glycogen storage

糖原贮存
  • 文章类型: Journal Article
    Lafora病(LD)是由EPM2A(laforin)或NHLRC1(malin)的隐性遗传性遗传病变引起的进行性肌阵挛性癫痫和累积性神经认知恶化的综合征。LD中的神经精神症状被认为是神经元和星形细胞聚葡聚糖聚集体的直接下游,称为拉福拉机构(LBs),在LD的所有小鼠模型中以年龄依赖性的方式忠实地积累。在这项研究中,我们应用家庭笼监测来检查malin缺陷型LD模型中神经行为恶化的程度,以此作为确定可靠的临床前终点的手段,这些终点可能指导新型基因治疗的选择.在6周,6-7个月,和12个月的年龄,malin缺陷小鼠(“KO”)和野生型(WT)同窝动物接受了标准化的家庭笼子行为评估,旨在非突发性地评估休息/唤醒的特征,消费行为,风险厌恶,和自愿的车轮运行。在所有时间点,在我们透明报告的一系列指标上,WT和KO小鼠基本上无法区分。相比之下,在WT小鼠中,在相同的时间点进行比较,我们发现了与年龄相关的夜间活动不足,蔗糖偏好减少,减少车轮运行。相同小鼠亚群的神经病理学检查显示预期的年龄依赖性LB积累,胶质增生,皮质和皮质下脑区域的小胶质细胞激活。在12个月大的时候,尽管有新皮质LBs的负担,我们在脑电图(EEG)调查中没有发现自发性癫痫发作,KO和WT小鼠表现出相似的频谱脑电图特征。然而,在新皮质功能的体外测定中,KO切片中网络活动的阵发性爆发(UP状态)在3个月和6个月大时延长,但在12个月时与WT相似。KO小鼠对戊四唑表现出明显的反应,阵挛性癫痫发作的发生率更高,运动的后期抑制更明显,喂养,和饮酒行为。一起,这些结果突出了LD小鼠模型的临床病理分离,其中LBs的累积可能会潜在地改变皮质回路功能和癫痫发作阈值,而不会使家笼行为发生有临床意义的变化。我们的发现暗示了LD的LB积累和神经行为下降之间的延迟:这可能为治疗提供了一个窗口,在实验室老鼠的典型寿命内,其确切持续时间可能很难确定。
    Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6-7 months, and ∼12 months of age, malin-deficient mice (\"KO\") and wild-type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age-dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home-cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.
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  • 文章类型: Case Reports
    先天性肌病是一组异质性遗传性疾病,主要表现为早发性肌张力减退和肌无力。临床表型谱可以是高度可变的,从非常温和到严重的演讲。该过程也有很大差异,导致在最严重的情况下致命的结果,但可以是良性的或导致改善,即使在严重的表现。肌肉活检分析对于识别病理形态学特征至关重要,如核心领域,线虫体或杆,核集中化和先天性1型纤维不均衡。然而,可以观察到同一肌肉中的多个异常,使肌肉病理情况变得更加复杂。
    这里,我们描述了一个意大利新生儿出现严重的低张力症,呼吸功能不全,无法吸吮和吞咽,需要机械通气和胃造口术喂养。通过光学显微镜分析的肌肉活检显示存在充满糖原的空泡,提示代谢性肌病,但也有嗜血的夹杂物。超微结构研究证实了正常结构糖原的存在,以及微型棒的存在,将诊断假设引导到线虫肌病。针对先天性肌病基因的扩展的下一代测序分析揭示了ACTA1基因中存在新的杂合c.965T>Ap。(Leu322Gln)变体,编码骨骼肌α-肌动蛋白。
    我们的案例扩展了在活动病中观察到的分子和病理特征。我们强调了超微结构检查的价值,以调查在组织学水平上检测到的异常。我们还强调了在神经肌肉患者的分子分析中使用扩展的基因面板,特别是对于那些出现多重活检改变的人。
    UNASSIGNED: Congenital myopathies are a group of heterogeneous inherited disorders, mainly characterized by early-onset hypotonia and muscle weakness. The spectrum of clinical phenotype can be highly variable, going from very mild to severe presentations. The course also varies broadly resulting in a fatal outcome in the most severe cases but can either be benign or lead to an amelioration even in severe presentations. Muscle biopsy analysis is crucial for the identification of pathognomonic morphological features, such as core areas, nemaline bodies or rods, nuclear centralizations and congenital type 1 fibers disproportion. However, multiple abnormalities in the same muscle can be observed, making more complex the myopathological scenario.
