Prolonged compression restricts blood flow, which can result in an insufficient supply of the oxygen and nutrients that are necessary for cells to live and thrive. A pressure ulcer (PU) is a pathological condition of prolonged ischemia and is associated with a loss of epidermis, which could expose the dermis and deeper tissues. It is necessary to remove the causative pressure and resume blood flow, but injurious damage to the ischemic area could occur with a delay after blood reflow, which could result in reperfusion injury. In the early stages of compression, muscle cells, which are highly dependent on aerobic respiration, are preferably damaged, and then the injury could spread to other dermal and epithelial cells. Infiltrated leukocytes release a variety of substances such as cytokines and reactive oxygen species (ROS) that act as anti-microorganisms, but these could also aggravate inflammation. The ROS are deeply involved in the pathogenesis of this condition, and, hence, antioxidant compounds and enzymes play ‍a vital role in preventing the progression of PUs. We focus on ‍oxidative stress in PUs, which is exacerbated by the actions of ‍ischemia/reperfusion, and we discuss effective prevention and ‍treatment from the perspectives of micronutrients and antioxidants.

Age-related decrease in joint flexibility leads to difficulties in activities of daily living and an increased risk of falls. The current study investigated whether nerve-directed stretching, which focuses on stretching neural tissue, could acutely improve joint flexibility and tissue stiffness more than muscle-directed stretching or not. Twenty-seven older men performed muscle- and nerve-directed stretching for 400 ‍‍s (40 s × 10 times) on separate days. ‍Before and after stretching, maximum ankle dorsiflexion angle was measured as range of motion (ROM). Shear wave propagation velocity (SWV) was also assessed as tissue stiffness of the sciatic nerve, medial gastrocnemius, posterior thigh fascia, and posterior leg fascia in anatomical position. In both stretching conditions, increment of ROM and reduction of sciatic nerve SWV were observed after stretching. The extent of these changes did not differ between the stretching conditions. The SWVs of tissues other than the sciatic nerve did not change before and after the stretching. These results suggest that acute effects of nerve-directed stretching on joint flexibility and tissue stiffness are not superior to muscle-directed stretching.

Microglia, the primary immune cells of the central nervous system, play a pivotal role in maintaining brain homeostasis. Recent studies have highlighted the involvement of microglial dysfunction in the pathogenesis of various age-related neuro­degenerative diseases, such as Alzheimer’s disease. Moreover, the metabolic state of microglia has emerged as a key factor in these diseases. Interestingly, aging and neurodegenerative diseases are associated with impaired mitochondrial function and a metabolic shift from oxidative phosphorylation to glycolysis in microglia. This metabolic shift may contribute to sustained microglial activation and neuroinflammation. Furthermore, the leakage of mitochondrial DNA into the cytoplasm, because of mitochondrial dysfunction, has been implicated in triggering inflammatory responses and disrupting brain function. This review summarizes recent advances in understanding the role of microglial metabolic shifts, particularly glycolysis, and mitochondrial dysfunction. It also explores the potential of targeting microglial metabolism, for instance by modulating mitophagy or intervening in specific metabolic pathways, as a novel therapeutic approach for changes in brain function and neurodegenerative diseases associated with aging.

The polymethoxylated flavonoid nobiletin has been shown to have a broad range of biological functions. We found that nobiletin regulates cytokine production from T cells. In this study, we examined the mechanism for enhancement of interleukin (IL)-4 production by nobiletin. We investigated the key molecules for production of IL-4 by deep data-based analysis and we identified nine candidate genes. The mRNA expression levels of ‍c-‍Maf, Gata-3, Nfat4, and Pparg genes were significantly elevated by treatment with nobiletin. From RNA sequence analysis, the T helper type 1 (Th1) and Th2 differentiation pathway was shown to be dominantly affected by nobiletin. Furthermore, molecular network analysis showed that GATA-3 is ‍one of the candidate molecules for enhancement of IL-4 production. Treatment of splenocytes including antigen-presenting cells with nobiletin was sufficient for the induction of IL-4 production from DO11.10 mouse CD4⁺ T cells. Treatment of B ‍cells and dendritic cells with nobiletin induced IL-4 production from CD4⁺ cells. Splenocytes from DO11.10 mice that had been treated with nobiletin produced more IL-4 than did splenocytes from control mice. These results revealed that the polymethoxylated flavonoid nobiletin specifically enhanced IL-4 production in vitro and in vivo.

