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Association of Estrogen Receptor-α and Aryl Hydrocarbon Receptor Gene Polymorphisms with Ischemic Stroke in an Egyptian Population: A Pilot Study 埃及人群中雌激素受体-α和芳香烃受体基因多态性与缺血性中风的关系:一项试点研究
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1007/s12031-024-02255-x
Sara A. Aboelroos, Dina Gamal El Segaey, Amr Kamal Abd Elgawad, Marwa Orabi, Marwa Hussein Mohamed, Nashwa R. Hassan

Stroke is the second leading cause of death and a major contributor to disability worldwide, with the highest prevalence in developing countries. Ischemic stroke (IS) is a complex disease resulting from genetic and environmental interactions. The present work is a pilot study exploring the association of estrogen receptor-α (ESR1) and aryl hydrocarbon receptor (AHR) SNPs with IS in a small Egyptian population of IS patients. Sixty IS patients and 60 matched healthy controls were included in this case–control study. Genotyping of ESR1 PvuII (rs2234693), ESR1 XbaI (rs9340799), and AHR rs2066853 SNPs was performed using real-time PCR. ESR1 PvuII TC and CC genotypes were associated with IS (odds ratio (OR) = 2.821, 95% confidence interval (CI) = 1.204–6.609, p = 0.017, and OR = 9.455, 95% CI = 2.222–40.237, p = 0.002, respectively), and TC genotype in female IS (OR = 4.018, 95% CI = 1.117–14.455, p = 0.033). Additionally, ESR1 XbaI GA and GG genotypes were associated with IS (OR = 2.833, 95% CI = 1.190–6.749, p = 0.019, and OR = 34.000, 95% CI = 6.965–165.980, p < 0.001, respectively), and the AG and GG genotypes in male IS (OR = 3.378, 95% CI = 1.103–10.347, p = 0.033 and OR = 22.8, 95% CI = 2.580–201.488, p = 0.005, respectively) and the GG genotype in female IS (95% CI = 7.259–1115.914, p < 0.001). ESR1 PvuII and XbaI haplotypes C—A, T—G, and C—A increased the risk of IS in both genders, in male IS, and in female IS apart from C—A. The AG genotype of AHR rs2066853 was associated with male IS (OR = 6.900, 95% CI = 2.120–22.457 p = 0.001). ESR1 PvuII, ESR1 XbaI, and AHR rs2066853 SNPs are associated with IS in Egyptians. However, this is a small sample, and the findings should be replicated in a larger population.

中风是全球第二大死因,也是导致残疾的主要因素,在发展中国家发病率最高。缺血性中风(IS)是一种由遗传和环境相互作用导致的复杂疾病。本研究是一项探索雌激素受体-α(ESR1)和芳基烃受体(AHR)SNPs 与缺血性中风关系的试验性研究。这项病例对照研究纳入了 60 名 IS 患者和 60 名匹配的健康对照者。采用实时 PCR 对 ESR1 PvuII(rs2234693)、ESR1 XbaI(rs9340799)和 AHR rs2066853 SNPs 进行了基因分型。ESR1 PvuII TC和CC基因型与IS相关(几率比(OR)= 2.821,95%置信区间(CI)= 1.204-6.609,p = 0.017;OR = 9.455,95% CI = 2.222-40.237,p = 0.002),女性IS的TC基因型与IS相关(OR = 4.018,95% CI = 1.117-14.455,p = 0.033)。此外,ESR1 XbaI GA和GG基因型与IS相关(分别为OR = 2.833,95% CI = 1.190-6.749,p = 0.019和OR = 34.000,95% CI = 6.965-165.980,p <0.001),男性IS中的AG和GG基因型与IS相关(OR = 3.378,95% CI = 1.103-10.347,p = 0.033 和 OR = 22.8,95% CI = 2.580-201.488,p = 0.005),以及女性 IS 中的 GG 基因型(95% CI = 7.259-1115.914,p <0.001)。ESR1的PvuII和XbaI单倍型C-A、T-G和C-A增加了男女两性、男性IS和女性IS(C-A除外)的IS风险。AHR rs2066853 的 AG 基因型与男性 IS 相关(OR = 6.900,95% CI = 2.120-22.457 p = 0.001)。ESR1 PvuII、ESR1 XbaI和AHR rs2066853 SNP与埃及人的IS有关。然而,这只是一个小样本,研究结果应在更大的人群中重复。
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引用次数: 0
Sex-Specific ADNP/NAP (Davunetide) Regulation of Cocaine-Induced Plasticity ADNP/NAP(达武内酯)对可卡因诱导的可塑性的性别特异性调控
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1007/s12031-024-02234-2
Yael Toren, Yarden Ziv, Shlomo Sragovich, R. Anne McKinney, Segev Barak, Shula Shazman, Illana Gozes

