Bladder cancer (BCa) is the most prevalent cancer of the urinary system in adults; the prognosis is dismal for BCa treated with gemcitabine (GEM) owing to intrinsic or acquired chemoresistance. This study investigated the potential of Qici Sanling decoction (QCSL), an herbal Chinese medicine, to augment the efficacy of GEM in treating GEM-resistant BCa via network pharmacology and RNA sequencing. We screened 103 active components of QCSL and their 226 targets from the TCMSP database and identified 3985 targets of GEM-resistant BCa via transcriptome sequencing. On the basis of the 69 common targets, a proteinprotein interaction (PPI) network was constructed to identify the top 7 targets. Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were conducted to uncover key pathways. CCK-8 assays, Western blotting, flow cytometry, colony formation, and EdU assays were used to assess the apoptosis and proliferation of GEM-resistant T24 and J82 cells treated with QCSL. The BCa gene set was among the top enriched gene sets in the DO analysis; GO analysis revealed enrichment of 2020 terms linked to GEM resistance, and KEGG analysis revealed 161 enriched signalling pathways. Molecular docking indicated that PTGS2 has high affinity for targets of QCSL components. In vitro experiments demonstrated that cells treated with both QCSL and GEM had significantly reduced viability, increased levels of apoptosis, and decreased proliferative capacity. Thus, QCSL enhances the therapeutic effects of GEM in BCa by promoting cell apoptosis and inhibiting cell proliferation. These findings have significant clinical implications, highlighting a potential combined treatment strategy for GEM-resistant BCa to improve patient outcomes.

The composition of the tumor immune microenvironment has become a major determinant of response to therapy, particularly immunotherapy. Clinically, a tumor microenvironment lacking lymphocytes, so-called "cold" tumors, are considered poor candidates for immune checkpoint inhibition. In this review, we describe the diversity of the tumor immune microenvironment in breast cancer and how radiation exposure alters carcinogenesis. We review the development and use of a radiation-genetic mammary chimera model to clarify the mechanism by which radiation acts. Using the chimera model, we demonstrate that systemic inflammation elicited by a low dose of radiation is key to the construction of an immunosuppressive tumor microenvironment, resulting in aggressive, rapidly growing tumors lacking lymphocytes. Our experimental studies inform the non-mutagenic mechanisms by which radiation affects cancer and provide insight into the genesis of cold tumors.

Two series of cyano (1a-l) and amino (2a-l) aryl piperazines were synthesized and evaluated for their inhibitory activity against 5-lipoxygenase (5-hLOX) and cyclooxygenase-2 (COX-2). The newly designed derivatives feature diphenyl methyl (a-d), phenyl (e-h), or methoxyphenyl (i-l) groups, respectively, and demonstrated significant inhibition of 5-hLOX. Noteworthy were compounds 1b, 1 g, 1 k, 2f, and 2 g, exhibiting IC50 values ranging from 2.2 to 3.3 μM. The most potent inhibitors (1b, 1 g, 1 k, 2c, and 2f) were characterized by a competitive inhibition mechanism, with Ki values ranging between 1.77 μM and 9.50 μM. Additionally, compounds 2a, 2b, 2 g, and 2 h displayed promising dual inhibition of 5-hLOX and COX-2, with IC50 values below 15 μM. Cytotoxicity assessments against HEK293 cells revealed that the cyano derivatives (1a-l) were non-cytotoxic (CC50 > 200 μM), whereas the amino derivatives (2a-l) exhibited moderate cytotoxicity (CC50 < 50 μM). Notably, the most active derivatives against both targets were non-cytotoxic at their respective inhibitory concentrations. Computational studies, including docking and molecular dynamics simulations, indicated that compound 1 g demonstrated greater stability within the catalytic site of 5-hLOX compared to compound 2f, correlating with the higher affinity observed in kinetic assays. Furthermore, quantitative structure-activity relationship (QSAR) analyses revealed strong correlations between theoretical and experimental IC50 values (97 % for 1a-l and 93 % for 2a-l). These findings, combined with absorption, distribution, metabolism, and excretion (ADME) predictions, suggest that these derivatives are promising candidates as dual inhibitors of 5-hLOX and COX-2.

Nowadays, photodynamic therapy (PDT) offers a non-invasive tumor treatment with high safety profiles and minimal side effects, implying a promising clinical application for patients with malignant tumors. However, the lack of efficacy in metastasis and recurrence still notably limits its application. To solve this problem, one promising strategy is to improve the immune response activated by PDT. Unfortunately, tumor cells derived PGE2 could create immunosuppressive microenvironments and impair the function of multiple immune cells, leading to a failure of immune system activation. Moreover, our research revealed the up-regulation of Ptgs2 in tumor cells after the PDT process, which is associated with a series of pro-tumor effects, including proliferation, invasion, metastasis, apoptotic resistance, and immune evasion. Consequently, controlling the PGE2 surge induced by PDT is crucial for optimizing the efficacy of photo-immunotherapy. Therefore, we combined the regulation of the COX2-PGE2 axis with PDT. The addition of COX inhibitors (COX-Is) could improve the efficiency of PDT, reduce the immunosuppressive effect of PGE2, and help dying tumor cells activate the immune system. Herein, a tumor-targeted nano-delivery platform (FI@T-Lipo) was developed using advanced microfluidic technology. FI@T-Lipo based PDT showed a systemic therapeutic effect in triple negative breast cancer through reclaiming the anti-tumor effect of the immune system under COX2-PGE2 blockage. In a word, we developed an in-situ tumor vaccination strategy based on COX-Is enhanced PDT, which could alleviate intra-tumoral immune suppression and boost immune system activation. Our study offers a promising modality for advancing clinical treatment strategies for metastatic malignant tumors.

Chemoresistance and tumor relapse remain major clinical problems. Evidence indicates that COX2/PGE2/EP axis has a critical role in tumorogenesis and chemoresistance. This study assessed the relation of the COX-2 gene expression with chemoresistance in colon cancer (CC) patients. Also, it explored the effect of chemotherapy on COX-2 expression. The study included 24 patients with CC without chemotherapeutic treatment and 24 chemoresistant CC patients. Tumor and adjacent non-neoplastic colon tissue samples were collected and COX-2 mRNA expression was measured. Also, COX-2 and its related genes; TROP2 and DUSP4 expression were analysed in 5 flurouracil and Oxalliplatin treated Caco-2 and SW-620 cells. The results indicated significant upregulation of COX-2 expression in tissues of chemoresistant CC patients when compared with that in CC tissues without chemotherapy (p < 0.001). There was a relation between COX-2 expression with lymph nodes, metastases and staging in both groups. Concerning in-vitro experiments, there was a dose dependent significant increase of COX-2, TROP2 and DUSP4 mRNA and protein expression levels in 5flurouracil and Oxalliplatin treated cells. These findings demonstrated that overexpression of COX-2 in the chemoresistant CC patients. Both 5 flurouracil and Oxalliplatin induced COX-2 overexpression and in turn COX-2 upregulation may decrease the response of cancer to chemotherapy.

