Introduction: This research aimed to investigate the effects of Nudix Hydrolase 1 (NUDT1) on Oral Squamous Cell Carcinoma (OSCC) cells, along with its relationship with the AMP-activated Protein Kinase (AMPK) signaling pathway. Methods: Immunohistochemical methods, Western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to assess the levels of NUDT1 expression in these OSCC tissues and normal tissues. The prognosis of all patients was followed up. The Kaplan‒Meier method was used to analyze the survival rate. Scratch, CCK8, and apoptosis assays were used to analyze the impact of NUDT1 downregulation on cell migration, proliferation, and apoptosis. Western blotting was used to assess AMPK activation after the downregulation of NUDT1. Results and Discussion: NUDT1 expression was substantially elevated in OSCC tissues and strongly correlated with pathological grade and tumor stage. All patients with high NUDT1 expression had lower Overall Survival (OS) (P = 0.0259) and Disease-Specific Survival (DSS) (P = 0.0129) rates than patients with low NUDT1 expression (P ＜ 0.05). In addition, the expression of NUDT1 was also greater in both CAL27 and HN30 OSCC cells than in normal cells. Downregulation of NUDT1 expression inhibits the migration and proliferation of Oral Squamous Cell Carcinoma (OSCC) cells and promotes their apoptosis. Furthermore, inhibition of NUDT1 also increased p-AMPK expression. Conclusion: This investigation thoroughly revealed the significance of NUDT1 in OSCC. NUDT1 plays an important role in the proliferation, migration, and apoptosis of OSCC cells and affects the AMPK signaling pathway.
Macrophages play a key role in organizing the immune system's response to different types of infections. Their remarkable plasticity enables them to develop and polarize into M1 (tumor-suppressing) and M2 (tumor-promoting) macrophages, in addition to Tumor-Associated Macrophages (TAMs). This thorough review examines how distinct signaling inducers affect macrophage polarization and behavior across various cancer types, including breast, lung, hepatocellular, prostate, and cervical cancers. In colorectal cancer, however, they have the opposite effect and are thought to help keep the tumor microenvironment immunosuppressive. This review also emphasizes how natural and synthetic modulators can prevent tumor growth by altering macrophage function or polarization. These innate immune cells are not only important in cancer but also play a crucial role in autoimmune diseases, allergic responses, and metabolic disorders. Learning about macrophage polarization will help scientists develop drugs that target TAMs, thereby helping tumors shrink.
Introduction: Lung ischemia-reperfusion injury (LIRI) is a serious complication of lung transplantation that causes respiratory distress and is associated with high mortality. Ferroptosis, a novel form of programmed cell death, contributes to the pathogenesis of LIRI. The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor that regulates a variety of physiological functions. However, the role and mechanism of AhR in ferroptosis during LIRI after lung transplantation remain to be further investigated. Materials and Methods: AhR signaling and ferroptosis were examined in a mouse LIRI model and a pulmonary vascular endothelial cell line following hypoxiareoxygenation (H/R) culture. The severity of LIRI was assessed based on histological architecture and cytokine levels. Cell viability and damage were evaluated using the CCK-8 and LDH assays. Ferroptosis biomarkers, including Fe²⁷, malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH), were measured using respective assay kits. PTGS2 (Prostaglandin-Endoperoxide Synthase 2), SLC7A11 (Solute Carrier Family 7 Member 11), and GPX4 (Glutathione Peroxidase 4) were analyzed by western blot. In vitro, lipid peroxidation was assessed by flow cytometry after DCFH-DA labeling. Transmission electron microscopy was used to observe mitochondrial ultrastructure. Results: Enhanced transcription of AhR and its downstream targets, CYP1A1 (Cytochrome P450 1A1) and CYP1B1 (Cytochrome P450 1B1), was observed. AhR deficiency exacerbated LIRI-induced ferroptosis and lung injury, whereas AhR activation mitigated lung injury and ferroptosis. H/R-induced cell injury and ferroptosis were alleviated by AhR activation. Increased ROS formation, primarily mitochondrial ROS (Mito-ROS), was triggered by AhR ablation or antagonism, and ROS inhibition subsequently reduced cell damage and ferroptosis. Discussion: Our findings indicate that AhR activation functions upstream by directly inhibiting excessive ROS accumulation triggered by I/R. This reduction in cellular oxidative stress prevents the lethal lipid peroxidation that drives ferroptosis. Conclusion: This study demonstrates the protective effect of AhR activation in LIRI by inhibiting ROS-induced ferroptosis, suggesting it may be a promising target for clinical prevention of LIRI.
