Mammalian cells contain thousands of metalloproteins and evolved systems to correctly incorporate metal cofactors into their designated sites. Among the transient metals in living cells, iron is the most abundant element that present as an iron sulfur cluster, mono- and dinuclear iron centers or heme for catalytic reactions. Iron homeostasis is tightly regulated by intestinal iron absorption in mammals owing to the lack of an iron excretive transport system, apart from superficial epithelial cell detachment and urinary outflow reabsorptive impairment. In mammals, the central site for iron absorption is in the duodenum, where the divalent metal transporter 1 is essential for iron uptake. The most notable manifestation of mutated divalent metal transporter 1 presents as iron deficiency anemia in humans. In contrast, the mutation of ferroportin, which exports iron, causes iron overload by either gain or loss of function. Furthermore, hepcidin secretion from the liver suppresses iron efflux by internalizing and degrading ferroportin; thus, the hepcidin/ferroportin axis is extensively investigated for its potential as a therapeutic target to treat iron overload. This review focuses on the divalent metal transporter 1-‍mediated intestinal iron uptake and hepcidin/ferroportin axis that regulate systemic iron homeostasis.

Vitamin D insufficiency, milder than deficiency, is common, and a risk of various diseases. Since vitamin D exert diverse actions, both skeletal and non-skeletal, its insufficiency is a risk of various diseases including osteoporosis, sarcopenia, cardiovascular disease, cancer, and even mortality. Regarding the association of vitamin D status and disease risk, a marked discrepancy exists between the results from the observational studies and intervention studies, mostly yielding the positive and negative results in the former and latter, respectively. Such inconsistency probably arises from methodological problems, of which the baseline vitamin D status would be the most important. Vitamin D intervention would be effective in the deficient/insufficient subjects, but not in sufficient subjects. Since the elderly subjects, especially the institutionalized people, are mostly vitamin D deficient/insufficient, they are likely to benefit from improvement of vitamin D status. Vitamin insuf­ficiency is a risk of various diseases, and correcting the vitamin status alone would reduce the risk of many diseases, and favorable to avoid the undesirable consequences of poly­pharmacy in the elderly. Additionally, disease prevention by nutritional improvement is cheap and free from side effects, and suited for the primary prevention of diseases.

Radiation therapy is a lower invasive local treatment than surgery and is selected as a primary treatment for solid tumors. However, when some cancer cells obtain radiotherapy tolerance, cytotoxicity of radiotherapy for cancer cells is attenuated. Photodynamic therapy (PDT) is a non-invasive cancer therapy combined with photosensitizers and laser irradiation with an appropriate wave­length. PDT is carried out for recurrent esophageal cancer patients after radiation chemotherapy and is an effective treatment for ‍radiation-resistant tumors. However, it is not clear why PDT is ‍effective against radioresistant cancers. In this study, we attempted to clear this mechanism using X-ray resistant cancer cells. X-ray resistant cells produce high amounts of mitochondria-derived ROS, which enhanced nuclear translocation of NF-κB, resulting in increased NO production. Moreover, the expression of PEPT1 that imports 5-aminolevulinic acid, the precursor of photo­sensitizers, was upregulated in X-ray resistant cancer cells. This was accompanied by an increase in intracellular 5-aminolevulinic acid-derived porphyrin accumulation, resulting in enhancement of PDT-induced cytotoxicity. Therefore, effective accumulation of photosensitizers induced by ROS and NO may achieve PDT after radiation therapy and PDT could be a promising treatment for radioresistant cancer cells.

Asthma is more prevalent and severe in women, especially after puberty. Studies suggest a potential link between dietary antioxidants, inflammation, and oxidative stress. This study aimed to compare the dietary intake of antioxidants in asthmatic and healthy women, evaluating their potential associations with inflammation and oxidative stress. This study analyzed 30 asthmatic and 30 healthy women’s lung function, anthropometry, biochemical parameters, and dietary antioxidant intake using a 161-itemized semi-quantitative food frequency questionnaire. Additionally, the study explored connections between serum inflammatory markers and oxidative stress indicators in relation to dietary intake of antioxidant nutrients and flavonoids. Asthmatic women exhibited higher serum IL-6 levels and lower total antioxidant status compared to healthy controls. Never­theless, no significant differences were observed in dietary antioxidant micronutrient intake. Healthy controls demonstrated a notably higher intake of anthocyanidins compared to asthmatic women. Furthermore, the study identified a negative correlation between flavonol intake and serum total oxidant status, as well as between flavan-3-ols intake and serum oxidative stress index. Dietary differences in flavonoid and flavonoid-rich foods intake among asthmatic women may affect their serum IL-6 levels and oxidative stress. Promoting a diverse diet rich in flavonoids could benefit women with asthma by mitigating inflammation and oxidative stress.