In recent years, photodynamic therapy (PDT) has emerged as a promising alternative to classical chemotherapy for treating cancer. PDT is based on a nontoxic prodrug called photosensitizer (PS) activated by light at the desired location. Upon irradiation, the PS reacts with the oxygen present in the tumor, producing cytotoxic reactive oxygen species (ROS). Compounds with highly conjugated π-bond systems, such as porphyrins and chlorins, have proven to be excellent light scavengers, and introducing a metal atom in their structure improved the generation of ROS. In this work, a series of tetrapyrrole-ruthenium(II) complexes derived from protoporphyrin IX and the commercial drug verteporfin were designed as photosensitizers for PDT. The complexes were almost nontoxic on human gastric cancer cells under dark conditions, revealing remarkable cytotoxicity upon irradiation with light. The ruthenium atom in the central cavity of the chlorin ligand allowed combined mechanisms in photodynamic therapy, as both singlet oxygen and superoxide radicals were detected. Additionally, one complex produced large amounts of singlet oxygen under hypoxic conditions. Biological assays demonstrated that the ruthenium derivatives caused cell death through a caspase 3 mediated apoptotic pathway and via CHOP, an endoplasmic reticulum stress-inducible transcription factor involved in apoptosis and growth arrest.

As cancer continues to rank among the leading causes of death, the demand for novel treatments has never been higher. Immunotherapy shows promise, yet many solid tumors such as pancreatic cancer or glioblastoma remain resistant. In these, the "cold" tumor microenvironment with low immune cell infiltration and inactive anti-tumoral immune cells leads to increased tumor resistance to these drugs. This resistance has driven the development of several drug candidates, including stimulators of interferon genes (STING) agonists to reprogram the immune system to fight off tumors. Preclinical studies demonstrated that STING agonists can trigger the cancer immunity cycle and increase type I interferon secretion and T cell activation, which subsequently induces tumor regression. Despite promising preclinical data, biological and physical challenges persist in translating the success of STING agonists into clinical trials. Nonetheless, novel combination strategies are emerging, investigating the combination of these agonists with other immunotherapies, presenting encouraging preclinical results. This review will examine these potential combination strategies for STING agonists and assess the benefits and challenges of employing them in cancer immunotherapy.

Inulin-type fructan CP-A, the main component of Codonopsis pilosula polysaccharides, has been found to have therapeutic effects on ulcerative colitis (UC). Herein, we established a colitis-associated cancer (CAC) mouse model by azomethane (AOM) and dextran sulfate sodium (DSS) and selected mouse colon cancer cells CT-26 to explore the therapeutic effects of the combined administration of CP-A and 5-fluorouracil (5-FU) in vivo and in vitro. High-throughput transcriptomics sequencing technology was used to identify differentially expressed genes (DEGs) in the mouse colon and enrich related pathways. 16S rRNA gene sequencing technology was used for gut microbiota research to identify microbial changes in mouse feces. Short-chain fatty acid (SCFA) content was identified in the mouse colon using gas chromatography-mass spectroscopy (GC-MS). In vivo experiments showed that compared with untreated CAC mice, those treated with the combined administration of CP-A and 5-FU had significantly restored body weight, fewer tumors, smaller tumor volume, and reduced disease activity index (DAI) and histopathological scores. The combination of CP-A and 5-FU increased the anti-inflammatory cytokine interleukin 10 (IL-10) and inhibited the expression of pro-inflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-gamma (IFN-γ). In vitro experiments indicated that a combination of CP-A and 5-FU promoted the apoptosis of CT-26 cells. The results of transcriptomics studies suggested that the therapeutic effect of the combined administration of CP-A and 5-FU on CAC may be related to the EGFR/AKT/ERK pathway. Both in vivo and in vitro experiments verified the regulatory effect of the combined administration of CP-A and 5-FU on the EGFR/AKT/ERK pathway. Moreover, the intestinal flora experiment manifested that compared with untreated CAC mice, the combined CP-A and 5-FU group had a more stable intestinal microbiota composition, and the combined administration of CP-A and 5-FU increased the abundance of SCFAs. Our experimental findings have demonstrated that the combination of CP-A and 5-FU exhibits promising efficacy in the treatment of CAC, warranting further clinical investigation in the future.

Cancer, uncontrolled cell growth due to the loss of cell cycle regulation, is often found to be associated with viral infections and, as recent studies show, with bacterial infections as well. Emerging reports also suggest a strong link between fungi and cancer. The crucial virulence trait of fungi, the switch from yeast (Y) to hyphal (H) form, is found to be associated with carcinogenesis. The physicochemical properties and signal transduction pathways involved in the switch to the hyphal form overlap with those of tumor cell formation. Inhibiting differentiation causes apoptosis in fungi, whereas preventing apoptosis leads to cancer in multicellular organisms. Literature on the fungi-cancer linkage, though limited, is increasing rapidly. This review examines cancer-specific fungal communities, the impact of fungal microbiome on cancer cell progression, similarities between fungal differentiation and cells turning cancerous at biochemical and molecular levels, including the overlaps in signal transduction pathways between fungi and cancer. Based on the available evidence, we suggest that molecules inhibiting the yeast-hyphal transition in fungi can be combined with those targeting tumor cell apoptosis for effective cancer treatment. The review points out fertile research areas where mycologists and cancer researchers can collaborate to unravel common molecular mechanisms. Moreover, antibodies targeting fungal-specific chitin and glucan can be used for the selective neutralization of tumor cells. These new combinations of potential therapies are expected to facilitate the development of target-specific, less harmful and commercially feasible anticancer therapies. We bring together available evidence to argue that fungal infections could either trigger cancer or have a significant role in the development and progression of cancer. Hence, cancer-associated fungal populations could be utilized as a target for a combination therapy involving the integration of anticancer and antifungal drugs as well as inhibitors of fungal morphogenesis to develop more effective anticancer therapies.

