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Enhancing adipose tissue functionality in obesity: senotherapeutics, autophagy and cellular senescence as a target. 增强肥胖症中脂肪组织的功能:以衰老治疗、自噬和细胞衰老为目标。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-08 DOI: 10.1186/s40659-024-00531-z
Consuelo Arias, Javiera Álvarez-Indo, Mariana Cifuentes, Eugenia Morselli, Bredford Kerr, Patricia V Burgos

Obesity, a global health crisis, disrupts multiple systemic processes, contributing to a cascade of metabolic dysfunctions by promoting the pathological expansion of visceral adipose tissue (VAT). This expansion is characterized by impaired differentiation of pre-adipocytes and an increase in senescent cells, leading to a pro-inflammatory state and exacerbated oxidative stress. Particularly, the senescence-associated secretory phenotype (SASP) and adipose tissue hypoxia further impair cellular function, promoting chronic disease development. This review delves into the potential of autophagy modulation and the therapeutic application of senolytics and senomorphics as novel strategies to mitigate adipose tissue senescence. By exploring the intricate mechanisms underlying adipocyte dysfunction and the emerging role of natural compounds in senescence modulation, we underscore the promising horizon of senotherapeutics in restoring adipose health. This approach not only offers a pathway to combat the metabolic complications of obesity, but also opens new avenues for enhancing life quality and managing the global burden of obesity-related conditions. Our analysis aims to bridge the gap between current scientific progress and clinical application, offering new perspectives on preventing and treating obesity-induced adipose dysfunction.

肥胖症是一场全球性健康危机,它扰乱了多个系统过程,通过促进内脏脂肪组织(VAT)的病理扩张,导致一连串的代谢功能障碍。这种扩张的特点是前脂肪细胞分化受损,衰老细胞增加,导致炎症状态和氧化应激加剧。尤其是衰老相关分泌表型(SASP)和脂肪组织缺氧会进一步损害细胞功能,促进慢性疾病的发展。这篇综述深入探讨了自噬调节的潜力,以及作为缓解脂肪组织衰老新策略的衰老素和衰老形态素的治疗应用。通过探索脂肪细胞功能障碍的复杂机制以及天然化合物在衰老调节中的新兴作用,我们强调了衰老治疗剂在恢复脂肪健康方面前景广阔。这种方法不仅提供了一种对抗肥胖代谢并发症的途径,还为提高生活质量和管理肥胖相关疾病的全球负担开辟了新的途径。我们的分析旨在弥合当前科学进展与临床应用之间的差距,为预防和治疗肥胖引起的脂肪功能障碍提供新的视角。
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引用次数: 0
Effects of a supplemented diet containing 7 probiotic strains (Honeybeeotic) on honeybee physiology and immune response: analysis of hemolymph cytology, phenoloxidase activity, and gut microbiome. 含有 7 种益生菌株的补充食物(Honeybeeotic)对蜜蜂生理和免疫反应的影响:血淋巴细胞学、酚氧化酶活性和肠道微生物组分析。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-08-07 DOI: 10.1186/s40659-024-00533-x
Patrizia Robino, Livio Galosi, Alessandro Bellato, Silvia Vincenzetti, Elena Gonella, Ilario Ferrocino, Evelina Serri, Lucia Biagini, Alessandra Roncarati, Patrizia Nebbia, Chiara Menzio, Giacomo Rossi

Background: In this study, a probiotic mixture (Honeybeeotic) consisting of seven bacterial strains isolated from a unique population of honeybees (Apis mellifera ligustica) was used. That honeybee population was located in the Roti Abbey locality of the Marche Region in Italy, an area isolated from human activities, and genetic contamination from other honeybee populations. The aim was to investigate the effects of this probiotic mixture on the innate immunity and intestinal microbiome of healthy common honeybees in two hives of the same apiary. Hive A received a diet of 50% glucose syrup, while hive B received the same syrup supplemented with the probiotics, both administered daily for 1 month. To determine whether the probiotic altered the immune response, phenoloxidase activity and hemolymph cellular subtype count were investigated. Additionally, metagenomic approaches were used to analyze the effects on gut microbiota composition and function, considering the critical role the gut microbiota plays in modulating host physiology.