    UNASSIGNED: Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding. Muscle biopsy analyzed by light microscopy showed the presence of vacuoles filled with glycogen, suggesting a metabolic myopathy, but also fuchsinophilic inclusions. Ultrastructural studies confirmed the presence of normally structured glycogen, and the presence of minirods, directing the diagnostic hypothesis toward a nemaline myopathy. An expanded Next Generation Sequencing analysis targeting congenital myopathies genes revealed the presence of a novel heterozygous c.965 T > A p. (Leu322Gln) variant in the ACTA1 gene, which encodes the skeletal muscle alpha-actin.
    UNASSIGNED: Our case expands the repertoire of molecular and pathological features observed in actinopathies. We highlight the value of ultrastructural examination to investigate the abnormalities detected at the histological level. We also emphasized the use of expanded gene panels in the molecular analysis of neuromuscular patients, especially for those ones presenting multiple bioptic alterations.
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  • 文章类型: Journal Article
    背景:自新石器时代以来,山羊产品在满足人们的饮食需求方面发挥了至关重要的作用,在全球范围内产生了许多具有不同特征和肉类品质的山羊品种。本研究的主要目的是通过DNA甲基化修饰确定海南黑山羊和杂种山羊中负责调节背最长肌(LDM)肌纤维生长的关键基因及其功能。
    方法:采用全基因组亚硫酸氢盐测序(WGBS)来仔细检查甲基化对LDM生长的影响。这是通过比较甲基化差异来实现的,基因表达,以及它们与生长相关性状的关联。
    结果:在这项研究中,我们从差异甲基化区域(DMR)中鉴定出总共3,269个基因,并通过RNA-seq分析检测到189个差异表达基因(DEGs)。HypoDMR基因主要富集在与肌肉发育相关的KEGG术语中,如MAPK和PI3K-Akt信号通路。我们从网络中选择了11个与DMR和DEG中的基因集相交的hub基因,9个基因与三个LDM生长性状中的一个或多个表现出显著的相关性,即面积,高度,和眼肌的重量。特别是,PRKG1与所有三个性状均呈负相关。前五个最关键的基因在肌纤维生长中起着至关重要的作用:FOXO3保护了肌纤维的免疫环境,FOXO6参与肌管发育和分化,和PRKG1促进血管舒张以释放更多的葡萄糖。这个,反过来,加速了葡萄糖从血管到肌纤维的转移,由ADCY5和AKT2调节,最终确保肌纤维中的糖原储存和能量供应。
    结论:本研究深入研究了影响关键基因的多种甲基化修饰,它们共同有助于维持肌纤维周围的糖原储存,最终支持肌肉纤维生长。
    Goat products have played a crucial role in meeting the dietary demands of people since the Neolithic era, giving rise to a multitude of goat breeds globally with varying characteristics and meat qualities. The primary objective of this study is to pinpoint the pivotal genes and their functions responsible for regulating muscle fiber growth in the longissimus dorsi muscle (LDM) through DNA methylation modifications in Hainan black goats and hybrid goats.
    Whole-genome bisulfite sequencing (WGBS) was employed to scrutinize the impact of methylation on LDM growth. This was accomplished by comparing methylation differences, gene expression, and their associations with growth-related traits.
