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Subarachnoid hemorrhage triggers neuroinflammation of the entire cerebral cortex, leading to neuronal cell death. 蛛网膜下腔出血引发整个大脑皮层的神经炎症,导致神经元细胞死亡。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-14 DOI: 10.1186/s41232-022-00236-4
Hiroki Yamada, Yoshitaka Kase, Yuji Okano, Doyoon Kim, Maraku Goto, Satoshi Takahashi, Hideyuki Okano, Masahiro Toda

Background: Subarachnoid hemorrhage (SAH) is a fatal disease, with early brain injury (EBI) occurring within 72 h of SAH injury contributes to its poor prognosis. EBI is a complicated phenomenon involving multiple mechanisms. Although neuroinflammation has been shown to be important prognosis factor of EBI, whether neuroinflammation spreads throughout the cerebrum and the extent of its depth in the cerebral cortex remain unknown. Knowing how inflammation spreads throughout the cerebrum is also important to determine if anti-inflammatory agents are a future therapeutic strategy for EBI.

Methods: In this study, we induced SAH in mice by injecting hematoma into prechiasmatic cistern and created models of mild to severe SAH. In sections of the mouse cerebrum, we investigated neuroinflammation and neuronal cell death in the cortex distal to the hematoma injection site, from anterior to posterior region 24 h after SAH injury.

Results: Neuroinflammation caused by SAH spread to all layers of the cerebral cortex from the anterior to the posterior part of the cerebrum via the invasion of activated microglia, and neuronal cell death increased in correlation with neuroinflammation. This trend increased with the severity of the disease.

Conclusions: Neuroinflammation caused by SAH had spread throughout the cerebrum, causing neuronal cell death. Considering that the cerebral cortex is responsible for long-term memory and movement, suppressing neuroinflammation in all layers of the cerebral cortex may improve the prognosis of patients with SAH.

背景:蛛网膜下腔出血(SAH)是一种致死性疾病,早期脑损伤(EBI)发生在SAH损伤后72h内是其预后较差的原因之一。EBI是一个涉及多种机制的复杂现象。虽然神经炎症已被证明是EBI的重要预后因素,但神经炎症是否在整个大脑中扩散及其在大脑皮层的深度尚不清楚。了解炎症如何在整个大脑中扩散,对于确定抗炎药是否是EBI的未来治疗策略也很重要。方法:采用交叉前池注射血肿法诱导小鼠SAH,建立轻、重度SAH模型。在小鼠大脑切片中,我们研究了SAH损伤24小时后,从前到后区域,血肿注射部位远端皮层的神经炎症和神经元细胞死亡。结果:SAH引起的神经炎症通过激活的小胶质细胞的侵袭,从大脑前部到后部扩散到大脑皮层的所有层,神经元细胞死亡增加与神经炎症相关。这种趋势随着疾病的严重程度而增加。结论:SAH引起的神经炎症已遍及整个大脑,导致神经元细胞死亡。考虑到大脑皮层负责长期记忆和运动,抑制大脑皮层各层的神经炎症可能改善SAH患者的预后。
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引用次数: 2
State-of-the-art liver disease research using liver-on-a-chip. 利用片上肝脏进行最先进的肝病研究。
IF 5 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-09 DOI: 10.1186/s41232-022-00248-0
Sayaka Deguchi, Kazuo Takayama

To understand disease pathophysiologies, models that recapitulate human functions are necessary. In vitro models that consist of human cells are preferred to ones using animal cells, because organ functions can vary from species to species. However, conventional in vitro models do not recapitulate human organ functions well. Organ-on-a-chip technology provides a reliable in vitro model of the functional units of human organs. Organ-on-a-chip technology uses microfluidic devices and their accessories to impart organ functions to human cells. Using microfluidic devices, we can co-culture multiple cell types that compose human organs. Moreover, we can culture human cells under physiologically relevant stresses, such as mechanical and shear stresses. Current organ-on-a-chip technology can reproduce the functions of several organs including the liver. Because it is difficult to maintain the function of human hepatocytes, which are the gold standard of in vitro liver models, under conventional culture conditions, the application of liver-on-a-chips to liver disease research is expected. This review introduces the current status and future prospects of liver-on-a-chips in liver disease research.

