Search Results (555)

WWOX and HIF1α proteins are involved in cancer progression; their functions are closely related. WWOX binds HIF1α through its WW domains, sequestering it in the cytoplasm and inhibiting its transcriptional activity. This study evaluates the prognostic significance of the WWOX/HIF1A interaction across cancers, breast cancer subtypes, glioblastoma (GBM), low-grade glioma (LGG), and hepatocellular carcinoma (HCC) through gene expression and pathway analysis focused on metabolism, ECM, and epithelial–mesenchymal transition. In breast cancer, metabolic pathways correlated with good prognosis in basal subtypes. HER2 subtypes showed enrichment in DNA replication pathways. Luminal A subtypes showed favourable prognosis via TNF and PI3K/AKT signalling, while luminal B subtypes had poor prognosis tied to metabolic activity; genes associated with good prognosis mirrored those tied to poor prognosis in luminal A. In HCC, enhanced metabolic activity was associated with good prognosis. In contrast, poor prognosis involved TNF signalling and cytoskeleton-related pathways, indicating more aggressive tumour behaviour. In LGG, good prognosis was linked to metabolic and cAMP pathways, while poor outcomes involved TNF, cell cycle, apoptosis, and focal adhesion pathways. GBM showed similar patterns: metabolic and cAMP pathways indicated better outcomes, while NFKB, TNF, JAK-STAT, and PI3K/AKT pathways marked poor prognosis. These findings suggest the WWOX/HIF1A ratio is a robust prognostic marker and a possible guide for developing targeted treatments. Full article

It is widely accepted that chronic inflammation constitutes a significant mechanism that promotes the biological aging process. The pineal gland is regarded as being closely related to the control of the “life clock”. The present study aimed to determine the inflammation associated with pinealectomy in the rat hippocampus and to investigate the extent to which age stage impacts the severity of this inflammation. We evaluated the expression of the Akt/NF-kB signaling pathway in neurons and gliosis level in the dorsal hippocampus (dHipp) of rats subjected to sham surgery or pinealectomy at 3, 14, or 18 months of age. The assessment was conducted using immunohistochemistry. Removal of the pineal gland resulted in significant, region-specific increases in NF-kB expression in neurons of the dHipp in the youngest and middle-aged groups. However, the change in expression of the phosphorylated form of Akt (pAkt1) in neurons went in the opposite direction in these two age groups, and there were also regional differences. Pinealectomy triggered microgliosis in both young and old rats, but middle-aged rats were resistant to microglia activation. Conversely, astrogliosis was observed in young adult and middle-aged groups with melatonin deficiency in certain regions of the dHipp. It is noteworthy that young adult rats demonstrated the highest degree of vulnerability to inflammation associated with the loss of melatonin as a hormone. In contrast, middle-aged rats with pinealectomy exhibited a complex and partial adaptive response. These findings emphasize the dynamic and age-dependent nature of neuroinflammation following pinealectomy, underscoring the developmental stage as a critical determinant of inflammatory susceptibility. Full article

Mechanical forces shape immune responses in both health and disease. PIEZO1 and PIEZO2, two mechanosensitive ion channels, have emerged as critical transducers of these forces, influencing inflammation, pain, fibrosis, and neuroimmune regulation. This review aims to synthesize the current evidence on the role of PIEZO channels in mechano-inflammation, with a specific focus on their regulatory function in neuroimmune crosstalk. A comprehensive narrative synthesis was performed using the literature from PubMed, Scopus, and Web of Science up to June 2025. Experimental, translational, and mechanistic studies involving PIEZO channels in inflammatory, fibrotic, and neuroimmune processes were included. PIEZO1 is broadly expressed in immune cells, fibroblasts, and endothelial cells, where it regulates calcium-dependent activation of pro-inflammatory pathways, such as NF-kB and STAT1. PIEZO2, enriched in sensory neurons, contributes to mechanosensory amplification of inflammatory pain. Both channels are mechanistically involved in neuroinflammation, glial activation, blood–brain barrier dysfunction, connective tissue fibrosis, and visceral hypersensitivity. PIEZO channels act as integrators of biomechanical and immunological signaling. Their roles as context-dependent gatekeepers of neuroimmune crosstalk make them attractive targets for novel therapies. Full article