Reactive oxygen species (ROS) and highly reactive oxygen species (hROS) secreted by leukocytes are crucial to innate immunity; however, they pose a risk of oxidative stress. To monitor their balance in daily health check-ups, optical technologies for the simultaneous measurement of ROS (superoxide radicals) and hROS (hypochlorite ions) that utilize only a few microliters of whole blood have been developed. The aim of this study was to clarify whether this system could assess the effects of fat ingestion on postprandial oxidative status. Eight healthy young Japanese women ingested a beverage containing oral fat tolerance test cream. Blood samples were collected before and 0.5, 1, 2, 4, and 6 ‍h after fat ingestion. Blood ROS and hROS levels, ‍oxidative stress markers, and biochemical markers were monitored. Consistent with previous studies, triglyceride levels significantly increased at 4 ‍h (p<0.01) and returned to near-baseline levels 6 ‍h after ingestion. ROS levels peaked significantly at 2 ‍h (p<0.05), and hROS levels peaked significantly at 1 (p<0.05) and 2 ‍h (p<0.01) after ingestion. This study offers an insight into the acute effects of fat ingestion on leukocyte activity and provides a methodology for monitoring postprandial oxidative status.

Quercetin is a natural flavonol and has various health beneficial functions. Our pervious study demonstrated that long-term feeding (13 weeks) of quercetin and its glycosides, isoquercitrin, rutin, and enzymatically modified isoquercitrin, which is a mixture of quercetin monoglycoside and its oligoglycosides, prevented hyperglycemia and adiposity in mice fed a high-fat diet but not standard diet. It is, however, unclear whether a single admin­istration of these compounds prevent postprandial hyperglycemia or not. In the present study, we estimated their prevention effect on acute hyperglycemia by an oral glucose tolerance test in ICR mice and investigated its mechanism. It was found that quercetin glycosides, but not the aglycone, suppressed acute hyperglycemia and isoquercitrin showed the strongest effect among the glycosides. As the underlying mechanism, quercetin glycosides promoted translocation of glucose transporter 4 to the plasma membrane of skeletal muscle of mice through phosphorylation of ‍adenosine monophosphate-activated protein kinase and its upstream Ca²⁺/calmodulin-dependent protein kinase kinase β without activating the insulin- and JAK/STAT-signal pathways. In conclusion, single oral administration of quercetin glycosides prevented a blood sugar spike by promoting glucose transporter 4 ‍translocation through activating the CAMKKβ/AMPK signaling pathway.

Several beneficial effects of poly-γ-glutamic acid (γ-PGA) have been reported. To test whether natto, a fermented soy food rich ‍in γ-PGA, can improve intestinal microbiota content and lipid ‍metabolism in a high-fat diet, we compared the intestinal microbiota content, plasma, liver, and fecal contents, and changes in gene expression in the livers and large intestines of a group of mice fed a high-fat diet supplemented with cooked soybeans (SC ‍group) and a group fed a high-fat diet supplemented with natto (NA group) for 42 days; high-fat diet-fed mice were used as a control (Con group). Hepatic lipid levels were significantly lower, the fecal bile acid and lipid levels were significantly greater, and the Bacteroidetes/Firmicutes ratio was significantly higher in the SC and NA groups as compared to Con group. Additionally, plasma glucose and triglyceride levels, the expression of liver ‍fatty acid synthase, and the relative abundance of Lactobacillaceae was significantly higher in the NA group than in ‍the Con group. Although both natto and cooked soybeans impacted the metabolic response to a high-fat diet, the addition of natto had a greater effect on glucose and lipid metabolism. γ-‍PGA may play an important role in natto functionality.

Immune checkpoint therapy has been shown to be an effective therapy for many types of tumors. Much attention has been paid to the development of an effector target would be helpful for immune checkpoint therapy. Genistein has been shown to have an anti-tumor effect both in vitro and in vivo. In this study, we examined the effect of genistein on immune checkpoint blockade therapy against B16F1 melanoma tumors. Mice treated with genistein or anti-programmed death (PD)-1 antibody showed a significant decrease in tumor growth. However, treatment with genistein had no effect on or attenuated the efficacy of immune checkpoint therapy. The percentages of T cell receptor (TCR)β⁺CD4⁺ and TCRβ⁺CD8⁺ cells and the concentrations of interferon-γ and tumor necrosis factor-α in tumor tissue were not different among the experimental groups. A significant difference was also not found in microbe composition. Interestingly, a high expression level of PD-ligand (L)1 closely reflected the outcome of therapy by ‍genistein or anti-PD-1 antibody. The study showed that a combination of genistein treatment does not improve the effect of immune blockade therapy. It also showed that a high PD-L1 expression level in tumors is a good prediction maker for the outcome of tumor therapy.

