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Safety and efficacy of melatonin supplementation as an add-on treatment for infantile epileptic spasms syndrome: A randomized, placebo-controlled, double-blind trial 补充褪黑激素作为婴儿癫痫痉挛综合征附加治疗的安全性和有效性:一项随机、安慰剂对照、双盲试验。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-01 DOI: 10.1111/jpi.12922
Yulin Sun, Jian Chen, Xiuyu Shi, Zhichao Li, Lin Wan, Huimin Yan, Yuehao Chen, Jiaxin Wang, Jing Wang, Liping Zou, Russel Reiter, Bo Zhang, Guang Yang
<p>This was a prospective, randomized, double-blind, single-center placebo-controlled trial to assess the efficacy and safety of melatonin as an add-on treatment for infantile epileptic spasms syndrome (IESS). Participants aged 3 months to 2 years with a primary diagnosis of IESS were recruited and assigned to two groups in a 1:1 ratio. Both treatment groups received a combination of adrenocorticotrophic hormone (ACTH) and magnesium sulfate (MgSO<sub>4</sub>) for 2 weeks, and the treatment group also received melatonin (3 mg) between 20:00 and 21:00 daily, 0.5–1 h before bedtime. The study's primary endpoint was the average reduction rate in spasm frequency assessed by seizure diaries. Secondary endpoints included assessment of the response rate, EEG hypsarrhythmia (Kramer score), and psychomotor development (Denver Developmental Screening Test, DDST). Sleep quality was assessed by using the Brief Infant Sleep Questionnaire (BISQ), the Infant Sleep Assessment Scale (ISAS), and actigraphy. Safety parameters were also evaluated. Statistical analyses were conducted on intention-to-treat and per-protocol populations. The trial is registered at Clinicaltrials.gov (ChiCTR2000036208). Out of 119 screened patients, 70 were randomized and 66 completed treatments. In the intention-to-treat population, there were no significant differences in the average percentage reduction of spasm frequency (median [interquartile range, IQR: Q3–Q1], 100% [46.7%] vs. 66.7% [55.3%], <i>p</i> = .288), the 3-day response rate (51.4% vs. 37.1%, <i>p</i> = .229), the 28-day response rate (42.9% vs. 28.6%, <i>p</i> = .212), EEG Kramer scores (2 [3.5] vs. 2 [3], <i>p</i> = .853), or DDST comprehensive months (5 [2.5] vs. 6 [6], <i>p</i> = .239) between the melatonin (<i>n</i> = 35) and placebo (<i>n</i> = 35) groups. However, caregivers reported improved sleep quality after melatonin treatment, with 85.7% reporting regular sleep compared to 42.9% with placebo (42.9%, <i>p</i> < .001). The melatonin group had lower ISAS scores in 4–11-month-old patients compared to the placebo (mean ± SD, 29.3 ± 4.4 vs. 35.2 ± 5.9, <i>p</i> < .001). Moreover, the median (IQR) value of sleep-onset latency was shortened by 6.0 (24.5) min after melatonin treatment, while that in the placebo group was extended by 3.0 (22.0) min (<i>p</i> = .030). The serum melatonin (6:00 h) level (pg/mL) of the children in the melatonin group after treatment was significantly higher than in the placebo group (median [IQR], 84.8 [142] vs. 17.5 [37.6], <i>p</i> < .001). No adverse effects related to melatonin were observed in the study, and there were no significant differences in adverse effects between the melatonin and placebo groups. Although not statistically significant, the results of this randomized clinical trial proved that melatonin supplementation, as an add-on treatment, can improve spasm control rate in the treatment of IESS. For IESS children treated with ACTH, the addition of melatonin was fou
这是一项前瞻性、随机、双盲、单中心安慰剂对照试验,旨在评估褪黑素作为婴儿癫痫痉挛综合征(IESS)的附加治疗药物的疗效和安全性。招募年龄在3个月至2岁之间、主要诊断为IESS的参与者,并按1:1的比例分为两组。两个治疗组均接受促肾上腺皮质激素(ACTH)和硫酸镁(MgSO4)联合治疗2周,治疗组还接受褪黑素(3 mg),每天20:00至21:00,0.5-1 睡前h。该研究的主要终点是通过癫痫日记评估的痉挛频率的平均降低率。次要终点包括反应率评估、脑电图高节律性(Kramer评分)和精神运动发育(Denver发育筛查测试,DDST)。采用简明婴儿睡眠问卷(BISQ)、婴儿睡眠评估量表(ISAS)和活动描记法对睡眠质量进行评估。还对安全参数进行了评估。对意向治疗人群和方案人群进行了统计分析。该试验在Clinicaltrials.gov上注册(ChiCTR200036208)。在119名筛查患者中,70人被随机分配,66人完成了治疗。在意向治疗人群中,痉挛频率的平均减少百分比没有显著差异(中位数[四分位间距,IQR:Q3-Q1],100%[46.7%]与66.7%[55.3%],p = .288),3天有效率(51.4%对37.1%,p = .229),28天有效率(42.9%对28.6%,p = .212),EEG Kramer评分(2[3.5]对2[3],p = .853),或DDST综合月数(5[2.5]vs.6[6],p = .239)在褪黑激素(n = 35)和安慰剂(n = 35)组。然而,护理人员报告褪黑素治疗后睡眠质量有所改善,85.7%的人报告有规律的睡眠,而安慰剂组为42.9%(42.9%,p
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引用次数: 0
Ramelteon attenuates hippocampal neuronal loss and memory impairment following kainate-induced seizures Ramelteon可减轻红藻氨酸诱导的癫痫发作后海马神经元的丧失和记忆障碍。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-17 DOI: 10.1111/jpi.12921
Jung Hoon Park, Yeonggwang Hwang, Yen Nhi Doan Nguyen, Hyoung-Chun Kim, Eun-Joo Shin