    In this study, we identified a total of 3,269 genes from differentially methylated regions (DMR), and detected 189 differentially expressed genes (DEGs) through RNA-seq analysis. Hypo DMR genes were primarily enriched in KEGG terms associated with muscle development, such as MAPK and PI3K-Akt signaling pathways. We selected 11 hub genes from the network that intersected the gene sets within DMR and DEGs, and nine genes exhibited significant correlation with one or more of the three LDM growth traits, namely area, height, and weight of loin eye muscle. Particularly, PRKG1 demonstrated a negative correlation with all three traits. The top five most crucial genes played vital roles in muscle fiber growth: FOXO3 safeguarded the myofiber\'s immune environment, FOXO6 was involved in myotube development and differentiation, and PRKG1 facilitated vasodilatation to release more glucose. This, in turn, accelerated the transfer of glucose from blood vessels to myofibers, regulated by ADCY5 and AKT2, ultimately ensuring glycogen storage and energy provision in muscle fibers.
    This study delved into the diverse methylation modifications affecting critical genes, which collectively contribute to the maintenance of glycogen storage around myofibers, ultimately supporting muscle fiber growth.
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  • 文章类型: Preprint
    Lafora病(LD)是由EPM2A(laforin)或NHLRC1(malin)的隐性遗传遗传损伤引起的进行性肌阵挛性癫痫和累积性神经认知恶化的综合征。LD中的神经精神症状被认为是神经元和星形细胞聚葡聚糖聚集体的直接下游,称为拉福拉机构(LBs),在LD的所有小鼠模型中以年龄依赖性的方式忠实地积累。在这项研究中,我们应用家庭笼监测来检查神经行为恶化的程度在一个模型的malin缺乏LD,作为确定可靠的临床前终点的手段,可以指导选择新的基因治疗。在6周,6-7个月和12个月的年龄,malin缺陷小鼠(“KO”)和野生型(WT)同窝进行了标准化的家庭笼子行为评估,旨在非突发性地评估休息/唤醒的特征,消费行为,风险规避和自愿车轮运行。在所有时间点,在我们透明报告的一系列指标上,WT和KO小鼠基本上无法区分。相比之下,在WT小鼠中,跨时间点进行比较,我们发现了与年龄相关的夜间活动不足,蔗糖偏好减少,车轮运行减少。相同小鼠亚群的神经病理学检查显示预期的年龄依赖性LB积累,皮质和皮质下脑区域的胶质增生和小胶质细胞活化。在12个月大的时候,尽管有新皮质LBs的负担,我们在脑电图(EEG)调查中没有发现自发性癫痫发作,KO和WT小鼠表现出相似的频谱脑电图特征。使用新皮层功能的体外测定,KO切片中网络活动的阵发性增加(UP状态)在3个月和6个月大时延长,但在12个月时与WT相似。KO小鼠对戊四唑表现出明显的反应,阵挛性癫痫发作的发生率更高,发作后运动抑制更明显,喂养和饮酒行为。一起,这些结果突出了LD小鼠模型的明显临床病理分离,LBs的积累基本上没有临床意义的整体健康变化。我们的发现暗示了LB积累和神经行为下降之间的延迟:这可能为治疗提供了一个窗口,在实验室老鼠的典型寿命内,其确切持续时间可能很难确定。
    Lafora Disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD, as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ~6-7 months and ~12 months of age, malin deficient mice (\"KO\") and wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age dependent LB accumulation, gliosis and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. Using an in vitro assay of neocortical function, paroxysmal increases in network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but were similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced post-ictal suppression of movement, feeding and drinking behavior. Together, these results highlight a stark clinicopathologic dissociation in a mouse model of LD, where LBs accrue substantially without clinically meaningful changes in overall wellbeing. Our findings allude to a delay between LB accumulation and neurobehavioral decline: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.