INTRODUCTION:HD is a hereditary neurodegenerative disease caused by the amplification of the CAG trinucleotide repeat in the HTT gene, leading to a Mutant Huntingtin (mHTT) protein that dysregulates transcription, promotes protein aggregation, induces neuroinflammation, and impairs mitochondrial function. Motor dysfunction, cognitive decline, and mental disorders are manifestations of these biochemical abnormalities. Effective disease-modifying treatments are still limited, even with recent improvements. This review investigates the increasing relevance of Klotho, an anti-aging protein with neuroprotective, antioxidant, and anti-inflammatory characteristics, as a possible therapeutic target in Huntington disease. METHODS:We did a comprehensive literature search across PubMed, Scopus, and Web of Science databases. Klotho's molecular functions in neural protection, energy metabolism, oxidative stress reduction, and anti-inflammatory signalling were investigated in the context of HD pathogenesis. RESULTS:Klotho appears to influence critical neurodegenerative processes involved in HD. It inhibits NF-κB and NLRP3 inflammasome activity, stimulates antioxidant enzyme expression (SOD, catalase), promotes GluN2B-NMDA receptor-mediated synaptic plasticity, and increases astrocytic aerobic glycolysis via FGFR1-ERK signaling. These functions may mitigate mHTT- induced neuronal damage. Pharmacologic treatments (e.g., PPAR-γ agonists), vitamin D, and lifestyle interventions can all modulate klotho expression. DISCUSSION:Klotho exhibits neuroprotective effects in Huntington's disease by reducing NF-κB/NLRP3- mediated inflammation, strengthening antioxidant defenses, promoting GluN2B-NMDA- dependent synaptic plasticity, and improving astrocytic metabolic support via FGFR1-ERK signaling. One intriguing treatment approach for mutant huntingtin-induced neurotoxicity is the modification of klotho expression. CONCLUSION:Klotho is a promising neurochemical modulator with disease-modifying properties in HD. Its multifunctional protective activities are consistent with important pathological markers of HD, necessitating more preclinical and clinical studies to confirm its translational value.
Introduction: The worldwide increasing incidence of colon adenocarcinoma (COAD) due to a lack of early diagnostic biomarkers and drug resistance makes it essential to identify new diagnostic, prognostic, and drug-resistance biomarkers of COAD. ABC transporters are the key players that confer resistance against chemotherapeutic drugs. This study was initiated to explore the diagnostic, prognostic, and therapeutic role of ABCC1 expression in COAD patients Methods: The cBioPortal database was used to extract the ABCC1 mutation data. Extensive bioinformatics tools were employed to predict the functional impact of mutations. UALCAN was employed to conduct ABCC1 expression, methylation, and overall survival analysis in COAD. Further, pan-cancer analysis was also performed by UALCAN. The correlation of ABCC1 methylation and mutations with overall survival was performed using the OncoDB database. The KM plotter was used for disease-free survival analysis of ABCC1. Meta-survival analysis was conducted using GENT2. The CCLE and GDSC databases were utilized for drug sensitivity analysis of ABCC1 expression in COAD and other cancers. Results: Mutation analysis revealed that ABCC1 harbors damaging and pathogenic mutations in COAD with a frequency of 6%. The expression analysis showed the upregulation of ABCC1 at both transcriptomic and proteomic levels. The ABCC1 promoter was detected to be hypomethylated in COAD patients. Overall survival analysis of ABCC1 expression, methylation, and mutation level showed no significant association with survival in COAD patients. However, disease-free survival analysis showed a significant correlation with ABCC1 expression. Lastly, the drug sensitivity analysis depicted a significant association of ABCC1 expression with reduced drug sensitivity in various cancers. Discussion: The high expression of ABCC1 suggested its role in COAD and highlighted its significance as a therapeutic target. Conclusion: The findings suggested that ABCC1 can be employed as a diagnostic and therapeutic biomarker of COAD and can be used as an indicator of disease-free survival. However, no prognostic potential of ABCC1 in COAD was identified, predicting it as a poor prognostic biomarker of COAD.