Results: The results revealed differences in hemocyte populations between the two hives, as hive A exhibited higher counts of oenocytoids and granulocytes. These findings indicated that the dietary supplementation with the probiotic mixture was safe and well-tolerated. Furthermore, phenoloxidase activity significantly decreased in hive B (1.75 ± 0.19 U/mg) compared to hive A (3.62 ± 0.44 U/mg, p < 0.005), suggesting an improved state of well-being in the honeybees, as they did not require activation of immune defense mechanisms. Regarding the microbiome composition, the probiotic modulated the gut microbiota in hive B compared to the control, retaining core microbiota components while causing both positive and negative variations. Notably, several genes, particularly KEGG genes involved in amino acid metabolism, carbohydrate metabolism, and branched-chain amino acid (BCAA) transport, were more abundant in the probiotic-fed group, suggesting an effective nutritional supplement for the host.

Conclusions: This study advocated that feeding with this probiotic mixture induces beneficial immunological effects and promoted a balanced gut microbiota with enhanced metabolic activities related to digestion. The use of highly selected probiotics was shown to contribute to the overall well-being of the honeybees, improving their immune response and gut health.

研究背景在这项研究中,使用了一种益生菌混合物(蜜蜂益生菌),该混合物由从蜜蜂(Apis mellifera ligustica)独特种群中分离出来的七种细菌菌株组成。该蜜蜂种群位于意大利马尔凯大区的罗蒂阿贝地区,该地区与人类活动和其他蜜蜂种群的遗传污染隔绝。目的是研究这种益生菌混合物对同一养蜂场两个蜂巢中健康普通蜜蜂的先天免疫和肠道微生物组的影响。蜂巢 A 的食物是 50%的葡萄糖浆,而蜂巢 B 的食物也是同样的葡萄糖浆,并添加了益生菌,每天给药,持续 1 个月。为了确定益生菌是否改变了免疫反应,对酚氧化酶活性和血淋巴细胞亚型计数进行了调查。此外,考虑到肠道微生物群在调节宿主生理方面的关键作用,还采用了元基因组学方法来分析对肠道微生物群组成和功能的影响:结果表明,两个蜂巢的血细胞数量存在差异,A 蜂巢的卵母细胞和粒细胞数量更高。这些结果表明,膳食中补充益生菌混合物是安全的,而且耐受性良好。此外,与蜂巢 A(3.62 ± 0.44 U/mg, p)相比,蜂巢 B 的酚氧化酶活性(1.75 ± 0.19 U/mg )明显降低:这项研究表明,饲喂这种益生菌混合物可诱导有益的免疫效应,促进肠道微生物群的平衡,增强与消化有关的代谢活动。研究表明,使用精选的益生菌有助于蜜蜂的整体健康,改善其免疫反应和肠道健康。
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引用次数: 0
Uncovering the role of the subcommissural organ in early brain development through transcriptomic analysis 通过转录组分析揭示亚组织器官在早期大脑发育中的作用
IF 6.7 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-27 DOI: 10.1186/s40659-024-00524-y
Maryori González, Felipe Maurelia, Jaime Aguayo, Roberto Amigo, Rodrigo Arrué, José Leonardo Gutiérrez, Marcela Torrejón, Carlos Farkas, Teresa Caprile
The significant role of embryonic cerebrospinal fluid (eCSF) in the initial stages of brain development has been thoroughly studied. This fluid contains crucial molecules for proper brain development such as members of the Wnt and FGF families, apolipoproteins, and retinol binding protein. Nevertheless, the source of these molecules remains uncertain since they are present before the formation of the choroid plexus, which is conventionally known as the primary producer of cerebrospinal fluid. The subcommissural organ (SCO) is a highly conserved gland located