Cocaine use disorder (CUD) is a chronic neuropsychiatric disorder estimated to effect 1–3% of the population. Activity-dependent neuroprotective protein (ADNP) is essential for brain development and functioning, shown to be protective in fetal alcohol syndrome and to regulate alcohol consumption in adult mice. The goal of this study was to characterize the role of ADNP, and its active peptide NAP (NAPVSIPQ), which is also known as davunetide (investigational drug) in mediating cocaine-induced neuroadaptations. Real time PCR was used to test levels of Adnp and Adnp2 in the nucleus accumbens (NAc), ventral tegmental area (VTA), and dorsal hippocampus (DH) of cocaine-treated mice (15 mg/kg). Adnp heterozygous (Adnp +/−)and wild-type (Adnp +/−) mice were further tagged with excitatory neuronal membrane-expressing green fluorescent protein (GFP) that allowed for in vivo synaptic quantification. The mice were treated with cocaine (5 injections; 15 mg/kg once every other day) with or without NAP daily injections (0.4 µg/0.1 ml) and sacrificed following the last treatment. We analyzed hippocampal CA1 pyramidal cells from 3D confocal images using the Imaris x64.8.1.2 (Oxford Instruments) software to measure changes in dendritic spine density and morphology. In silico ADNP/NAP/cocaine structural modeling was performed as before. Cocaine decreased Adnp and Adnp2 expression 2 h after injection in the NAc and VTA of male mice, with mRNA levels returning to baseline levels after 24 h. Cocaine further reduced hippocampal spine density, particularly synaptically weaker immature thin and stubby spines, in male Adnp+/+) mice while increasing synaptically stronger mature (mushroom) spines in Adnp+/−) male mice and thin and stubby spines in females. Lastly, we showed that cocaine interacts with ADNP on a zinc finger domain identical to ketamine and adjacent to a NAP-zinc finger interaction site. Our results implicate ADNP in cocaine abuse, further placing the ADNP gene as a key regulator in neuropsychiatric disorders. Ketamine/cocaine and NAP treatment may be interchangeable to some degree, implicating an interaction with adjacent zinc finger motifs on ADNP and suggestive of a potential sex-dependent, non-addictive NAP treatment for CUD.

可卡因使用障碍(CUD)是一种慢性神经精神疾病,据估计影响着1%-3%的人口。活动依赖性神经保护蛋白(ADNP)对大脑的发育和功能至关重要,在胎儿酒精综合征中具有保护作用,并能调节成年小鼠的饮酒量。本研究的目的是确定 ADNP 及其活性肽 NAP(NAPVSIPQ)在介导可卡因诱导的神经适应中的作用。利用实时 PCR 检测了可卡因(15 毫克/千克)处理小鼠的伏隔核(NAc)、腹侧被盖区(VTA)和海马背侧(DH)中 Adnp 和 Adnp2 的水平。Adnp 杂合子(Adnp +/-)和野生型(Adnp +/-)小鼠进一步标记了兴奋性神经元膜表达的绿色荧光蛋白(GFP),以便进行体内突触定量。小鼠接受可卡因治疗(5 次注射;15 毫克/千克,隔天一次),每天注射或不注射 NAP(0.4 微克/0.1 毫升),最后一次治疗后处死。我们使用 Imaris x64.8.1.2 (Oxford Instruments) 软件对三维共聚焦图像中的海马 CA1 锥体细胞进行分析,以测量树突棘密度和形态的变化。ADNP/NAP/可卡因的结构建模同前。可卡因注射后 2 小时,雄性小鼠 NAc 和 VTA 中 Adnp 和 Adnp2 的表达量减少,24 小时后 mRNA 水平恢复到基线水平。 可卡因进一步降低了雄性 Adnp+/+) 小鼠的海马棘突密度,尤其是突触较弱的未成熟细长棘突,同时增加了雄性 Adnp+/-) 小鼠突触较强的成熟(蘑菇状)棘突,以及雌性小鼠的细长棘突。最后,我们发现可卡因与 ADNP 的锌指结构域相互作用,该结构域与氯胺酮相同,并且毗邻 NAP 锌指相互作用位点。我们的研究结果表明,ADNP与可卡因滥用有关,进一步将ADNP基因定位为神经精神疾病的关键调节因子。氯胺酮/可卡因和 NAP 治疗可能在某种程度上可以互换,这意味着与 ADNP 上相邻锌指基团的相互作用,并暗示了一种潜在的性依赖性、非成瘾性 NAP 治疗 CUD 的方法。
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引用次数: 0
REV-ERBα Mitigates Astrocyte Activation and Protects Dopaminergic Neurons from Damage REV-ERBα 可减轻星形胶质细胞的激活并保护多巴胺能神经元免受损伤
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1007/s12031-024-02264-w
Xiaoyu Wang, Hui Zhi, Zongqin Zhang, Jingwei Li, Dongkai Guo