Evidence suggests that the neuroprotective effects of melatonin involve both receptor-dependent and -independent actions. However, little is known about the effects of melatonin receptor activation on the kainate (KA) neurotoxicity. This study examined the effects of repeated post-KA treatment with ramelteon, a selective agonist of melatonin receptors, on neuronal loss, cognitive impairment, and depression-like behaviors following KA-induced seizures. The expression of melatonin receptors decreased in neurons, whereas it was induced in astrocytes 3 and 7 days after seizures elicited by KA (0.12 μg/μL) in the hippocampus of mice. Ramelteon (3 or 10 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) mitigated KA-induced oxidative stress and impairment of glutathione homeostasis and promoted the nuclear translocation and DNA binding activity of Nrf2 in the hippocampus after KA treatment. Ramelteon and melatonin also attenuated microglial activation but did not significantly affect astroglial activation induced by KA, despite the astroglial induction of melatonin receptors after KA treatment. However, ramelteon attenuated KA-induced proinflammatory phenotypic changes in astrocytes. Considering the reciprocal regulation of astroglial and microglial activation, these results suggest ramelteon inhibits microglial activation by regulating astrocyte phenotypic changes. These effects were accompanied by the attenuation of the nuclear translocation and DNA binding activity of nuclear factor κB (NFκB) induced by KA. Consequently, ramelteon attenuated the KA-induced hippocampal neuronal loss, memory impairment, and depression-like behaviors; the effects were comparable to those of melatonin. These results suggest that ramelteon-mediated activation of melatonin receptors provides neuroprotection against KA-induced neurotoxicity in the mouse hippocampus by activating Nrf2 signaling to attenuate oxidative stress and restore glutathione homeostasis and by inhibiting NFκB signaling to attenuate neuroinflammatory changes.