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  • 文章类型: Case Reports
    糖原储存型V(GSDV-McArdle综合征)是一种罕见的神经肌肉疾病,其特征是在身体活动开始后早期出现严重疼痛。最近的一系列研究表明,诊断延迟了29年;因此,关于受该疾病影响的儿童的报道很少见(Lucia等人。,2021年,神经肌肉病,31,1296-1310)。本文介绍了8例患者,中位发病年龄为5.5岁,诊断为9.5岁。6例患者发生横纹肌溶解症,肌酸激酶升高>50000IU/L。大多数发作与偏心的非预测活动有关,而不是定期运动。其中一名患者进行了非缺血性前臂测试。一名患者在骨骼肌活检后被诊断出,并且都有确证的分子遗传学诊断。三个是普通PYGM的纯合子:c.148C>T(p。Arg50*)变体。除一名患者外,所有患者都有截短的变体。所有患者都接受了结构化运动测试,以帮助他们识别“第二风”,并计划锻炼方案。此外,所有人还进行了25g麦芽糖糊精的运动测试,这对改善感知的劳累程度具有统计学上的显着影响。GSDV在儿科实践中被低估。基因检测可以很容易地诊断病情。在多学科小组的协助下,在锻炼过程中仔细检查第二风症状,允许孩子管理活动和容忍运动。麦芽糊精可用于结构化运动,但是过度使用可能会导致体重增加。早期干预和教育可以改善成人生活的结果。
    Glycogen storage type V (GSD V-McArdle Syndrome) is a rare neuromuscular disorder characterised by severe pain early after the onset of physical activity. A recent series indicated a diagnostic delay of 29 years; hence reports of children affected by the disorder are uncommon (Lucia et al., 2021, Neuromuscul Disord, 31, 1296-1310). This paper presents eight patients with a median onset age of 5.5 years and diagnosis of 9.5 years. Six patients had episodes of rhabdomyolysis with creatine kinase elevations >50 000 IU/L. Most episodes occurred in relation to eccentric non-predicted activities rather than regular exercise. One of the patients performed a non-ischaemic forearm test. One patient was diagnosed subsequent to a skeletal muscle biopsy, and all had confirmatory molecular genetic diagnosis. Three were homozygous for the common PYGM:c.148C > T (p.Arg50*) variant. All but one patient had truncating variants. All patients were managed with structured exercise testing to help them identify \'second-wind\', and plan an exercise regimen. In addition all also had an exercise test with 25 g maltodextrin which had statistically significant effect on ameliorating ratings of perceived exertion. GSD V is under-recognised in paediatric practice. Genetic testing can readily diagnose the condition. Careful identification of second-wind symptomatology during exercise with the assistance of a multi-disciplinary team, allows children to manage activities and tolerate exercise. Maltodextrin can be used for structured exercise, but excessive utilisation may lead to weight gain. Early intervention and education may improve outcomes into adult life.
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  • 文章类型: Journal Article
    遗传性代谢紊乱是由参与生物发生的基因突变引起的。装配,或代谢酶的活性,导致酶缺乏和严重的代谢障碍。代谢酶对于细胞的正常功能是必不可少的,并且参与氨基酸的产生,脂肪酸和核苷酸,对细胞生长至关重要,分裂与生存。当代谢酶的活性由于突变或表达水平的变化而被破坏时,它可以导致各种代谢紊乱,这些代谢紊乱也与癌症的发展有关。然而,关于癌细胞中代谢酶失调与代谢适应之间的关系,还有很多需要学习的东西。在这次审查中,我们探讨了由于癌细胞中代谢酶的改变或变化而导致的代谢失调在肿瘤发展中起着至关重要的作用,programming,转移和耐药性。此外,这些新陈代谢的变化为癌细胞提供了许多优势,包括增加扩散,抵抗细胞凋亡和逃避免疫系统的能力。肿瘤微环境,遗传背景,和不同的信号通路进一步影响癌症和代谢之间的相互作用。本文旨在探讨代谢酶在特定通路中的失调,包括尿素循环,糖原储存,溶酶体贮存,脂肪酸氧化,和线粒体呼吸,有助于代谢紊乱和癌症的发展。此外,这篇综述试图阐明为什么这些酶是各种癌症中关键的潜在治疗靶点和生物标志物.
    Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types.
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  • 文章类型: Journal Article
    女性代谢性疾病的发病率低于男性,更年期女性代谢性疾病的发病率增加,说明卵巢产生的激素可能影响糖脂代谢的稳态。但潜在的机制仍不清楚。探讨卵巢对女性糖脂代谢的调节作用,对8周龄的C57BL/6小鼠进行卵巢切除术并给予正常食物饮食(NFD)或高脂肪饮食(HFD)。卵巢切除术后6周,检测血液生化指标,检查肝脏形态和组织学。通过转录组分析检测肝脏糖脂代谢相关基因的表达水平,qPCR和蛋白质印迹测定。进行16SrDNA序列分析卵巢切除和不同饮食的小鼠的肠道微生物群。饲喂NFD(OVXN)的去卵巢(OVX)小鼠血清总胆固醇(TC)显著升高,OVXN小鼠和饲喂HFD(OVXH)的OVX小鼠的血清低密度脂蛋白胆固醇(LDL-C)均显着增加。OVXN组37.5%小鼠肝脏中发现糖原贮积过多,在其他62.5%OVXN小鼠的肝脏中检测到脂质积累。根据肝脏的组织学结果,将OVXN组进一步分为OVXN-Gly和OVXN-TG亚组。OVXH小鼠肝脏中的脂滴比其他组更多和更大。OVXN小鼠肝脏中与脂肪生成相关的基因表达水平显著升高,与β-氧化相关的基因表达水平显著下调。卵巢切除术也引起OVXN和OVXH小鼠的肠道菌群失调。这些结果表明,卵巢产生的激素在调节女性肝脏葡萄糖和脂质代谢以及与肠道菌群的沟通中起着重要作用。
    The lower incidence of metabolic diseases of women than men and the increasing morbidity of metabolic disorders of menopausal women indicated that hormones produced by ovaries may affect homeostasis of glucose and lipid metabolism, but the underlying mechanisms remain unclear. To explore the functions of ovaries on regulating glucose and lipid metabolism in females, 8 weeks old C57BL/6 mice were preformed ovariectomy and administrated with normal food diet (NFD) or high fat diet (HFD). Six weeks after ovariectomy, blood biochemical indexes were tested and the morphology and histology of livers were checked. The expression levels of genes related to glucose and lipid metabolism in liver were detected through transcriptome analysis, qPCR and western blot assays. 16S rDNA sequence was conducted to analyze the gut microbiota of mice with ovariectomy and different diets. The serum total cholesterol (TC) was significantly increased in ovariectomized (OVX) mice fed with NFD (OVXN), and serum low density lipoprotein-cholesterol (LDL-C) was significantly increased in both OVXN mice and OVX mice fed with HFD (OVXH). The excessive glycogen storage was found in livers of 37.5% mice from OVXN group, and lipid accumulation was detected in livers of the other 62.5% OVXN mice. The OVXN group was further divided into OVXN-Gly and OVXN-TG subgroups depending on histological results of the liver. Lipid drops in livers of OVXH mice were more and larger than other groups. The expression level of genes related with lipogenesis was significantly increased and the expression level of genes related with β-oxidation was significantly downregulated in the liver of OVXN mice. Ovariectomy also caused the dysbiosis of intestinal flora of OVXN and OVXH mice. These results demonstrated that hormones generated by ovaries played important roles in regulating hepatic glucose and lipid metabolism and communicating with the gut microbiota in females.