Herein, we report the design, synthesis, and characterization of novel organoselenium (OSe) hybrids (5-19) via modifications of the lead, N-(4-selaneylphenyl)-2-selaneylacetamide. The OSe-based thiazol 9 showed the highest growth inhibition % (GI%) of 64.72% relative to the positive reference doxorubicin (DOX), with a GI% of 79.5%. Furthermore, the novel OSe derivatives showed low GI% values compared to the normal cell lines employed, demonstrating their selectivity. The OSe tethered N-chloroacetamide 5 and Schiff base 19 showed a cytotoxic effect with an IC50 of (25.07 and 11.61 µM), respectively, against the A549 tumor cell line and IC50 of (34.22 and 20.12 µM), respectively, against the HELA cancer cell line. Enzyme-linked immunosorbent assay to study the JAK1 and the STAT3 inhibitory potentials of OSe compounds 5 and 19 in the A549 cancer cells both showed promising inhibitory activities with IC50 values of 25.07 and 11.61 µM, respectively. Protein expression analysis on the A549 cancer cell line on OSe compounds 5 and 19 showed upregulation of P53, BAX, and Caspases 3, 6, 8, and 9 as apoptotic proteins. However, both candidates expressed downregulation of the antiapoptotic proteins (BCL2, MMP2, and MMP9). Moreover, OSe compounds 5 and 19 described the downregulation of the examined inflammatory proteins: COX2, IL-6, and IL-1β. In addition, OSe compound 19 showed potential cell cycle arrest at the G0, S, and G2-M layers, with an increase in cellular levels. Finally, molecular docking studies of OSe compound 19 showed the most promising inhibitory potential toward the JAK1 and STAT3 target receptors, with binding scores and interactions exceeding that of the cocrystallized inhibitor of JAK1.

Oxidative stress and inflammation may initiate carcinogenesis and facilitate metastasis via activation of pro-inflammatory signaling network. The side product of arachidonic acid processing by cyclooxygenase-2 (COX-2), the prostaglandin E2 (PGE2), plays a key role in various metabolic disorders and during inflammation-mediated tumorigenesis. It has been demonstrated that PGE2 increases the proliferation, migration, invasion, metastasis, and resistance of cancer cells to apoptosis and other forms of programmed cell death. The expression level of PGE2 metabolizing enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is often decreased in various malignancies. However, the role of 15-PGDH and PGE2 in the regulation of carcinogenesis remains controversial. Numerous cancer cell lines and mouse models have demonstrated the role of 15-PGDH as a tumor suppressor. Downregulation of 15-PGDH increased cancer cell proliferation, migration, anchorage independent growth, colony formation while overexpression reversed these effects, by inducing apoptosis and cell cycle arrest in vitro and in vivo. The expression of 15-PGDH is regulated by various mechanisms, including (a) epigenetic alterations (methylation of promoter region, histone deacetylases, microRNAs (miR-21, miR-26a/b, miR-106b-5p, miR-146b-3p, miR-155, miR-218-5p, and miR-620)); and (b) dysregulated oxidative stress and associated mediators (elevated levels of growth factors and proinflammatory cytokines (such as IL1β and TNFα)). Several transcription factors, such as HNF3β, β-catenin, Snail, Slug, can bind to 15-PGDH promoter region and downregulate the enzyme expression. In contrast, the expression of 15-PGDH can be upregulated by several anti-inflammatory cytokines and anti-cancer agents, such as IL10 and vitamin D. The functional activity of 15-PGDH protein can be modulated by signaling effectors and oxidative stress, including increased production of reactive oxygen species (ROS). However, the role of oxidative stress regulator protein, i.e., nuclear factor erythroid 2-related factor 2 (Nrf2), in the control of 15-PGDH expression remains unclear. This article provides insights and comprehensive overview of the tumor suppressor role of 15-PGDH in various cancers. Epigenetic and post-translational mechanisms regulating 15-PGDH expression and the role of novel ROS-Nrf2-15-PGDH axis were discussed and accented as potential drug targets.

Increasing evidence has showed that tumorigenesis is closely linked to inflammation, regulated by multiple signaling pathways. Among these, the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) axis plays a crucial role in the progression of both inflammation and cancer. Inhibiting the activity of COX-2 can reduce PGE2 secretion, thereby suppressing tumor growth. Therefore, COX-2 inhibitors are considered potential therapeutic agents for cancers. However, their clinical applications are greatly hindered by poor physicochemical properties and serious adverse effects. Fortunately, the advent of nanotechnology offers solutions to these limitations, enhancing drug delivery efficiency and mitigating adverse effects. Given the considerable progress in this area, it is timely to review emerging COX-2 inhibitors-based nanotherapeutics for cancer diagnosis and therapy. In this review, we first outline the various antineoplastic mechanisms of COX-2 inhibitors, then comprehensively summarize COX-2 inhibitors-based nanotherapeutics for cancer monotherapy, combination therapy, and diagnosis. Finally, we highlight and discuss future perspectives and challenges in the development of COX-2 inhibitors-based nanomedicine.

Low immunogenicity and immunosuppressive tumor microenvironment (TME) are two pivotal factors restricting tumor immunotherapy. Photodynamic therapy (PDT) directly destroys cancer cells by producing reactive oxygen species (ROS), and enhances the immunogenicity of "cold" tumors by inducing immunogenic cell death (ICD), thereby promoting T cell development against tumors. However, PDT also deteriorates immunosuppression through overactivating the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway. To this end, biocompatible albumin nanoassemblies co-delivering IR780 and diclofenac are herein developed for enhanced therapy against triple-negative breast cancer. PDT-exacerbated PGE2 overexpression is effectively abolished by diclofenac-mediated COX-2 inhibition, which reprograms immunosuppressive TME via downregulating the infiltration of various immunosuppressive cells and their cytokine secretion to enhance effector T cell infiltration. Consequently, the enhanced antitumor immunity effectively inhibits tumor growth, prevents the recurrency and metastasis, and remarkably boosts the treatment efficacy of PD-L1 blockade. This study sets an intriguing example for overcoming the COX-2/PGE2 pathway-exacerbated immunosuppression alongside immune activation, thus enhancing synergistic cancer immunotherapy potentiated by various ROS-producing therapies (e.g., PDT and radiotherapy) and chemotherapy.

Head and neck cancer is the seventh most common cancer worldwide and its development is associated with viral infection. Human papillomavirus (HPV) is the major cause of oropharyngeal cancer and encodes three known oncoproteins, E5, E6, and E7. Epstein-Barr virus (EBV), which is the causative agent of most nasopharyngeal carcinoma, also employs several immunosuppressive mechanisms that contribute to the development of the disease. In this review, we synthesize and discuss several mechanisms used by these viruses to evade and escape the host immune system. In particular, we focus on the evasive tactics of HPV E5 which, we argue, is critical to establishing persistent infection and the development and progression of carcinomas. Importantly the mechanisms by which these viruses suppress immune responses may also play a key role in resistance to checkpoint blockade immunotherapies and thus impact patient outcomes.

