Biomedical Research-tokyo最新文献

Reactive oxygen species (ROS) production in disused skeletal muscle induces capillary regression, which disrupts the balance of pro- and anti-angiogenic factors. We tested whether green coffee bean extract containing rich chlorogenic acid, which has antioxidant properties, can prevent capillary regression caused by muscle atrophy. The study included 24 female Sprague-Dawley rats, randomly assigned to four groups: control (CON), 2-week hindlimb unloading (HU), 2-week hindlimb unloading supplemented with coffee extract rich in chlorogenic acids (HU+50%CGA), and 2-week hindlimb unloading supplemented with trace amounts of chlorogenic acids (HU+5%CGA). Rats in the HU+50%CGA and HU+5%CGA groups received an oral dose of coffee extract at 850 mg/kg per day. The effects of chlorogenic acids in coffee extracts were investigated by comparing these groups. Unloading increased oxidative stress, disrupted mitochondrial oxidative activity, and upregulated TSP-1 expression, triggering endothelial cell apoptosis and leading to capillary regression. In contrast, the supplementation with coffee extract containing rich chlorogenic acids prevented ROS overproduction and improved metabolic activity, promoting angiogenesis by correcting the imbalance of pro- and anti-angiogenic factors, and inhibiting endothelial cell apoptosis. In conclusion, green coffee bean extract rich in chlorogenic acids inhibits ROS production, enhances mitochondrial metabolism, mitigates capillary regression by promoting angiogenesis and preventing apoptosis.

Gastric cancer (GC) has benefited from treatment improvements such as minimally invasive surgery, molecular-targeted drugs, and immune check point inhibitors. However, the prognosis of advanced GC is still unfavorable. Minimally invasive pre-treatment detection of drug sensitivity (MI-PDDS) has increasing importance in view of improved chemotherapy. Gastric biopsy specimens are obtained with relative ease but have not been considered an appropriate source for generating cell lines because of their minute amounts. We therefore materialized the idea of MI-PDDS using biopsy-derived cell lines obtained from endoscopic biopsy specimens. Here, a cell line designated TCC-GC1-C1 was established from a biopsy specimen of a histologically confirmed adenocarcinoma of the stomach. The cell line showed the ability of forming spheroid with deeply stained nuclei and disturbed cellular morphology indicative of malignancy. Single-nucleotide polymorphism (SNP) genotyping of the cell line revealed a duplication of chromosome19q and a deletion of chromosome 8p. A drug screening test with 221 anticancer drugs showed that the cell line had high sensitivity to the proteasome inhibitor (Carfilzomib) and the fibroblast growth factor receptor inhibitor (Erdafitinib), with a low IC50 value of under 0.1 μM. Our MI-PDDS approach holds promise in making a treatment decision for advanced GC.

During the delayed emesis phase, methotrexate tended to increase 5-hydroxytryptamine (5-HT) levels in midbrain and significantly increased 5-hydroxyindole-acetic acid (5-HIAA), a metabolite of 5-HT, levels in the area postrema and in the cerebral cortex in rats. However, methotrexate did not increase mRNA expression of 5-HT biosynthesis/metabolism enzyme in the area postrema. The increased 5-HIAA levels in the area postrema may result from enhanced intestinal 5-HT synthesis, with 5-HIAA reaching the area postrema via circulation. Additionally, the rise in cortical 5-HIAA levels might reflect stress-related increases in brain tryptophan influx.

Transient receptor potential ankyrin 1 (TRPA1) is a nociceptive receptor activated by chemical compounds such as allyl isothiocyanate, cinnamaldehyde, and carvacrol, found in spices and herbs. Since the intake of some TRPA1 agonists inhibits visceral fat accumulation, TRPA1 agonists are expected to serve as ingredients in anti-obesity foods. Recently, it has been reported that anisaldehyde, tiglic aldehyde, and cuminaldehyde activate TRPA1. In the present study, we measured metabolic changes after a single intragastric administration of each of these three compounds by respiratory gas analysis in mice, revealing cuminaldehyde's outstanding carbohydrate metabolism-enhancing effect. Next, mice were fed a high-fat diet for 4 weeks, during which they received daily administration of either cuminaldehyde or vehicle. The cuminaldehyde-treated group exhibited a significant suppression of visceral fat accumulation. Respiratory gas analysis confirmed that oxygen consumption and fat oxidation in normal conditions were significantly higher in the cuminaldehyde group than in the vehicle group at 2 weeks post-administration. These results suggest that the intake of cuminaldehyde, a TRPA1 agonist, enhances energy metabolism and reduces visceral fat accumulation.

Periodontitis, a chronic inflammatory disease driven by oral microbiota dysbiosis, is associated with systemic diseases; however, the mechanisms remain poorly understood. Using a silk-ligation-induced periodontitis mouse model, we investigated the changes in oral microbiota, immune responses, and systemic effects, including respiratory disease. Oral dysbiosis persisted for five weeks and was characterized by an increased abundance of genera Enterococcus, Proteus, and Escherichia_Shigella, and a decrease in genera Lactococcus. Antibiotic treatment effectively reduced alveolar bone resorption and suppressed both oral and systemic inflammation, suggesting that the dysbiosis induced innate immune activation in the gingiva which led to alveolar bone resorption and systemic immune activation. Notably, while gingival inflammation and bone resorption subsided within 2-3 weeks, systemic immune activation persisted throughout the experimental period with elevated levels of Th17 cytokines, particularly IL-17A and IL-22. To further examine the systemic impact, we induced pulmonary fibrosis with bleomycin after the onset of periodontitis. Periodontitis exacerbated initial lung inflammation, marked by increased production of IL-17A, IL-22, and IL-1β, along with significant T-cell infiltration in lung tissue. These findings reveal a chronic systemic inflammation induced by periodontitis and highlight its potential role in exacerbating respiratory diseases.

