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[J-TEC's efforts to industrialize regenerative medicine in Japan]. [J-TEC 在日本实现再生医学产业化的努力]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.23048
Masukazu Inoie

Japan Tissue Engineering Co., Ltd., J-TEC, was launched in 1999 to industrialize regenerative medicine in Japan. We developed the first regenerative medicine product, JACE (autologous cultured epidermis), which received PMDA approval for treating serious burns in 2007. Then, JACC (autologous cultured cartilage), the second product, was approved in 2012 for efficacy on traumatic cartilage defects. In 2014, the Pharmaceutical Affairs Law was revised to the Pharmaceutical and Medical Device Act, and regenerative medicine products, including gene therapies, were newly classified to accelerate productization. Subsequently, Nepic (autologous cultured corneal epithelium) and Ocural (autologous cultured oral mucosal epithelium) for epithelialization of limbal stem cell deficiencies in ophthalmology were approved in 2020 and 2021, respectively. Furthermore, a new product, JACEMIN (autologous cultured epidermis maintaining melanocyte) for vitiligo treatment was approved in 2023. We have developed five products of regenerative medicine that construct human tissues to graft rather than injectable cell suspensions like drugs. To develop regenerative medicine products, it is necessary to ensure the safety of raw materials, standardize the cultivation process, examine cell characteristics on GLP tests, construct transportation methods, build GCTP facilities, and conduct clinical trials on GCP. Re-examinations of JACE for serious burns and JACC for cartilage defects were completed after 7 years of all-case postmarketing surveillance. The commercialization of these products has become a benchmark for domestic regulation and has induced the development of a regenerative medicine industry promoted by Japan.

日本组织工程株式会社(Japan Tissue Engineering Co., Ltd., J-TEC)成立于 1999 年,致力于在日本实现再生医学的产业化。我们开发了第一个再生医学产品 JACE(自体培养表皮),并于 2007 年获得 PMDA 批准用于治疗严重烧伤。随后,第二款产品 JACC(自体培养软骨)于 2012 年获得批准,用于治疗创伤性软骨缺损。2014 年,《药事法》修订为《药品和医疗器械法》,包括基因疗法在内的再生医学产品被新分类,以加快产品化进程。随后,用于眼科角膜缘干细胞缺失上皮化的 Nepic(自体培养角膜上皮)和 Ocural(自体培养口腔粘膜上皮)分别于 2020 年和 2021 年获得批准。此外,用于白癜风治疗的新产品 JACEMIN(自体培养表皮维持黑素细胞)于 2023 年获得批准。我们已开发出五种再生医学产品,这些产品是构建人体组织进行移植,而不是像药物那样注射细胞悬液。要开发再生医学产品,就必须确保原材料的安全性、培养过程的标准化、GLP试验中细胞特性的检查、运输方法的构建、GCTP设施的建设以及GCP临床试验的开展。严重烧伤用 JACE 和软骨缺损用 JACC 经过 7 年的全病例上市后监测后完成了复查。这些产品的商业化已成为日本国内监管的基准,并促进了日本再生医学产业的发展。
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引用次数: 0
[Universal roles of the TRPA1 channel in oxygen-sensing]. [TRPA1通道在氧感应中的普遍作用】。]
Pub Date : 2024-01-01 DOI: 10.1254/fpj.23086
Akito Nakao, Ke Liu, Nobuaki Takahashi, Yasuo Mori

Molecular oxygen suffices the ATP production required for the survival of us aerobic organisms. But it is also true that oxygen acts as a source of reactive oxygen species that elicit a spectrum of damages in living organisms. To cope with such intrinsic ambiguity of biological activity oxygen exerts, aerobic mechanisms are equipped with an exquisite adaptive system, which sensitively detects partial pressure of oxygen within the body and controls appropriate oxygen supply to the tissues. Physiological responses to hypoxia are comprised of the acute and chronic phases, in the former of which the oxygen-sensing remains controversial particularly from mechanistic points of view. Recently, we have revealed that the prominently redox-sensitive cation channel TRPA1 plays key roles in oxygen-sensing mechanisms identified in the peripheral tissues and the central nervous system. In this review, we summarize recent development of researches on oxygen-sensing mechanisms including that in the carotid body, which has been recognized as the oxygen receptor organ central to acute oxygen-sensing. We also discuss how ubiquitously the TRPA1 contributes to the mechanisms underlying the acute phase of adaptation to hypoxia.