有证据表明褪黑激素的神经保护作用包括受体依赖性和非依赖性作用。然而,人们对褪黑素受体激活对红藻氨酸(KA)神经毒性的影响知之甚少。本研究检测了用褪黑素受体的选择性激动剂拉梅尔顿重复KA后治疗对KA诱导的癫痫发作后神经元损失、认知障碍和抑郁样行为的影响。褪黑素受体在神经元中的表达减少,而在KA引发的癫痫发作后3和7天,星形胶质细胞中的表达被诱导(0.12 μg/μL)。Ramelteon(3或10 mg/kg,i.p.)和褪黑素(10 mg/kg,i.p.)减轻KA诱导的氧化应激和谷胱甘肽稳态损伤,并促进KA治疗后海马中Nrf2的核转位和DNA结合活性。Ramelteon和褪黑素也减弱了小胶质细胞的激活,但没有显著影响KA诱导的星形胶质细胞激活,尽管KA治疗后星形胶质细胞诱导了褪黑素受体。然而,拉梅尔顿减弱了KA诱导的星形胶质细胞的促炎表型变化。考虑到星形胶质细胞和小胶质细胞活化的相互调节,这些结果表明拉梅尔顿通过调节星形胶质细胞表型变化来抑制小胶质细胞的活化。这些作用伴随着KA诱导的核因子κB(NFκB)的核转位和DNA结合活性的减弱。因此,拉梅尔顿减轻了KA诱导的海马神经元损失、记忆障碍和抑郁样行为;其效果与褪黑素相当。这些结果表明,拉梅尔顿介导的褪黑素受体的激活通过激活Nrf2信号来减轻氧化应激和恢复谷胱甘肽稳态,并通过抑制NFκB信号来减轻神经炎症变化,从而对小鼠海马中KA诱导的神经毒性提供神经保护。
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引用次数: 0
Melatonin suppresses tumor proliferation and metastasis by targeting GATA2 in endometrial cancer 褪黑激素通过靶向子宫内膜癌症中的GATA2抑制肿瘤增殖和转移。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-09 DOI: 10.1111/jpi.12918
Yangyou Liao, Ruiling Li, Jingyuan Pei, Juan Zhang, Bo Chen, Haojie Dong, Xiaoyu Feng, Hongshuo Zhang, Yuhong Shang, Linlin Sui, Ying Kong

Endometrial cancer (EC) is a reproductive system disease that occurs in perimenopausal and postmenopausal women. However, its etiology is unclear. Melatonin (MT) has been identified as a therapeutic agent for EC; however, its exact mechanism remains unclear. In the present study, we determined that GATA-binding protein 2 (GATA2) is expressed at low levels in EC and regulated by MT. MT upregulates the expression of GATA2 through MT receptor 1A (MTNR1A), whereas GATA2 can promote the expression of MTNR1A by binding to its promoter region. In addition, in vivo and in vitro experiments showed that MT inhibited the proliferation and metastasis of EC cells by upregulating GATA2 expression. The protein kinase B (AKT) pathway was also affected. In conclusion, these findings suggest that MT and GATA2 play significant roles in EC development.

子宫内膜癌症(EC)是一种发生在围绝经期和绝经后妇女的生殖系统疾病。然而,其病因尚不清楚。褪黑素(MT)已被确定为EC的治疗剂;然而,其确切机制尚不清楚。在本研究中,我们确定GATA结合蛋白2(GATA2)在EC中低水平表达,并受MT调节。MT通过MT受体1A(MTNR1A)上调GATA2的表达,而GATA2可以通过与其启动子区结合来促进MTNR1A的表达。此外,体内和体外实验表明,MT通过上调GATA2的表达来抑制EC细胞的增殖和转移。蛋白激酶B(AKT)通路也受到影响。总之,这些发现表明MT和GATA2在EC的发展中起着重要作用。
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引用次数: 0
Melatonin alters the excitability of mouse cerebellar granule neurons by inhibiting voltage-gated sodium, potassium, and calcium channels 褪黑素通过抑制电压门控的钠、钾和钙通道来改变小鼠小脑颗粒神经元的兴奋性。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-05 DOI: 10.1111/jpi.12919
Karolos-Philippos Pissas, Maria Schilling, Ahmet Korkmaz, Yuemin Tian, Stefan Gründer