要了解疾病的病理生理学,就必须建立能再现人体功能的模型。由人体细胞组成的体外模型比使用动物细胞的模型更受欢迎,因为器官功能会因物种而异。然而,传统的体外模型并不能很好地再现人体器官功能。芯片上器官技术提供了可靠的人体器官功能单元体外模型。芯片上器官技术利用微流体设备及其附件将器官功能赋予人体细胞。利用微流体设备,我们可以共同培养组成人体器官的多种细胞类型。此外,我们还可以在生理应力(如机械应力和剪切应力)条件下培养人体细胞。目前的芯片上器官技术可以再现包括肝脏在内的多个器官的功能。人肝细胞是体外肝脏模型的金标准,在传统培养条件下很难维持其功能,因此肝脏芯片有望应用于肝脏疾病研究。本综述介绍了片上肝脏在肝病研究中的应用现状和前景。
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引用次数: 0
Research hotspots and trends for axon regeneration (2000-2021): a bibliometric study and systematic review. 轴突再生研究热点与趋势(2000-2021):文献计量学研究与系统评价。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-07 DOI: 10.1186/s41232-022-00244-4
Yuyu Chou, Homaira Nawabi, Jingze Li

Background: Axons play an essential role in the connection of the nervous system with the rest of the body. Axon lesions often lead to permanent impairment of motor and cognitive functions and the interaction with the outside world. Studies focusing on axon regeneration have become a research field with considerable interest. The purpose of this study is to obtain an overall perspective of the research field of axonal regeneration and to assist the researchers and the funding agencies to better know the areas of greatest research opportunities.

Methods: We conducted a bibliometric analysis and Latent Dirichlet Allocation (LDA) analysis of the global literature on axon regeneration based on the Web of Science (WoS) over the recent 22 years, to address the research hotspots, publication trends, and understudied areas.

Results: A total of 21,018 articles were included, which in the recent two decades has increased by 125%. Among the top 12 hotspots, the annual productions rapidly increased in some topics, including axonal regeneration signaling pathway, axon guidance cues, neural circuits and functional recovery, nerve conduits, and cells transplant. Comparatively, the number of studies on axon regeneration inhibitors decreased. As for the topics focusing on nerve graft and transplantation, the annual number of papers tended to be relatively stable. Nevertheless, the underlying mechanisms of axon regrowth have not been completely uncovered. A lack of notable research on the epigenetic programs and noncoding RNAs regulation was observed. The significance of cell-type-specific data has been highlighted but with limited research working on that. Functional recovery from neuropathies also needs further studies.

Conclusion: The last two decades witnessed tremendous progress in the field of axon regeneration. There are still a lot of challenges to be tackled in translating these technologies into clinical practice.

背景:轴突在神经系统与身体其他部分的连接中起着至关重要的作用。轴突病变通常会导致运动和认知功能以及与外界相互作用的永久性损害。轴突再生的研究已成为一个备受关注的研究领域。本研究的目的是获得轴突再生研究领域的整体视角,并帮助研究人员和资助机构更好地了解最大的研究机会领域。方法:对近22年来基于Web of Science (WoS)的全球轴突再生相关文献进行文献计量学分析和潜狄利克雷分配(Latent Dirichlet Allocation, LDA)分析,找出轴突再生的研究热点、发表趋势和研究不足。结果:共纳入文献21,018篇,近20年来增长了125%。在前12大热点中,轴突再生信号通路、轴突引导线索、神经回路与功能恢复、神经导管、细胞移植等课题的年度产量快速增长。相比之下,轴突再生抑制剂的研究数量减少了。关于神经移植的主题,每年的论文数量趋于稳定。然而,轴突再生的潜在机制尚未完全揭示。在表观遗传程序和非编码rna调控方面的研究较少。细胞类型特异性数据的重要性已经得到强调,但在这方面的研究有限。神经病变的功能恢复也需要进一步的研究。结论:近二十年来,轴突再生研究取得了巨大进展。在将这些技术转化为临床实践方面仍有许多挑战需要解决。
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引用次数: 1
Neutralizing and enhancing antibodies against SARS-CoV-2. 中和和增强针对SARS-CoV-2的抗体。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-05 DOI: 10.1186/s41232-022-00233-7
Yafei Liu, Hisashi Arase