分子氧足以产生我们这些有氧生物生存所需的 ATP。但氧气也是活性氧的来源之一,会对生物体造成一系列损害。为了应对氧气在生物体内所发挥的这种固有的模糊作用,有氧机制配备了一个精巧的适应系统,它能灵敏地检测到体内的氧分压,并控制对组织的适当供氧。对缺氧的生理反应包括急性和慢性两个阶段,其中前者的氧传感仍然存在争议,特别是从机理角度来看。最近,我们发现对氧化还原反应敏感的阳离子通道 TRPA1 在外周组织和中枢神经系统的氧传感机制中发挥着关键作用。在这篇综述中,我们总结了氧传感机制研究的最新进展,包括颈动脉体中的氧传感机制,该器官已被认为是急性氧传感的核心氧受体器官。我们还讨论了 TRPA1 如何普遍存在于适应缺氧的急性阶段的机制中。
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引用次数: 0
[Identification of NCX inhibitor-binding domain to human Na+/Ca2+ exchanger 1]. [鉴定人类 Na+/Ca2+ 交换子 1 的 NCX 抑制剂结合域]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.24048
Takahiro Iwamoto, Satomi Kita
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引用次数: 0
[Preface]. [序言]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.24035
Yasuhiro Tsukimi
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引用次数: 0
[Unveiling RNA isoform diversity in the brain using long-read RNA sequencing]. [利用长读核糖核酸测序揭示大脑中核糖核酸同工酶的多样性]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.24044
Kazuki Nagayasu
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引用次数: 0
[Fibrosis signaling in endometrial cells and endometriosis development]. [子宫内膜细胞中的纤维化信号和子宫内膜异位症的发展]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.24030
Kazuya Kusama, Kazuhiro Tamura

In endometriosis, the tissues similar to the endometrial tissue attaches outside the uterine cavity, causing inflammation and fibrosis. The retrograde menstruation theory is the most plausible mechanism, though the detailed pathogenesis remains unclear. Our observations suggest that endometriosis-like lesions occur more often at sites of ovarian excision causing bleeding in mouse models. Additionally, prostaglandin E2 (PGE2) and thrombin, a protease-activated receptor (PAR) agonist in menstrual blood exacerbate inflammation in these lesions. Focusing on the hypoxic conditions of menstrual blood, we investigated the effects of PGE2/thrombin on inflammation and fibrosis using primary cultured endometrial stromal cells (ESCs) and glandular epithelial cells (EECs) under low oxygen conditions. Chemokine CXCL12 secreted by endometrial stromal cells under hypoxia acts on CXCR4 receptors on glandular epithelial cells, inducing epithelial-mesenchymal transition (EMT), suggesting a possible role in endometriosis progression. RNA-seq analysis of PGE2/thrombin effects on endometrial stromal cells revealed activation of the transforming growth factor (TGF)-β pathway, particularly increased production and secretion of activin A, a member of the TGFβ family. Activin A, via increased connective tissue growth factor (CTGF) expression, promotes differentiation of endometrial stromal cells from fibroblast-like to myofibroblast transdifferentiation (FMT) of ESCs. In conclusion, targeting the CXCL12/CXCR4 and activin A/CTGF signaling pathways holds promise for improving fibrosis in endometriosis lesions.