Osteoarthritis (OA) is a chronic progressive joint disease characterized by cartilage degradation, subchondral bone remodeling, and synovial inflammation. This complex disorder arises from the interplay between mechanical stress and inflammatory processes, which is mediated by interconnected molecular signaling pathways. This review explores the dual roles of inflammatory and mechanical signaling in OA pathogenesis, focusing on crucial pathways such as NF-kB, JAK/STAT, and MAPK in inflammation, as well as Wnt/β-catenin, Integrin-FAK, and Hippo-YAP/TAZ in mechanotransduction. The interplay between these pathways highlights a vicious cycle wherein mechanical stress exacerbates inflammation, and inflammation weakens cartilage, increasing its vulnerability to mechanical damage. Additionally, we discuss emerging therapeutic strategies targeting these pathways, including inhibitors of cartilage-degrading enzymes, anti-inflammatory biologics, cell-based regenerative approaches, and non-pharmacological mechanical interventions. By dissecting the molecular mechanisms underlying OA, this review aims to provide insights into novel interventions that address both inflammatory and mechanical components of the disease, paving the way for precision medicine in OA management. Full article

Background: Short-chain fatty acids (SCFAs), microbial metabolites also known as postbiotics, are essential for maintaining gut health. However, their antiproliferative effects on gastric cancer cells and potential interactions with conventional therapies remain underexplored. This study aimed to investigate the effects of three SCFA salts—magnesium acetate (A), sodium propionate (P), and sodium butyrate (B)—individually and in combination (APB), as well as in combination with dexamethasone (Dex), on AGS gastric adenocarcinoma cells. Methods: AGS cells were treated with PB, AP, AB, APB, Dex, and APB+Dex. Cell viability was assessed to determine antiproliferative effects, and the IC₅₀ of APB was calculated. Flow cytometry was used to evaluate apoptosis and necrosis. Reactive oxygen species (ROS) levels were measured to assess oxidative stress. Proteomic analysis via LC-MS was performed to identify differential protein expression and related pathways impacted by the treatments. Results: SCFA salts showed significant antiproliferative effects on AGS cells, with APB exhibiting a combined IC₅₀ of 568.33 μg/mL. The APB+Dex combination demonstrated strong synergy (combination index = 0.76) and significantly enhanced growth inhibition. Both APB and APB+Dex induced substantial apoptosis (p < 0.0001) with minimal necrosis. APB alone significantly increased ROS levels (p < 0.0001), while Dex moderated this effect in the combination group APB+Dex (p < 0.0001). Notably, the APB+Dex treatment synergistically targeted multiple tumour-promoting mechanisms, including the impairment of redox homeostasis through SLC7A11 suppression, and inhibition of the haemostasis, platelet activation network and NF-κB signalling pathway via downregulation of NFKB1 (−1.34), exemplified by increased expression of SERPINE1 (1.99) within the “Response to elevated platelet cytosolic Ca²⁺” pathway. Conclusions: These findings showed a multifaceted anticancer mechanism by APB+Dex that may collectively impair cell proliferation, survival signalling, immune modulation, and tumour microenvironment support in gastric cancer. Full article

Mycotoxins represent a group of highly toxic secondary metabolites produced by diverse fungal pathogens. Mycotoxin contaminations frequently occur in foods and feed and pose significant risks to human and animal health due to their carcinogenic, mutagenic, and immunosuppressive properties. Notably, deoxynivalenol, zearalenone, fumonisins (mainly including fumonisins B1, B2, and FB3), aflatoxin B1 (AFB1), and T-2/HT-2 toxins are the major mycotoxin contaminants in foods and feed. Undoubtedly, exposure to these mycotoxins can disrupt gut health, particularly damaging the intestinal epithelium in humans and animals. In this review, we summarized the detrimental effects caused by these mycotoxins on the intestinal health of humans and animals. The fundamental molecular mechanisms, which cover the induction of inflammatory reaction and immune dysfunction, the breakdown of the intestinal barrier, the triggering of oxidative stress, and the intestinal microbiota imbalance, were explored. These signaling pathways, such as MAPK, Akt/mTOR, TNF, TGF-β, Wnt/β-catenin, PKA, NF-kB, NLRP3, AHR, TLR2, TLR4, IRE1/XBP1, Nrf2, and MLCK pathways, are implicated. The abnormal expression of micro-RNA also plays a critical role. Finally, we anticipate that this review can offer new perspectives and theoretical foundations for controlling intestinal health issues caused by mycotoxin contamination and promote the development of prevention and control products. Full article