Neurite degeneration is seen in the early stages of many neurodegenerative diseases, and is strongly related to oxidative damage. Possible mechanisms underlying this morphological change include dysruption of calcium homeostasis, increased membrane oxidation, and destabilization of cytoskeletal proteins. However, the detailed mechanisms leading to neuronal damage has not been elucidated. Calcium plays an important role in neuronal changes caused by oxidative stress. Mitochondria and endoplasmic reticulum (ER) play roles in intracellular calcium storages. One mechanism of neurite degeneration associated with oxidative stress may be related to calcium-mediated interactions between mitochondria and ER. In this study, we evaluated intracellular calcium homeostasis, mitochondria, and ER locali­zation when neurite degeneration was induced in neuroblastoma cells that had extended neurites. Treatment with hydrogen peroxide (H₂O₂) and the calcium ionophore ionomycin induced mitochondria-dependent superoxide production and membrane oxidation. When examining the involvment of calcium efflux from the ER and mitochondria, treatment with a ryanodine receptor inhibitor ruthenium red significantly reduced intracellular calcium concentrations in ionomycin-treated cells. Electron microscopy in neurite degeneration areas revealed numerous fragmented mitochondria in ionomycin-treated cells, and mitochondrial swelling was observed in the same area of H₂O₂-treated cells. Next, we investigated proteins related to fusion and fission by western blotting. However, mitochondrial dysfunction occurs in both cases and is therefore thought to be associated with neurite degeneration. Our results suggest that H₂O₂ and ionomycin cause neurite degeneration via different mechanisms. Interactions between mitochondria and the ER through unknown crosstalk pathways and calcium transfer may play an important role in maintaining neurite function.

Lactococcus lactis subsp. lactis (L. lactis) is a common species of ‍lactic acid bacteria (LAB). There is increasing evidence that probiotic L. lactis ameliorates experimental colitis in mice, whereas few studies have revealed the effects of the para­probiotics, i.e., inactivated forms of bacteria. L. lactis L8 strain is a newly identified plant-derived LAB. The present study aimed to investigate the effects of heat-killed L. lactis L8 on dextran sulfate sodium (DSS)-induced colitis in mice. C57BL/6J mice were orally administered L. lactis L8 for 12 days. Colitis was induced by adding 3.5% DSS to the drinking water for 7 days. Mice were euthanized on day 12, and colon tissues and fecal samples were collected. Results demonstrated that administration of L. lactis L8 alleviated the clinical score of the colitis and the histological abnormalities. Additionally, L. lactis L8 led to a significant reduction in the level of colon tumor necrosis factor (TNF)-α. Administration of L. lactis L8 did not affect the gut microbial structure, whereas it altered the relative abundance of Clostridiaceae and Rikenellaceae in colitis mice. Our findings suggest that paraprobiotic L. lactis L8 has an immunomodulatory effect on intestinal inflammation in mice, providing important insight into the biological function of L. lactis L8.

Sarcopenic obesity is associated with metabolic disorders and physical limitations. Intramyocellular lipid (IMCL) accumulation is a critical factor affecting muscle strength, independent of muscle mass, in obesity. While diet plays an important role in regulating IMCL, the effects of specific dietary combinations remain poorly understood. This study examined the effects of different combi­nations of dietary carbohydrates and fats on skeletal muscle quality and function in obese rats. Female Zucker diabetic fatty rats were fed diets containing either sucrose or palatinose combined with either oleic or linoleic acid for 12 weeks. Body and muscle weights, IMCL content, and grip strength were measured. C2C12 myotubes were treated in vitro with varying concen­trations of glucose or insulin, along with fatty acids (oleic acid or linoleic acid), to mimic the exposure of each diet. The diet combining sucrose and linoleic acid (SL) significantly increased IMCL accumulation in the extensor digitorum longus (EDL) muscle and reduced grip strength. A negative correlation was observed between IMCL and grip strength. Cluster of differentiation 36 (CD36) protein levels tended to increase in the EDL of the SL diet-fed group. In vitro experiments demonstrated that high glucose levels combined with linoleic acid increased IMCL and CD36 expression. In conclusion, diets high in sucrose and linoleic acid exacerbate IMCL accumulation and reduce muscle strength in obese rats through hyperglycemia-induced interaction.

Growing knowledge reveals the association between the gut microbiome and skin, rendering the gut microbiome an appealing potential therapeutic target for atopic dermatitis (AD). In this study, we assessed the effect of partially hydrolyzed guar gum (PHGG) on AD-like symptoms induced by topical 1-Chloro-2,4-dinitrobenzene (DNCB) in BALB/c mice. Four weeks of PHGG feeding prevented the loss of epidermal barrier integrity and epithelial hyperplasia in the AD lesion (p<0.05, effect size >0.80), indicating a reduction in AD-like symptoms. According to the postulated mechanism, PHGG ingestion modulates the gut microbiome resulting in enhanced butyrate production (p<0.05). Butyrate suppresses Th2 function in gut immunity, which is believed to have significance in systemic immune regulation. The lowering of blood Th2 cytokines (IL-4 and IL-10, p<0.05) in the PHGG-fed group confirmed the existence of such a pathway, and ‍butyrate can possibly be considered to have an indirect involvement in the suppression of Th2 immune response in the AD lesions. These findings encourage support for an association between gut microbiome and skin through the immune system, implying that daily PHGG ingestion may be beneficial for suppressing AD symptoms across the gut-immune-skin axis.