在子宫内膜异位症中,与子宫内膜组织相似的组织附着在子宫腔外,引起炎症和纤维化。逆行月经理论是最合理的机制,但详细的发病机制仍不清楚。我们的观察结果表明,在小鼠模型中,子宫内膜异位症样病变更多地发生在导致出血的卵巢切除部位。此外,经血中的前列腺素 E2(PGE2)和凝血酶(一种蛋白酶激活受体(PAR)激动剂)会加剧这些病变部位的炎症。针对经血中的低氧条件,我们利用低氧条件下原代培养的子宫内膜基质细胞(ESCs)和腺上皮细胞(EECs)研究了 PGE2/凝血酶对炎症和纤维化的影响。缺氧条件下子宫内膜基质细胞分泌的趋化因子CXCL12作用于腺上皮细胞上的CXCR4受体,诱导上皮-间质转化(EMT),可能在子宫内膜异位症的进展中发挥作用。PGE2/thrombin 对子宫内膜基质细胞影响的 RNA-seq 分析显示,转化生长因子(TGF)-β 通路被激活,特别是 TGFβ 家族成员之一的活化素 A 的生成和分泌增加。活化素 A 可通过增加结缔组织生长因子(CTGF)的表达,促进子宫内膜基质细胞从成纤维细胞样分化为肌成纤维细胞样分化(FMT)。总之,靶向 CXCL12/CXCR4 和激活素 A/CTGF信号通路有望改善子宫内膜异位症病灶的纤维化。
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引用次数: 0
[Exploring the molecular and neuronal bases involved in central amygdala-dependent control of emotional behaviors]. [探索杏仁核中枢控制情感行为的分子和神经元基础]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.23052
Shuhei Ueda, Sayaka Takemoto-Kimura

The central extended amygdala, including the central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNSTL), is a pivotal brain region involved in the threat processing responsible for emotional states such as fear and anxiety. These brain regions alter their circuit activities and exhibit necessary functions to adapt to environmental changes. When faced with excessive threats or stress, it is thought that these neural circuit functions are disrupted and cause various stress-related psychiatric disorders. The CeA and BNSTL were suggested to be the same nuclei separated during development because of their dense neural connections, and the similarities in cellular composition and connectivity patterns with other brain regions. On the other side, some recent studies suggested functional differences between these two regions in controlling emotional behaviors. However, functional segregation at the subnuclei level was insufficient since the two regions have complex circuit structures composed of multiple subnuclei. In this review, we introduce the similarities and differences between the CeA and BNSTL that have been clarified from our recent comparative studies of gene expression profiles and circuit functions at the subnuclei level. Additionally, we also discuss how it can contribute to understanding the molecular pathogenesis of neuropsychiatric disorders, including stress-related psychiatric disorders.

中央扩展杏仁核(包括杏仁核中央核(CeA)和纹状体末端床核外侧分部(BNSTL))是一个关键的脑区,参与恐惧和焦虑等情绪状态的威胁处理。这些脑区会改变其回路活动,并表现出适应环境变化的必要功能。当面临过度威胁或压力时,人们认为这些神经回路功能会受到破坏,从而导致各种与压力相关的精神疾病。CeA和BNSTL被认为是在发育过程中分离出来的同一个核团,因为它们有密集的神经连接,而且在细胞组成和连接模式上与其他脑区相似。另一方面,最近的一些研究表明,这两个区域在控制情绪行为方面存在功能差异。然而,由于这两个区域具有由多个亚核组成的复杂回路结构,因此在亚核水平上进行功能分隔是不够的。在这篇综述中,我们将介绍 CeA 和 BNSTL 的异同点,这些异同点是我们最近在亚核水平上对基因表达谱和回路功能进行比较研究后明确的。此外,我们还将讨论它如何有助于理解神经精神疾病(包括应激相关精神疾病)的分子发病机制。
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引用次数: 0
[Development of a nanomachine for efficient drug delivery to the brain]. [开发向大脑高效递送药物的纳米机械]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.23042
Hayato Laurence Mizuno, Yasutaka Anraku

Recently, bottom-up technologies, in particular the utilization of self-assembly of functional polymers to form nanostructures in solutions have been collecting attention. These technologies are being explored for various applications, especially for usage in therapeutics. One of the goals of such studies is to develop a drug delivery system (DDS) that delivers bioactive substances to specific targets within our body, eliciting the desired functionality. The authors have been developing "nanomachines" using biocompatible polymers to safely and efficiently deliver drugs mainly to tumors. The aim of this study is to utilize our expertise in designing a nanomachine to develop a cutting-edge nanomachine that can efficiently penetrate the blood-brain barrier (BBB) and deliver drugs to the brain parenchyma. Furthermore, leveraging this "nanomachine" technology, the authors are advancing the "Hayabusa Nanomachine," which can non-invasively collect and detect brain molecules, correlating them with various biological processes, ultimately leading to a better understanding of brain function and diseases. This paper also introduces the concept and ongoing efforts to the development of "Hayabusa Nanomachines," which have the potential to revolutionize existing approaches in this field.