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  • 文章类型: Journal Article
    背景:越来越多的数据表明,肝脏的生理是性激素依赖性的,某些类型的肝功能衰竭在男性中更常见,还有一些女性。在男性中,在生理条件下,睾酮通过雄激素受体(AR)增加胰岛素受体(IR)表达和糖原合成,并减少由肝脏特异性葡萄糖转运蛋白2(GLUT-2)控制的葡萄糖摄取。我们先前的研究表明非那雄胺可能损害了这种机制,一种常用于泌尿科和皮肤科的药物,抑制5α-还原酶2,将睾酮(T)转化为双氢睾酮(DHT)。我们的研究还表明,暴露于非那雄胺的大鼠的后代的T-DHT比率发生了变化,并显示出睾丸和附睾的变化。因此,这项研究的目的是评估非那雄胺的给药是否对(i)GLUT-2依赖性糖原在肝脏中的积累有跨代作用,(ii)雄性大鼠后代肝细胞中的IR和AR表达,(iii)血清T和DHT水平与GLUT2,IR表达之间的关系,和ARmRNA,(iv)血清葡萄糖水平及其与GLUT-2mRNA的相关性。
    方法:对7、14、21、28和90天大的Wistar雄性大鼠(F1:Fin)的肝脏(雄激素依赖性器官)进行了研究。对照组是未处理的Wistar父母的后代(F1:对照)。在肝脏的组织学切片中,高碘酸希夫(PAS)染色(可视化糖原)和IHC(检测GLUT-2,IR,和AR)进行。肝脏匀浆用于qRT-PCR评估GLUT2,IR,和ARmRNA表达。PAS阳性糖原面积百分比与GLUT-2的免疫表达相关,血清T和DHT水平与GLUT-2、IR相关,和AR转录水平,血清葡萄糖浓度与动物年龄和GLUT-2mRNA相关,采用Spearman的等级相关系数。
    结果:在F1:Fin大鼠的每个年龄组中,糖原的积累升高,但与GLUT-2表达的变化无关。GLUT-2,IR,在F1:Fin动物中,AR转录物及其免疫反应性在统计学上显着降低。在F1:Fin大鼠中,T和DHT的血清水平与雄激素受体mRNA呈负相关。来自F1:Fin组的动物具有统计学上升高的葡萄糖水平。此外,在成年F1中:鳍大鼠,在肝脏中观察到脂肪变性(见附录A).
    结论:似乎用非那雄胺治疗成年雄性大鼠会导致其后代肝脏中碳水化合物代谢的变化。这可能导致不适当的肝能量稳态或甚至高血糖,胰岛素抵抗,以及代谢综合征和肝脏脂肪变性的一些症状。
    BACKGROUND: A growing body of data indicates that the physiology of the liver is sex-hormone dependent, with some types of liver failure occurring more frequently in males, and some in females. In males, in physiological conditions, testosterone acts via androgen receptors (AR) to increase insulin receptor (IR) expression and glycogen synthesis, and to decrease glucose uptake controlled by liver-specific glucose transporter 2 (GLUT-2). Our previous study indicated that this mechanism may be impaired by finasteride, a popular drug used in urology and dermatology, inhibiting 5α-reductase 2, which converts testosterone (T) into dihydrotestosterone (DHT). Our research has also shown that the offspring of rats exposed to finasteride have an altered T-DHT ratio and show changes in their testes and epididymides. Therefore, the goal of this study was to assess whether the administration of finasteride had an trans-generational effect on (i) GLUT-2 dependent accumulation of glycogen in the liver, (ii) IR and AR expression in the hepatocytes of male rat offspring, (iii) a relation between serum T and DHT levels and the expression of GLUT2, IR, and AR mRNAs, (iv) a serum glucose level and it correlation with GLUT-2 mRNA.