Background: Alzheimer's Disease (AD) has a critical pathology that causes neurodegeneration and mitochondrial dysfunctions via the amyloid deposition. The temporal lobe plays a role in converting sensory input into derived meanings for appropriate processing of visual memory, language comprehension, and emotional association. The cerebellum plays a critical role in the control of motor systems, cognitive, and emotional functions. Aβ42 accumulates between nerve cells in the brain, disrupting synaptic functions and negatively affecting memory and other cognitive functions. VDAC1 is a protein located in the cell membrane that facilitates energy transport to the mitochondria. TGF-β1 is a cytokine that plays a role in many biological functions, including cell growth, differentiation, and tissue repair. Objective: The aim of the study was to investigate the effect of TGF-β1 on scopolamine-induced neurodegeneration of the temporal lobe and cerebellum in experimental AD. Methods and Results: The evaluation showed that, according to light and electron microscopic results, edema areas, cytoplasmic vacuolization, and cellular damage were increased in the scopolamine group, while these changes were significantly reduced in the treatment group. According to immunohistochemical findings, the expression levels of Aβ42 and VDAC1 were significantly higher in the scopolamine group than in the control and TGF-β1 groups, while in the treatment group, a low expression was observed compared to the scopolamine group. Conclusion: When all these results are considered together, it has been concluded that TGF-β1 application may regulate the expression of Aβ42 and VDAC1 in critical control centers such as the temporal lobe and cerebellum in a Scopolamin-induced neurodegeneration model, potentially alleviating cellular damage. Discussion: Previous studies have reported that TGF-β1 exerts both antineurodegenerative and neuroprotective effects. In our study, evaluation of the effects of TGF-β1 demonstrated beneficial effects on both mitochondrial damage and amyloid accumulation. Nevertheless, further detailed investigations of these effects may provide valuable insights for future studies.
Introduction: According to the WHO, post-COVID-19 sequelae impose an increased burden of illness and comorbidities among survivors. The present study evaluated systemic clinical complications associated with the dysregulation of circulatory cytokines in post-COVID-19 patients and compared them with those of healthy controls. Methods: This cross-sectional study included 147 participants divided into symptomatic post-COVID-19, asymptomatic post-COVID-19, and healthy control groups. After obtaining informed consent, peripheral blood samples were collected and analyzed using ELISA and RT-qPCR. Circulating levels of pro-inflammatory (IL-6, IL1β, TNFα) and anti-inflammatory cytokine IL-10 were measured in relation to clinical sequelae. Results: Common symptoms were fatigue (48%), headache (48%), anxiety (64%), general weakness (70%), muscle pain (70%), joint pain (54%), chest pain (32%), dyspnea (36%), and post-activity tachypnea (40%) among post COVID-19 individulas. A higher prevalence of post-COVID-19 sequelae was observed in females aged >40 years and in those with a post-COVID-19 duration of <30 months. ELISA showed higher levels of IL-6, TNF-α, and IL-10 in post-COVID-19 patients than in controls (p < 0.01). RT-qPCR revealed upregulation of IL-6, TNF-α, IL-1β, and IL-10 mRNA, which correlated with post-COVID-19 sequelae (p < 0.01). Discussion: Older age and shorter duration of post-COVID-19 are associated with more symptom burden, implying incomplete immune recovery during early convalescence. Elevated IL-6, IL-1β, TNF-α, and IL-10 levels indicate persistent immune dysregulation, supporting the view that post-COVID-19 is a chronic inflammatory state with clinical effects. Conclusion: IL-6, TNFα, IL-1β, and IL-10 are dysregulated in post-COVID-19 systemic sequelae, and longitudinal studies are necessary to better understand and potentially reduce this dysregulation in post-COVID-19.
Introduction: Disuse muscle atrophy is strongly associated with oxidative stress, with antioxidants such as melatonin emerging as potential therapeutic agents, particularly due to their protective effects on mitochondrial function. This study aimed to investigate the effects of melatonin on redox balance, cellular morphology, and expression of atrophy-related genes, Atrogin-1 and MuRF1, in an H2O2-induced muscle atrophy model using the C2C12 cell line. Materials and Methods: Four experimental groups were established, namely Control, Melatonin, H2O2, and Melatonin + H2O2. Morphological alterations were evaluated by measuring myotube diameters. Redox status was assessed using the Oxidative Stress Index (OSI), calculated from Total Antioxidant Status (TAS) and Total Oxidant Status (TOS). The expression levels of Atrogin-1 and MuRF1 were analyzed using quantitative real-time PCR. Results: Significant differences in myotube diameters were observed among the groups (p < 0.05). The Melatonin + H2O2 group exhibited the lowest OSI values, indicating improved redox balance. Although the differences were not statistically significant, melatonin treatment was associated with lower expression levels of Atrogin-1 and MuRF1 compared to other groups. Discussion: The findings suggest that melatonin may alleviate oxidative stressinduced muscle atrophy by preserving myotube morphology and improving cellular redox balance. The observed trends in Atrogin-1 and MuRF1 expression indicate a potential modulatory effect of melatonin on atrophy-related pathways; however, additional time-course and protein-level analyses are needed to further clarify these mechanisms. Conclusion: Melatonin demonstrated protective effects against HⁿOⁿ-induced muscle atrophy in C2C12 cells, particularly through the preservation of myotube morphology and enhancement of cellular antioxidant status. These findings support the potential role of melatonin as a therapeutic candidate for oxidative stress-related muscle atrophy.