The high transmissibility and rapid global spread of SARS-CoV-2 since 2019 has led to a huge burden on healthcare worldwide. Anti-SARS-CoV-2 neutralizing antibodies play an important role in not only protecting against infection but also in clearing the virus and are essential to providing long-term immunity. On the other hand, antibodies against the virus are not always protective. With the emergence of SARS-CoV-2 immune escape variants, vaccine design strategies as well as antibody-mediated therapeutic approaches have become more important. We review some of the findings on SARS-CoV-2 antibodies, focusing on both basic research and clinical applications.

2019年以来,SARS-CoV-2的高传播性和全球快速传播给全球医疗保健带来了巨大负担。抗sars - cov -2中和抗体不仅在防止感染方面发挥重要作用,而且在清除病毒方面发挥重要作用,对于提供长期免疫至关重要。另一方面,针对病毒的抗体并不总是具有保护作用。随着SARS-CoV-2免疫逃逸变异的出现,疫苗设计策略以及抗体介导的治疗方法变得更加重要。本文从基础研究和临床应用两方面综述了SARS-CoV-2抗体的研究进展。
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引用次数: 3
Role of the Hippo pathway in liver regeneration and repair: recent advances. Hippo通路在肝脏再生和修复中的作用:最新进展。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-05 DOI: 10.1186/s41232-022-00235-5
Monica Pibiri, Gabriella Simbula

Although the signaling pathways involved in normal liver regeneration have been well characterized, less has been done for livers affected by chronic tissue damage. These "abnormal livers" have an impaired regenerative response that leads to liver repair and fibrosis. The tumor suppressor Hippo pathway plays a key role in liver regeneration and repair. On this basis, this review discusses recent studies focusing on the involvement of the Hippo signaling pathway during "normal healthy liver regeneration" (i.e., in a normal liver after 2/3 partial hepatectomy) and "abnormal liver regeneration" (i.e., in a liver damaged by chronic disease). This could be an important question to address with respect to new therapies aimed at improving impaired liver regenerative responses. The studies reported here have shown that activation of the Hippo coactivators YAP/TAZ during normal liver regeneration promotes the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. Moreover, YAP/TAZ signaling interaction with other signaling pathways mediates the recruitment and activation of Kupffer cells, which release mitogenic cytokines for parenchymal and/or non-parenchymal cells and engage in phagocytosis of cellular debris. In addition, YAP-mediated activation of stellate cells (HSCs) promotes liver regeneration through the synthesis of extracellular matrix. However, in chronically diseased livers, where the predetermined threshold for proper liver regeneration is exceeded, YAP/TAZ activation results in a reparative process characterized by liver fibrosis. In this condition, YAP/TAZ activation in parenchymal and non-parenchymal cells results in (i) differentiation of quiescent HSCs into myofibroblastic HSCs; (ii) recruitment of macrophages releasing inflammatory cytokines; (iii) polarization of macrophages toward the M2 phenotype. Since accumulation of damaged hepatocytes in chronic liver injury represent a significant risk factor for the development of hepatocarcinoma, this review also discussed the involvement of the Hippo pathway in the clearance of damaged cells.