The number of eosinophilic esophagitis (EoE) patients has been rapidly increasing worldwide in recent years, though remains relatively lower in Japan. To determine whether Japanese EoE ‍cases have pathogenic differences, microRNA (miRNA) transcriptome analyses of esophageal biopsy specimens from patients with EoE were performed to identify involved miRNAs and the results were compared with those for cases reported in Western countries. Japanese patients with EoE (n = 9) or reflux esophagitis (RE) (n = 4) were enrolled, with the latter serving as controls. Biopsies of esophageal mucosal tissue were performed as a part of an upper gastrointestinal endoscopy, followed by comprehensive miRNA expression analysis (2,588 target human miRNAs) using microarray technology. The EoE patients were then treated with a proton pomp inhibitor, and miRNA expression in the esophagus was compared before and after treatment. Hierarchical cluster analysis findings showed clear differences in miRNA expression patterns between the EoE and RE patients, with increased expression of 13 and decreased expression of 10 miRNAs noted in the EoE cases. These results were then compared with miRNA expression in esophageal mucosa of EoE patients presented in Western reports and the expression profiles were found to be very similar. In addition, changes in expression profiles of several miRNAs before and after treatment were observed in the present EoE patients. miRNA microarray analysis of Japanese EoE patients demonstrated a significant overlap of ‍miRNA expression in comparison with Western patients, indicating that EoE likely represents the same disease among diverse racial populations and shows a consistent pathogenesis worldwide.

Zinc plays a role in immune function. This study aimed to investigate the clinical significance of zinc levels in patients with severe trauma by examining the association between serum zinc ‍levels and infectious complications. Inclusion criteria were hospitalization of 2 weeks or more; Abbreviated Injury Scale score of 3 or more; zinc levels measured on admission and at 2 weeks later. Among the 141 included patients on admission, 136 (96.5%) had zinc deficiency, whereas at two weeks later, serum zinc levels increased significantly, with the number of patients with zinc deficiency decreasing to 31 (22.0%). Between the zinc-deficient group and zinc-sufficient group stratified by serum zinc level at two weeks, there were significant differences in lengths of ICU stay and mechanical ventilation, the complication of infection, and positive blood cultures. Logistic regression showed that zinc level at two weeks after admission were significantly associated with the complication of infection (p = 0.03). In addition, age, initial nutrition, Sequential Organ Failure Assessment score, probability of survival, serum phosphate on admission were highly associated with zinc deficiency at two weeks after admission by logistic regression. In the patients with risk factors on admission, zinc supplementation started on the first day of hospitalization might be beneficial.

Osteoporosis is associated with low bone mineral density and poor bone quality in patients with type 2 diabetes mellitus (T2DM). Reports on the association between serum metabolome and osteoporosis in diabetes mellitus are rare. We aimed to identify osteoporosis-related factors in patients with T2DM. This ‍prospective observational study included 67 patients with T2DM without osteoporosis and 24 patients with T2DM with osteoporosis who were treated with teriparatide. The association between the serum metabolome at baseline and changes in bone mineral density and the bone quality of the lumbar spine and proximal femur over 1 year was evaluated. In the teriparatide-treated group, bone mineral density, young adult mean values, and trabecular bone scores (T-scores) of the lumbar spine significantly increased 1 year after baseline compared with those at baseline. Improvements in these bone assessment indices were significantly higher in the teriparatide-treated group than in the non-treated group. Baseline alkaline phosphatase, bone-specific alkaline phosphatase, and malonic acid levels were significantly negatively correlated with bone mineral density, young adult mean values, and T-scores. Changes in bone mineral density, young adult mean values, and T-score 1 year after baseline were significantly positively correlated with baseline alkaline phospha­tase, bone-specific alkaline phosphatase, oxalic acid, and aspartic acid levels in the teriparatide-treated group. Serum oxalic acid and malonic acid levels may be novel markers of osteoporosis. Teriparatide may be more effective in patients with higher baseline serum oxalic acid and aspartic acid levels than in those with lower levels.

Early predictive markers of bone resorption are required to plan intervention strategies ensuring a healthy aging. Collagen I C-telopeptide (CTX) as bone activity marker shows a fair biological variability, that cause the lack of a well-defined reference range. Given the well-established role of vitamin D in bone remodeling, the aim of this study was to assess the influence of vitamin D status on the variability of CTX serum levels in 131 pre-menopausal (45–54 years) and 951 post-menopausal women (55–90 years). Serum CTX and vitamin D levels were assessed, respectively, by ELISA and HPLC determination of 25-hydroxy-vitamin D3. A significantly negative dependence of CTX on vitamin D3, but not age, was found in the whole study cohort (B = −0.170, p<0.0001). A significantly negative correlation between CTX and vitamin D3 was found both in pre-menopausal (r = −0.2614; p = 0.0061) and post-menopausal women (r = −0.2220; p<0.0001), and confirmed in post-menopausal women aged 55 to 59 years (r = −0.2840, p = 0.0061), 60 to 64 years (r = −0.2143, p = 0.0129), and 70 to 74 years (r = −0.3078, p<0.0001). These findings suggest that vitamin D status determination and early vitamin D supplementation may be required in women at higher risk of bone resorption because of the physiologically reduced protective effects of estrogens.