Gastric cardia adenocarcinoma (GCA) is a highly invasive type of gastric cancer (GC), with an increasing incidence in recent years and a poor prognosis. Chemotherapy combined with surgery is currently considered a good treatment strategy. This study aimed to explore the regulatory mechanism of ZNF649 on 5-FU sensitivity in GCA. The expression level of ZNF649 in GCA was analyzed based on The Cancer Genome Atlas (TCGA) database. The relationship between ZNF649 expression and methylation level, as well as the distribution of CpG islands in the promoter region of ZNF649, were analyzed separately using MethylMix and MethPrimer. Furthermore, the GCA data was used to predict ZNF649-related signaling pathways by utilizing gene set enrichment analysis (GSEA). The expression level of ZNF649 was detected using qPCR. Western blot (WB) was employed to measure the protein expression levels of ZNF649 and Hedgehog pathway-related proteins (SMO, GLI1, Shh). We utilized immunohistochemistry to detect the protein expression level of ZNF649 in tissues. MSP was employed to detect the methylation level of ZNF649 in clinical samples or cells. Cell viability and apoptosis ability were detected by CCK8 and flow cytometry. We uncovered that the downregulation of ZNF649 expression in GCA tissues and cells was negatively correlated with the DNA methylation level. The DNA methylation of ZNF649 occurred in the promoter region. Overexpression of ZNF649 facilitated the sensitivity of GCA to 5-FU, reduced the IC₅₀ value of cancer cells to 5-FU, and enhanced the apoptosis ability of cancer cells. In addition, ZNF649 negatively modulated the Hedgehog signaling pathway. When ZNF649 was knocked down, the Hedgehog signaling pathway was activated in cancer cells, leading to decreased cell sensitivity to 5-FU. This study suggested that the ZNF649 gene is downregulated after DNA methylation, leading to the activation of the Hedgehog signaling pathway and the weakening of GCA cells’ sensitivity to 5-FU. The project indicated that targeting ZNF649 and the Hedgehog signaling pathway may be key factors in improving 5-FU resistance in GCA patients.

Myocardial ischemia-reperfusion (I/R) injury remains a devastating clinical problem, contributing substantially to morbidity and mortality worldwide. In the present study, we investigated the potential role of Micheliolide (MCL) in attenuating cardiac I/R injury. H9c2 cardiomyocytes were pretreated with MCL for 24 hours and then subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cellular injury was evaluated by measuring cell viability and lactate dehydrogenase (LDH) release, while cell death was assessed using propidium iodide (PI) staining. Oxidative stress was determined by assessing superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and glutathione peroxidase (GSH-Px) activity, while the expression levels of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and pyroptosis-related proteins were examined by Western blotting. The results demonstrated that MCL significantly alleviated OGD/R-induced damage in H9c2 cells. Moreover, MCL inhibited OGD/R-induced oxidative stress and pyroptosis while enhancing AMPK pathway activation. Importantly, the protective effect of MCL was attenuated in the presence of the AMPK inhibitor Compound C, indicating that activation of the AMPK signaling pathway is required for MCL-mediated cytoprotection.

Iron (Fe) and heme are essential for numerous biological processes, but their dysregulation contributes to cancer, neuro­degeneration, and ferroptosis. This review summarizes the develop­ment and applications of N-oxide chemistry-based fluores­cent probes and 1,2,4-trioxolane-based probes for selective monitoring of labile Fe(II) and heme in living systems over the past decade. We describe our discovery that Fe(II) selectively deoxygenates tertiary amine N-oxides, enabling conversion of non-fluorescent N-oxide compounds into highly fluorescent tertiary amines. This approach has yielded a comprehensive palette of Fe(II)-selective probes with diverse colors and organelle-targeting capabilities. Key developments include RhoNox-4 (FerroOrange), a highly sensitive probe demonstrating >100-fold fluorescence enhancement that enabled high-throughput screening applications, and organelle-targeted probes that revealed labile Fe(II) accumulation in lysosomes and endoplasmic reticulum during ferroptosis. We also discuss H-FluNox, the first highly selective heme probe exhibiting >200-fold fluorescence increase, which successfully monitors endogenous heme dynamics and revealed simultaneous upregulation of both labile Fe(II) and heme during ferroptosis. Another approach is based on the chemical reactivity of 1,2,4-trioxolane, where the O–O bond cleavage reaction is induced by Fe(II) or heme. The 1,2,4-trioxolane motif could facilitate ferroptosis, but in contrast, the N-oxide-based probes function as ferroptosis inhibitors through selective deple­tion of labile Fe(II) involved in lipid peroxidation. We highlight the unexpected discovery that these N-oxide-based probes function as ‍ferroptosis inhibitors through selective Fe(II) depletion, with activity dependent on cellular localization. These chemical tools have provided unprecedented insights into iron and heme biology, offering new opportunities for understanding oxidative stress mechanisms and developing therapeutic strategies for iron-related disorders.

Several similarities between shear-stress-induced mechanically damaged erythrocytes and physiologically aged erythrocytes have ‍been reported, including mechanical fragility, increased aggregability, altered membrane charge, and loss of membrane lipid. Additionally, we found that mechanically circulated blood using a centrifugal blood pump showed an increase in erythrocyte membrane oxidation. This raised the question of how much oxidation can be induced under shear stress and how it relates to cellular aging. Therefore, we investigated membrane oxidation in density-isolated erythrocytes (young and old) exposed to shear conditions. Human stored blood was exposed to shear stresses of 5, 10, 30, 60, and 90 ‍‍Pa for exposure times of 0, 5, 10, and 15 ‍‍min. The sheared blood was then layered onto a centrifuge tube preloaded with two Percoll density solutions (1.10 and 1.12 ‍‍g/ml). After centrifugation, erythrocytes from the two density layers were collected and designated as young and old erythrocytes, which were used as the study samples. Across all shear condi­tions, old erythrocytes showed higher lipid peroxide fluorescence per unit area compared with young erythrocytes. However, the rate of increase in oxidation before and after shear exposure was greater in young erythrocytes. These findings suggest that there may be a limit to the extent of membrane oxidation.