Introduction: Liver inflammation in Non-Alcoholic Fatty Liver Disease (NAFLD) is shaped by immune regulation. This study examines the contribution of immune-related genes to NAFLD pathogenesis. Methods: Single-cell analysis identified key immune cell clusters and subtypes. Differential expression, machine learning, and expression profiling were used to screen key genes, which were then used to construct a nomogram predicting NAFLD risk. Immune infiltration analysis characterized immune states, and pseudotime analysis tracked key gene expression along T-cell differentiation. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to validate gene expression. Results: T cells were identified as the key immune cells, with regulatory T cells (Tregs) as the critical subtype. CXCR4, DUSP1, and ID2 were downregulated in NAFLD and supported a nomogram with good predictive performance. Immune infiltration analysis showed differences in six immune cell types, including Tregs, between NAFLD and controls. Pseudotime analysis showed increased CXCR4, DUSP1, and ID2 expression in Tregs and cytotoxic T lymphocytes (CTLs) at late differentiation, while NAFLD samples showed reduced DUSP1 and ID2 expression in RT-qPCR and Western blot assays. Discussion: Treg-centered immune dysregulation and the downregulation of CXCR4, DUSP1, and ID2 are closely linked to NAFLD pathology. The context-dependent nature of these genes precludes simple protective or pathogenic labels. The nomogram capturing single-cell-derived immune signatures outperforms conventional clinical predictors and offers mechanistic insight. Pseudotime analysis provides the first continuous view of T-cell activation trajectories in NAFLD. A ceRNA network involving NEAT1/XIST and miR-15b-5p may explain DUSP1 suppression. However, small validation cohorts (n = 3/group), the absence of functional experiments, and PBMC-based profiling limit causal inference; replication in larger intrahepatic cohorts is necessary before clinical translation. Conclusion: T cells, especially Tregs, and CXCR4, DUSP1, and ID2 are central to Non-Alcoholic Fatty Liver Disease and may serve as diagnostic and therapeutic targets.
Introduction: Diabetic Nephropathy (DN), a severe complication, involves endoplasmic reticulum stress. Calycosin, an isoflavone derived from Mongolian Milkvetch Root, may mitigate DN by targeting proto-oncogene tyrosine-protein kinase SRC (SRC)/Spleen Tyrosine Kinase (SYK)-dependent Reactive Oxygen Species (ROS)-mediated ER stress. Methods: Human Renal Glomerular Endothelial Cells (HRGECs) were exposed to high glucose to mimic DN, and then treated with calycosin or transfected with SRC overexpression plasmids. Quantitative real-time PCR was performed to assess transfection efficiency, and a western blot was conducted to examine the expression of proteins associated with endothelial dysfunction and endoplasmic reticulum stress. Cell viability, cytotoxicity, apoptosis, and ROS levels were assessed via cell counting kit-8, lactate dehydrogenase assay, flow cytometry, and DCFH-DA probes. Results: Calycosin barely affected HRGEC viability in normal glucose medium, but apparently reversed high glucose-induced suppression of viability. High glucose increased cytotoxicity, apoptosis, ROS content, and levels of intercellular cell adhesion molecule-1 (ICAM-1), Glucose-Regulated Protein 78 kD (GRP78), Phosphorylated (P)- Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)/ total (t)-PERK ratio, C/EBP-Homologous Protein (CHOP), SYK, and SRC protein, which were all counteracted by calycosin. Overexpression of SRC attenuated the effects of calycosin on promoting cell viability and repressing apoptosis, ROS, ICAM-1, and endoplasmic reticulum stress-related proteins in high-glucose-treated HRGECs. Discussion: These findings are in line with prior research linking SRC/SYK-ROS signaling to endoplasmic reticulum stress in the context of DN, highlighting the therapeutic potential of calycosin, although the lack of in vivo evidence necessitates future investigation using animal models. Conclusion: Calycosin attenuates high glucose-induced endoplasmic reticulum stress injury in HRGECs by inhibiting SRC/SYK-dependent ROS.