最近,自下而上的技术,特别是利用功能聚合物的自组装在溶液中形成纳米结构的技术受到了关注。人们正在探索这些技术的各种应用,尤其是在治疗方面的应用。此类研究的目标之一是开发一种药物输送系统(DDS),将生物活性物质输送到人体内的特定靶点,激发所需的功能。作者一直在开发使用生物相容性聚合物的 "纳米机器",以安全高效地将药物主要输送到肿瘤部位。本研究的目的是利用我们在设计纳米机械方面的专业知识,开发一种能有效穿透血脑屏障(BBB)并将药物输送到脑实质的尖端纳米机械。此外,作者利用这种 "纳米机械 "技术,正在推进 "隼鸟纳米机械",它可以无创收集和检测脑分子,并将其与各种生物过程相关联,最终使人们更好地了解大脑功能和疾病。本文还介绍了 "隼鸟纳米机械 "的概念和正在进行的开发工作,它有可能彻底改变这一领域的现有方法。
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引用次数: 0
[Generation of disease-specific amyloid structures and analysis of pathogenesis]. [生成疾病特异性淀粉样蛋白结构并分析发病机制]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.24039
Yasushi Yabuki
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引用次数: 0
[Elucidation of the pathology of mental disorders focusing on polyunsaturated fatty acids and FABPs]. [以多不饱和脂肪酸和 FABPs 为重点阐明精神障碍的病理学]。
Pub Date : 2024-01-01 DOI: 10.1254/fpj.23093
Yui Yamamoto

Polyunsaturated fatty acids (PUFAs) are essential for brain development and function, and an imbalance of brain PUFAs is linked to mental disorders like autism and schizophrenia. However, the cellular and molecular mechanisms underlying the effects of PUFAs on the brain remain largely unknown. Since they are insoluble in water, specific transporters like fatty acid binding proteins (FABPs), are required for transport and function of PUFAs within cells. We focused on the relationship between FABP-mediated homeostasis of brain PUFAs and neural plasticity. We found that FABP3, with a high affinity for n-6 PUFAs, is predominantly expressed in the GABAergic inhibitory interneurons of the anterior cingulate cortex (ACC) in the adult mouse brain. FABP3 knockout (KO) mice show increased GABA synthesis and inhibitory synaptic transmission in the ACC. We also found that FABP7 controls lipid raft function in astrocytes, and astrocytes lacking FABP7 exhibit changes in response to external stimuli. Furthermore, in FABP7 KO mice, dendritic protrusion formation in pyramidal neurons becomes abnormal, and we have reported a decrease in spine density and excitatory synaptic transmission. Here, we introduced recent advances in the understanding of the functions of PUFAs and FABPs in the brain, focusing especially on FABP3 and FABP7, in relation to human mental disorders.

多不饱和脂肪酸(PUFAs)对大脑的发育和功能至关重要,而大脑中的多不饱和脂肪酸失衡与自闭症和精神分裂症等精神疾病有关。然而,PUFAs 对大脑产生影响的细胞和分子机制在很大程度上仍然未知。由于 PUFAs 不溶于水,因此需要脂肪酸结合蛋白(FABPs)等特异性转运体来实现 PUFAs 在细胞内的转运和功能。我们重点研究了 FABP 介导的脑内 PUFAs 平衡与神经可塑性之间的关系。我们发现,对 n-6 PUFAs 具有高亲和力的 FABP3 主要表达于成年小鼠大脑前扣带回皮层(ACC)的 GABA 能抑制性中间神经元。FABP3 基因敲除(KO)小鼠显示出 ACC 中 GABA 合成和抑制性突触传递的增加。我们还发现 FABP7 控制着星形胶质细胞的脂筏功能,缺乏 FABP7 的星形胶质细胞对外界刺激的反应会发生变化。此外,在 FABP7 KO 小鼠中,锥体神经元的树突突起形成变得异常,我们还报道了棘突密度和兴奋性突触传递的下降。在此,我们介绍了最近在理解 PUFAs 和 FABPs 在大脑中的功能方面取得的进展,尤其侧重于 FABP3 和 FABP7 与人类精神疾病的关系。
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引用次数: 0
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Folia Pharmacologica Japonica
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