尽管参与正常肝脏再生的信号通路已经被很好地表征,但对慢性组织损伤影响的肝脏的研究却很少。这些“异常肝脏”的再生反应受损,导致肝脏修复和纤维化。肿瘤抑制因子Hippo通路在肝脏再生和修复中起关键作用。在此基础上,本文综述了近期关于Hippo信号通路参与“正常健康肝脏再生”(即2/3肝部分切除后的正常肝脏)和“异常肝脏再生”(即慢性疾病损伤的肝脏)的研究。对于旨在改善受损肝脏再生反应的新疗法而言,这可能是一个需要解决的重要问题。本文报道的研究表明,在正常肝脏再生过程中,Hippo共激活因子YAP/TAZ的激活通过直接BEC增殖或/和肝细胞去分化为可转分化为BECs的HPCs,促进了新的胆管网络的形成。此外,YAP/TAZ信号通路与其他信号通路的相互作用介导Kupffer细胞的募集和激活,Kupffer细胞为实质细胞和/或非实质细胞释放有丝分裂细胞因子,并参与细胞碎片的吞噬。此外,yap介导的星状细胞(hsc)激活通过合成细胞外基质促进肝脏再生。然而,在慢性疾病肝脏中,当超过肝脏再生的预定阈值时,YAP/TAZ激活导致以肝纤维化为特征的修复过程。在这种情况下,实质细胞和非实质细胞中的YAP/TAZ激活导致(i)静止hsc分化为肌成纤维hsc;(ii)巨噬细胞募集,释放炎性细胞因子;(iii)巨噬细胞向M2表型极化。由于慢性肝损伤中受损肝细胞的积累是肝癌发展的一个重要危险因素,本综述还讨论了Hippo通路在清除受损细胞中的作用。
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引用次数: 5
Correction: IL-6 production through repression of UBASH3A gene via epigenetic dysregulation of super-enhancer in CD4+ T cells in rheumatoid arthritis. 校正:类风湿关节炎患者CD4+ T细胞超增强子表观遗传失调,通过抑制UBASH3A基因产生IL-6。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-02 DOI: 10.1186/s41232-022-00246-2
Kaoru Yamagata, Shingo Nakayamada, Tong Zhang, Anh Phuong Nguyen, Naoaki Ohkubo, Shigeru Iwata, Shigeaki Kato, Yoshiya Tanaka
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引用次数: 0
Autoinflammatory disease: clinical perspectives and therapeutic strategies. 自身炎症性疾病:临床观点和治疗策略。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-02 DOI: 10.1186/s41232-022-00217-7
Atsushi Kawakami, Endo Yushiro, Koga Tomohiro, Yoshiura Koh-Ichiro, Migita Kiyoshi

The molecular platforms of the innate immune system are essential to recognize pathologic external factors that are crucial to differentiate these danger signals from host motifs. A set of sensors recognizing pathologic factors is present and defined as a membrane-bound family of Toll-like receptors as well as the cytosolic ones including the family of nucleotide-binding domain leucine-rich repeat proteins. In this regard, the inflammasomes have been identified as an innate immune sensor toward pathologic external factors as well as endogenous damage-associated molecular pattern signals transducing from the above-mentioned receptors to gene expressions. Recent research has shown novel findings in inflammasome biology and genetics which lead to the alteration of diagnosis and management in autoinflammatory diseases as well as developing novel treatments, including the examples of nucleotide-binding domain leucine-rich repeat proteins-inflammasomes and pyrin-inflammasomes. The pyrin protein is encoded by the Mediterranean Fever gene on chromosome 16 that acts as a major regulatory component of the inflammasome, and is responsible for familial Mediterranean fever. We have recently examined the whole nucleotide sequence of the Mediterranean Fever gene in Japanese familial Mediterranean fever patients and revealed single nucleotide variants associated with the susceptibility of familial Mediterranean fever from a nation-wide survey by the next-generation sequencing. In a cytokine profile analysis of familial Mediterranean fever patients, we have found that interleukin-6 is considered to be one of the most crucial cytokines in familial Mediterranean fever attack since interleukin-6 had the best performance for distinguishing familial Mediterranean fever in attack from healthy controls or familial Mediterranean fever in remission, and in vitro interleukin-6 production is regulated by microRNAs-204-3p/phosphoinositide 3-kinase g pathway. Accordingly, we have been investigating the efficacy and safety of anti-human interleukin-6 receptor monoclonal antibody, tocilizumab, in patients with familial Mediterranean fever refractory or intolerant to colchicine through an investigator-initiated clinical trial supported by the Japan Agency for Medical Research and Development. Like interleukin-1b, interleukin-18 can be processed by caspase-1 and proteinase-3 to be activated within the inflammasomes. We have also found the importance of interleukin-18 in several autoinflammatory conditions. Recently, the concept of autoinflammation is widely distributed into many common diseases; thus, the attention to a wide spectrum of diseases MEFV gene deeply involved is required.

