Copper (Cu), an essential micronutrient, participates in several physiological processes, including cell proliferation and develop­ment. Notably, the disturbance of Cu homeostasis promotes tumor progression through the generation of oxidative stress. Chronic or excessive accumulation of reactive oxygen species (ROS) causes lipid peroxidation, protein denaturation, and enzyme inactivation, which leads to a breakdown of intracellular homeostasis and exacerbates tumor progression. The disruption of the ROS scavenging mechanism also reduces resistance to oxidative stress, leading to further deterioration in a disease state, and maintenance of redox homeostasis is thought to inhibit the onset and progression of various diseases. Superoxide dismutase 3 (SOD3), a Cu-containing secretory antioxidative enzyme, plays a key role in extracellular redox regulation, and the significant reduction in SOD3 facilitates tumor progression. Furthermore, the significant induction of SOD3 participates in tumor metastasis. This review focuses on the role of Cu homeostasis and antioxidative enzymes, including SOD3, in tumor progression, to help clarify the role of redox regulation.

Caveolae, consisting of caveolin-1 proteins, are ubiquitously present in endothelial cells and contribute to normal cardio­vascular functions by acting as a platform for cellular signaling pathways as well as transcytosis and endocytosis. However, caveolin-1 is thought to have a proatherogenic role by inhibiting endothelial nitric oxide synthase activity and Nrf2 activation, or by promoting inflammation through NF-κB activation. Dietary polyphenols were suggested to exert anti-atherosclerotic effects by a mechanism involving the inhibition of endothelial dysfunc­tion, by which they can regulate redox-sensitive signaling pathways in relation to NF-κB and Nrf2 activation. Some monomeric polyphenols and microbiota-derived catabolites from monomeric polyphenols or polymeric tannins might be respon­sible for the inhibition, because they can be transferred into the circulation from the digestive tract. Several polyphenols were reported to modulate caveolin-1 expression or its localization in caveolae. Therefore, we hypothesized that circulating poly­phenols affect caveolae functions by altering its structure leading to the release of caveolin-1 from caveolae, and attenuating redox-sensitive signaling pathway-dependent caveolin-1 over­expres­sion. Further studies using circulating polyphenols at a physio­logically relevant level are necessary to clarify the mechanism of action of dietary polyphenols targeting caveolae and caveolin-1.

Neutrophil extracellular trap (NET) formation is a unique self-defense mechanism of neutrophils; however, it is also involved in many diseases, including atherosclerosis. Resveratrol and catechin are antioxidants with anti-atherosclerotic properties. Here, we examined the effects of resveratrol, catechin, and other related compounds on NET formation. HL-60-derived neutrophils were pretreated with resveratrol and other compounds before stimu­lation with phorbol-myristate acetate (PMA). DNA and myelo­peroxidase released from neutrophils were determined. Res­ver­a­trol suppressed the DNA release from neutrophils in a dose-dependent manner. NET formation was enhanced by 1-palmitoyl-2-oxovaleroyl phosphatidylcholine (POVPC), a truncated form of oxidized phospholipid, and resveratrol suppressed NET formation induced by POVPC and PMA. Furthermore, we designed several analogs of resveratrol or catechin whose conformation was restricted by the inhibition of the free rotation of aromatic rings. The conformationally constrained analogs were more effective at ‍inhibiting NET formation; however, their inhibitory function decreased when compound was a large, hydrophobic analog. The ‍most potent compounds, planar catechin and resveratrol, suppressed myeloperoxidase release from activated neutrophils. In addition, these compounds suppressed DNA release from neutrophils stimulated with calcium ionophore. These results suggest that resveratrol, catechin and their analogs exert anti-NET effects, and that constraining the geometry of these compounds enhanced their inhibitory effects.

The endosomal–lysosomal system represents a crucial degradation pathway for various extracellular substances, and its dysfunction is linked to cardiovascular and neurodegenerative diseases. This degradation process involves multiple steps: (1) the uptake of extracellular molecules, (2) transport of cargos to lysosomes, and (3) digestion by lysosomal enzymes. While cellular uptake and lysosomal function are reportedly regulated by the mTORC1–TFEB axis, the key regulatory signal for cargo transport remains unclear. Notably, our previous study discovered that isorhamnetin, a dietary flavonoid, enhances endosomal–lysosomal proteolysis in the J774.1 cell line independently of the mTORC1–TFEB axis. This finding suggests the involvement of another signal in the mechanism of isorhamnetin. This study analyzes the molecular mechanism of isorhamnetin using transcriptome analysis and reveals that the transcription factor GATA3 plays a critical role in ‍enhanced endosomal–lysosomal degradation. Our data also demonstrate that mTORC2 regulates GATA3 nuclear translocation, and the mTORC2–GATA3 axis alters endosomal formation and maturation, facilitating the efficient transport of cargos to lysosomes. This study suggests that the mTORC2–GATA3 axis might be a novel target for the degradation of abnormal substances.