Besides its role in the circadian rhythm, the pineal gland hormone melatonin (MLT) also possesses antiepileptogenic, antineoplastic, and cardioprotective properties, among others. The dosages necessary to elicit beneficial effects in these diseases often far surpass physiological concentrations. Although even high doses of MLT are considered to be largely harmless to humans, the possible side effects of pharmacological concentrations are so far not well investigated. In the present study, we report that pharmacological doses of MLT (3 mM) strongly altered the electrophysiological characteristics of cultured primary mouse cerebellar granule cells (CGCs). Using whole-cell patch clamp and ratiometric Ca2+ imaging, we observed that pharmacological concentrations of MLT inhibited several types of voltage-gated Na+, K+, and Ca2+ channels in CGCs independently of known MLT-receptors, altering the character and pattern of elicited action potentials (APs) significantly, quickly and reversibly. Specifically, MLT reduced AP frequency, afterhyperpolarization, and rheobase, whereas AP amplitude and threshold potential remained unchanged. The altered biophysical profile of the cells could constitute a possible mechanism underlying the proposed beneficial effects of MLT in brain-related disorders, such as epilepsy. On the other hand, it suggests potential adverse effects of pharmacological MLT concentrations on neurons, which should be considered when using MLT as a pharmacological compound.

除了在昼夜节律中的作用外,松果体激素褪黑素(MLT)还具有抗癫痫、抗肿瘤和心脏保护等特性。在这些疾病中产生有益效果所需的剂量往往远远超过生理浓度。尽管即使是高剂量的MLT也被认为在很大程度上对人类无害,但迄今为止,药物浓度可能产生的副作用还没有得到很好的研究。在本研究中,我们报告了MLT(3 mM)强烈改变了培养的原代小鼠小脑颗粒细胞(CGCs)的电生理特性。使用全细胞膜片钳和比率Ca2+成像,我们观察到药理学浓度的MLT独立于已知的MLT受体抑制了CGCs中几种类型的电压门控Na+、K+和Ca2+通道,显著、快速和可逆地改变了诱发动作电位(AP)的特征和模式。具体而言,MLT降低了AP频率、后超极化和变阻性基底,而AP振幅和阈值电位保持不变。细胞的生物物理特征的改变可能构成MLT对癫痫等脑相关疾病有益作用的潜在机制。另一方面,它表明药理学MLT浓度对神经元的潜在不良影响,在使用MLT作为药理学化合物时应考虑这一点。
{"title":"Melatonin alters the excitability of mouse cerebellar granule neurons by inhibiting voltage-gated sodium, potassium, and calcium channels","authors":"Karolos-Philippos Pissas,&nbsp;Maria Schilling,&nbsp;Ahmet Korkmaz,&nbsp;Yuemin Tian,&nbsp;Stefan Gründer","doi":"10.1111/jpi.12919","DOIUrl":"10.1111/jpi.12919","url":null,"abstract":"<p>Besides its role in the circadian rhythm, the pineal gland hormone melatonin (MLT) also possesses antiepileptogenic, antineoplastic, and cardioprotective properties, among others. The dosages necessary to elicit beneficial effects in these diseases often far surpass physiological concentrations. Although even high doses of MLT are considered to be largely harmless to humans, the possible side effects of pharmacological concentrations are so far not well investigated. In the present study, we report that pharmacological doses of MLT (3 mM) strongly altered the electrophysiological characteristics of cultured primary mouse cerebellar granule cells (CGCs). Using whole-cell patch clamp and ratiometric Ca<sup>2+</sup> imaging, we observed that pharmacological concentrations of MLT inhibited several types of voltage-gated Na<sup>+</sup>, K<sup>+</sup>, and Ca<sup>2+</sup> channels in CGCs independently of known MLT-receptors, altering the character and pattern of elicited action potentials (APs) significantly, quickly and reversibly. Specifically, MLT reduced AP frequency, afterhyperpolarization, and rheobase, whereas AP amplitude and threshold potential remained unchanged. The altered biophysical profile of the cells could constitute a possible mechanism underlying the proposed beneficial effects of MLT in brain-related disorders, such as epilepsy. On the other hand, it suggests potential adverse effects of pharmacological MLT concentrations on neurons, which should be considered when using MLT as a pharmacological compound.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12919","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41092766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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: 0
Melatonin prevents EAAC1 deletion-induced retinal ganglion cell degeneration by inhibiting apoptosis and senescence 褪黑素通过抑制细胞凋亡和衰老来预防EAAC1缺失诱导的视网膜神经节细胞变性。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-03 DOI: 10.1111/jpi.12916
Chenyang Hu, Yanlin Feng, Guangyi Huang, Kaixuan Cui, Matthew Fan, Wu Xiang, Yuxun Shi, Dan Ye, Huiwen Ye, Xue Bai, Fan Xu, Yue Xu, Jingjing Huang