先天免疫系统的分子平台对于识别病理外部因素至关重要,这些外部因素对于区分这些危险信号与宿主基序至关重要。一组识别病理因子的传感器存在,并被定义为膜结合的toll样受体家族以及包括核苷酸结合结构域富含亮氨酸重复蛋白家族的细胞质受体。在这方面,炎性小体已被确定为对病理性外部因素的先天免疫传感器,以及从上述受体到基因表达的内源性损伤相关分子模式信号转导。最近的研究显示了炎症小体生物学和遗传学的新发现,这些发现导致了自身炎症疾病的诊断和管理的改变,以及开发新的治疗方法,包括核苷酸结合结构域富含亮氨酸的重复蛋白-炎症小体和pyrin-炎症小体的例子。pyrin蛋白由16号染色体上的地中海热基因编码,该基因是炎症小体的主要调节成分,并负责家族性地中海热。我们最近检查了日本家族性地中海热患者的地中海热基因的全核苷酸序列,并通过下一代测序在全国范围内调查发现了与家族性地中海热易感性相关的单核苷酸变异。在对家族性地中海热患者的细胞因子谱分析中,我们发现白细胞介素-6被认为是家族性地中海热发作中最重要的细胞因子之一,因为白细胞介素-6在区分家族性发作型地中海热与健康对照或缓解型家族性地中海热方面的表现最好,并且体外白细胞介素-6的产生受micrornas - 2043p /磷酸肌肽3-激酶g途径的调控。因此,我们一直在通过一项由日本医学研究与发展机构支持的研究者发起的临床试验,研究抗人白细胞介素-6受体单克隆抗体tocilizumab对秋水仙碱难治性或不耐受的家族性地中海热患者的疗效和安全性。与白细胞介素-1b一样,白细胞介素-18也可通过caspase-1和蛋白酶-3在炎性小体内活化。我们还发现白细胞介素-18在几种自身炎症条件下的重要性。近年来,自体炎症的概念被广泛应用于许多常见疾病;因此,需要关注MEFV基因深涉的广谱疾病。
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引用次数: 5
Cytokines and cytokine receptors as targets of immune-mediated inflammatory diseases-RA as a role model. 细胞因子和细胞因子受体作为免疫介导的炎症性疾病的靶标--以 RA 为榜样。
IF 5 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-01 DOI: 10.1186/s41232-022-00221-x
Tsutomu Takeuchi

Recent advances in our understanding in the immune-mediated inflammatory diseases (IMID) are explored and promoted by the targeted treatment. Among these targets, cytokines and cytokine receptors have become the good candidates for the drug development. In this review, the cytokine and cytokine receptors, which are approved in IMID, are overviewed, and modalities of the treatment, the role of cytokines and cytokine receptors in each disease, and the updated molecular information by modern technologies in rheumatoid arthritis as a role model are shown and discussed for the future perspectives.

最近,我们对免疫介导的炎症性疾病(IMID)的认识取得了进展,并通过靶向治疗进行了探索和推广。在这些靶点中,细胞因子和细胞因子受体已成为药物开发的最佳候选靶点。在这篇综述中,综述了在免疫介导的炎症性疾病(IMID)中被批准使用的细胞因子和细胞因子受体,并展示了治疗方式、细胞因子和细胞因子受体在每种疾病中的作用,以及以类风湿性关节炎为例,通过现代技术更新的分子信息,并对未来前景进行了讨论。
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引用次数: 0
Quercetin enhances survival and axonal regeneration of motoneurons after spinal root avulsion and reimplantation: experiments in a rat model of brachial plexus avulsion. 槲皮素促进脊髓根撕脱和再植后运动神经元的存活和轴突再生:臂丛撕脱大鼠模型的实验。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-12-01 DOI: 10.1186/s41232-022-00245-3
Yanfeng Huang, Xie Zhang, Qionghui Huang, Yaoxing Dou, Chang Qu, Qingqing Xu, Qiuju Yuan, Yan-Fang Xian, Zhi-Xiu Lin