The amounts of Reactive oxygen species (ROS) become higher by strenuous exercises which consume larger amounts of oxygen in active muscles. Since these ROS directly injured muscles, the high ROS concentration involves muscle fatigue. Thus, an immediate ROS scavenging system in the muscle is desired. Since Monascus pigment (MP) involves physiologically active substances which scavenge ROS, it may be a clue to save the muscle injury. However, there are no reports examining MP effects on oxidative stress in skeletal muscle. In this study, we investigated the effect and mechanism of MP on skeletal muscle cells damaged by oxidative stress. The ability to directly eliminate ROS was evaluated by mixing MP solutions with ^•OH and O₂^•−, a type of ROS. The effect of peroxidation in C2C12 cells was evaluated by cell viability assay and Western blotting. MP scavenges ^•OH and O₂^•−. MP treatment increases the survival rate under oxidative stress. At that time, the expression of catalase was increased: the enzyme change H₂O₂ into H₂O to rescue the cells under oxidative stress. We conclude that monascus pigment suppressed myotube damage under oxidative stress by both non-enzymatic ROS scavenging and up-‍regulation of catalase expression.

Trans-resveratrol, a widely used supplement for humans, aims to enhance the body’s antioxidant defense. Studies suggest that it exerts anti-inflammatory and antioxidant effects by activating the ‍nuclear factor erythroid 2-related factor 2 (Nrf2). In order to evaluate this hypothesis, LDLr^(−/−) mice were fed a Western diet to induce liver inflammation and oxidative stress. One group was fed a diet containing 0.60 ‍mg/day of trans-resveratrol (RESV), while another group received no dietary supplementation (CONT). Oxidative stress biomarkers and inflammatory cytokines were assessed in liver homogenates. It was observed that trans-resveratrol decreased hepatic oxidative stress by increasing the GSH/GSSG ratio and reducing malondialdehyde (MDA) concen­tration. However, the RESV group exhibited a reduction in Nrf2 relative expression compared to CONT. Additionally, trans-resveratrol supplementation reduced nuclear factor-κB (NF-κB) expression but led to an increase in IL-6, with no significant changes observed in tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) concentrations. Overall, these findings indicate that the in vivo antioxidant impact induced by trans-resveratrol supplementation in hepatic tissue did not correlate with increase of inflammatory cytokines and Nrf2 relative expres­sion. Further exploration of alternative mechanisms, such as direct ‍radical scavenger activity, is warranted to elucidate the antioxidant effect.

Neutrophils express protein arginine deiminase 2 and PAD4, both ‍of which mediate the citrullination of target proteins to induce production of neutrophil extracellular traps. Although PAD-dependent NETs trigger inflammatory bowel disease, the mechanisms governing the expression of PAD2 and PAD4 are poorly understood. In this study, we tried to clarify expression mechanisms of PAD2 and PAD4 in the colonic mucosa of patients with ulcerative colitis and Crohn’s disease. Administration of Cl-amidine, a pan PAD-inhibitor, attenuated the development of dextran sodium sulfate-induced colitis, the effects of which were accompanied by reduced IL-6 and TNF-α production by colonic lamina propria mononuclear cells upon exposure to Toll-like receptor ligands. The mRNA expression of colonic PAD2 and PAD4 was negatively and positively correlated with disease activity and ‍pro-inflammatory cytokine responses in patients with UC, respectively. Reciprocal regulation of PAD2 and PAD4 mRNA expression was observed in the colonic mucosa of UC patients, but not in those of CD patients. PAD4 mRNA expression was correlated with disease activity and pro-inflammatory cytokine responses in patients with CD. Collectively, these data suggest that reciprocal regulation of PAD2 and PAD4 expression is associated with disease activity in UC patients.

Observational studies have suggested a relationship between antioxidants and birth weight. However, the causal association remains unclear. The aim of this study was to assess the causal relationship between antioxidants and birth weight. Genome wide association study (GWAS) summary statistics for 4 endogenous and 7 exogenous antioxidants, as well as birth weight were obtained from GWAS studies and UK biobank. A ‍two-sample Mendelian randomization (MR) analysis was conducted with fixed-effects model inverse variance weighted (IVW) as the primary analytical method, while MR Egger and weighted median used as auxiliary. A series of sensitivity analyses were conducted to verify the robustness of the results. The MR results revealed that genetically predicted higher superoxide dismutase (SOD) (β = 0.025; 95% CI: 0.008, 0.043; p ‍= 0.005) and zinc (β = 0.030; 95% CI: 0.013, 0.047; p ‍= 0.001) levels were associated with higher birth weight. Sensitivity analysis verified the robustness of the MR results. Our study reinforced the existing evidence supporting a significant positive association between SOD and zinc with birth weight, providing new genetic evidence for antioxidant supplementation during pregnancy to prevent low birth weight infants. Further deeper comprehension studies are warranted to confirm these findings.