Normal tension glaucoma (NTG) is referred to as a progressive degenerative disorder of the retinal ganglion cells (RGCs), resulting in nonreversible visual defects, despite intraocular pressure levels within the statistically normal range. Current therapeutic strategies for NTG yield limited benefits. Excitatory amino acid carrier 1 (EAAC1) knockout (EAAC1−/−) in mice has been shown to induce RGC degeneration without elevating intraocular pressure, mimicking pathological characteristics of NTG. In this study, we explored whether daily oral administration of melatonin could block RGCs loss and prevent retinal morphology and function defects associated with EAAC1 deletion. We also explored the molecular mechanisms underlying EAAC1 deletion-induced RGC degeneration and the neuroprotective effects of melatonin. Our RNA sequencing and in vivo data indicated EAAC1 deletion caused elevated oxidative stress, activation of apoptosis and cellular senescence pathways, and neuroinflammation in RGCs. However, melatonin administration efficiently prevented these detrimental effects. Furthermore, we investigated the potential role of apoptosis- and senescence-related redox-sensitive factors in EAAC1 deletion-induced RGCs degeneration and the neuroprotective effects of melatonin administration. We observed remarkable upregulation of p53, whereas NRF2 and Sirt1 expression were significantly decreased in EAAC1−/− mice, which were prevented by melatonin treatment, suggesting that melatonin exerted its neuroprotective effects possibly through modulating NRF2/p53/Sirt1 redox-sensitive signaling pathways. Overall, our study provided a solid foundation for the application of melatonin in the management of NTG.

正常眼压性青光眼(NTG)被称为视网膜神经节细胞(RGCs)的进行性退行性疾病,导致不可逆的视觉缺陷,尽管眼压水平在统计正常范围内。目前NTG的治疗策略产生的益处有限。小鼠兴奋性氨基酸载体1(EAAC1)敲除(EAAC1-/-)已被证明在不升高眼压的情况下诱导RGC变性,模拟NTG的病理特征。在这项研究中,我们探讨了每天口服褪黑素是否可以阻断RGCs的损失,并预防与EAAC1缺失相关的视网膜形态和功能缺陷。我们还探讨了EAAC1缺失诱导RGC变性的分子机制以及褪黑素的神经保护作用。我们的RNA测序和体内数据表明,EAAC1缺失导致RGCs氧化应激升高、细胞凋亡和细胞衰老途径激活以及神经炎症。然而,褪黑素的使用有效地防止了这些有害影响。此外,我们研究了细胞凋亡和衰老相关氧化还原敏感因子在EAAC1缺失诱导的RGCs变性中的潜在作用以及褪黑素的神经保护作用。我们观察到p53的显著上调,而在EAAC1-/-小鼠中,NRF2和Sirt1的表达显著降低,这被褪黑素治疗所阻止,这表明褪黑素可能通过调节NRF2/p53/Sirt1氧化还原敏感的信号通路发挥其神经保护作用。总的来说,我们的研究为褪黑素在NTG管理中的应用提供了坚实的基础。
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引用次数: 0
Erratum to: Mitochondrial cytochrome P450 (CYP) 1B1 is responsible for melatonin-induced apoptosis in neural cancer cells 勘误:线粒体细胞色素P450(CYP)1B1负责美拉通素诱导的神经癌症细胞凋亡。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-03 DOI: 10.1111/jpi.12917

DOI: 10.1111/jpi.12478

Zhenlong Yu1,+, Xiangge Tian1,+, Yuling Peng1,+, Zheng Sun1, Chao Wang 1, Ning Tang1, Bin Li2, Yuqing Jian2, Wei Wang2,*, Xiaokui Huo1, Xiaochi Ma1,*

*Correspondence: Professor Xiaochi Ma, E-mail: [email protected] (Xiaochi Ma); Professor Wei Wang, E-mail: [email protected] (Wei Wang).

+These authors equally contributed to this work.