Background: Brachial plexus avulsion (BPA) physically involves the detachment of spinal nerve roots themselves and the associated spinal cord segment, leading to permanent paralysis of motor function of the upper limb. Root avulsion induces severe pathological changes, including inflammatory reaction, oxidative damage, and finally massive motoneuron apoptosis. Quercetin (QCN), a polyphenolic flavonoid found in abundance in fruit and vegetables, has been reported to possess anti-oxidative, anti-inflammatory, and neuroprotective effects in many experimental models of both central nervous system (CNS) and peripheral nervous system (PNS) disorders. The purpose of this study was to investigate whether QCN could improve motor function recovery after C5-7 ventral root avulsion and C6 reimplantation in a rat model of BPA.

Methods: The right fifth cervical (C5) to C7 ventral roots were avulsed followed by re-implantation of only C6 to establish the spinal root avulsion plus re-implantation model in rats. After surgery, rats were treated with QCN (25, 50, and 100 mg/kg) by gavage for 2 or 8 consecutive weeks. The effects of QCN were assessed using behavior test (Terzis grooming test, TGT) and histological evaluation. The molecular mechanisms were determined by immunohistochemistry analysis and western blotting.

Results: Our results demonstrated that QCN significantly expedited motor function recovery in the forelimb as shown by the increased Terzis grooming test score, and accelerated motor axon regeneration as evidenced by the ascending number of Fluoro-Ruby-labeled and P75-positive regenerative motoneurons. The raised ChAT-immunopositive and cresyl violet-stained neurons indicated the enhanced survival of motoneurons by QCN administration. Furthermore, QCN treatment markedly alleviated muscle atrophy, restored functional motor endplates in biceps and inhibited the microglial and astroglia activation via modulating Nrf2/HO-1 and neurotrophin/Akt/MAPK signaling pathway.

Conclusions: Taken together, these findings have for the first time unequivocally indicated that QCN has promising potential for further development into a novel therapeutic in conjunction with reimplantation surgery for the treatment of BPA. .

背景:臂丛撕脱症(Brachial plexus avulsion, BPA)在物理上涉及脊神经根本身和相关脊髓段的脱离,导致上肢运动功能的永久性瘫痪。根撕脱引起严重的病理改变,包括炎症反应、氧化损伤,最终导致大量运动神经元凋亡。槲皮素(QCN)是一种在水果和蔬菜中大量发现的多酚类黄酮,据报道,槲皮素在中枢神经系统(CNS)和周围神经系统(PNS)疾病的许多实验模型中具有抗氧化、抗炎和神经保护作用。本研究的目的是探讨QCN是否能改善大鼠双酚a模型C5-7腹根撕脱和C6再植后的运动功能恢复。方法:取大鼠右侧第五颈椎(C5) ~ C7椎弓根撕脱后仅C6椎弓根再植入术,建立脊髓根撕脱+再植入术模型。术后大鼠分别给予QCN(25、50、100 mg/kg)灌胃,连续2、8周。采用行为学测试(Terzis grooming test, TGT)和组织学评估QCN的效果。通过免疫组织化学和免疫印迹分析确定其分子机制。结果:我们的研究结果表明,QCN显著加速了前肢运动功能的恢复,这可以从Terzis修饰测试分数的增加中看出;QCN显著加速了前肢运动轴突的再生,这可以从氟红宝石标记和p75阳性再生运动神经元的数量增加中看出。chat免疫阳性和甲酚紫染色神经元升高,表明给药后运动神经元存活增强。此外,QCN通过调节Nrf2/HO-1和神经营养因子/Akt/MAPK信号通路,显著缓解肌肉萎缩,恢复二头肌功能运动终板,抑制小胶质细胞和星形胶质细胞的激活。结论:综上所述,这些发现首次明确表明,QCN有希望进一步发展成为一种新的治疗方法,与再植手术一起治疗BPA。
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引用次数: 1
2D and 3D cultured human umbilical cord-derived mesenchymal stem cell-conditioned medium has a dual effect in type 1 diabetes model in rats: immunomodulation and beta-cell regeneration. 2D和3D培养人脐带间充质干细胞条件培养基对大鼠1型糖尿病模型具有双重作用:免疫调节和β细胞再生。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-11-30 DOI: 10.1186/s41232-022-00241-7
Basak Isildar, Serbay Ozkan, Merve Ercin, Selda Gezginci-Oktayoglu, Mahmut Oncul, Meral Koyuturk