in the diencephalon and is one of the earliest differentiating brain structures. The SCO secretes molecules into the eCSF, prior to the differentiation of the choroid plexus, playing a pivotal role in the homeostasis and dynamics of this fluid. One of the key molecules secreted by the SCO is SCO-spondin, a protein involved in maintenance of the normal ventricle size, straight spinal axis, neurogenesis, and axonal guidance. Furthermore, SCO secretes transthyretin and basic fibroblast growth factor 2, while other identified molecules in the eCSF could potentially be secreted by the SCO. Additionally, various transcription factors have been identified in the SCO. However, the precise mechanisms involved in the early SCO development are not fully understood. To uncover key molecular players and signaling pathways involved in the role of the SCO during brain development, we conducted a transcriptomic analysis comparing the embryonic chick SCO at HH23 and HH30 stages (4 and 7 days respectively). Additionally, a public transcriptomic data from HH30 entire chick brain was used to compare expression levels between SCO and whole brain transcriptome. These analyses revealed that, at both stages, the SCO differentially expresses several members of bone morphogenic proteins, Wnt and fibroblast growth factors families, diverse proteins involved in axonal guidance, neurogenic and differentiative molecules, cell receptors and transcription factors. The secretory pathway is particularly upregulated at stage HH30 while the proliferative pathway is increased at stage HH23. The results suggest that the SCO has the capacity to secrete several morphogenic molecules to the eCSF prior to the development of other structures, such as the choroid plexus.
胚胎脑脊液(eCSF)在大脑发育初始阶段的重要作用已得到深入研究。脑脊液中含有大脑正常发育所需的重要分子,如 Wnt 和 FGF 家族成员、脂蛋白和视黄醇结合蛋白。然而,这些分子的来源仍不确定,因为它们在脉络丛形成之前就已存在,而脉络丛通常被认为是脑脊液的主要产生者。硬脑膜下器官(SCO)是位于间脑中的一个高度保守的腺体,是最早分化的大脑结构之一。在脉络丛分化之前,SCO 向脑脊液中分泌分子,对脑脊液的平衡和动态起着关键作用。SCO分泌的关键分子之一是SCO-spondin,这是一种参与维持正常脑室大小、直脊柱轴、神经发生和轴突导向的蛋白质。此外,SCO 还能分泌转甲状腺素和碱性成纤维细胞生长因子 2,而电子脑脊液中已确定的其他分子也可能由 SCO 分泌。此外,在 SCO 中还发现了各种转录因子。然而,SCO 早期发育的确切机制尚未完全明了。为了揭示 SCO 在大脑发育过程中发挥作用的关键分子和信号通路,我们对胚胎小鸡 SCO 在 HH23 和 HH30 阶段(分别为 4 天和 7 天)进行了转录组分析。此外,我们还使用了来自 HH30 整个小鸡大脑的公开转录组数据来比较 SCO 和整个大脑转录组的表达水平。这些分析表明,在这两个阶段,SCO都不同程度地表达了骨形态发生蛋白、Wnt和成纤维细胞生长因子家族的多个成员、参与轴突导向的多种蛋白、神经原和分化分子、细胞受体和转录因子。分泌途径尤其在 HH30 阶段上调,而增殖途径则在 HH23 阶段增加。结果表明,在脉络丛等其他结构发育之前,SCO有能力向eCSF分泌多种形态发生分子。
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引用次数: 0
A preclinical mice model of multiple sclerosis based on the toxin-induced double-site demyelination of callosal and cerebellar fibers. 基于毒素诱导的胼胝体和小脑纤维双部位脱髓鞘的多发性硬化症临床前小鼠模型。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-22 DOI: 10.1186/s40659-024-00529-7
Sebastián Vejar, Ignacio S Pizarro, Raúl Pulgar-Sepúlveda, Sinay C Vicencio, Andrés Polit, Cristian A Amador, Rodrigo Del Rio, Rodrigo Varas, Juan A Orellana, Fernando C Ortiz