Correction:

Unfortunately, the original version of this article1 contained the errors. The band of p-p38 in Figure 1F (SH-SY5Y) was mistakenly uploaded, during the arrangement of the figure panels. The mistake did not affect our results or discussion as the text refers to the correct experimental values. The corrected Figure 1F is provided here. Additionally, an error was also identified in the authors' names, where Yulin Peng's name was mistakenly written as “Yuling Peng”.

We regret any inconvenience this has caused.

Corrected Figure 1F

DOI: 10.1111/jpi.12478Zhenlong Yu1,+, Xiangge Tian1,+, Yuling Peng1,+, Zheng Sun1, Chao Wang 1, Ning Tang1, Bin Li2, Yuqing Jian2, Wei Wang2,*, Xiaokui Huo1, Xiaochi Ma1,**Correspondence:马晓驰教授,电子邮件:[email protected] (马晓驰电子邮件:[email protected] (Xiaochi Ma);王伟教授,电子邮件:[email protected] (Wei Wang):[Correction:Unfortunately, the original version of this article1 contained the errors.图1F(SH-SY5Y)中p-p38的条带在编排时被错误上传。这个错误并不影响我们的结果或讨论,因为文中提到的是正确的实验值。现提供更正后的图 1F。此外,我们还发现了作者姓名中的一处错误,彭玉林的名字被误写为 "Yuling Peng"。
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引用次数: 0
Melatonin, a potentially effective drug for the treatment of infected bone nonunion 褪黑素,一种治疗感染性骨不连的潜在有效药物。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-27 DOI: 10.1111/jpi.12914
Han-jun Qin, Si-ying He, Ke Shen, Qing-rong Lin, Yan-jun Hu, Zi-lin Chen, Bin Yu, Nan Jiang

Osteomyelitis (OM), characterized by heterogeneity and complexity in treatment, has a high risk of infection recurrence which may cause limb disability. Management of chronic inactive osteomyelitis (CIOM) without typical inflammatory symptoms is a great challenge for orthopedic surgeons. On the basis of data analysis of 1091 OM cases, we reported that latent osteogenic decline in CIOM patients was the main cause of secondary surgery. Our research shows that impairment of osteoblasts capacity in CIOM patients is associated with ferroptosis of osteoblasts caused by internalization of Staphylococcus aureus. Further studies show that melatonin could alleviate ferroptosis of osteoblasts in infected states through Nox4/ROS/P38 axis and protect the osteogenic ability of CIOM patients. Knockout of NADPH oxidase 4 (Nox4) in vivo could effectively relieve ferroptosis of osteoblasts in the state of infection and promote osteogenesis. Through a large number of clinical data analyses combined with molecular experiments, this study clarified that occult osteogenic disorders in CIOM patients were related to ferroptosis of osteoblasts. We revealed that melatonin might be a potential therapeutic drug for CIOM patients and provided a new insight for the treatment of OM.

骨髓炎(OM)具有治疗的异质性和复杂性,感染复发的风险很高,可能导致肢体残疾。没有典型炎症症状的慢性非活动性骨髓炎(CIOM)的治疗对骨科医生来说是一个巨大的挑战。在对1091例OM病例进行数据分析的基础上,我们报告了CIOM患者潜在的成骨能力下降是二次手术的主要原因。我们的研究表明,CIOM患者成骨细胞能力受损与金黄色葡萄球菌内化引起的成骨细胞脱铁性贫血有关。进一步的研究表明,褪黑素可以通过Nox4/ROS/P38轴减轻感染状态下成骨细胞的脱铁性贫血,并保护CIOM患者的成骨能力。体内敲除NADPH氧化酶4(Nox4)可有效缓解感染状态下成骨细胞的脱铁性,促进成骨。通过大量临床数据分析结合分子实验,本研究阐明CIOM患者的隐性成骨性疾病与成骨细胞脱铁性贫血有关。我们发现褪黑素可能是CIOM患者的一种潜在治疗药物,并为OM的治疗提供了新的见解。
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引用次数: 0
Orchestrated feedback regulation between melatonin and sex hormones involving GPER1-PKA-CREB signaling in the placenta 褪黑激素和性激素之间的协调反馈调节,涉及胎盘中GPER1-PKA-CREB信号传导
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-25 DOI: 10.1111/jpi.12913
Xuan Shao, Yun Yang, Yanlei Liu, Yongqing Wang, Yangyu Zhao, Xin Yu, Juan Liu, Yu-Xia Li, Yan-Ling Wang

Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre-eclampsia (PE), a gestational complication, is a leading cause of maternal and perinatal morbidity and mortality. Aberrant elevation of testosterone (T0) synthesis, reduced estradiol (E2), and melatonin productions have been identified in preeclamptic placentas. However, the precise contribution of disrupted homeostasis among these hormones to the occurrence of PE remains unknown. In this study, we established a strong correlation between suppressed melatonin production and decreased E2 as well as elevated T0 synthesis in PE placentas. Administration of the T0 analog testosterone propionate (TP; 2 mg/kg/day) to pregnant mice from E7.5 onwards resulted in PE-like symptoms, along with elevated T0 production and reduced E2 and melatonin production. Notably, supplementation with melatonin (10 mg/kg/day) in TP-treated mice had detrimental effects on fetal and placental development and compromised hormone synthesis. Importantly, E2, but not T0, actively enhanced melatonin synthetase AANAT expression and melatonin production in primary human trophoblast (PHT) cells through GPER1-PKA-CREB signaling pathway. On the other hand, melatonin suppressed the level of estrogen synthetase aromatase while promoting the expressions of androgen synthetic enzymes including 17β-HSD3 and 3β-HSD1 in PHT cells. These findings reveal an orchestrated feedback mechanism that maintains homeostasis of placental sex hormones and melatonin. It is implied that abnormal elevation of T0 synthesis likely serves as the primary cause of placental endocrine disturbances associated with PE. The suppression of melatonin may represent an adaptive strategy to correct the imbalance in sex hormone levels within preeclamptic placentas. The findings of this study offer novel evidence that identifies potential targets for the development of innovative therapeutic strategies for PE.

维持胎盘内分泌稳态对成功怀孕至关重要。先兆子痫(PE)是一种妊娠并发症,是孕产妇和围产期发病率和死亡率的主要原因。在先兆子痫胎盘中发现了睾酮(T0)合成异常升高、雌二醇(E2)减少和褪黑素产生异常。然而,这些激素中稳态紊乱对PE发生的确切贡献仍然未知。在这项研究中,我们在PE胎盘中建立了褪黑素产生抑制与E2降低以及T0合成升高之间的强相关性。T0类似物丙酸睾酮(TP;2 mg/kg/天)导致PE样症状,同时T0产生增加,E2和褪黑素产生减少。值得注意的是,补充褪黑激素(10 mg/kg/天)对胎儿和胎盘发育具有不利影响,并损害激素合成。重要的是,E2,而不是T0,通过GPER1-PKA-CREB信号通路,积极增强原代人类滋养层(PHT)细胞中褪黑素合成酶AANAT的表达和褪黑素的产生。另一方面,褪黑素抑制了PHT细胞中雌激素合成酶芳香化酶的水平,同时促进了包括17β-HSD3和3β-HSD1在内的雄激素合成酶的表达。这些发现揭示了维持胎盘性激素和褪黑激素稳态的协调反馈机制。这意味着T0合成的异常升高可能是PE相关胎盘内分泌紊乱的主要原因。褪黑素的抑制可能是纠正先兆子痫胎盘性激素水平失衡的一种适应性策略。这项研究的发现为PE创新治疗策略的开发提供了新的证据。
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引用次数: 0
Corrigendum to “melatonin ameliorates PM2.5-induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis” “褪黑激素通过调节线粒体氧化还原稳态改善PM2.5诱导的心脏血管周围纤维化”更正。
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-20 DOI: 10.1111/jpi.12915

After publication of the paper “Melatonin ameliorates PM2.5-induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis” by Jinjin Jiang et al. it was noticed that the paper contains error in Figure 4D and Figure 6D. During the assembly of certain figure panel of this article showing representative immunoblot, Ac-SOD2 and GPADH (Figure 4D) and GAPDH (Figure 6D) were presented incorrectly, due to unintended duplication mistake. Using the original source data, the rectified version of the incorrectly presented panel of Figure 4D and Figure 6D were generated and is shown below. Here we provided the revised Figure 4 and Figure 6. The authors apologize for the oversight and declare that the correction does not affect the description, interpretation, or conclusions detailed in the original manuscript.