The biggest challenge in cancer therapy is tumor resistance to the classical approach. Thus, research interest has shifted toward the cancer stem cell population (CSC). CSCs are a small subpopulation of cancer cells within tumors with self-renewal, differentiation, and metastasis/malignant potential. They are involved in tumor initiation and development, metastasis, and recurrence. Method. A narrative review of significant scientific publications related to the topic and its applicability in endometrial cancer (EC) was performed with the aim of identifying current knowledge about the identification of CSC populations in endometrial cancer, their biological significance, prognostic impact, and therapeutic targeting. Results: Therapy against the tumor population alone has no or negligible effect on CSCs. CSCs, due to their stemness and therapeutic resistance, cause tumor relapse. They target CSCs that may lead to noticeable persistent tumoral regression. Also, they can be used as a predictive marker for poor prognosis. Reverse transcription–polymerase chain reaction (RT-PCR) demonstrated that the cultured cells strongly expressed stemness-related genes, such as SOX-2 (sex-determining region Y-box 2), NANOG (Nanog homeobox), and Oct 4 (octamer-binding protein 4). The expression of surface markers CD133+ and CD44+ was found on CSC as stemness markers. Along with surface markers, transcription factors such as NF-kB, HIF-1a, and b-catenin were also considered therapeutic targets. Hypoxia is another vital feature of the tumor environment and aids in the maintenance of the stemness of CSCs. This involves the hypoxic activation of the WNT/b-catenin pathway, which promotes tumor survival and metastasis. Specific antibodies have been investigated against CSC markers; for example, anti-CD44 antibodies have been demonstrated to have potential against different CSCs in preclinical investigations. Anti-CD-133 antibodies have also been developed. Targeting the CSC microenvironment is a possible drug target for CSCs. Focusing on stemness-related genes, such as the transcription pluripotency factors SOX2, NANOG, and OCT4, is another therapeutic option. Conclusions: Stemness surface and gene markers can be potential prognostic biomarkers and management approaches for cases with drug-resistant endometrial cancers. Full article

Bone tissue regeneration is a complex process that takes place at the level of osteoblasts derived from mesenchymal cells and occurs under the action of multiple signaling pathways and through the expression of osteoregenerative markers. The leaf extract of Juglans regia L. (JR) is rich in polyphenols with demonstrated osteoregeneration effects. In the present study, we investigated the extract’s effects on three types of cells with various stages of differentiation: adult mesenchymal stem cells (MSCs), osteoblasts at low passage (O6) and osteoblasts at advanced passage (O10). To assess the efficacy of the walnut leaf extract, in vitro treatments were performed in comparison with ellagic acid (EA) and catechin (CAT). The osteoregenerative properties of the leaf extract were evaluated in terms of cell viability, bone mineralization (by staining with alizarin red) and the expression of osteogenesis markers such as osteocalcin (OC), osteopontin (OPN), dentin matrix acidic phosphoprotein 1 (DMP1) and collagen type 1A. Another compound implicated in oxidative stress response, but also a bone homeostasis regulator, nuclear factor erythroid 2-related factor 2 (NRF2), was studied by immunocytochemistry. Together with collagen amount, alkaline phosphatase (ALP) activity and NF-kB levels were measured in cell lysates and supernatants. The obtained results demonstrate that JR treatment induced osteogenic differentiation and bone mineralization, and it showed protective effects against oxidative stress. Full article

