酢酸摂取と運動が脂肪代謝と運動耐久性に及ぼす影響

Previously, we found that acetic acid had effects on lipid metabolism in skeletal muscles and has functions that work against obesity and obesity-linked type 2 diabetes through the activation of AMPactivated protein kinase (AMPK). During exercise, AMPK is activated in skeletal muscle according to exercise intensity and it increases fatty acid oxidation. The purpose of this study was to investigate the interactive effects of chronic intake of acetic acid and exercise training on lipid metabolism and endurance performance. Six-week-old SD rats were randomly assigned to four groups: water-injected (rest-water), acetic acid-injected (rest-ace), exercise-trained after injection of water (water-ex), and exercise-trained after injection of acetic acid (ace-ex) for 4 weeks. Body weight (BW) in rest-ace and ace-ex groups was significantly lower than rest-water group. Exercise-training groups showed an increase of exercise capacity, by the addition of intake of acetic acid, lipid oxidation was promoted during exercise tolerance test. Skeletal muscle of rats treated with acetic acid and exercise training led to higher expressions of cytochrome c (cycs), and tended to stimulate expressions of peroxisome proliferator-activated receptor coactivator 1-α (PGC1-α ) and MHC1 genes than those of rest-water group. Those results indicate that treatments both of exercise training and intake of acetic acid contribute to enhancement of lipid metabolism and improvement of exercise capacity.これまで我々は、酢酸の摂取が骨格筋内のAMP活性化プロテインキナーゼ（AMPK）の活性化を介して脂質代謝と肥満、肥満に関連した2型糖尿病の予防に効果があることを示唆してきた。AMPKは運動によって骨格筋で活性化し、脂肪酸酸化を促進する。この研究は、4週間の継続的な酢酸摂取と運動トレーニングが運動中の脂肪代謝と運動耐久性に及ぼす影響について調べることを目的とした。　6週齢のSD系雄ラットを安静期に水を摂取するrest-water群、酢酸を摂取するrest-ace群、運動前に水を摂取するwater-ex群、運動前に酢酸を摂取するace-ex群に無作為に分け実験を行った。酢酸を継続的に摂取すると水摂取に比較して腹腔内脂肪量の減少と体重増加の抑制がみられた。また継続的な酢酸摂取および運動トレーニングにより、耐久性運動下でのグルコース利用の抑制および脂肪酸酸化の促進が見られた。酢酸摂取および運動トレーニング群の腓腹筋では、MHCIおよびcytochrome c等の遅筋線維マーカー遺伝子が増加していた。継続的な酢酸摂取と運動トレーニングにより、脂肪代謝と運動耐久性の向上が示唆された

Internet-Based Inquiries From Users With the Intention to Overdose With Over-the-Counter Drugs: Qualitative Analysis of Yahoo! Chiebukuro

市販薬乱用に関して投稿された質問の分析 --Yahoo!知恵袋内テキストデータの定性分析--. 京都大学プレスリリース. 2023-12-05.[Background:] Public concern with regard to over-the-counter (OTC) drug abuse is growing rapidly across countries. OTC drug abuse has serious effects on the mind and body, such as poisoning symptoms, and often requires specialized treatments. In contrast, there is concern about people who potentially abuse OTC drugs whose symptoms are not serious enough to consult medical institutions or drug addiction rehabilitation centers yet are at high risk of becoming drug dependent in the future. [Objective:] Consumer-generated media (CGM), which allows users to disseminate information, is being used by people who abuse (and those who are trying to abuse) OTC drugs to obtain information about OTC drug abuse. This study aims to analyze the content of CGM to explore the questions of people who potentially abuse OTC drugs. [Methods:] The subject of this research was Yahoo! Chiebukuro, the largest question and answer website in Japan. A search was performed using the names of drugs commonly used in OTC drug abuse and the keywords overdose and OD, and the number of questions posted on the content of OTC drug abuse was counted. Furthermore, a thematic analysis was conducted by extracting text data on the most abused antitussive and expectorant drug, BRON. [Results:] The number of questions about the content of overdose medications containing the keyword BRON has increased sharply as compared with other product names. Furthermore, 467 items of question data that met the eligibility criteria were obtained from 528 items of text data on BRON; 26 codes, 6 categories, and 3 themes were generated from the 578 questions contained in these items. Questions were asked about the effects they would gain from abusing OTC drugs and the information they needed to obtain the effects they sought, as well as about the effects of abuse on their bodies. Moreover, there were questions on how to stop abusing and what is needed when seeking help from a health care provider if they become dependent. It has become clear that people who abuse OTC drugs have difficulty in consulting face-to-face with others, and CGM is used as a means to obtain the necessary information anonymously. [Conclusions:] On CGM, people who abused or tried to abuse OTC drugs were asking questions about their abuse expectations and anxieties. In addition, when they became dependent, they sought advice to quit their abuse. CGM was used to exchange information about OTC drug abuse, and many questions on anxieties and hesitations were posted. This study suggests that it is necessary to produce and disseminate information on OTC drug abuse, considering the situation of those who abuse or are willing to abuse OTC drugs. Support from pharmacies and drugstores would also be essential to reduce opportunities for OTC drug abuse