蒋津津等人的论文《褪黑素通过调节线粒体氧化还原稳态改善PM2.5诱导的心脏血管周围纤维化》发表后,我们发现论文中的图4D和图6D有误。在组装本文某些显示代表性免疫印迹的图板时,由于无意中的重复错误,Ac-SOD2 和 GPADH(图 4D)以及 GAPDH(图 6D)的显示不正确。利用原始数据,我们生成了图 4D 和图 6D 的更正版本,如下所示。在此,我们提供了修改后的图 4 和图 6。作者对疏忽表示歉意,并声明更正并不影响原稿中详细的描述、解释或结论。
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引用次数: 0
Biosynthesis of neuroprotective melatonin is dysregulated in Huntington's disease 神经保护性褪黑激素的生物合成在亨廷顿舞蹈症中失调
IF 10.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-18 DOI: 10.1111/jpi.12909
Jinho Kim, Wei Li, Jingjing Wang, Sergei V. Baranov, Brianna E. Heath, Jiaoying Jia, Yalikun Suofu, Oxana V. Baranova, Xiaomin Wang, Timothy M. Larkin, William R. Lariviere, Diane L. Carlisle, Robert M. Friedlander

Huntington's disease (HD) is a progressive neurodegenerative brain disorder associated with uncontrolled body movements, cognitive decline, and reduced circulating melatonin levels. Melatonin is a potent antioxidant and exogenous melatonin treatment is neuroprotective in experimental HD models. In neurons, melatonin is exclusively synthesized in the mitochondrial matrix. Thus, we investigated the integrity of melatonin biosynthesis pathways in pineal and extrapineal brain areas in human HD brain samples, in the R6/2 mouse model of HD and in full-length mutant huntingtin knock-in cells. Aralkylamine N-acetyltransferase (AANAT) is the rate-limiting step enzyme in the melatonin biosynthetic pathway. We found that AANAT expression is significantly decreased in the pineal gland and the striatum of HD patients compared to normal controls. In the R6/2 mouse forebrain, AANAT protein expression was decreased in synaptosomal, but not nonsynaptosomal, mitochondria and was associated with decreased synaptosomal melatonin levels compared to wild type mice. We also demonstrate sequestration of AANAT in mutant-huntingtin protein aggregates likely resulting in decreased AANAT bioavailability. Paradoxically, AANAT mRNA expression is increased in tissues where AANAT protein expression is decreased, suggesting a potential feedback loop that is, ultimately unsuccessful. In conclusion, we demonstrate that pineal, extrapineal, and synaptosomal melatonin levels are compromised in the brains of HD patients and R6/2 mice due, at least in part, to protein aggregation.

亨廷顿舞蹈症(HD)是一种进行性神经退行性脑疾病,与身体运动失控、认知能力下降和循环褪黑素水平降低有关。褪黑素是一种强效抗氧化剂,外源性褪黑素治疗对实验性HD模型具有神经保护作用。在神经元中,褪黑激素仅在线粒体基质中合成。因此,我们研究了人类HD脑样本、HD的R6/2小鼠模型和全长突变亨廷顿蛋白敲除细胞中松果体和线外脑区域褪黑素生物合成途径的完整性。阿拉伯烷基胺N-乙酰转移酶(AANAT)是褪黑激素生物合成途径中的限速步进酶。我们发现,与正常对照组相比,HD患者松果体和纹状体中AANAT的表达显著降低。在R6/2小鼠前脑中,与野生型小鼠相比,AANAT蛋白在突触体、线粒体中的表达减少,但在非突触体和线粒体中没有,并且与突触体褪黑素水平降低有关。我们还证明了AANAT在突变亨廷顿蛋白聚集体中的螯合可能导致AANAT生物利用度降低。矛盾的是,在AANAT蛋白表达降低的组织中,AANAT mRNA表达增加,这表明潜在的反馈回路最终是不成功的。总之,我们证明HD患者和R6/2小鼠大脑中的松果体、松果体外和突触体褪黑素水平受损,至少部分原因是蛋白质聚集。
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引用次数: 0
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Journal of Pineal Research
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