INTRODUCTION:Type 2 diabetes mellitus (T2DM) is a major risk factor for diabetic nephropathy (DN), yet the molecular mechanisms connecting these conditions remain unclear. Identifying shared hub genes and regulatory networks may provide insight into common pathogenic pathways. METHODS:Four GEO microarray datasets associated with T2DM (GSE23343, GSE29226) and DN (GSE30528, GSE142153) were analyzed using limma in R to identify differentially expressed genes (DEGs). Overlapping DEGs were assessed using Venn analysis and integrated into a STRING-based protein-protein interaction network. Hub genes were identified in Cytoscape. Their expression under high-glucose conditions was validated in HK-2 and NRK-52E cells using RT-qPCR and Western blotting. Predicted miRNAs were obtained from TargetScan and evaluated experimentally. Functional assays assessed the effects of hub gene overexpression. RESULTS:Thirty-six common DEGs were identified, with APP, RHEB, FRYL, and SOS1 exhibiting highest network connectivity. All four genes were consistently downregulated in patient datasets and high-glucose cell models. ROC analyses indicated moderate discriminatory capacity within datasets. Four candidate miRNAs (miR-26b-5p, miR-18a-5p, miR-199a-5p, miR-148a-3p) were elevated under highglucose conditions. Functional enrichment linked hub genes to mTOR, PI3K-Akt, and cytoskeletal pathways. Overexpression of hub genes reduced proliferation, clonogenicity, and migration in vitro. DISCUSSION:The convergence of transcriptomic and experimental findings suggests that reduced expression of these hub genes may contribute to glucose-induced cellular dysfunction. However, miRNA-gene relationships remain correlative, and validation in additional renal cell types and independent patient cohorts is needed. CONCLUSION:APP, RHEB, FRYL, and SOS1 represent shared molecular signatures of T2DM and DN and may offer potential targets for future mechanistic and therapeutic studies.
It has come to our attention that in the published version of this article [1], reference [86] was cited erroneously; this has now been corrected. The original article can be found online at: https://www.eurekaselect.com/article/145963 Details of the correction are as follows: Original: These contradictory reports regarding the sortilin function in lipid metabolism may result from variations in employed animal models or lipid metabolic milieu. Once the intracellular level of apoB-100 is elevated, sortilin may primarily act as "the degrader," whereby sortilin can target VLDL to the lysosomal degradation and thus reduce the secretion of VLDL particles [28]. Oppositely, in situations of reduced expression of apoB-100, like in the DKO mouse model, sortilin can also exhibit "the chaperone" activity and assist the formation and secretion of VLDL particles [86]. According to such a theory, the impacts of sortilin on liver lipid metabolism depend on the physiological demands and the metabolic context. Moreover, sortilin can target lipid-related proteins and regulate their expression and functions, consequently influencing lipid metabolism. Thus, it is essential to consider whether deficiency or overexpression of the SORT1 gene or sortilin protein disrupts the expression of other lipid genes and corresponding proteins. Corrected: These contradictory reports regarding the sortilin function in lipid metabolism may result from variations in employed animal models or lipid metabolic milieu. Once the intracellular level of apoB-100 is elevated, sortilin may primarily act as "the degrader," whereby sortilin can target VLDL to the lysosomal degradation and thus reduce the secretion of VLDL particles [28]. Oppositely, in situations of reduced expression of apoB-100, like in the DKO mouse model, sortilin can also exhibit "the chaperone" activity and assist the formation and secretion of VLDL particles [36]. According to such a theory, the impacts of sortilin on liver lipid metabolism depend on the physiological demands and the metabolic context. Moreover, sortilin can target lipid-related proteins and regulate their expression and functions, consequently influencing lipid metabolism. Thus, it is essential to consider whether deficiency or overexpression of the SORT1 gene or sortilin protein disrupts the expression of other lipid genes and corresponding proteins.
INTRODUCTION:Currently, effective methods for the early diagnosis of Chronic Pancreatitis (CP) remain limited. PANCREATIC STELLATE CELLS (PSCs) in pancreatitis are critical drivers of CP progression, and PSCs are known to overexpress Fibroblast Activation Protein (FAP) in inflamed pancreatic tissue. This study aims to investigate the correlation between the dynamic changes in FAP expression by PSCs and CP progression, and to evaluate the feasibility of three FAP inhibitor (FAPI)-based tracers for early CP diagnosis. METHOD:Caerulein-treated PRSS1 transgenic mice (PRSS1Tg) were categorized into four groups based on the development stage of CP. The pancreatic pathology was observed using HE and Masson staining. Moreover, immunohistochemistry, immunofluorescence, and qRT-PCR were employed to further analyze the pancreas. Additionally, near-infrared in vivo fluorescence imaging was performed with ICG-FAPI- 04, whereas Micro-PET/CT was performed with 68Ga-FAPI-04 and 18F-FAPI-42. The results were subsequently observed and analyzed. RESULTS:Experiments revealed that FAP was overexpressed in CP, with its expression peaking at 2 weeks. In vivo near-infrared imaging using ICG-FAPI-04 failed to effectively assess pancreatic morphology and fibrosis at the 2-week time point in the CP model mice. In micro-PET/CT evaluations of CP model mice at two weeks, 18FFAPI- 42 demonstrated superior visualization of pancreatic morphology and fibrosis compared to 68Ga-FAPI-04. DISCUSSION:The near-infrared probe ICG-FAPI-04 shows limited efficacy, but its performance could be improved by increasing hydrophilicity or adopting NIR-II imaging. In comparison, FAPI-based PET/CT-especially using 18F-FAPI-42-offers clear visualization of pancreatic morphology, positioning it as a highly promising tool for CP detection. CONCLUSION:This study demonstrated dynamic FAP expression during CP progression. FAP-targeted tracers were shown to sensitively visualize the pancreatic morphology reflecting fibrosis severity, validating their feasibility for early CP diagnosis.