A 33 yr old female grey seal Halichoerus grypus presented with inappetence and progressive weight loss. Medical management included blood analysis, imaging, and fecal evaluation, along with multimodal supportive therapy, which periodically improved the overall medical condition. Six months after the initial presentation, the clinical condition deteriorated significantly, including severe hyporexia, hematemesis, and marked neutrophilic leukocytosis, which led to the decision to euthanise based on welfare grounds. Necropsy findings included severe thickening of the distal esophagus, cardia, and proximal gastric fundus, as well as multiple nodular to cystic structures over the stomach's serosa, omentum, and mesentery. Histologically, a mucinous gastric adenocarcinoma was diagnosed, with metastasis to the gastric lymph nodes and prominent carcinomatosis involving the omentum, mesentery, and diaphragm. Immunohistochemically, the gastric adenocarcinoma was positive for cytokeratin AE1/AE3, weakly positive for COX-2 and E-cadherin, and negative for vimentin. The Ki-67 proliferative index was low (0.8). Although rare, this case offers further insights into the clinical presentation, histopathology, and immunohistochemical profile of gastric tumors in pinnipeds.

Eight indole-boron-difluoride complexes were synthesized from 2,3-arylpyridylindole derivatives via Sonogashira coupling and Larock heteroannulation. These complexes exhibited distinct photophysical properties. Solvent polarity influenced their spectral behavior showing hypsochromic absorption, bathochromic emission shifts, and aggregation-induced emission (AIE) in mixed solvents. The ¹⁹F NMR shifts and photophysical properties, including excitation, emission maxima, and Stokes shift, correlated with Hammett substituent constants highlighting electronic effects on molecular properties. The synthesized complexes exhibited a range of intramolecular charge transfer (ICT) behaviors, as evidenced by their Lippert-Mataga parameters. TD-DFT calculations aligned with experimental data, offering insight into spectroscopic behavior. Notably, the indole-boron-difluoride complex bearing a methyl ester group exhibited significant anticancer activity against HeLa cells and potential for fluorescence imaging, indicating its promise for biomedical applications in cell imaging and therapy.

Triple-negative breast cancer (TNBC) poses as a daunting and intricate manifestation of breast cancer, highlighted by few treatment options and a poor outlook. The crucial element in fostering tumor growth and immune resistance is the polarization of tumor-associated macrophages (TAMs) into the M2 state within the tumor microenvironment (TME). To address this, we developed M2 targeting peptide-chitosan-curcumin nanoparticles (M2pep-Cs-Cur NPs), a targeted delivery system utilizing chitosan (Cs) as a carrier, curcumin (Cur) as a therapeutic agent, and targeting peptides for specificity. These NPs effectively inhibited TNBC cell proliferation (~ 70%) and invasion (~ 70%), while increasing the responsiveness of tumors to anti-PD-L1 treatment (~ 50% survival enhancement) in vitro and in vivo. Bioinformatics analysis suggested that Cur modulates TAM polarization by influencing key genes such as COX-2, offering insights into its underlying mechanisms. This study highlights the potential of M2pep-Cs-Cur NPs to reverse M2 polarization in TAMs, providing a promising targeted therapeutic strategy to overcome immunotherapy resistance and improve TNBC outcomes.

Formononetin (FMN) is a common natural metabolite that can be extracted and isolated from some common botanical drugs. In recent years, FMN has garnered increasing attention due to its beneficial biological activities. In this paper, we systematically summarize the sources of FMN and provide a comprehensive review of its pharmacological activities and molecular mechanisms, co-administration, toxicity, derivatives, and drug delivery systems in the last 5 years. The study results found that FMN has a wide range of pharmacological activities in neurological disorders, organ damage and cancer, showing great potential for clinical application and broad prospects. Researchers are exploring various types of delivery systems, including nanoparticle carriers, ligand modifications and polymer microspheres. These advanced delivery systems can enhance the stability of FMN, prolong its release time in vivo, and improve targeting, thereby optimizing its therapeutic efficacy and reducing side effects, and greatly improving its bioavailability. In conclusion, FMN is a natural metabolite with considerable research value, and its diverse biological activities make it a promising candidate for drug development and medical research.

Macrophages are central to the progression from hepatitis to hepatocellular carcinoma (HCC), with their remarkable plasticity and ability to adapt to the changing liver microenvironment. Chronic inflammation, fibrosis, and ultimately tumorigenesis are driven by macrophage activation, making them key regulators of liver disease progression. This review explores the diverse roles of macrophages in the transition from hepatitis to HCC. In the early stages of hepatitis, macrophages are essential for pathogen clearance and tissue repair. However, chronic activation leads to prolonged inflammation, which exacerbates liver damage and promotes fibrosis. As the disease progresses to liver fibrosis, macrophages interact with hepatic stellate cells, fostering a pro-tumorigenic microenvironment that supports HCC development. In hepatocarcinogenesis, macrophages contribute to tumor initiation, growth, metastasis, immune evasion, cancer stem cell maintenance, and angiogenesis. Their functional plasticity enables them to adapt to the tumor microenvironment, thereby promoting tumor progression and resistance to therapy. Targeting macrophages represents a promising strategy for preventing and treating HCC. Therapeutic approaches, including reprogramming macrophage phenotypes to enhance anti-tumor immunity, blocking macrophage recruitment and activation, and utilizing nanoparticle-based drug delivery systems, may provide new avenues for combating HCC by modulating macrophage functions and tumor microenvironment dynamics.

The research aimed to evaluate the connection between pre-treatment inflammatory biomarkers and clinical results in advanced esophageal squamous cell carcinoma (ESCC) receiving immune checkpoint inhibitors.

Between 2019 and 2022, we analyzed 354 individuals diagnosed with metastatic ESCC who underwent immunotherapy. The study sought to evaluate the impact of specific inflammatory biomarkers (Neutrophil/Lymphocyte Ratio (NLR), C-reactive protein to albumin ratio (CRP/ALB) and Glasgow Prognostic Score (GPS), Cyclooxygenase-2 (COX-2) inhibitors or steroids usage on the effectiveness and survival outcomes of immunotherapy in advanced ESCC. The research utilized Kaplan‒Meier and Cox regression models alongside propensity score matching for analysis.

The findings revealed that elevated pre-treatment NLR (11.0 vs. 14.6 months, p = 0.021) and CRP/ALB (11.4 vs. 14.6 months, p = 0.022) levels were significantly associated with poorer overall survival (OS) outcomes, while the use of steroids did not show a significant difference in OS (15.5 vs. 15.4 months, p = 0.685) between groups. Similarly, no notable disparity in OS was observed between patients treated withCOX-2 inhibitors and those who were not (13.8 vs. 11.0 months, p = 0.054).

Lower levels of NLR and CRP/ALB prior to treatment were linked to better effectiveness and OS in immunotherapy for advanced ESCC. The study did not identify a significant relationship between OS in patients with esophageal cancer and the use of either steroids or COX-2 inhibitors.