Parkinson’s disease (PD) is characterized by astrocyte activation and disruptions in circadian rhythm. Within the astrocyte population, two distinct reactive states exist: A1 and A2. A1 astrocytes are associated with neurotoxicity and inflammation, while A2 astrocytes exhibit neuroprotective functions. Our investigation focused on the role of REV-ERBα, a member of the nuclear receptor superfamily and a key regulator of the circadian clock, in astrocyte activation. We observed that REV-ERBα expression in A1 astrocytes was reduced to one-third of its normal level. Notably, activation of REV-ERBα prompted a transformation of astrocytes from A1 to A2. Mechanistically, REV-ERBα inhibition was linked to the classical NF-κB pathway, while it concurrently suppressed the STAT3 pathway. Furthermore, astrocytes with low REV-ERBα expression were associated with dopaminergic neurons apoptosis. Intriguingly, the opposite effect was observed when using a REV-ERBα agonist, which mitigated astrocyte activation and reduced dopaminergic neuron damage by 50%. In summary, our study elucidates the pivotal role of REV-ERBα in modulating astrocyte function and its potential implications in PD pathogenesis.

帕金森病(PD)的特点是星形胶质细胞活化和昼夜节律紊乱。在星形胶质细胞群中,存在两种截然不同的反应状态:A1 和 A2。A1 星形胶质细胞与神经毒性和炎症有关,而 A2 星形胶质细胞则具有神经保护功能。我们的研究重点是 REV-ERBα在星形胶质细胞活化中的作用,REV-ERBα是核受体超家族的成员,也是昼夜节律时钟的关键调节因子。我们观察到,REV-ERBα在A1星形胶质细胞中的表达量减少到正常水平的三分之一。值得注意的是,REV-ERBα的激活促使星形胶质细胞从A1转变为A2。从机理上讲,REV-ERBα的抑制与经典的NF-κB通路有关,同时它也抑制了STAT3通路。此外,REV-ERBα低表达的星形胶质细胞与多巴胺能神经元凋亡有关。耐人寻味的是,当使用 REV-ERBα 激动剂时,却观察到了相反的效果,它能减轻星形胶质细胞的激活,并使多巴胺能神经元的损伤减少 50%。总之,我们的研究阐明了REV-ERBα在调节星形胶质细胞功能中的关键作用及其在帕金森病发病机制中的潜在影响。
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引用次数: 0
Sedative Effects of Daidzin, Possibly Through the GABAA Receptor Interaction Pathway: In Vivo Approach with Molecular Dynamic Simulations Daidzin可能通过GABAA受体相互作用途径产生的镇静作用:体内方法与分子动力学模拟。
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1007/s12031-024-02261-z
Md. Torequl Islam, Md. Shimul Bhuia, Salehin Sheikh, Rubel Hasan, Mehedi Hasan Bappi, Raihan Chowdhury, Siddique Akber Ansari, Md. Amirul Islam, Md. Saifuzzaman