Co-administration of Molnupiravir and Remdesivir, treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), inhibits viral replication and infectivity. Previous studies indicate that the neuropeptide Y sub-receptor 1 (NPY-Y1) is involved in influenza virus aggravation in mouse pulmonary phagocytes, but the exact mechanisms remain unclear. Understanding the NPY-Y1 receptor's involvement in influenza and SARS-CoV-2 in both mice and hamsters may help explore its potential as an indicator of viral infections and support the development of preventive care. This study examined the effects of Molnupiravir and Remdesivir on infected Syrian hamsters and the NPY pathway during SARS-CoV-2 infection. SARS-CoV-2 infection increased mRNA expression of NPY, NPY-Y1 receptors, and inflammatory cytokines and chemokines in hamster lungs. Co-administration of the drugs significantly reduced these expressions. Changes in NPY-Y1 receptor expression were correlated with NPY, IL-10, IL-12, and IFN-γ, implying a role in the antiviral response pathway. These findings highlight that changes in the mRNA expression levels of NPY and NPY-Y1 receptor are influenced by SARS-CoV-2 infection and that the antiviral drugs impact the NPY-NPY-Y1 receptor cascade. This implies the pathway's involvement in inflammatory responses during viral infection and its potential as a therapeutic target.

Following accidental radiation exposure due to a radiological or nuclear emergency, a dose assessment should be performed based on biological samples from exposed individuals. Although previous biological dose assessment approaches have focused on nuclear DNA damage in peripheral lymphocytes, this study investigated the radiation-induced impact on the mitochondrial genome, particularly the chronological changes in the mitochondrial DNA copy number (mtDNAcn) following exposure to radiation. We used B-lymphoblastoid cell lines transformed by Epstein-Barr virus established from 12 healthy individuals in their 20s (six males, six females) with or without a history of smoking. Using real-time quantitative PCR, we determined the mtDNAcn from the B cells cultured for 6, 24, and 96 h and after exposure to 0, 1, 2, and 4 Gy X-rays. We found a significant relationship between the exposed dose and mtDNAcn in the 96-hour post-irradiation cells for non-smoking males, suggesting the possible role of mtDNAcn as a biomarker for dose assessment.

Cleft lip is a birth defect associated with environmental and genetic factors. Recently, microRNAs (miRNAs) have been reported to play a crucial role in lip formation, with the disruption of miRNAs influencing the development of cleft lip. Exposure to medicinal agents in pregnant women is one of the reasons for cleft lip. Although an association between pharmaceuticals-induced cleft lip and miRNAs has been suggested, it remains to be fully elucidated. This study aimed to clarify the molecular mechanism of mycophenolate mofetil (MPM)-induced inhibition of cell proliferation and miRNA expression in human lip fibroblast (KD) cells. Cell viability, apoptosis, and cell cycle-related markers were evaluated after 72 h of MPM treatment. In addition, miRNA levels and the expression of their downstream genes were measured, and a rescue experiment was performed by overexpressing PAX9. We showed that MPM dose-dependently reduced the viability of KD cells. In addition, MPM treatment suppressed cyclin-D1 and cyclin dependent kinase-6 expression in KD cells. Furthermore, MPM upregulated miR-205 expression and downregulated the expression of PAX9 (downstream gene). Moreover, PAX9 overexpression alleviated MPM-induced inhibition of cell proliferation. These results suggest that MPM suppresses cell viability by modulating miR-205-PAX9 expression.

Electromagnetic fields (EMFs) noninvasively promote fracture healing, prevent osteoporosis, promote diaphyseal growth, enhance differentiation, and stimulate cell division. However, no good model systems for analyzing bone regeneration have been reported. In this study, we examined the in vivo regeneration of scales having osteoblasts and osteoclasts using a new magnetic field generator for exposing aquatic animals to EMFs at a sine-wave frequency of 60 Hz. Goldfish scales were put into a fish-breeding space with the developed magnetic field generator and exposed to extremely low-frequency electromagnetic fields (ELF-EMFs) of 60 Hz at an intensity of 1, 3, and 5 mT for 10 days while being regenerated the scales. After exposure, alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activities in the goldfish scales were measured as markers of osteoblasts and osteoclasts, respectively. As a result, both ALP and TRAP activities in regenerating scales exposed to 3 mT ELF-EMFs were higher than those in regenerating scales exposed to 1 and 5 mT ELF-EMFs. Exposure of scales to 3 mT ELF-EMFs significantly enhanced the scale regeneration rate. Exposure of rat calvaria to 3 mT ELF-EMFs also increased both ALP and TRAP activities like in goldfish scales. Thus, we concluded that 3 mT ELF-EMFs contribute to the medical treatment of bone diseases.