Metastatic endometrial cancer continues to be a common cause of death as of 2024, even after maximal use of all currently available standard treatments. To address this problem of metastatic cancer generally in 2025, the drug repurposing movement within oncology identifies medicines in common general medical use that have clinical or preclinical experimental data indicating that they interfere with or inhibit a specific growth driving element identified in a given cancer. The drug repurposing movement within oncology also uses data from large scale in vitro screens of thousands of drugs, looking for simple empirical growth inhibition in a given cancer type. This paper outlines the data showing that five drugs from general medical practice meet these evidence criteria for inhibition of endometrial cancer growth, the EC5 regimen. The EC5 regimen uses the osteoporosis treatment drug, alendronate; the analgesic drug, celecoxib; the antifungal drug, itraconazole; the sleep aid, ramelteon; and the cholesterol lowering drug, simvastatin. Side effects seen with these drugs are usually minimal and easily tolerated by patients.

Metabolic reprogramming in cancer cells involves changes in glucose metabolism, glutamine utilization, and lipid production, as well as promoting increased cell proliferation, survival, and immune resistance by altering the tumor microenvironment. Our study analyzes metabolic reprogramming in neoplastically transformed cells, focusing on changes in glucose metabolism, glutaminolysis, and lipid synthesis. Moreover, we discuss the therapeutic potential of targeting cancer metabolism, focusing on key enzymes involved in glycolysis, the pentose phosphate pathway, and amino acid metabolism, including lactate dehydrogenase A, hexokinase, phosphofructokinase and others. The review also highlights challenges such as metabolic heterogeneity, adaptability, and the need for personalized therapies to overcome resistance and minimize adverse effects in cancer treatment. This review underscores the significance of comprehending metabolic reprogramming in cancer cells to engineer targeted therapies, personalize treatment methodologies, and surmount challenges, including metabolic plasticity and therapeutic resistance.

The cholinergic anti-inflammatory pathway (CAP) is comprised of the vagus nerve, acetylcholine, nicotinic acetylcholine receptors, the spleen, and the splenic nerve. It represents a sophisticated neuroimmune axis that critically regulates the crosstalk between the nervous system and the immune response via the vagus nerve. Here, we provided a nuanced exploration of the CAP's role in curbing inflammatory processes and its broad therapeutic potential across a spectrum of diseases. We meticulously dissect the intricate mechanisms by which the CAP modulates key signaling cascades, including the NF-κB, JAK2/STAT3, MAPK/ERK, PI3K/AKT, COX2/PGE2, and NRF2/HO-1 pathways, which are quintessential in the pathogenesis of various conditions. Additionally, we also summarized the CAP's profound implications in the management of inflammatory diseases, neurodegenerative disorders, metabolic syndromes, and oncological malignancies, elucidating its capacity to mitigate disease severity and progression through sophisticated immune modulation. The modulation of the CAP is suggested as a novel strategy that could potentially transform treatment approaches for a variety of conditions. However, the precise cellular and molecular underpinnings of the CAP's effects, as well as its translatability to clinical settings, remain subjects of ongoing investigation. The review calls for further research to demystify the mechanisms of the CAP and to harness its therapeutic potential fully, with the aim of developing innovative and efficacious treatment modalities that exploit the pathway's unique attributes.

Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer development. We conducted quantitative analysis of biomarkers for necroptosis [transient receptor potential cation channel subfamily M member 7 (TRPM7) and phosphorylated mixed lineage kinase domain-like protein], inflammation [cyclooxygenase-2 (COX-2)], apoptosis [BCL2-associated X (BAX) and terminal deoxynucleotidyl transferase dUTP nick end labeling], and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma-carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early colorectal cancer stages (Ptrend = 0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend = 0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio = 3.04; 95% confidence interval, 1.07-8.61; Ptrend = 0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps, whereas combined scores of phosphorylated mixed lineage kinase domain-like protein or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis. Prevention Relevance: Our findings suggest that COX-2 expression and combined scores of COX-2, TRPM7, and BAX hold promise for predicting the risk of metachronous polyps and could potentially serve as a tool for assessing the effectiveness of chemopreventive agents in preventing colorectal cancer during intervention trials.

Ferroptosis is a key process in doxorubicin (DOX)-induced cardiotoxicity and is a potentially important therapeutic target. Thymoquinone (TQ) is a monoterpenoid compound isolated from black cumin extract that exhibits antitumor effects and acts as a powerful mitochondrial-targeted antioxidant. In this study, we investigated the effect of TQ on DOX-induced cardiotoxicity and the potential underlying mechanisms.

Mice were randomly assigned to the control (CON) group, DOX (20 mg/kg) group, TQ10 (10 mg/kg/d) group, and TQ20 (20 mg/kg/d) group and intraperitoneally injected with DOX and different doses of TQ. The electrocardiogram, blood pressure, and cardiac ultrasound changes during the experiments showed that TQ exerted a protective effect against DOX-induced cardiotoxicity. The glutathione (GSH), malondialdehyde (MDA), and total antioxidant capacity (T-AOC) levels in the mouse heart tissue were significantly different from those in the CON group. Western blot analysis revealed that the expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in the DOX group was lower than that in the control group. TQ treatment decreased these changes, indicating that TQ alleviated DOX-induced cardiotoxicity and increased the antioxidant capacity of murine cardiomyocytes. The mechanism might involve activating the Nrf2/HO-1 signaling pathway and reducing iron-mediated death. Immunohistochemical staining revealed similar effects on the expression levels of NQO1, COX-2, and NOX4. Moreover, transmission electron microscopy indicated that TQ protected murine cardiomyocytes against DOX-induced mitochondrial damage.

The results of this study suggested that TQ can decrease oxidative stress levels and DOX-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway to alleviate ferroptosis in murine cardiomyocytes.

In this concept, we present a comprehensive study on the development and application of COX-2-specific fluorescent probes for cancer imaging and diagnosis. To target cancer cells and measuring cancer-related activities in specific organelles quickly and accurately are crucial factors for early diagnosis and research on cancer pathology and treatment. This concept explores a variety of probes based on indomethacin (IMC), celecoxib, rofecoxib as well as CoxFluor and each one demonstrates unique mechanisms and high selectivity towards COX-2 enzymes. These probes were designed to enhance fluorescence upon binding to COX-2 which enable precise visualization of tumor and inflamed tissues. The research emphasizes the importance of COX-2 as a biomarker in cancer diagnostics, particularly in identifying cancer stem cells and inflamed tissues. This concept highlights the potentiality of these probes in non-invasive imaging techniques which offering significant advancements in cancer diagnosis and monitoring. The in vivo and in vitro experiments, including applications in mouse models and human tissue samples, confirm the efficacy of these probes in providing detailed imaging for clinical and research applications.