The soy isoflavone daidzin (DZN) has been considered a hopeful bioactive compound having diverse biological activities, including anxiolytic, memory-enhancing, and antiepileptic effects, in experimental animals. However, its sedative and hypnotic effects are yet to be discovered. This study aimed to evaluate its sedative/hypnotic effect on Swiss mice. Additionally, in silico studies were also performed to see the possible molecular mechanisms behind the tested neurological effect. For this, male Swiss albino mice were treated with DZN (5, 10, or 20 mg/kg) intraperitoneally (i.p.) with or without the standard GABAergic medication diazepam (DZP) and/or flumazenil (FLU) and checked for the onset and duration of sleeping time using thiopental sodium-induced as well as DZP-induced sleeping tests. A molecular docking study was also performed to check its interaction capacity with the α1 and β2 subunits of the GABAA receptor. Findings suggest that DZN dose-dependently and significantly reduced the latency while increasing the duration of sleep in animals. In combination therapy, DZN shows synergistic effects with the DZP-2 and DZP-2 + FLU-0.01 groups, resulting in significantly (p < 0.05) reduced latency and increased sleep duration. Further, molecular docking studies demonstrate that DZN has a strong binding affinity of − 7.2 kcal/mol, which is closer to the standard ligand DZP (− 8.3 kcal/mol) against the GABAA (6X3X) receptor. Molecular dynamic simulations indicated stability and similar binding locations for DZP and DZN with 6X3X. In conclusion, DZN shows sedative effects on Swiss mice, possibly through the GABAA receptor interaction pathway.

大豆异黄酮大豆异黄酮(DZN)被认为是一种有希望的生物活性化合物,在实验动物中具有多种生物活性,包括抗焦虑、增强记忆和抗癫痫作用。然而,它的镇静和催眠作用尚未被发现。本研究旨在评估其对瑞士小鼠的镇静/催眠作用。此外,研究人员还进行了硅学研究,以了解所测试的神经效应背后可能的分子机制。为此,雄性瑞士白化小鼠腹腔注射(i.p.)DZN(5、10 或 20 毫克/千克),同时注射或不注射标准 GABA 能药物地西泮(DZP)和/或氟马西尼(FLU)。还进行了分子对接研究,以检查其与 GABAA 受体 α1 和 β2 亚基的相互作用能力。研究结果表明,DZN 可剂量依赖性地显著降低动物的睡眠潜伏期,同时延长睡眠时间。在联合治疗中,DZN与DZP-2组和DZP-2 + FLU-0.01组显示出协同效应,从而显著(p A(6X3X)受体。分子动力学模拟表明,DZP 和 DZN 与 6X3X 的结合稳定且结合位置相似。总之,DZN 对瑞士小鼠有镇静作用,可能是通过 GABAA 受体相互作用途径。
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引用次数: 0
Regulation of Hippocamposeptal Synaptic Transmission by GABABRs Is Altered in 5XFAD Mice in a Sex- and Age-Dependent Manner GABABRs 对海马突触传递的调控在 5XFAD 小鼠中发生了改变,其改变与性别和年龄有关。
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-30 DOI: 10.1007/s12031-024-02260-0
Joanne C. Damborsky, Jerrel L. Yakel

Hippocamposeptal (HS) neurons send GABAergic projections from the hippocampus to the medial septum/diagonal band of Broca (MS/DBB) as part of a reciprocal loop that is critical for memory. HS neurons are proposed to be particularly sensitive to the deleterious effects of pathological exposure to amyloid-β (Aβ), as would occur during Alzheimer’s disease (AD). However, it is not known how HS GABA release in the MS/DBB is altered during the progression of AD. To target HS neurons in a mouse model of AD, we crossed SST-Cre mice to 5XFAD mice and performed stereotaxic injections of Cre-dependent AAV containing mCherry/channelrhodopsin-2 (ChR2) into the hippocampus of offspring at 4, 6, 9, and 12 months. We used optogenetics to selectively stimulate HS terminals while performing whole-cell patch-clamp recordings from MS/DBB neurons in slices. There was a transient reduction in HS-inhibitory postsynaptic current (IPSC) amplitude in female 5XFAD mice at 6 months, but no difference in males at any age, and no difference in paired-pulse ratio in either sex at any age. When bath applying the GABABR agonist, baclofen, we found a larger decrease in HS-IPSC amplitude in 5XFAD females at 9 months and 5XFAD males at 12 months. In 12-month-old 5XFAD females, response to baclofen was significantly reduced. These data suggest that there is a transient increase in responsiveness to GABABR activation in 5XFAD mice that occurs earlier in females than in males. These sex-specific changes to HS function are likely to impact the relay of information between the hippocampus and MS/DBB.