BACKGROUND:Though advances in technologies have created an arena for multiple vaccinology platforms, the world population is still facing health challenges from the deadliest pathogens with a high mutation rate and their tremendous ability of immune evasion. Presently, there is a constant exigence to shift the vaccine development efforts from traditional vaccines to broad-spectrum vaccines for the effective prevention of contagious diseases. MATERIALS AND METHODS:Using several databases, a comprehensive systematic review of the literature pertinent to this article's discussion was carried out. RESULTS:The present review article aims to provide a comprehensive understanding of the key characteristics and benefits of broad-spectrum vaccines over conventional vaccines. Further, it unveils the diverse range of broad-spectrum vaccines that have been developed so far, in addition to those that are currently under pre-clinical and clinical studies. Along with the illustration of the obstacles and possibilities concerned with their safety profile and viability of development, it also examines their potential for further research. DISCUSSION:The development of broad-spectrum vaccines benefits greatly from the combination of several immunisation strategies. The scope and effectiveness of broadspectrum vaccinations have been shown to be greatly increased by combining various vaccination tactics, such as using multiple immunisation techniques, multivalent antigens, or heterologous boosters. CONCLUSION:The development and practical validation of broad-spectrum vaccines have been impeded thus far by biological complexity (rapid pathogen evolution, immune imprinting, host variability), logistical limitations, and regulatory frameworks intended for strain-specific products, leaving the majority of candidates at preclinical stages. To turn promising ideas into gradual, population-level protection, policy support, and focused research improving evaluation techniques, altering regulatory pathways, and advancing mRNA, multiepitope, and T-cell approaches are required.
The interaction between cellular metabolism and immune function, termed immunometabolism, has been regarded as a crucial determinant of anti-tumor immunity and the efficacy of cancer immunotherapy. Understanding the metabolic dependencies and vulnerabilities of various immune cell subsets and cancer cells is enabling researchers to study novel therapeutic strategies. These strategies aim to reprogram the metabolic landscape of the TME to enhance stronger anti-tumor immune responses and overcome resistance to current immunotherapies. This review provides a comprehensive overview of the fundamental principles of immunometabolism, detailing the key metabolic pathways and regulators in immune and cancer cells. We explore the distinct metabolic profiles of various immune cell subsets and how they are altered during an anti-tumor response. Furthermore, we discuss the metabolic hallmarks of cancer cells, considering variations across different cancer types. Then, we discuss how current immunotherapies, such as checkpoint inhibitors and CAR-T cell therapy, impact and are influenced by cellular metabolism. Finally, we highlight promising therapeutic opportunities for targeting immunometabolism, including metabolic inhibitors, modulators, and combination strategies. This review aims to introduce immunometabolic reprogramming as a new frontier to enhance the efficacy of cancer immunotherapy and improve patient outcomes.
BACKGROUND:Given the known therapeutic properties of gold compounds such as auranofin, this study aimed to evaluate the anticancer potential of a newly synthesized gold(III) Schiff base complex. We hypothesized that this complex could selectively induce apoptosis in cancer cells while minimizing inflammatory responses in normal cells. METHODS:A gold(III) complex bearing a tetradentate Schiff base ligand was synthesized, and its cytotoxicity was assessed using MTT assay and sulforhodamine B staining. KYSE-30 esophageal cancer cells and NIH/3T3 normal fibroblasts were treated with the complex and compared to cisplatin. Gene expression analysis was performed to evaluate apoptotic and inflammatory genes. RESULTS:The gold(III) Schiff base complex significantly inhibited KYSE-30 cell proliferation more effectively than cisplatin after 48 hours. Unlike cisplatin, it did not induce cytotoxicity in NIH/3T3 cells. The complex elevated the BAK1/Bcl-xL ratio by 2.22-fold, suggesting activation of the intrinsic mitochondrial apoptotic pathway, which was not observed with cisplatin. It also downregulated the anti-apoptotic Bcl-xL gene (0.662-fold) and the resistance-associated AKT1 gene (0.0544-fold). Both the gold(III) Schiff base complex and cisplatin activated the extrinsic apoptotic pathway via Caspase-3. Importantly, neither compound induced TNF-α expression, indicating no inflammatory response in normal cells. DISCUSSION:These findings demonstrate that the gold(III) Schiff base complex selectively targets esophageal cancer cells through dual apoptotic pathways while sparing normal cells from cytotoxicity and inflammation. Its ability to suppress resistance-related genes further highlights its therapeutic promise. CONCLUSION:The gold(III) Schiff base complex represents a compelling alternative to cisplatin, offering enhanced anticancer efficacy, reduced toxicity to normal cells, and minimal inflammatory activation. Further investigation into its clinical potential is warranted.