Background: Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease characterized by the irreversible destruction of insulin-producing β-cells in pancreatic islets. Helper and cytotoxic T-cells and cytokine production, which is impaired by this process, take a synergetic role in β-cell destruction, and hyperglycemia develops due to insulin deficiency in the body. Mesenchymal stem cells (MSCs) appear like an excellent therapeutic tool for autoimmune diseases with pluripotent, regenerative, and immunosuppressive properties. Paracrine factors released from MSCs play a role in immunomodulation by increasing angiogenesis and proliferation and suppressing apoptosis. In this context, the study aims to investigate the therapeutic effects of MSC's secretomes by conditioned medium (CM) obtained from human umbilical cord-derived MSCs cultured in 2-dimensional (2D) and 3-dimensional (3D) environments in the T1D model.

Methods: First, MSCs were isolated from the human umbilical cord, and the cells were characterized. Then, two different CMs were prepared by culturing MSCs in 2D and 3D environments. The CM contents were analyzed in terms of total protein, IL-4, IL-10, IL-17, and IFN-λ. In vivo studies were performed in Sprague-Dawley-type rats with an autoimmune T1D model, and twelve doses of CM were administered intraperitoneally for 4 weeks within the framework of a particular treatment model. In order to evaluate immunomodulation, the Treg population was determined in lymphocytes isolated from the spleen after sacrification, and IL-4, IL-10, IL-17, and IFN-λ cytokines were analyzed in serum. Finally, β-cell regeneration was evaluated immunohistochemically by labeling Pdx1, Nkx6.1, and insulin markers, which are critical for the formation of β-cells.

Results: Total protein and IL-4 levels were higher in 3D-CM compared to 2D-CM. In vivo results showed that CMs induce the Treg population and regulate cytokine release. When the immunohistochemical results were evaluated together, it was determined that CM application significantly increased the rate of β-cells in the islets. This increase was at the highest level in the 3D-CM applied group.

Conclusion: The dual therapeutic effect of MSC-CM on immunomodulation and homeostasis/regeneration of β-cells in the T1D model has been demonstrated. Furthermore, this effect could be improved by using 3D scaffolds for culturing MSCs while preparing CM.