海马(HS)神经元从海马向布罗卡内侧隔/对角带(MS/DBB)发出GABA能投射,这是一个对记忆至关重要的相互环路的一部分。HS 神经元被认为对淀粉样蛋白-β(Aβ)的病理暴露的有害影响特别敏感,阿尔茨海默病(AD)期间就会出现这种情况。然而,目前还不清楚在阿兹海默病发展过程中,MS/DBB中的HS GABA释放是如何改变的。为了在 AD 小鼠模型中靶向 HS 神经元,我们将 SST-Cre 小鼠与 5XFAD 小鼠杂交,并在小鼠 4、6、9 和 12 个月大时将含有 mCherry/channelrhodopsin-2 (ChR2) 的 Cre 依赖性 AAV 立体定向注射到后代的海马中。在对切片中的 MS/DBB 神经元进行全细胞膜片钳记录时,我们使用光遗传学方法选择性地刺激 HS 终末。雌性5XFAD小鼠在6个月大时,HS抑制性突触后电流(IPSC)的振幅会短暂降低,但雄性小鼠在任何年龄段都没有差异,而且任何年龄段的雌雄小鼠配对脉冲比率都没有差异。当浴用 GABABR 激动剂巴氯芬时,我们发现 9 个月大的 5XFAD 雌鼠和 12 个月大的 5XFAD 雄鼠的 HS-IPSC 振幅下降幅度更大。在 12 个月大的 5XFAD 雌性中,对巴氯芬的反应明显减弱。这些数据表明,5XFAD小鼠对GABABR激活的反应性有短暂的增加,雌性比雄性发生得早。HS 功能的这些性别特异性变化可能会影响海马和 MS/DBB 之间的信息传递。
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引用次数: 0
Assessment of Expression of lncRNAs in Autistic Patients 自闭症患者体内 lncRNAs 的表达评估
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-26 DOI: 10.1007/s12031-024-02258-8
Saba Sane, Vera Ebrahimi, Zeinab Shirvani Farsani, Soudeh Ghafouri-Fard

Autism is a severe neurodevelopmental condition with unknown pathobiology. Nevertheless, multiple pieces of evidence suggest long non-coding RNA (lncRNA) dysregulation may be a contributing factor to this disorder. We investigated the association between the expression of five specific lncRNAs and autism. Peripheral blood was collected from 30 children with autism and 41 healthy children. The expression levels of PCAT-29, lincRNA-ROR, LINC-PINT, lincRNA-p21, and PCAT-1 were calculated. Then, their significance as biomarkers was also evaluated. The expression of LincRNA-ROR (27 times), LINC-PINT (5.26 times), LincRNA-p21 (4.54 times), PCAT-29 (16.66 times), and PCAT-1 (25 times) genes was significantly decreased in patients compared to the control group (p values < 0.05). According to the ROC curve analysis for each lncRNA, LincRNA-ROR, LINC-PINT, LincRNA-p21, PCAT-29, and PCAT-1 lncRNAs with diagnostic power of 0.85, 0.67, 0.64, 0.74, and 0.84, respectively, could be used as diagnostic biomarkers for autism. Additionally, significant positive correlations were reported between expression levels of PCAT-1 and PCAT-29 genes. Moreover, a positive correlation was detected between expression levels of lincRNA-ROR and patients’ age. The current study shows further pieces of evidence for deregulation of lncRNAs in autistic patients that show these lncRNAs may play an important part in the pathogenesis of ASD. However, the role of lncRNA in the neurobiology of autism needs to be investigated further.

自闭症是一种严重的神经发育疾病,其病理生理学尚不清楚。然而,多种证据表明,长非编码 RNA(lncRNA)失调可能是导致这种疾病的一个因素。我们研究了五种特定 lncRNA 的表达与自闭症之间的关系。我们收集了 30 名自闭症儿童和 41 名健康儿童的外周血。计算了 PCAT-29、lincRNA-ROR、LINC-PINT、lincRNA-p21 和 PCAT-1 的表达水平。然后,还评估了它们作为生物标志物的意义。与对照组相比,患者体内 LincRNA-ROR(27 倍)、LINC-PINT(5.26 倍)、LincRNA-p21(4.54 倍)、PCAT-29(16.66 倍)和 PCAT-1 (25 倍)基因的表达量均显著下降(P 值为
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引用次数: 0
Associations Between Gut Microbiota and Alcohol Abuse: A Mendelian Randomisation and Bioinformatics Study 肠道微生物群与酗酒之间的关系:孟德尔随机化和生物信息学研究》。
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-26 DOI: 10.1007/s12031-024-02259-7
Xu Wang, Lei Pan, Jingyan Gu, Lianping Gu, Meiqing Lou, Yaohua Liu