INTRODUCTION:The study was designed to explore the role of Growth Differentiation Factor 15 (GDF15) and its underlying mechanisms in coagulation dysfunction, the inflammatory response, and multi-organ damage using a rat model of cecal ligation and puncture (CLP)-induced sepsis. METHODS:A CLP-induced sepsis model was established in Sprague-Dawley rats. Adenovirus vectors were used to overexpress or knockdown GDF15. A PI3K inhibitor (LY294002) was administered to specific groups. Serum levels of GDF15, apoptosis markers (cleaved-caspase3), endothelial injury markers (syndecan-1, heparan sulfate), coagulation markers (D-dimer), inflammatory cytokines (IL-6, TNF-α), and PI3K/AKT/mTOR phosphorylation were measured by ELISA. Coagulation parameters and platelet counts were assessed. Organ damage was evaluated via H&E staining of the liver, heart, and kidneys. RESULTS:GDF15 levels were significantly elevated in CLP rats. High GDF15 levels were associated with increased cleaved-caspase3, syndecan-1, heparan sulfate, Ddimer, IL-6, and TNF-α; prolonged APTT, PT, and TT; decreased platelet count and fibrinogen (FIB); aggravated multi-organ damage; and enhanced PI3K, AKT, and mTOR phosphorylation. Silencing GDF15 or inhibiting PI3K with LY294002 reversed these effects, whereas GDF15 overexpression exacerbated them. The detrimental effects of GDF15 overexpression were attenuated by co-administration of LY294002. DISCUSSION:GDF15 exacerbates coagulopathy, inflammatory responses, and multiorgan damage in septic rats, likely by activating the PI3K/AKT/mTOR signaling pathway. These results establish GDF15 as a potential mediator of sepsis pathophysiology and a therapeutic target warranting further investigation. CONCLUSION:The findings of this study suggest that GDF15 is associated with coagulation dysfunction, inflammatory responses, and multi-organ injury in septic rats, and these effects may involve modulation of the PI3K/AKT/mTOR signaling pathway. Regarding translational implications, GDF15 has potential as a biomarker, but human validation is required. It may represent a potential therapeutic target that warrants further investigation, and its clinical relevance requires confirmation in human studies. It is important to emphasize that these findings are derived from a preclinical rat model and may not directly translate to human sepsis.
INTRODUCTION:Sepsis is a life-threatening condition with heterogeneous pathogenesis. This study aimed to identify ferroptosis-related hub genes, construct their regulatory network, and evaluate their potential as biomarkers and therapeutic targets to elucidate the molecular mechanisms underlying sepsis heterogeneity. METHODS:Transcriptomic data from 1,042 sepsis patients and 42 controls were integrated from public databases (GEO and ArrayExpress). Based on the expression of 47 ferroptosis-related genes, consensus clustering was performed to identify molecular subtypes. Differentially Expressed Genes (DEGs) between subtypes were identified and analyzed by functional enrichment. Key gene modules were identified using Weighted Gene Co-Expression Network Analysis (WGCNA), and hub genes were screened by intersecting WGCNA results with a Protein-Protein Interaction (PPI) network. An in silico-predicted multi-factor (TF-miRNA-mRNA) regulatory network was constructed using the starBase and Harmonizome databases. Key findings were preliminarily validated in a mouse model of E. coli-induced sepsis using quantitative real-time PCR (qRT-PCR). RESULTS:Sepsis patients were stratified into two distinct ferroptosis-based subtypes (Cluster 1, n=702; Cluster 2, n=340). A total of 3,608 DEGs were identified, which were enriched in neutrophil activation, ubiquitination, and bacterial infection. WGCNA identified a key sepsis-associated module, leading to the selection of 21 hub genes from the co-expression network. In the septic mouse model, 9 of these genes (including ANK1, HMBS, and SIAH2) were significantly upregulated, and 2 genes (CA1, HBD) were downregulated in septic mice, providing preliminary experimental support for the bioinformatic findings. A comprehensive in silico-predicted regulatory network involving these 21 hub genes, 146 transcription factors, and 70 miRNAs was established as a resource for hypothesis generation. DISCUSSION:The identified hub genes and their regulatory network shed light on the role of ferroptosis in sepsis heterogeneity and pathogenesis. Genes such as SIAH2 and HMBS were differentially expressed between surviving and non-surviving patients, warranting further investigation as potential prognostic biomarkers in future studies. The constructed network identifies actionable targets (e.g., the E3 ligase SIAH2 and specific miRNAs) for therapeutic intervention. Limitations include the retrospective nature of the bioinformatic analysis and the need for further experimental validation of mechanistic roles. CONCLUSION:This study delineates a ferroptosis-associated gene signature and regulatory network in sepsis, providing a hypothesis-generating foundation for future research. The identified hub genes and their regulatory interactions warrant further investigation to explore their potential as prognostic biomarkers or therapeutic targets. However, given the lack of significant association with survival outcomes in the current dataset, these findings should be considered preliminary and require validation in independent cohorts with comprehensive clinical annotation before any clinical applications can be considered.