Despite substantial progress in the management of cardiovascular disease (CVD), lipoprotein(a) [Lp(a)] persists as a genetically determined risk factor that remains insufficiently explored. Both extremely high and low levels of Lp(a) are linked to adverse outcomes. Current diagnostic assays for Lp(a) lack standard­ization, and conventional lipid-lowering therapies exert minimal effects on its levels, resulting in limited treatment options specif­ically targeting Lp(a). To address these gaps, we conducted a comprehensive molecular and clinical review of Lp(a), examining its unique structure, genetic determinants, metabolic pathways, and the factors influencing its plasma concentration. Furthermore, we discuss emerging therapeutic strategies aimed at targeting Lp(a).

Photodynamic therapy is a cancer treatment that is minimally invasive and combines photosensitizers with laser irradiation. Among the photosensitizers used in photodynamic therapy, porphyrin compounds have been widely applied because they specifically accumulate in cancer cells, and this approach has already been introduced into clinical practice. However, the detailed mechanism of porphyrin accumulation in cancer cells has not yet been clarified. The authors focused on the structural similarity between heme and porphyrin and demonstrated that the heme carrier protein 1 (HCP1) functions as an importer not only for heme but also for porphyrins. In addition, the expression of HCP1 was found to be regulated by reactive oxygen species (ROS) generated in mitochondria. Certain adjuvant treatments—such as hyperthermia, radiation, and chemical compounds including anticancer drugs—induced mitochondrial ROS production and increased the accumulation of porphyrin compounds through the upregulation of HCP1, thereby enhancing the effectiveness of cancer therapy by laser irradiation. Furthermore, ROS derived from mitochondria were also implicated in the excretion mechanism of porphyrins. Since mitochondria are a major source of ROS through respiratory metabolism, their accurate regulation is essential for optimizing cancer therapy using photodynamic therapy.

Near-infrared photothermal cancer therapy has attracted increasing attention due to its non-invasiveness, high selectivity, and spatiotemporally controllable local treatment. A novel near-infrared photothermal agent was developed, consisting of a plasma membrane-adhesive indocyanine green conjugated with a polycation bearing quaternary ammonium salt groups, called adhesive indocyanine green, for locally administered near-infrared photothermal cancer therapy. In this study, the photothermal effects of adhesive indocyanine green on the plasma membrane were investigated using a rat gastric mucosal cancer cell line. Upon light irradiation, adhesive indocyanine green exhibited a photothermal effect without generating singlet oxygen. Due to electrostatic interaction, adhesive indocyanine green adhered to negatively charged polysaccharides on the plasma membrane of rat gastric mucosal cancer cells. When the cells were irradiated with near-infrared light at 808 nm at 108 J/cm², levels of intracellular reactive oxygen species significantly increased despite the absence of a detectable temperature rise in the cell culture medium. These results indicate the generation of intracellular reactive oxygen species by the photothermal effects of plasma membrane-adhesive near-infrared photothermal agents.

Recommended levels of dietary carotenoids remain uncertain, although their health benefits have gained renewed interest. One reason is that humans have a unique bioavailability of carotenoids compared to other mammals, which is not well understood. This position paper suggests that humans’ bioavailability of dietary carotenoids reflects the mammalian nocturnal bottleneck—a period when the ancestors of modern mammals became nocturnal during the Mesozoic era to avoid predatory dinosaurs. The roles of carotenoids are closely linked to evolutionary processes involving light and vision. Vertebrates developed advanced color vision by using specific xanthophylls in their photoreceptor cells. In contrast, mammals' color vision declined due to their nocturnal lifestyle. Primates later returned to daytime activity and accumulated two xanthophylls, lutein and zeaxanthin, from their diet, in the macular lutea of the eyes, to protect color vision. Additionally, humans uniquely store β-carotene and lycopene in exposed skin. Throughout primate evolution, humans’ ability to accumulate dietary carotenoids shifted from xanthophylls toward less polar carotenoids, including β-carotene and lycopene, unlike the high selectivity of xanthophylls observed in birds. Overall, carotenoid deposition in human tissues is not highly specialized, likely due to remnants of the mammalian nocturnal bottleneck. We should consider this when evaluating recommended carotenoid intake.

The rising incidence of chronic metabolic diseases places a significant economic burden on healthcare systems. Although the efficacy of lifestyle interventions has been reported, clinical nutrition typically emphasizes total energy and macronutrient intake without consensus on ideal dietary patterns. The Dietary Inflammatory Index (DII) assesses the inflammatory potential of diets and has been linked to diseases like cardiovascular disease, cancer, and type 2 diabetes. However, DII use in clinical practice is limited by its complexity. In this study, we developed a method to calculate DII scores using a clinically available food frequency questionnaire (FFQ). Thirty healthy volunteers provided 3-day dietary records (DR) and completed the FFQ. Dietitians calculated the intake of 29 nutrients from the DR. A created table of nutrient content per FFQ item enabled nutrient intake and DII score calculation from the FFQ. Statistical analysis showed significant correlations between 27 of 29 nutrient intakes and DII scores from the DR and FFQ. Regression equations were developed to predict actual nutrient intakes from the FFQ. The estimated DII (eDII) calculated using the equations correlated strongly with the DR-derived DII (r = 0.716, p < 0.0001). With low bias and variance, our method supports individualized and inflammation-targeted dietary interventions.