Alcohol abuse, also known as Alcohol Use Disorder (AUD), is a substance dependency psychiatric disorder. We aimed to establish a causal relationship between specific gut microbiota and alcohol abuse using Mendelian Randomisation (MR) and bioinformatics methods. We acquired summary data of genome-wide association studies (GWAS) for gut microbiota and alcohol abuse from the Mibiogen and Finngen databases, respectively. We conducted MR analyses using various methodologies and mapped the single nucleotide polymorphisms (SNPs) to genes via the FUMA GWAS platform. We further performed multiple enrichment analyses and a Multi-variable Mendelian Randomisation (MVMR) approach to examine whether gut microbiota influences alcohol abuse by modulating neurotransmitter-related amino acids. The MR analysis revealed an inverse relationship between the genus Eubacterium ventriosum group and the Porphyromonadaceae family with alcohol abuse. Gene enrichment analysis showed that these genes are expressed in brain tissue and are involved in addictive disorders, psychiatric conditions, immunological processes, neurotransmitter synthesis and synaptic regulation. MVMR analysis suggested that the Porphyromonadaceae family as well as genus Eubacterium ventriosum group may suppress alcohol abuse through the metabolism of neurotransmitter-related amino acids, especially Tryptophan. The MR analysis and bioinformatics investigations indicate that the genus Eubacterium ventriosum group and Porphyromonadaceae family confer a protective effect against alcohol abuse, potentially through the modulation of synaptic function.

酗酒又称酒精使用障碍(AUD),是一种药物依赖性精神疾病。我们旨在利用孟德尔随机化(MR)和生物信息学方法确定特定肠道微生物群与酗酒之间的因果关系。我们分别从 Mibiogen 和 Finngen 数据库中获取了有关肠道微生物群和酗酒的全基因组关联研究(GWAS)的汇总数据。我们使用各种方法进行了磁共振分析,并通过 FUMA GWAS 平台将单核苷酸多态性(SNPs)映射到基因上。我们进一步进行了多重富集分析和多变量孟德尔随机化(MVMR)方法,以研究肠道微生物群是否通过调节神经递质相关氨基酸来影响酗酒。MR分析表明,Eubacterium ventriosum属和Porphyromonadaceae科与酗酒之间存在反向关系。基因富集分析表明,这些基因在脑组织中表达,参与成瘾性疾病、精神疾病、免疫过程、神经递质合成和突触调节。MVMR分析表明,卟啉菌科(Porphyromonadaceae)和文曲霉属(Eubacterium ventriosum)可能通过代谢神经递质相关氨基酸(尤其是色氨酸)来抑制酒精滥用。磁共振分析和生物信息学研究表明,文曲霉属和卟啉单胞菌科细菌可能通过调节突触功能,对酗酒具有保护作用。
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引用次数: 0
Electroacupuncture Alleviates Streptozotocin-Induced Diabetic Neuropathic Pain via the TRPV1-Mediated CaMKII/CREB Pathway in Rats 电针通过 TRPV1 介导的 CaMKII/CREB 通路缓解大鼠链脲佐菌素诱发的糖尿病神经病理性疼痛
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1007/s12031-024-02256-w
Yinmu Zheng, Siyi Li, Yurong Kang, Qunqi Hu, Yu Zheng, Xiaoxiang Wang, Hengyu Chi, Keying Guo, Minjian Jiang, Zhouyuan Wei, Xiaomei Shao, Chi Xu, Boyu Liu, Junying Du, Xiaofen He, Jianqiao Fang, Zhenzhong Lu, Yongliang Jiang

Diabetic neuropathic pain (DNP) is a diabetic complication that causes severe pain and deeply impacts the quality of the sufferer’s daily life. Currently, contemporary clinical treatments for DNP generally exhibit a deficiency in effectiveness. Electroacupuncture (EA) is recognized as a highly effective and safe treatment for DNP with few side effects. Regrettably, the processes via which EA alleviates DNP are still poorly characterized. Transient receptor potential vanilloid 1 (TRPV1) and phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) are overexpressed on spinal cord dorsal horn (SCDH) in DNP rats, and co-localization is observed between them. Capsazepine, a TRPV1 antagonist, effectively reduced nociceptive hypersensitivity and downregulated the overexpression of phosphorylated CaMKIIα in rats with DNP. Conversely, the CaMKII inhibitor KN-93 did not have any impact on TRPV1. EA alleviated heightened sensitivity to pain caused by nociceptive stimuli and downregulated the level of TRPV1, p-CaMKIIα, and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in DNP rats. Intrathecal injection of capsaicin, on the other hand, reversed the above effects of EA. These findings indicated that the CaMKII/CREB pathway on SCDH is located downstream of TRPV1 and is affected by TRPV1. EA alleviates DNP through the TRPV1-mediated CaMKII/CREB pathway.