Gastrointestinal bleeding (GIB) is a significant public health concern, predominantly associated with high morbidity. However, there have been no reports investigating the trends of GIB in Japan using nationwide data. This study aims to identify current trends and issues in the management of GIB by assessing Japan’s national data. We analyzed National Database sampling data from 2012 to 2019, evaluating annual hospitalization rates for major six types of GIB including hemorrhagic gastric ulcers, duodenal ulcers, esophageal variceal bleeding, colonic diverticular bleeding, ischemic colitis, and rectal ulcers. In this study, hospi­talization rates per 100,000 indicated a marked decline in hemorrhagic gastric ulcers, approximately two-thirds from 41.5 to 27.9, whereas rates for colonic diverticular bleeding more than doubled, escalating from 15.1 to 34.0. Ischemic colitis rates increased 1.6 times, from 20.8 to 34.9. In 2017, the hospitalization rate per 100,000 for colonic diverticular bleeding and ischemic colitis surpassed those for hemorrhagic gastric ulcers (31.1, 31.3, and 31.0, respectively). No significant changes were observed for ‍duodenal ulcers, esophageal variceal bleeding, or rectal ulcers. ‍The findings of this study underscore a pivotal shift in hospi­talization frequencies from upper GIB to lower GIB in 2017, ‍indicating a potential shift in clinical focus and resource allocation.

In the present study, the authors examined the association between gastric bacterial infection and gastric endoscopic findings in Helicobacter pylori (H. pylori)-negative patients. The subjects were 105 H. pylori-negative patients. The mean age was 72.8 ‍± 9.1 years. Endoscopy and gastric juice culture were performed. The presence or absence of endoscopic findings was checked according to the Kyoto classification of gastritis. Culture was positive in 69 patients (65.7%), with Streptococcus α-hemolytic being the most common (51 patients), followed by Neisseria sp. (43 patients). According to the univariate analysis, there was a significant difference between the results of culture and background factors in the use of gastric antisecretory drugs and between the results of culture and various endoscopic findings in atrophic gastritis, intestinal metaplasia, regular arrangement of collecting venule, mucosal swelling, sticky mucus, hyperplastic polyps, hematin, and gastric cobblestone-like lesions. Furthermore, multivariate analysis revealed significant differences in background factors such as the use of gastric antisecretory drugs and endoscopic findings only in ‍patients with mucosal swelling. Endoscopic findings of non-H. ‍pylori bacteria-positive gastritis differed from endoscopic findings of H. pylori-infected gastritis in several respects. In conclusion, our results suggest that non-H. pylori bacteria may infect the stomach and cause gastric inflammation, especially in patients who long term use gastric antisecretory drugs.

We aimed to describe nutritional status and body composition profiles perioperative head and neck cancer (HNC) patients managed with whole-course nutritional support. Scored Nutritional Risk Screening (NRS 2002), Patient-Generated Subjective Global Assessment (PG-SGA), and body composition were conducted. The factors related to weight loss and skeletal muscle mass (SMM) were identified. Lower weight and body composition levels in low skeletal muscle index (SMI≤9.90 ‍kg/m²) group were observed. Levels of albumin, prealbumin, prognostic nutritional index (PNI), and lymphocyte-to-monocyte ratio (LMR) were lower than pre-operative, but the values after 2 weeks were higher than 1 week post-operatively (all p<0.01). The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were increased at 1 and 2 weeks post-operative compared to pre-operative (both p<0.01). Post-operatively, NLR at 2 weeks was lowed than 1 week (p = 0.02). A negative correlation was observed between SMM loss and serum prealbumin (r = −0.255, p = 0.029). Pre-operative BMI (p<0.01), tumor differentiation (p = 0.003), and nutritional risk (p = 0.049) were risk factors for weight loss. In conclusions, for perioperative HNC patients, loss of adipose tissue occurred earlier than muscle. Prealbumin should be considered as an indicator for monitoring of recovery in clinical practice.

The prevalence of chronic kidney disease (CKD) is increasing owing to the elderly population. Here, we investigated the effects of heat-treated Enterococcus faecalis (FK-23) and lysozyme-treated FK-23 (LFK) on the progression of CKD in rats. A CKD model was established using male Wistar rats by subjecting them to right nephrectomy (1K), followed by ischemia and reperfusion (IR). FK-23 or LFK was fed ad libitum as a mixed diet after right nephrectomy. Animals subjected to renal ischemia-reperfusion injury (IRI) showed increased plasma creatinine and blood urea nitrogen levels. Furthermore, in the kidneys, collagen accumu­lation and α-smooth muscle actin, indicative of fibroblast activation and fibrosis-related gene and protein expression, increased 3 weeks after IRI. FK-23 and LFK suppressed the increase in the mRNA levels of some of these genes. The increase in oxidative stress markers, 4-hydroxy-2-nonenal, endothelial nitric oxide synthase, and nitrotyrosine in the kidney, as well as increased plasma uremic toxins after IRI, were also ameliorated by FK-23 and LFK. Metagenomic analysis of fecal samples revealed that gut microbial alteration caused by IRI was also ameliorated by LFK treatment. These results suggest that Enterococcus faecalis ingre­dients may improve CKD progression by suppressing oxidative stress and correcting the balance of the intestinal microflora.