Gastrointestinal (GI) cancers are a major global health burden, representing 20% of all cancer diagnoses and 22.5% of global cancer-related deaths. Their aggressive nature and resistance to treatment pose a significant challenge, with late-stage survival rates below 15% at five years. Therefore, there is an urgent need to delve deeper into the mechanisms of gastrointestinal cancer progression and optimize treatment strategies. Increasing evidence highlights the active involvement of abnormal arachidonic acid (AA) metabolism in various cancers. AA is a fatty acid mainly metabolized into diverse bioactive compounds by three enzymes: cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes. Abnormal AA metabolism and altered levels of its metabolites may play a pivotal role in the development of GI cancers. However, the underlying mechanisms remain unclear. This review highlights a unique perspective by focusing on the abnormal metabolism of AA and its involvement in GI cancers. We summarize the latest advancements in understanding AA metabolism in GI cancers, outlining changes in AA levels and their potential role in liver, colorectal, pancreatic, esophageal, gastric, and gallbladder cancers. Moreover, we also explore the potential of targeting abnormal AA metabolism for future therapies, considering the current need to explore AA metabolism in GI cancers and outlining promising avenues for further research. Ultimately, such investigations aim to improve treatment options for patients with GI cancers and pave the way for better cancer management in this area.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays a dual role in cancer initiation and progression. Identifying signals that modulate the function of SHP2 can improve current therapeutic approaches for IFN-α/β in HCC. We showed that cAMP-dependent PKA suppresses IFN-α/β-induced JAK/STAT signaling by increasing the phosphatase activity of SHP2, promoting the dissociation of SHP2 from the receptor for activated C-kinase 1 (RACK1) and binding to STAT1. Additionally, cAMP-degrading phosphodiesterase 4D (PDE4D) physically interacts with RACK1 to regulate PKA-mediated SHP2 activity and STAT1 phosphorylation. IFN-α activates PKA by inducing the expression of cyclooxygenase 2 (COX2) and the production of prostaglandin E2 (PGE2), which in turn stimulates the binding of SHP2 to IFNAR2 via RACK1. A COX inhibitor aspirin potently increases the antitumor effects of IFN-α in the suppression of HCC cell proliferation in vivo. Higher expression of COX2 and phosphorylated STAT3 is associated with poor development and prognosis in HCC patients by analyzing human HCC clinical samples. These observations suggest that a fundamental PKA/SHP2-dependent negative feedback loop acts on IFN signaling, and inhibition of this signaling by the selective COX2 inhibitors may enhance the clinical efficacy of type I IFNs in treating HCC.

Long-term exposure to hexavalent chromium [Cr(VI)] has been linked to lung cancer, and cyclooxygenase-2 (COX-2) is a well-known inflammatory factor. However, the role and mechanism of COX-2 in Cr(VI)-induced carcinogenesis are not clear yet. To address this question, we employed a mouse model exposed to Cr(VI) through intranasal instillation of particulate zinc chromate (ZnCrO4) for 12 weeks. Metabolomics and RNA-seq assays revealed enhanced activity of the arachidonic acid (AA)/eicosanoid metabolism pathway in lung tissues from mice exposed to Cr(VI). COX-2, the key enzyme of the AA/eicosanoid pathway, was significantly upregulated in Cr(VI)-exposed lung tissues, as well as in the Cr(VI)-induced transformed (Cr-T) cells compared to parental BEAS-2B (B2B) cells. We then employed multidisciplinary in vitro and in vivo functional assays to characterize the role of COX-2 in Cr(VI)-induced lung cancer. The results indicated that COX-2 functioned as an oncogene to promote the malignant transformation of B2B cells and enhance the proliferation, migration, tumor growth, and angiogenesis of Cr-T cells. Nuclear factor E2-related factor-2 (Nrf2) was identified as a transcription factor for COX-2. Nrf2 was upregulated in response to Cr(VI) exposure and contributed to Cr(VI)-induced lung cancers, in part by upregulating COX-2 expression. Moreover, microRNA-379 (miR-379) was found to target COX-2 to inhibit its expression posttranscriptionally. MiR-379 was downregulated in Cr(VI)-exposed lung tissues and Cr-T cells, and ectopic miR-379 expression reduced Cr-T cell viability and migration, with partial reversal upon COX-2 restoration. In summary, our study revealed the oncogenic role of COX-2 and identified two novel regulatory mechanisms for COX-2 overexpression in Cr(VI)-induced carcinogenesis.

Acute, uncontrolled and/or long-lasting inflammation causes a breakdown in immunological tolerance, leading to chronicity and contributing to a series of significant local or systemic tissue changes. Anti-inflammatory efficacy, fewer adverse effects, improved selectivity, and curative action are imminent issues for patients suffering from chronic inflammation-related pathologies. Then, we performed a complete and critical review about anthelmintics, discussing the main classes and the available preclinical evidence on repurposing to treat inflammation-based conditions. Despite low bioavailability, many benzimidazoles (albendazole and mebendazole), salicylanilides (niclosamide), macrocyclic lactones (avermectins), pyrazinoisoquinolones (praziquantel), thiazolides (nitazoxanide), piperazine derivatives, and imidazothiazoles (levamisole) indicate that repositioning is a promising strategy. They may represent a lower cost and time-saving course to expand anti-inflammatory options. Although mechanisms of action are not fully elucidated and well-delineated, in general, anthelmintics disrupt mitogen-activated protein kinases, the synthesis of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-12, and IFN-γ), the migration and infiltration of leukocytes, and decrease COX-2 expression, which impacts negatively on the release of prostanoids and leukotrienes. Moreover, some of them reduce nuclear accumulation of NF-κB (niclosamide, albendazole, and ivermectin), levels of nitric oxide (nitazoxanide and albendazole), and mucus, cytokines, and bronchoconstriction in experimental inflammatory pulmonary diseases (ivermectin and niclosamide). Considering the linking between cytokines, bradykinin, histamine, and nociceptors with algesia, anthelmintics also stand out for treating inflammatory pain disorders (ivermectin, niclosamide, nitazoxanide, mebendazole, levamisole), including for cancer-related pain status. There are obstacles, including the low bioavailability and the first-pass metabolism.

Through transcriptomic analysis of patient-derived glioblastoma tissues, we identify an overactivation of inflammatory pathways that contribute to the development of a tumor-promoting microenvironment and therapeutic resistance. To address this critical mechanism, we present NanoAid, a biomimetic nanoplatform designed to target inflammatory pro-tumor processes to advance glioblastoma chemotherapy. NanoAid employs macrophage-membrane-liposome hybrids to optimize the delivery of COX-2 inhibitor parecoxib and paclitaxel. By inheriting macrophage characteristics, NanoAid not only efficiently traverses the blood-brain barrier and precisely accumulates within tumors but also enhances cancer cell uptake, thereby improving overall anticancer efficacy. Notably, the combination of parecoxib and paclitaxel effectively disrupts inflammatory pro-tumor processes while inducing a synergistic effect that inhibits tumor growth, overcomes therapeutic resistance, and minimizes adverse effects. This results in substantial tumor growth inhibition and extends the median survival of tumor-bearing mice. Thus, our study bridges clinical insights with fundamental research, potentially revolutionizing tumor therapy paradigms.