糖尿病神经性疼痛(DNP)是一种糖尿病并发症,会引起剧烈疼痛,严重影响患者的日常生活质量。目前,针对 DNP 的当代临床疗法普遍存在疗效不足的问题。电针(EA)是公认的治疗 DNP 的高效、安全且副作用小的疗法。遗憾的是,电针缓解 DNP 的过程仍不甚明了。瞬时受体电位香草素 1(TRPV1)和磷酸化钙/钙调蛋白依赖性蛋白激酶 II(p-CaMKII)在 DNP 大鼠的脊髓背角(SCDH)上过度表达,并且它们之间存在共定位。辣椒素是一种 TRPV1 拮抗剂,它能有效降低 DNP 大鼠的痛觉过敏性,并下调磷酸化 CaMKIIα 的过度表达。相反,CaMKII 抑制剂 KN-93 对 TRPV1 没有任何影响。EA 缓解了 DNP 大鼠对痛觉刺激引起的疼痛敏感性的提高,并下调了 TRPV1、p-CaMKIIα 和磷酸化环磷酸腺苷反应元件结合蛋白(p-CREB)的水平。另一方面,鞘内注射辣椒素可逆转 EA 的上述效应。这些发现表明,SCDH 上的 CaMKII/CREB 通路位于 TRPV1 下游,并受到 TRPV1 的影响。EA通过TRPV1介导的CaMKII/CREB途径缓解DNP。
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引用次数: 0
GDNF's Role in Mitigating Intestinal Reactive Gliosis and Inflammation to Improve Constipation and Depressive Behavior in Rats with Parkinson’s disease GDNF 在减轻肠道反应性胶质细胞增多和炎症以改善帕金森病大鼠便秘和抑郁行为中的作用
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-19 DOI: 10.1007/s12031-024-02254-y
Qin Xiaoling, Guo Yurong, Xue Ke, Qiu Yuxiang, An Panpan, Du Yinzhen, Li Xue, Liu Tingting, Tang Chuanxi

Constipation is a common symptom in patients with Parkinson's disease (PD) and is often associated with depression. Enteric glial cells (EGCs) are crucial for regulating intestinal inflammation and colon motility, and their activation can lead to the death of intestinal neurons. Glial cell line-derived neurotrophic factor (GDNF) has been recognized for its neuroprotective properties in various neurological disorders, including PD. This study explores the potential of GDNF in alleviating intestinal reactive gliosis and inflammation, thereby improving constipation and depressive behavior in a rat model of PD. A PD model was established via unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA). Five weeks post-injury, AAV5-GDNF (2 ~ 5 × 10^11) was intraperitoneally injected into experimental and control rats. Fecal moisture percentage (FMP) and colonic propulsion rate (CPPR) were used to evaluate colon motility. Colon-related inflammation and colonic epithelial morphology were assessed, and depressive behavior was analyzed one week before sampling. PD rats exhibited reduced colonic motility and GDNF expression, along with increased EGC reactivity and elevated levels of pro-inflammatory cytokines IL-1, IL-6, and TNF-α. Additionally, there was an up-regulation of CX43 and a decrease in PGP 9.5 expression. The intraperitoneal injection of AAV-GDNF significantly protected colonic neurons by inhibiting EGC activation and down-regulating CX43. This treatment also led to a notable reduction in depressive-like symptoms in PD rats with constipation. GDNF effectively reduces markers of reactive gliosis and inflammation, and promotes the survival of colonic neurons, and improves colonic motility in PD rats by regulating CX43 activity. Furthermore, GDNF treatment alleviates depressive behavior, suggesting that GDNF or its agonists could be promising therapeutic agents for managing gastrointestinal and neuropsychiatric symptoms associated with PD.