Background: The progressive course of coronavirus disease 2019 (COVID-19) is more frequently observed in individuals with obesity, diabetes, pulmonary and cardiovascular disease, or arterial hypertension. Many patients with these conditions are prescribed statins to treat hypercholesterolaemia. However, statins exhibit additional pleiotropic effects. The present study aims to investigate the effects of all eight currently existing statins on the expression of genes whose products have been reported to be directly associated with complicated COVID-19 disease. Methods: We extended the interpretation of the whole-genome DNA microarray analyses of pancreatic cancer cells MiaPaCa-2 and whole-transcriptome analyses of adipose tissue-derived mesenchymal stem cells AD-MSC that we had performed in the past. From the number of genes with altered expression induced by statins, we focused on those reported to be involved in a complicated course of COVID-19, including APOE and ACE2, genes encoding proteins involved in innate antiviral immunity and respiratory failure genes. Results: Although we did not observe statin-induced changes in the expression of APOE, ACE2 and any of the six genes clustered in the locus associated with respiratory failure in patients with COVID-19, some statins induced changes in the expression of genes encoding their interaction partners. Among genes associated with the immune system, all statins, which are effective in vitro affected the expression of genes encoding IL-6 and IL-8 and interaction partners of NF-kB, which may influence the duration of viral persistence. Conclusions: Statins act on multiple pathways simultaneously, some of which support COVID-19 development, while others suppress it. Full article

Plant secondary metabolites possess significant antioxidant and anti-inflammatory properties, but their complex polypharmacological mechanisms remain poorly understood. Network pharmacology has emerged as a powerful systems-level approach for investigating multi-target interactions of natural products. This review systematically analyzes network pharmacology applications in elucidating the antioxidant and anti-inflammatory mechanisms of plant metabolites, evaluating concordance between computational predictions and experimental validation. A comprehensive literature search was conducted across major databases (2015–2025), focusing on network pharmacology studies with experimental validation. Analysis revealed remarkable convergence toward common molecular mechanisms, despite diverse chemical structures. For antioxidant activities, the Nrf2/KEAP1/ARE pathway emerged as the most frequently validated mechanism, along with PI3K/AKT, MAPK, and NF-κB signaling. Anti-inflammatory mechanisms consistently involved NF-κB, MAPK, and PI3K/AKT pathways. Key targets, including AKT1, TNF-α, COX-2, NFKB1, and RELA, were repeatedly identified. Flavonoids, phenolic acids, and terpenoids dominated as bioactive compounds. Molecular docking studies supported predicted interactions, with experimental validation showing good concordance for pathway modulation and cytokine regulation. Network pharmacology provides a valuable framework for investigating the complex bioactivities of plant metabolites. The convergence toward common regulatory hubs suggests that natural compounds achieve protective effects by modulating central nodes that integrate redox balance and inflammatory responses. Despite limitations, including database dependency, integrating network pharmacology with experimental validation accelerates mechanistic understanding in natural-product drug discovery. Full article

Tanshinones are a class of lipophilic diterpenoid quinones extracted from Salvia miltiorrhiza (Dan shen), a widely used herb in traditional Chinese medicine. These compounds, particularly tanshinone IIA (T-IIA) and sodium tanshinone sulfonate (STS), have been acknowledged for their broad spectrum of biological activities, including anti-inflammatory, antioxidant, anti-tumor, antiresorptive, and antimicrobial effects. Recent studies have highlighted the potential of tanshinones in the treatment of osteolytic diseases, characterized by excessive bone resorption, such as osteoporosis, rheumatoid arthritis, and periodontitis. The therapeutic effects of tanshinones in these diseases are primarily attributed to their ability to inhibit osteoclast differentiation and activity, suppress inflammatory cytokine production (e.g., tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6), and modulate critical signaling pathways, including NF-kB, MAPK, PI3K/Akt, and the RANKL/RANK/OPG axis. Additionally, tanshinones promote osteoblast differentiation and mineralization by enhancing the expression of osteogenic markers such as Runx2, ALP, and OCN. Preclinical models have demonstrated that T-IIA and STS can significantly reduce bone destruction and inflammatory cell infiltration in arthritic joints and periodontal tissues while also enhancing bone microarchitecture in osteoporotic conditions. This review aims to provide a comprehensive overview of the pharmacological actions of tanshinones in osteolytic diseases, summarizing current experimental findings, elucidating underlying molecular mechanisms, and discussing the challenges and future directions for their clinical application as novel therapeutic agents in bone-related disorders, especially periodontitis. Despite promising in vitro and in vivo findings, clinical evidence remains limited, and further investigations are necessary to validate the efficacy, safety, and pharmacokinetics of tanshinones in human populations. Full article