Aortic aneurysm and dissection (AAD) represent a highly lethal cardiovascular condition. Ferroptosis has recently been implicated in AAD development and progression. However, ferroptosis-related genes (FRGs) have not been systematically identified and verified in AAD.

Seven human AAD datasets downloaded from Gene Expression Omnibus were analyzed, and 113 potential AAD-related FRGs were identified. Function enrichment analyses revealed that the FRGs were mainly associated with responses to chemical stress and cytokine signaling in the immune system. Protein-protein interaction network analyses identified 8 hub FRGs including EZH2, EGFR, HIF1A, IL6, PTGS2, MAPK1, IL1B and SRC. All these FRGs were significantly increased in patients with aortic aneurysm. Additionally, immune cell infiltration analyses revealed these FRGs were strongly correlated with the higher CD4+ Tem and macrophages fraction in AAD patients. Particularly, increased expression of PTGS2 in AAD patients was further validated using our newly collected clinical aortic specimens. Importantly, we found that PTGS2 knockdown could reduce the expression of MMP9 and MMP2 but increase GPX4 expression in macrophages. Conversely, while PTGS2 overexpression upregulated MMP9 and MMP2 expression but downregulated GPX4 expression, the regulatory effects of PTGS2 on these genes were largely blunted by ferroptosis inhibitors. Functionally, administration of celecoxib, a PTGS2-specific inhibitor, into mice significantly reduced β-aminopropionitrile-induced AAD development and progression.

Through an integrative bioinformatics analysis, we have identified multiple key AAD-related FRGs including PTGS2. Functional studies also suggest a functional role of PTGS2 in ferroptosis and AAD development, offering novel insights into pathogenesis of human AAD.

Cystitis glandularis (CG) is a chronic hyperplastic disorder of the bladder, and the available clinical drug therapy is insufficient currently. Glycyrrhetinic acid (GA), a bioactive compound extracted from the roots of Glycyrrhiza glabra, is found with beneficial actions, including anti-inflammatory and anti-oxidative effects. We previously reported that GA relieves CG symptoms in animal model, implying the potential application of GA to treat CG. However, the action mechanisms of GA against CG remain unclear. In this study, we aimed to identify the pivotal targets and therapeutic effects of GA through integrated bioinformatics analysis and experimental validation. Integrated bioinformatics analysis screened eleven potential therapeutic targets for GA against CG, and seven pivotal targets were identified subsequently. Enrichment gene analysis revealed GA exhibiting biological activities against CG via regulating multiple pharmacological targets and molecular pathways associated with inflammatory reaction and oxidative stress. Molecular docking computation revealed potent affinity and interaction between GA and prostaglandin-endoperoxide synthase 2 (PTGS2) and mucin 1 (MUC1) proteins in CG. To validate biochemically, increased mRNA and protein expressions of PTGS2 and MUC1 were observed in human CG samples. Compared to CG mice, GA-treated CG mice exhibited reduced inflammatory cytokine contents and downregulated PTGS2 and MUC1 mRNA and protein levels. These integrated findings suggest the potential therapeutic effects of GA against CG via the regulation of targeting genes and pathways. However, further studies are necessary to perform and facilitate the clinical application of GA for treating CG.

Breast cancer (BC) is a malignant tumor that occurs in breast tissue. This project aims to predict the prognosis of BC patients using genes related to hypoxia and endoplasmic reticulum stress (ERS). RNA-seq and clinical data for BC were downloaded from TCGA and GEO databases. Hypoxia and ERS-related genes were collected from the Genecards database. Univariate/multivariate Cox regression and Lasso regression analyses were used to screen genes and construct prognostic models. Patients were divided into high-risk (HR) and low-risk (LR) groups based on risk scores. The CIBERSORT algorithm was used to analyze differences in immune infiltration between the two groups. The mutations of the two groups were analyzed statistically. The CellMiner database was used for drug prediction and the TISCH database for single-cell sequencing analysis. We screened 8 feature genes to construct a prognostic model. Patients in the HR group had a remarkably worse prognosis. TP53 exhibited a higher mutation frequency in the HR group. CIBERSORT analysis uncovered a remarkable increase in the infiltration levels of Macrophages M0 and Tregs in cancer patients and HR patients. Drug sensitivity prediction demonstrated that the expression of IVL was greatly negatively linked with the sensitivity of COLCHICINE. PTGS2 had a remarkably negative correlation with the Vincristine sensitivity. The prognostic model based on 8 hypoxia and ERS-related genes can predict the survival, immune status, and potential drugs of BC patients, bringing a new perspective on individualized treatment.

Biotin receptors, as biomarkers for cancer cells, are overexpressed in various tumor types. Compared to other vitamin receptors, such as folate receptors and vitamin B12 receptors, biotin receptor-based targeting strategies exhibit superior specificity and broader potential in treating aggressive cancers, including ovarian cancer, leukemia, colon cancer, breast cancer, kidney cancer, and lung cancer. These strategies promote biotin transport via receptor-mediated endocytosis, which is triggered upon ligand binding. Biotin, as the ligand of the biotin receptor, can be conjugated to anti-cancer drugs to form targeted therapies that bind to receptors overexpressed on tumor cells, thus increasing drug uptake. Despite these advantages, many candidate drugs have progressed slowly and remain in the preclinical stage, impeding clinical translation. This is mainly due to the effects of various conjugation methods and drug formulations on their functionality and efficacy. Therefore, developing novel biotin-based therapeutics is crucial. The innovation of this strategy lies in its multifunctionality-researchers can use different conjugation methods to design and synthesize these drugs, enabling precise targeting of various tumor types while minimizing toxicity to normal cells. These drugs include small-molecule-biotin conjugates (SMBCs) and nano-biotin conjugates (NBCs). This dual-platform approach represents a significant advancement in targeted therapy, offering unprecedented flexibility in drug design and delivery. Compared to chemotherapy drugs and traditional delivery systems, biotin-based drugs with tumor-specific targeting demonstrate enhanced targeting, improved efficacy, and reduced toxicity. This review examines strategies and applications for enhancing the delivery of chemotherapy drugs to cancer cells, highlighting the need for high-quality conjugates and strategies. It not only summarizes the latest progress but also provides key insights into how this emerging field could revolutionize personalized cancer treatment, especially in the context of precision medicine. Additionally, it offers perspectives on future research directions in this field.