    METHODS: The study was conducted on the liver (an androgen-dependent organ) from 7, 14, 21, 28, and 90-day old Wistar male rats (F1:Fin) born by females fertilized by finasteride-treated rats. The control group was the offspring (F1:Control) of untreated Wistar parents. In the histological sections of liver the Periodic Acid Schiff (PAS) staining (to visualize glycogen) and IHC (to detect GLUT-2, IR, and AR) were performed. The liver homogenates were used in qRT-PCR to assess GLUT2, IR, and AR mRNA expression. The percentage of PAS-positive glycogen areas were correlated with the immunoexpression of GLUT-2, serum levels of T and DHT were correlated with GLUT-2, IR, and AR transcript levels, and serum glucose concentration was correlated with the age of animals and with the GLUT-2 mRNA by Spearman\'s rank correlation coefficients.
    RESULTS: In each age group of F1:Fin rats, the accumulation of glycogen was elevated but did not correlate with changes in GLUT-2 expression. The levels of GLUT-2, IR, and AR transcripts and their immunoreactivity statistically significantly decreased in F1:Fin animals. In F1:Fin rats the serum levels of T and DHT negatively correlated with androgen receptor mRNA. The animals from F1:Fin group have statistically elevated level of glucose. Additionally, in adult F1:Fin rats, steatosis was observed in the liver (see Appendix A).
    CONCLUSIONS: It seems that treating male adult rats with finasteride causes changes in the carbohydrate metabolism in the liver of their offspring. This can lead to improper hepatic energy homeostasis or even hyperglycaemia, insulin resistance, as well as some symptoms of metabolic syndrome and liver steatosis.
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  • 文章类型: Journal Article
    Fatigue may cause the efficiency of the organ in human body to decrease, which may affect the daily life and exercise performance of the general people and athletes. Mare\'s milk powder (MMP) is a lactose rich supplement. The research of the study is to evaluate the whether MMP has anti-fatigue effect. Forty male ICR mice were randomly divided into four group to receive vehicle or MMP by oral gavage at 0 (Vehicle), 0.27 (MMP-1X), 0.54 (MMP-2X), 1.35 (MMP-5X) g/kg/day for 14 days. The forelimb grip of the MMP-2X, and MMP-5X group were significantly higher than the vehicle group. The swim-to-exhaustion times of the MMP-1X, MMP-2X, and MMP-5X group were significantly greater than the vehicle group. Glycogen levels in liver and muscle were significantly larger in the MMP-1X, MMP-2X, and MMP-5X groups than the vehicle group. Receive MMP supplement for 14 days can promoting exercise performance and amelioration of exercise-induced fatigue.
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  • 文章类型: Journal Article
    Ubiquinol (QH), a reduced form of coenzyme Q10, is a lipid antioxidant that is hydro-soluble and is commonly formulated in commercial supplements. Ubiquinol has been increasingly reported to exert antioxidant functions, in addition to its role in the cell energy-producing system of mitochondria and adenosine triphosphate (ATP) production. The aim of this study was to assess the potential beneficial effects of QH on anti-fatigue and ergogenic functions following physiological challenge. Forty 8-week-old male Institute of Cancer Research (ICR) mice were divided into four groups (n = 10 for each group): Group 1 (vehicle control or oil only); Group 2 (1X QH dose or 102.5 mg/kg); Group 3 (2X QH dose or 205 mg/kg); Group 4 (6X QH dose or 615 mg/kg). Anti-fatigue activity and exercise performance were studied using the forelimb grip strength experiment and exhaustive weight-loaded swimming time, and levels of serum lactate, ammonia, glucose, BUN (blood urea nitrogen), creatine kinase (CK), and free fatty acids (FFA) after an acute exercise challenge. The forelimb grip strength and exhaustive weight-loaded swimming time of the QH-6X group were significantly higher than those of the other groups. QH supplementation dose-dependently reduced serum lactate, ammonia, and CK levels and increased the FFA concentration after acute exercise. In addition, QH increased the liver and muscle glycogen content, an important energy source during exercise. Therefore, the results suggest that QH formulation is a safe dietary supplement for amelioration of fatigue and for promoting exercise performance.
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