Objectives: This study investigated the properties of a neutral exopolysaccharide (EPS-LP1) with an average molecular weight of 55,637 Da, isolated from Lactiplantibacillus plantarum DMDL 9010 (LP9010). Results: The composition of EPS-LP1 includes galactose (Gal), glucose (Glu) and mannose (Man) in a molar ratio of 5.35:86.25:8.40. Notably, EPS-LP1 exhibits a smooth and rod-like surface along with thermal stability. Methylation combined with nuclear magnetic resonance analysis revealed that EPS-LP1 structured as t-Galp(1→, →6)-Glcp(1→, 4)-Glcp(1→ and →4,6)-Galp(1→), with relative molar ratio of 1.016:9.874:4.355:78.693:6.062, respectively. In the concentration range of 50 to 400 mg/mL, we observed the absence of cytotoxic effects from EPS-LP1 on RAW264.7 cells. Furthermore, EPS-LP1 demonstrated protective effects on RAW264.7 cells against oxidative damage by reducing the production of reactive oxygen species (ROS), malondialdehyde (MDA), and lactate dehydrogenase (LDH) release. Conversely, an increase in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and concentrations of glutathione (GSH) was observed. Immunoreactivity assays indicated that EPS-LP1 can effectively reduce the production of nitric oxide (NO) and inhibit the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Additionally, it inhibited the activation of the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B gene binding (NF-kB) signaling pathway. Conclusions: This research provides a foundation basis for further investigations into the neutral exopolysaccharide derived from LP9010. Full article

Background/Objectives: Contrast agents can damage renal tissue through multiple mechanisms, particularly by increasing reactive oxygen species (ROS), which contribute to DNA oxidation, lipid peroxidation, and endothelial injury. This prospective, comparative study aimed to evaluate the changes in ROS-related gene expressions—NFKB1, SIRT1, NFE2L2, and FOXO1—in patients who developed contrast-induced nephropathy (CIN) following coronary angiography versus those who did not. Methods: A total of 48 patients undergoing primary percutaneous coronary intervention were enrolled. Twenty-three patients who developed CIN (Group 1) were compared to 25 matched controls without CIN (Group 2) based on age, gender, and comorbidities. Blood and serum samples were collected 72 h post-contrast exposure to assess biochemical markers and mRNA expression levels of the target genes. Results: The mean age was similar between the groups (63 ± 7 vs. 62 ± 6 years; p > 0.05), as was gender distribution. Group 1 showed significant increases in serum creatinine and reductions in e-GFR post-procedure. Importantly, NFKB1, NFE2L2, and FOXO1 mRNA expression levels were significantly upregulated in CIN patients—by 5.7-, 5.8-, and 4.97-fold, respectively, while SIRT1 expression was downregulated by 0.76-fold (p < 0.05). Conclusions: These findings indicate enhanced activation of inflammatory and oxidative stress pathways in CIN patients, particularly through the NF-κB signaling axis. Conversely, reduced SIRT1 expression suggests diminished antioxidant protection. The study highlights that ROS-related gene expression changes may serve as potential biomarkers for CIN progression. Further studies at the protein level are needed to clarify cytokine roles in these pathways. Full article

