in this paper are based on a systematic review of the current literature with an emphasis on nanotechnology and regenerative medicine strategies that incorporate polyphenols and metallic nanoparticles (NPs). The key studies which described the action mechanisms, efficacy, and safety of these hybrid formulations were reviewed.

Nanocomposites of polyphenol and metal promote healing by activating signaling pathways such as PI3K/Akt and ERK1/2, which in turn improve fibroblast migration and proliferation. Nanoparticles of silver and copper have antibacterial, angiogenesis-promoting, inflammation-modulating capabilities. With their ability to induce apoptosis and restrict cell growth, these composites have the potential to cure skin malignancies in addition to facilitating wound healing.

Nanocomposites of polyphenols and metals provide hope for the treatment of cancer and chronic wounds. Their antimicrobial capabilities, capacity to modulate inflammatory responses, and enhancement of fibroblast activity all point to their medicinal potential. Furthermore, these composites have the ability to decrease inflammation associated with tumors while simultaneously inducing cell death in cancer cells. Clarifying their mechanisms, guaranteeing stability, and enhancing effective delivery techniques for clinical usage should be the focus of future studies.

IKKα is known as an essential protein for skin homeostasis. However, the lack of suitable models to investigate its functions in the skin has led to IKKα being mistakenly considered as a suppressor of non-melanoma skin cancer (NMSC) development. In this study, using our previously generated transgenic mouse models expressing exogenous IKKα in the cytoplasm (C-IKKα mice) or in the nucleus (N-IKKα mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKα differently regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, and for the cutaneous inflammatory response. In addition, each type of IKKα-transgenic mice shows different predisposition to the development of spontaneous NMSC. Specifically, N-IKKα mice display an atrophic epidermis with exacerbated terminal differentiation, signs of premature skin aging, premalignant lesions, and develop squamous cell carcinomas (SCCs). Conversely, C-IKKα mice, whose keratinocytes are nearly devoid of endogenous nuclear IKKα, do not develop skin SCCs, although they exhibit hyperplastic skin with deficiencies in terminal epidermal differentiation, chronic cutaneous inflammation, and constitutive activation of STAT-3 and NF-κB signaling pathways. Altogether, our data demonstrate that alterations in the localization of IKKα in the nucleus or cytoplasm of keratinocytes cause opposite skin changes and differentially predispose to the growth of skin SCCs.

Mesenchymal stem cells (MSCs) are emerging as promising therapeutic agents due to their immunomodulatory effects, primarily mediated via paracrine signaling. Similarly, anthocyanins, such as cyanidin-3-glucoside (C3G), have demonstrated significant anti-inflammatory properties. In this context, this study investigated the immunomodulatory potential of C3G on MSCs, and subsequent effects on macrophage and lymphocyte responses. Cytotoxicity assays identified 50 µM as the highest nontoxic C3G concentration for MSCs. Flow cytometry confirmed that C3G treatment did not affect MSC viability or cell cycle distribution, even under LPS stimulation. Cytokine production by MSCs was evaluated after treatment with C3G and LPS. While no significant changes were observed in IL-6, IL-10, TGF-β, or PGE2 levels, IL-1β production was significantly reduced in LPS-stimulated MSCs treated with C3G. Protein expression analysis revealed decreased NFκB phosphorylation in LPS-stimulated MSCs treated with C3G, with no changes detected in STAT-3 or PCNA expression. The immunomodulatory effects of MSC-derived conditioned media on macrophages and lymphocytes were also assessed. In LPS-stimulated macrophages, conditioned media from MSCs reduced the production of IL-1β, IL-6, and IL-12. Interestingly, conditioned media from C3G-treated MSCs specifically decreased TNF-α levels, enhanced IL-10 secretion, and further inhibited NFκB phosphorylation. In LPS-stimulated lymphocytes, conditioned media from C3G-treated MSCs suppressed IL-2 production while increasing IL-10 levels. In summary, these findings demonstrate that conditioned media from C3G-treated MSCs modulates immune cell responses more effectively than C3G alone. C3G influences the paracrine activity of MSCs, resulting in a shift in the secretory profile and subsequent effects on immune cell behavior.