This study investigated the effects of miso, a traditional fermented soybean food in Japan, on muscle mass atrophy. Eight week old male C57BL/6J mice were fed high fat/high sucrose diet with or without miso for 12 weeks. A miso diet increased soleus muscle weights (p<0.05) and reduced intraperitoneal glucose tolerance and insulin tolerance (p<0.05). The miso diet down­regulated the Tnfα and Ccl2 expression, related to inflammation, and Trim63 and Fbxo32 expression, related to muscle atrophy, in the soleus muscle (p<0.05). The miso diet increased short-chain fatty acids levels, including acetic, propanoic, and butanoic acids, in the feces, serum, and soleus muscle (p<0.05). According to the LEfSe analysis, the miso diet increased family Prevotellaceae, family Christensenellaceae, family Dehalobacterium, family Desulfitibacter; family Deferribacteraceae, order Deferri­bacte­rales, class Deferribacteres; and family Gemmatimonadaceae, order Gemmatimonadetes, and class Gemmatimonadales, whereas the miso diet decreased family Microbacteriaceae, order Micrococcales, class Actinobacteria, and family Lactobacillaceae. Miso suppressed high fat/high sucrose diet induced impaired glucose tolerance, low muscle strength, and muscle atrophy by improving dysbiosis and increasing short-chain fatty acids production and provides new insights into the preventive effects of fermented foods on sarcopenia.

Simplifying the diagnostic criteria for sarcopenia is key to establishing effective interventions. Herein, we aimed to clarify novel diagnostic factors. We calculated novel fat indices [total fat ‍index (TFI) and limb fat index (LFI)] and clarified factors leading to pre-sarcopenia and sarcopenia in 594 enrolled older adults. Physical measurements [height, weight, body mass index (BMI), gait speed, grip strength, and skeletal muscle mass] were ‍performed. Sarcopenia was determined using established diagnostic criteria (pre-sarcopenia, n = 102; sarcopenia, n = 42). Age was associated with sarcopenia status. BMI, TFI, and LFI were lower in patients with pre-sarcopenia and sarcopenia. Logistic regression analysis showed the following odds ratios (ORs) for pre-sarcopenia: BMI [OR: 0.787, 95% confidence interval (CI): 0.7–0.885], LFI (OR: 0.589, 95% CI: 0.402–0.863), and age (OR: 1.06, 95% CI: 1.02–1.1). ORs for sarcopenia (vs pre-sarcopenia) were as follows: LFI (OR: 50.6, 95% CI: 10.2–250.0), age (OR: 1.1, 95% CI: 1.0–1.2), and BMI (OR: 0.418, 95% CI: 0.28–0.608). Our findings contribute to informing medical guidelines.

The impact of nutrition therapy in the acute phase on post-intensive care syndrome (PICS) remains unclear. We conducted a multicenter prospective study on adult patients with COVID-19 who required mechanical ventilation for more than three days. The questionnaire was mailed after discharge. Physical PICS, defined as less than 90 points on the Barthel index (BI), was assigned as the primary outcome. We examined the types of nutrition therapy in the first week that affected PICS components. 269 eligible patients were evaluated 10 months after discharge. Supplemental parenteral nutrition (SPN) >400 ‍kcal/day correlated with a lower occurrence of physical PICS (10% vs 21.92%, p = 0.042), whereas the amounts of energy and protein provided, early enteral nutrition, and a gradual increase in nutrition delivery did not, and none correlated with cognitive or mental PICS. A multivariable regression analysis revealed that SPN had an independent impact on physical PICS (odds ratio 0.33, 95% CI 0.12–0.92, p = 0.034), even after adjustments for age, sex, body mass index and severity. Protein provision ≥1.2 ‍g/kg/day was associated with a lower occurrence of physical PICS (odds ratio 0.42, 95% CI 0.16–1.08, p = 0.071). In conclusion, SPN in the acute phase had a positive impact on physical PICS for ventilated patients with COVID-19.

This study investigated the trends in idiopathic peptic ulcers, examined the characteristics of refractory idiopathic peptic ulcer, and identified the optimal treatment. The characteristics of 309 patients with idiopathic peptic ulcer were examined. We allocated idiopathic peptic ulcers that did not heal after 8 weeks’ treatment (6 weeks for duodenal ulcers) to the refractory group and those that healed within this period to the healed group. The typical risk factors for idiopathic peptic ulcer (atherosclerosis-related underlying disease or liver cirrhosis complications) were absent in 46.6% of patients. Absence of gastric mucosal atrophy (refractory group: 51.4%, healed group: 28.4%; p = 0.016), and gastric fundic gland polyps (refractory group: 17.6%, healed group: 5.9%; p = 0.045) were significantly more common in the refractory group compared to the healed group. A history of H. pylori eradication (refractory group: 85.3%, healed group: 66.0%; p = 0.016), previous H. pylori infection (i.e., gastric mucosal atrophy or history of H. pylori eradication) (refractory group: 48.5%, healed group: 80.0%; p = 0.001), and potassium-competitive acid blocker treatment (refractory group: 28.6%, healed group, 64.1%; p = 0.001) were significantly more frequent in the healed group compared to the refractory group. Thus, acid hypersecretion may be a major factor underlying the refractoriness of idiopathic peptic ulcer.