Oral squamous cell carcinoma (OSCC) is a malignancy that affects the oral mucosa and is characterized by indurated oral lesions. The RNAseq of formalin-fixed, paraffin-embedded (FFPE) samples is readily available in clinical settings. Such samples have long-term preservation and can provide highly accurate transcriptomic information regarding gene fusions, isoforms, and allele-specific expression. We determined differentially expressed genes using the transcriptomic profiles of oral potentially malignant disorder (OPMD) FFPE oral lesion samples of patients who developed OSCC over years. A technical comparison was completed comparing breast cancer (BC) FFPE publicly available data in this proof-of-concept pilot study. OSCC FFPE samples were collected from patients (N = 3) who developed OSCC 3 to 5 years following OPMD diagnosis (n = 3) and were analyzed using RNAseq. RNAseq sequences from the FFPE OSCC samples and publicly available FFPE samples of BC patients (n = 6) (Gene Expression Omnibus Database, GSE58135) aligned to human reference (GRCh38.p13). Genes were counted using the Spliced Transcripts Alignment to a Reference (STARv2.7.9a) software. Differential expression was determined in R using DESeq2v1.40.2 comparing OSCC to BC samples. Principal component analysis (PCA) plots were completed. Differential Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were determined via the Pathviewv.1.40.0 program. STRING v12.0 was used to determine protein–protein interactions between genes represented in more than one KEGG pathway. STARv2.7.9a identified 27,237 and 30,343 genes among the OSCC and BC groups, respectively. DESeq2v1.40.2 determined 9194 differentially expressed genes (DEPs), 4466 being upregulated (OSCC > BC) and 4728 being downregulated (BC > OSCC) (padj < 0.05). Most significant genes included KRT6B, SERPINB5, and DSC3 (5- to 10-fold change range; padj < 10 × 10−100). PCA showed that BC and OSCC samples clustered as separate groups. Pathviewv.1.40.0 identified 17 downregulated KEGG pathways in OSCC compared to the BC group. No upregulated KEGG pathways were identified. STRINGv12.0 determined Gene Ontology Biological Process enrichments for leukocytes and apoptosis in upregulated KEGG genes including multiple PIK3 genes and NIK/NF-kappaB signaling and metabolic responses from lipopolysaccharides in downregulated KEGG genes including CHUK and NFKB1. Using FFPE samples, we determined DEPs characteristic of OSCC and distinct from BC. KRT-family genes and lipopolysaccharide producing periodontal pathogens may be further investigated for their involvement in the OPMD to OSCC transition. Full article

Background: Head and neck cancer (HNC) remains a global health challenge with a poor 5-year survival rate among patients with relapsed or advanced-stage disease. Immune checkpoint blockade therapies have emerged as a promising approach to improve outcomes; however, their effectiveness is limited, with response rates of only 15–20% because of immune evasion mechanisms. MicroRNA (miRNA) dysregulation plays a key role in facilitating such immune evasion. In this study, we aim to identify specific miRNAs whose altered expression contributes to immune escape in HNC. Methods: We employed an integrated bioinformatics approach, incorporating differential expression analysis, survival analysis, target prediction, KEGG immune pathway analysis, a protein–protein interaction network, and the identification of hub genes using in silico tools. Results: Our analysis revealed that a high expression of miR-18a and miR-2355 was associated with reduced survival, with the median survival decreasing from 42.9 to 27.8 months, respectively, in advanced-stage patients. Conversely, a low expression of let-7c and miR-6510 was linked to poor prognosis, with survival decreasing from 40.1 to 19.2 months and from 50.1 to 26.8 months, respectively, across disease progression. Further pathway analysis revealed that these miRNAs are significantly involved in the regulation of key immune evasion signaling pathways, including T cell receptor, PD-L1/PD-1 checkpoint, JAK-STAT, TGF-beta, NF-kappa B, and TNF signaling pathways. Hub gene analysis identified AKT1, STAT3, NFKB1, CD4, IL2RB, TLR4, and CTLA-4 as potential dysregulated miRNA targets, with enrichment in immune-related signaling pathways. Conclusions: Taken together, these findings suggest that targeting these miRNAs could modulate immune evasion mechanisms and potentially enhance the efficacy of ICB therapies in HNC. Full article