背景:1型糖尿病(T1D)是一种t细胞介导的自身免疫性疾病,其特征是胰岛中产生胰岛素的β细胞的不可逆破坏。辅助性和细胞毒性t细胞以及细胞因子的产生在这一过程中受损,在β细胞破坏中起协同作用,并且由于体内胰岛素缺乏而产生高血糖。间充质干细胞(MSCs)具有多能性、再生性和免疫抑制特性,是治疗自身免疫性疾病的良好工具。MSCs释放的旁分泌因子通过增加血管生成和增殖,抑制细胞凋亡,发挥免疫调节作用。在此背景下,本研究旨在研究在T1D模型中,在二维(2D)和三维(3D)环境中培养的人脐带源性间充质干细胞获得的条件培养基(CM)对MSC分泌组的治疗作用。方法:首先从人脐带分离骨髓间充质干细胞,并对其进行表征。然后,通过在二维和三维环境中培养MSCs制备两种不同的CMs。以总蛋白、IL-4、IL-10、IL-17和IFN-λ为指标分析CM的含量。在sprague - dawley型自身免疫性T1D模型大鼠中进行体内研究,在特定治疗模型框架内,腹腔注射12剂CM,持续4周。为了评估免疫调节作用,我们测定了牺牲后脾脏分离淋巴细胞中的Treg群体,并分析了血清中的IL-4、IL-10、IL-17和IFN-λ细胞因子。最后,通过标记Pdx1、Nkx6.1和胰岛素标记物来评估β细胞再生,这些标记物对β细胞的形成至关重要。结果:3D-CM的总蛋白和IL-4水平高于2D-CM。体内实验结果表明,CMs可诱导Treg种群,调节细胞因子的释放。将免疫组化结果结合评估,可以确定CM的应用显著增加了胰岛中β-细胞的比例。这种增加在3D-CM应用组中达到最高水平。结论:mscs - cm在T1D模型中具有免疫调节和β-细胞稳态/再生的双重治疗作用。此外,在制备CM的同时使用3D支架培养MSCs可以改善这种效果。
{"title":"2D and 3D cultured human umbilical cord-derived mesenchymal stem cell-conditioned medium has a dual effect in type 1 diabetes model in rats: immunomodulation and beta-cell regeneration.","authors":"Basak Isildar,&nbsp;Serbay Ozkan,&nbsp;Merve Ercin,&nbsp;Selda Gezginci-Oktayoglu,&nbsp;Mahmut Oncul,&nbsp;Meral Koyuturk","doi":"10.1186/s41232-022-00241-7","DOIUrl":"https://doi.org/10.1186/s41232-022-00241-7","url":null,"abstract":"<p><strong>Background: </strong>Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease characterized by the irreversible destruction of insulin-producing β-cells in pancreatic islets. Helper and cytotoxic T-cells and cytokine production, which is impaired by this process, take a synergetic role in β-cell destruction, and hyperglycemia develops due to insulin deficiency in the body. Mesenchymal stem cells (MSCs) appear like an excellent therapeutic tool for autoimmune diseases with pluripotent, regenerative, and immunosuppressive properties. Paracrine factors released from MSCs play a role in immunomodulation by increasing angiogenesis and proliferation and suppressing apoptosis. In this context, the study aims to investigate the therapeutic effects of MSC's secretomes by conditioned medium (CM) obtained from human umbilical cord-derived MSCs cultured in 2-dimensional (2D) and 3-dimensional (3D) environments in the T1D model.</p><p><strong>Methods: </strong>First, MSCs were isolated from the human umbilical cord, and the cells were characterized. Then, two different CMs were prepared by culturing MSCs in 2D and 3D environments. The CM contents were analyzed in terms of total protein, IL-4, IL-10, IL-17, and IFN-λ. In vivo studies were performed in Sprague-Dawley-type rats with an autoimmune T1D model, and twelve doses of CM were administered intraperitoneally for 4 weeks within the framework of a particular treatment model. In order to evaluate immunomodulation, the Treg population was determined in lymphocytes isolated from the spleen after sacrification, and IL-4, IL-10, IL-17, and IFN-λ cytokines were analyzed in serum. Finally, β-cell regeneration was evaluated immunohistochemically by labeling Pdx1, Nkx6.1, and insulin markers, which are critical for the formation of β-cells.</p><p><strong>Results: </strong>Total protein and IL-4 levels were higher in 3D-CM compared to 2D-CM. In vivo results showed that CMs induce the Treg population and regulate cytokine release. When the immunohistochemical results were evaluated together, it was determined that CM application significantly increased the rate of β-cells in the islets. This increase was at the highest level in the 3D-CM applied group.</p><p><strong>Conclusion: </strong>The dual therapeutic effect of MSC-CM on immunomodulation and homeostasis/regeneration of β-cells in the T1D model has been demonstrated. Furthermore, this effect could be improved by using 3D scaffolds for culturing MSCs while preparing CM.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"42 1","pages":"55"},"PeriodicalIF":8.1,"publicationDate":"2022-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9710085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10333098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 6
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Inflammation and Regeneration
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