This study investigated tempol action on genes and miRNAs related to NFκB pathway in androgen dependent or independent cell lines and in TRAMP model in the early and late-stages of cancer progression. A bioinformatic search was conducted to select the miRNAs to be measured based on the genes of interest from NFκB pathway. The miR-let-7c-5p, miR-26a-5p and miR-155-5p and five target genes (BCL2, BCL2L1, RELA, TNF, PTGS2) were chosen for RT-PCR and gene enrichment analyses. In vitro, PC-3 and LNCaP cells were exposed, respectively, to 1.0 or 2.0 mM of tempol during 48 h. In vivo, five experimental groups were evaluated regarding tempol effects in the early (CT12 and TPL12 groups) and late-stages (CT20, TPL20-I and TLP20-II) of PCa development. TPL groups were treated with 50 mg/kg or 100 mg/kg of tempol. The ventral lobe of the prostate and the plasma was collected. Tempol treatment increased miRs expression in PC-3 and LNCaP. For both cell lines, tempol decreased RELA expression. In TRAMP model, tempol increased miRNA expression in prostate for all treated groups. Tempol upregulated the miRNA expressions related to the NFκB pathway in the prostate tissue and human tumor cell lines. Their increase is mainly linked to increased cell death and delayed CaP aggressivenes. Thus, tempol's capacity for miRNA-mediated gene silencing to decrease tissue proliferation and cell survival processes is part of its tissue mechanics.

Photothermal therapy is a novel and promising method for cancer treatment due to its controllable property, noninvasive nature, and high selectivity. Nevertheless, tumor recurrence of inflammatory response and tumor tolerance of heat shock protein over-expression remain serious challenges in current photothermal therapy. Additionally, the high dosage requirement of nanomaterial for optimal imaging and therapeutic effect would result in various side effects, organ excretion burdens, and long-term accumulation in the body. In this work, RD/Qu nanoplatform is designed and prepared with near-infrared (NIR) absorbance, high photothermal conversion efficiency, and great chemotherapy effect for synergetic cancer chemo/photothermal therapy at an ultralow-dose. More importantly, both in vitro and in vivo studies demonstrate that it could decrease the expression of HSP70 to fight hyperthermia tumor tolerance and inhibit inflammatory factor COX-2 to suppress tumor recurrence. Therefore, the RD/Qu nanoparticles show excellent outcome in tumor ablation at a quite low dosage, providing a promising avenue for cancer treatment.

Metastasis is a major cause of poor prognosis of pancreatic cancer. Exosomes (Exos) regulate cancer progression by modulating macrophage polarization. This study aimed to investigate the effects of cancer-associated fibroblast (CAF)-released Exos on macrophage polarization in pancreatic cancer and the molecular mechanisms. THP-1 cells or xenografted tumor mice were treated with Exos from CAFs, and macrophage polarization was analyzed using quantitative real-time PCR (qPCR) and flow cytometry. THP-1 cells were cocultured with BXPC-3 cells, and metastasis was analyzed using Transwell assay and scratch test. Exosomal PTGS2 was detected using qPCR, and the NOD1 pathway was evaluated using western blot analysis. The results showed that Exos promoted M2-type polarization and inhibited M1-type polarization, and then facilitated pancreatic cancer cell migration, invasion, and epithelial-mesenchymal transition. PTGS2 expression was increased in Exo-treated macrophages, and its knockdown in CAFs facilitated M2 to M1 macrophage polarization. Moreover, Exos promoted the NOD1 pathway via PTGS2, and inhibition of NOD1 reversed the polarization caused by Exos. Additionally, NOD1 was required in M1/M2 polarization in vivo mediated by Exos. In conclusion, CAF-secreted Exos facilitated M2 macrophage polarization by carrying PTGS2 to activate the NOD1 pathway, thereby promoting pancreatic cancer metastasis, providing evidence that CAF-Exos accelerating pancreatic cancer progression.

Fenamates as classical nonsteroidal anti-inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo-preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/β-catenin, TGF-β, p38 MAPK, and NF-κB pathway, and the regulation of the expressions of Sp, EGR-1, NAG-1, ATF-3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs.

Nucleus pulposus cells (NPC) are important for the development of intervertebral disc degeneration (IVDD). miR-4478 can aggravate IVDD, but whether it can aggravate IVDD by regulating ferroptosis in NPC remains unclear. The optimal level of ferroptosis activator RSL3 for eliciting ferroptosis in NPC was screened by Western blot and CCK-8 assay. The targeting relationship between miR-4478 and its potential target solute carrier family 7 member 11 (SLC7A11) was explored based on dual luciferase assay. On this basis, IVDD models were constructed. After over-expression or knockdown of miR-4478 or SLC7A11, CCK-8 and calcein-AM/PI assays were employed to evaluate cell damage. Flow cytometry, Western blot and Prussian blue staining were employed to evaluate oxidation and ferroptosis levels, and histopathological staining was applied to evaluate the intervertebral disc tissue injury degree. The optimal concentration of RSL3 was 1 μM. Under these conditions, miR-4478 or SLC7A11 can be effectively over-expressed or knocked down after transfection. Knockdown of miR-4478 can improve the survival rate of NPC, the level of Fe2+ ions, improve the pathological damage of intervertebral disc structure, reduce iron deposition in tissues, and significantly reduce expression of reactive oxygen species (ROS) and ferroptosis-related protein. The levels of antioxidant enzymes were significantly increased. When miR-4478 was over-expressed, the above phenomenon was reversed. On this basis, after SLC7A11 was over-expressed, the effect of miR-4478 up-regulation was weakened, and NPC ferroptosis was improved. miR-4478 can target SLC7A11 to promote NPC damage, peroxide accumulation and iron metabolism disorders, leading to ferroptosis, thereby inducing IVDD.

Highly spatiotemporal-resolved photomodulation demonstrates promise for investigating key biological events in vivo and in vitro, such as cell signaling pathways, neuromodulation, and tumor treatment without side effects. However, enhancing the performance of photomodulation tools remains challenging due to the limitations of the physicochemical properties of the photoactive molecules. Here, a compact, stable intramolecular π-π stacking conformation forming between the target molecule (naproxen) and the perylene-based photoremovable protecting group is discovered to confine the motion of the photolabile bond and then enhance the photocleavage quantum yield. In conjunction with a red-absorbing photosensitizer, the photocleavage wavelength is extended to the red region via triplet-triplet annihilation. In particular, the triplet lifetime of the prodrug can be extended via the linked steric hindrance to improve the conversion yield via TTA. Using the new photomodulation tool, it is precisely photoreleased cyclooxygenase-2 inhibitors for tumor vascular growth suppression in vivo. In combination with cisplatin, over 90% efficient inhibition of malignant breast tumors is observed via the synergistic tumor treatment strategy. These findings provide a new concept for the rational design of efficient photocleavage and have implications for photomodulating cell signaling pathways in tumor therapy, as well as laying a solid foundation for the development of phototherapeutic approaches.