便秘是帕金森病(PD)患者的常见症状,而且常常与抑郁有关。肠胶质细胞(EGCs)对调节肠道炎症和结肠运动至关重要,它们的激活可导致肠道神经元死亡。胶质细胞系源性神经营养因子(GDNF)在包括帕金森病在内的多种神经系统疾病中的神经保护特性已得到认可。本研究探讨了 GDNF 在缓解肠道反应性神经胶质细胞增多和炎症方面的潜力,从而改善 PD 大鼠模型中的便秘和抑郁行为。通过单侧立体定向注射 6-羟基多巴胺(6-OHDA)建立了一种帕金森病模型。损伤后五周,实验鼠和对照组大鼠腹腔注射 AAV5-GDNF(2 ~ 5 × 10^11)。粪便水分百分比(FMP)和结肠推进率(CPPR)用于评估结肠运动。评估结肠相关炎症和结肠上皮形态,并在取样前一周分析抑郁行为。帕金森病大鼠的结肠运动和 GDNF 表达减少,EGC 反应性增加,促炎细胞因子 IL-1、IL-6 和 TNF-α 水平升高。此外,CX43 表达上调,PGP 9.5 表达下降。腹腔注射 AAV-GDNF 可抑制 EGC 的激活并下调 CX43,从而显著保护结肠神经元。这种治疗方法还明显减轻了患有便秘的帕金森病大鼠的抑郁症状。GDNF 可有效降低反应性神经胶质增生和炎症的标志物,促进结肠神经元的存活,并通过调节 CX43 的活性改善帕金森病大鼠的结肠运动能力。此外,GDNF治疗还能缓解抑郁行为,这表明GDNF或其激动剂可能是治疗与帕金森病相关的胃肠道和神经精神症状的有效药物。
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引用次数: 0
A Holistic Analysis of Alzheimer’s Disease-Associated lncRNA Communities Reveals Enhanced lncRNA-miRNA-RBP Regulatory Triad Formation Within Functionally Segregated Clusters 对阿尔茨海默病相关lncRNA群落的整体分析揭示了在功能分隔的群落中增强的lncRNA-miRNA-RBP调控三元组的形成。
IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1007/s12031-024-02244-0
Somenath Sen, Debashis Mukhopadhyay

Recent studies on the regulatory networks implicated in Alzheimer’s disease (AD) evince long non-coding RNAs (lncRNAs) as crucial regulatory players, albeit a poor understanding of the mechanism. Analyzing differential gene expression in the RNA-seq data from the post-mortem AD brain hippocampus, we categorized a list of AD-dysregulated lncRNA transcripts into functionally similar communities based on their k-mer profiles. Using machine-learning-based algorithms, their subcellular localizations were mapped. We further explored the functional relevance of each community through AD-dysregulated miRNA, RNA-binding protein (RBP) interactors, and pathway enrichment analyses. Further investigation of the miRNA–lncRNA and RBP–lncRNA networks from each community revealed the top RBPs, miRNAs, and lncRNAs for each cluster. The experimental validation community yielded ELAVL4 and miR-16-5p as the predominant RBP and miRNA, respectively. Five lncRNAs emerged as the top-ranking candidates from the RBP/miRNA-lncRNA networks. Further analyses of these networks revealed the presence of multiple regulatory triads where the RBP–lncRNA interactions could be augmented by the enhanced miRNA–lncRNA interactions. Our results advance the understanding of the mechanism of lncRNA-mediated AD regulation through their interacting partners and demonstrate how these functionally segregated but overlapping regulatory networks can modulate the disease holistically.

最近关于阿尔茨海默病(AD)相关调控网络的研究表明,长非编码 RNA(lncRNA)是重要的调控因子,尽管人们对其机制还不甚了解。通过分析AD死后大脑海马区RNA-seq数据中的差异基因表达,我们根据其k-mer图谱将AD失调的lncRNA转录本列表归类为功能相似的群体。利用基于机器学习的算法,我们绘制了它们的亚细胞定位图。我们通过AD失调的miRNA、RNA结合蛋白(RBP)相互作用者和通路富集分析,进一步探索了每个群落的功能相关性。对每个群落的 miRNA-lncRNA 和 RBP-lncRNA 网络的进一步研究揭示了每个群落的顶级 RBP、miRNA 和 lncRNA。在实验验证群落中,ELAVL4 和 miR-16-5p 分别是最主要的 RBP 和 miRNA。五个 lncRNA 成为 RBP/miRNA-lncRNA 网络中排名最高的候选者。对这些网络的进一步分析表明,存在多个调控三元组,在这些三元组中,RBP-lncRNA的相互作用可通过增强的miRNA-lncRNA相互作用而得到加强。我们的研究结果加深了人们对 lncRNA 通过其相互作用伙伴介导的 AD 调控机制的理解,并证明了这些功能分离但相互重叠的调控网络是如何从整体上调节疾病的。
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引用次数: 0
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Journal of Molecular Neuroscience
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