Angiosarcoma is a rare, highly aggressive endothelial malignancy comprising less than 1% of soft tissue sarcomas, with a 5-year overall survival of only 41-43%. Despite advances in cancer therapeutics, angiosarcoma remains critically understudied due to limited case prevalence, perpetuating a knowledge gap in molecular mechanisms and therapeutic strategies. Recent clinical trials (Axi-STS, TAPPAS) demonstrated that single-agent anti-angiogenic inhibitors (axitinib, pazopanib) achieve modest efficacy (median progression-free survival (PFS) 3.0-4.3 months, response rates 5-13%), underscoring angiosarcoma's complex, multipathway-driven pathogenesis. This review synthesizes the mutational landscape and molecular crosstalk of angiosarcoma, emphasizing four key mechanisms - (1) genepathway interactions-MYC amplification (>95% in radiation-associated angiosarcoma (RAAS)), TP53 mutations, and PIK3CA alterations converging to drive aggressive angiogenesis; (2) endothelial-specific dysregulation-TP53-driven disruption of VEcadherin junctions, VEGF-induced vascular permeability, and endothelial-tomesenchymal transition; (3) microenvironmental contributions- Transforming Growth Factor-Beta (TGF-β), IL-10, and VEGF-mediated immunosuppression and tumor progression; and (4) emerging biomarker-driven combinations-dual Vascular Endothelial Growth Factor (VEGF) + endoglin inhibition, chemotherapy + anti-PD-L1 immunotherapy, and multi-targeted TKI + Immune Checkpoint Inhibitors (ICI) strategies showing improved outcomes. Environmental exposures (vinyl chloride, thorotrast, radiation) drive distinct angiosarcoma subtypes with subtype-specific mutational profiles. We propose that precision-medicine approaches integrating molecular stratification, pathway crosstalk analysis, and biomarker-guided combination therapies represent the rational next steps to overcome therapeutic resistance and improve clinical outcomes in this lethal malignancy.
OBJECTIVE:To explore the role of the Nrf2 signaling pathway in sappanone A (SA)-mediated protection against cisplatin (CP)-induced renal injury, we investigated the impact of Nrf2 knockdown on cell apoptosis, oxidative stress, NF-κB activation, and IL-1β release in human renal proximal tubular cell line HK-2 cells. MATERIALS AND METHODS:siRNA-mediated knockdown of the Nrf2 gene was performed in HK-2 cells. Oxidative stress markers, including malondialdehyde (MDA) and hydroxyl radical (•OH), were quantified using colorimetric assays. Apoptotic cell death was evaluated by both TUNEL staining and flow cytometry. Western blot analysis was employed to detect protein expression levels of Nrf2, heme oxygenase-1 (HO-1), p65, and phosphorylated p65 (p-p65). The level of interleukin-1β (IL-1β) in cell culture supernatants was measured using ELISA. RESULTS:Down-regulation of Nrf2 significantly suppresses SA's protective effect against CP-induced oxidative stress, as reflected by increased MDA and •OH as well as reduced the expression of HO-1 in HK-2 cells. Nrf2 depletion eliminates SA's capacity to reduce cell apoptosis. SA attenuates CP-induced phosphorylation of NF- κB p65 (p-p65), but this inhibition is reversed by Nrf2 depletion. ELISA analysis further demonstrates that Nrf2 knockdown elevates IL-1β secretion in HK-2 cells, indicating enhanced inflammatory response upon Nrf2 loss. DISCUSSION:SA, an active compound from Caesalpinia sappan L. with antioxidant, anti-inflammatory, and anti-apoptotic properties, mitigates CP-induced nephrotoxicity in HK-2 cells by suppressing oxidative stress, inflammation, and apoptosis through activating the Nrf2 pathway (enhancing Nrf2 and HO-1 expression), as confirmed by experiments showing SA reduces biomarkers of these processes and that Nrf2 silencing abolishes such effects, aligning with classical Nrf2 activation patterns. CONCLUSION:Nrf2-mediated inhibition of oxidative stress, apoptosis, and inflammation contributes to the protective effect of Sappanone A against cisplatininduced cytotoxicity in HK-2 cells.