Histopathological changes in surrounding tissue of the sciatic nerve after spinal cord injury in rats

[Purpose] The purpose of this study was to examine histopathological changes in tissue surrounding the sciatic nerve after spinal cord injury (SCI) in rats. [Subjects and Methods] Thirty adult, nine-week-old, female Wistar rats were used in this study. Fifteen experimental rats underwent spinal cord transection at the level of Th8-9 and the other fifteen control rats were raised normally. Animals were assessed at 1, 2, 4, 8, and 12 weeks following surgery. After the experimental period, we obtained tissue surrounding the sciatic nerve of the thigh after hematoxylin and eosin staining under a microscope. [Results] Adherence between the nerve bundle and perineural innermost layer was observed in tissue surrounding the sciatic nerve in the SCI group. Adherence among the interperineurium was evident at 2 weeks after SCI. It had declined at 4 weeks after SCI, but was still evident at 8 and 12 weeks after SCI. [Conclusion] Histopathological findings in the SCI model may be related to compression of the nerve bundle and neurogenic contracture of tissue surrounding the nerve bundle.Thesis of Ippei Kitade / 北出 一平 博士論文 金沢大学医薬保健学総合研究科（保健学専攻

Transfer profile of intramuscularly administered tetrodotoxin to artificial hybrid specimens of pufferfish, Takifugu rubripes and Takifugu niphobles.

Tetrodotoxin (TTX) was intramuscularly administered to artificially hybridized specimens of the pufferfish Takifugu rubripes and Takifugu niphobles to investigate toxin accumulation in hybrids, and TTX transfer/accumulation profiles in the pufferfish body. In the test fish administered 146 MU TTX in physiologic saline, TTX rapidly transferred from the muscle via the blood to other organs. Toxin transfer to the ovary rapidly increased to 53.5 MU/g tissue at the end of the 72-h test period. The TTX content in the liver and skin was, at most, around 4-6 MU/g tissue, and in the testis it was less than 0.01 MU/g tissue. On the other hand, based on the total amount of toxin per individual (% of the administered toxin), the skin and the liver contained higher amounts (20-54% and 2-24%, respectively), but the amount in the liver rapidly decreased after 8-12 h, and fell below the level in the ovary after 48 h. These findings suggest that part of the TTX is first taken up in the liver and then transferred/accumulated in the skin in male specimens and in the ovary in female specimens

Macrophage SREBP1 regulates skeletal muscle regeneration

Macrophages are essential for the proper inflammatory and reparative processes that lead to regeneration of skeletal muscle after injury. Recent studies have demonstrated close links between the function of activated macrophages and their cellular metabolism. Sterol regulatory element-binding protein 1 (SREBP1) is a key regulator of lipid metabolism and has been shown to affect the activated states of macrophages. However, its role in tissue repair and regeneration is poorly understood. Here we show that systemic deletion of Srebf1, encoding SREBP1, or macrophage-specific deletion of Srebf1a, encoding SREBP1a, delays resolution of inflammation and impairs skeletal muscle regeneration after injury. Srebf1 deficiency impairs mitochondrial function in macrophages and suppresses the accumulation of macrophages at sites of muscle injury. Lipidomic analyses showed the reduction of major phospholipid species in Srebf1-/- muscle myeloid cells. Moreover, diet supplementation with eicosapentaenoic acid restored the accumulation of macrophages and their mitochondrial gene expression and improved muscle regeneration. Collectively, our results demonstrate that SREBP1 in macrophages is essential for repair and regeneration of skeletal muscle after injury and suggest that SREBP1-mediated fatty acid metabolism and phospholipid remodeling are critical for proper macrophage function in tissue repair

Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid

Kakuda K., Ikenaka K., Araki K., et al. Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid. Scientific Reports 9, 6001 (2019); https://doi.org/10.1038/s41598-019-42399-0.α-Synuclein aggregates, a key hallmark of the pathogenesis of Parkinson’s disease, can be amplified by using their seeding activity, and the evaluation of the seeding activity of cerebrospinal fluid (CSF) is reportedly useful for diagnosis. However, conventional shaking-based assays are time-consuming procedures, and the clinical significance of the diversity of seeding activity among patients remains to be clarified. Previously, we reported a high-throughput ultrasonication-induced amyloid fibrillation assay. Here, we adapted this assay to amplify and detect α-synuclein aggregates from CSF, and investigated the correlation between seeding activity and clinical indicators. We confirmed that this assay could detect α-synuclein aggregates prepared in vitro and also aggregates released from cultured cells. The seeding activity of CSF correlated with the levels of α-synuclein oligomers measured by an enzyme-linked immunosorbent assay. Moreover, the seeding activity of CSF from patients with Parkinson’s disease was higher than that of control patients. Notably, the lag time of patients with Parkinson’s disease was significantly correlated with the MIBG heart-to-mediastinum ratio. These findings showed that our ultrasonication-based assay can rapidly amplify misfolded α-synuclein and can evaluate the seeding activity of CSF

The histological effect of immobilization and unloading/reloading on articular cartilage of rat knee joint

これまで、ラット膝関節の不動化による関節周囲組織の組織学的変化が報告されているが、臨床の場においてギプス固定がなされる場合には非荷重の状態となることが多い。荷重の除去が長期に及ぶと膝半月板内の機械受容器数が減少し、長期臥床や免荷直後は関節損傷の危険性が高いとの報告もある。今回ラット膝関節をギプス固定するだけでなく、後肢懸垂法を用いて非荷重モデルと非荷重の後に再荷重を加えたモデルを作成し、荷重の有無による影響を調査した。　 ２ 週間片側下肢のギプス固定と後肢懸垂を行った群 ( ２ IS 群 )、 4 週間片側下肢のギプス固定と後肢懸垂を行った群 ( 4 IS 群 )、 ２ 週間片側下肢のギプス固定と後肢懸垂を行い、その後 ２ 週間ケージ内にて自由飼育とし再荷重を行った群 ( ２ IS+IL 群 )、 ２ 週間通常飼育の対照群( ２C 群)、4 週間通常飼育の対照群( 4C 群)で比較した。　 ２ IS 群では膝関節軟骨表面の不整が確認され、 4 IS 群では軟骨表面の変化はさらに進行していた。 ２ IS+IL 群では関節軟骨と周囲組織の癒着は確認されず、軟骨表面の変化は２ IS 群よりも軽減していた。　不動と非荷重が組み合わさった際には膝関節軟骨組織の変化について相加的な影響をもたらす可能性が明らかになり、再荷重により関節軟骨は修復されうることが考えられる。関節軟骨の正常状態維持には適切な関節運動と荷重が必要である。Purpose: Joint movement and loading are thought to maintain articular cartilage. In this study, we performed histological examination of the effects of immobilization and unloading/reloading on articular cartilage in the rat knee joint.　Materials and Methods: Twenty-five adult, 9-week-old, male rats were used in this study. The animals were randomly divided into five groups of equal size: two-week caged control (２C), 4-week caged control (4C), ２-week hind limb suspension with cast immobilization (２IS), 4-week hind limb suspension with cast immobilization (4IS), and ２-week hind limb suspension with cast immobilization and ２-week reloading with cast immobilization (２IS+IL). Rats in the experimental groups had one knee joint immobilized for ２ or 4 weeks in maximum flexion with a plaster cast of our own making and aluminum wire netting. After the end of each experimental period, tissue specimens of the knee joint were prepared for observation in the sagittal plane and examined under a light microscope with hematoxylin-eosin staining.　Results: In the control groups (２C or 4C), the surface of the articular cartilage was smooth and continuous. On the other hand, the surface of the femoral articular cartilage was irregular in the experimental groups. The pathological changes in the cartilage surfaces showed greater progression in the 4IS group than that the ２IS group. We observed adhesions between the cartilage surface layer and synovial membrane in some specimens in the 4IS group. The pathological changes in the cartilage surfaces were less severe in the ２IS+IL group than the ２IS group.　Conclusion: Immobilization and unloading caused irregularity of the femoral articular cartilage surface as well as adhesions between the cartilage surface layer and synovial membrane in some specimens. Reloading may be related to cartilage repair

Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy

Hypoglycosylation and reduced laminin-binding activity of α-dystroglycan are common characteristics of dystroglycanopathy, which is a group of congenital and limb-girdle muscular dystrophies. Fukuyama-type congenital muscular dystrophy (FCMD), caused by a mutation in the fukutin gene, is a severe form of dystroglycanopathy. A retrotransposal insertion in fukutin is seen in almost all cases of FCMD. To better understand the molecular pathogenesis of dystroglycanopathies and to explore therapeutic strategies, we generated knock-in mice carrying the retrotransposal insertion in the mouse fukutin ortholog. Knock-in mice exhibited hypoglycosylated α-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact α-dystroglycan, and solid-phase assays determined laminin binding levels to be ∼50% of normal. In contrast, intact α-dystroglycan is undetectable in the dystrophic Largemyd mouse, and laminin-binding activity is markedly reduced. These data indicate that a small amount of intact α-dystroglycan is sufficient to maintain muscle cell integrity in knock-in mice, suggesting that the treatment of dystroglycanopathies might not require the full recovery of glycosylation. To examine whether glycosylation defects can be restored in vivo, we performed mouse gene transfer experiments. Transfer of fukutin into knock-in mice restored glycosylation of α-dystroglycan. In addition, transfer of LARGE produced laminin-binding forms of α-dystroglycan in both knock-in mice and the POMGnT1 mutant mouse, which is another model of dystroglycanopathy. Overall, these data suggest that even partial restoration of α-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes might effectively deter dystroglycanopathy progression and thus provide therapeutic benefits

Upregulation of ANGPTL6 in mouse keratinocytes enhances susceptibility to psoriasis

Psoriasis is a chronic inflammatory skin disease marked by aberrant tissue repair. Mutant mice modeling psoriasis skin characteristics have provided useful information relevant to molecular mechanisms and could serve to evaluate therapeutic strategies. Here, we found that epidermal ANGPTL6 expression was markedly induced during tissue repair in mice. Analysis of mice overexpressing ANGPTL6 in keratinocytes (K14-Angptl6 Tg mice) revealed that epidermal ANGPTL6 activity promotes aberrant epidermal barrier function due to hyperproliferation of prematurely differentiated keratinocytes. Moreover, skin tissues of K14-Angptl6 Tg mice showed aberrantly activated skin tissue inflammation seen in psoriasis. Levels of the proteins S100A9, recently proposed as therapeutic targets for psoriasis, also increased in skin tissue of K14-Angptl6 Tg mice, but psoriasis-like inflammatory phenotypes in those mice were not rescued by S100A9 deletion. This finding suggests that decreasing S100A9 levels may not ameliorate all cases of psoriasis and that diverse mechanisms underlie the condition. Finally, we observed enhanced levels of epidermal ANGPTL6 in tissue specimens from some psoriasis patients. We conclude that the K14-Angptl6 Tg mouse is useful to investigate psoriasis pathogenesis and for preclinical testing of new therapeutics. Our study also suggests that ANGPTL6 activation in keratinocytes enhances psoriasis susceptibility