Background: Multiple sclerosis (MS) is an irreversible progressive CNS pathology characterized by the loss of myelin (i.e. demyelination). The lack of myelin is followed by a progressive neurodegeneration triggering symptoms as diverse as fatigue, motor, locomotor and sensory impairments and/or bladder, cardiac and respiratory dysfunction. Even though there are more than fourteen approved treatments for reducing MS progression, there are still no cure for the disease. Thus, MS research is a very active field and therefore we count with different experimental animal models for studying mechanisms of demyelination and myelin repair, however, we still lack a preclinical MS model assembling demyelination mechanisms with relevant clinical-like signs.

Results: Here, by inducing the simultaneous demyelination of both callosal and cerebellar white matter fibers by the double-site injection of lysolecithin (LPC), we were able to reproduce CNS demyelination, astrocyte recruitment and increases levels of proinflammatory cytokines levels along with motor, locomotor and urinary impairment, as well as cardiac and respiratory dysfunction, in the same animal model. Single site LPC-injections either in corpus callosum or cerebellum only, fails in to reproduce such a complete range of MS-like signs.

Conclusion: We here report that the double-site LPC injections treatment evoke a complex MS-like mice model. We hope that this experimental approach will help to deepen our knowledge about the mechanisms of demyelinated diseases such as MS.

背景:多发性硬化症(MS)是一种以髓鞘脱失(即脱髓鞘)为特征的不可逆的进行性中枢神经系统病变。髓鞘缺失后,神经逐渐变性,引发疲劳、运动、运动和感觉障碍和/或膀胱、心脏和呼吸功能障碍等多种症状。尽管目前有超过 14 种已获批准的治疗方法可减轻多发性硬化症的进展,但仍无法治愈该疾病。因此,多发性硬化症的研究是一个非常活跃的领域,我们利用不同的实验动物模型来研究脱髓鞘和髓鞘修复的机制,但我们仍然缺乏一个将脱髓鞘机制与相关临床症状相结合的临床前多发性硬化症模型:结果:在这里,通过双部位注射溶血卵磷脂(LPC)诱导胼胝体和小脑白质纤维同时脱髓鞘,我们能够在同一动物模型中再现中枢神经系统脱髓鞘、星形胶质细胞募集和促炎细胞因子水平升高,以及运动、运动和排尿障碍,以及心脏和呼吸功能障碍。而仅在胼胝体或小脑注射单部位 LPC,则无法再现如此全面的 MS 样征:我们在此报告,双部位 LPC 注射治疗可诱发复杂的多发性硬化症样小鼠模型。我们希望这种实验方法有助于加深我们对多发性硬化症等脱髓鞘疾病机制的认识。
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引用次数: 0
Renoprotective effect of a novel combination of 6-gingerol and metformin in high-fat diet/streptozotocin-induced diabetic nephropathy in rats via targeting miRNA-146a, miRNA-223, TLR4/TRAF6/NLRP3 inflammasome pathway and HIF-1α. 通过靶向 miRNA-146a、miRNA-223、TLR4/TRAF6/NLRP3 炎性体通路和 HIF-1α ,6-姜酚和二甲双胍的新型组合对高脂饮食/链脲佐菌素诱导的大鼠糖尿病肾病具有肾保护作用
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-20 DOI: 10.1186/s40659-024-00527-9
Merna G Aboismaiel, Mohamed N Amin, Laila A Eissa

Background: MiRNA-146a and miRNA-223 are key epigenetic regulators of toll-like receptor 4 (TLR4)/tumor necrosis factor-receptor-associated factor 6 (TRAF6)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway, which is involved in diabetic nephropathy (DN) pathogenesis. The currently available oral anti-diabetic treatments have been insufficient to halt DN development and progression. Therefore, this work aimed to assess the renoprotective effect of the natural compound 6-gingerol (GR) either alone or in combination with metformin (MET) in high-fat diet/streptozotocin-induced DN in rats. The proposed molecular mechanisms were also investigated.

Methods: Oral gavage of 6-gingerol (100 mg/kg) and metformin (300 mg/kg) were administered to rats daily for eight weeks. MiRNA-146a, miRNA-223, TLR4, TRAF6, nuclear factor-kappa B (NF-κB) (p65), NLRP3, caspase-1, and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA expressions were measured using real-time PCR. ELISA was used to measure TLR4, TRAF6, NLRP3, caspase-1, tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1β) renal tissue levels. Renal tissue histopathology and immunohistochemical examination of fibronectin and NF-κB (p65) were performed.

Results: 6-Gingerol treatment significantly reduced kidney tissue damage and fibrosis. 6-Gingerol up-regulated miRNA-146a and miRNA-223 and reduced TLR4, TRAF6, NF-κB (p65), NLRP3, caspase-1, TNF-α, IL-1β, HIF-1α and fibronectin renal expressions. 6-Gingerol improved lipid profile and renal functions, attenuated renal hypertrophy, increased reduced glutathione, and decreased blood glucose and malondialdehyde levels. 6-Gingerol and metformin combination showed superior renoprotective effects than either alone.

Conclusion: 6-Gingerol demonstrated a key protective role in DN by induction of miRNA-146a and miRNA-223 expression and inhibition of TLR4/TRAF6/NLRP3 inflammasome signaling. 6-Gingerol, a safe, affordable, and abundant natural compound, holds promise for use as an adjuvant therapy with metformin in diabetic patients to attenuate renal damage and stop the progression of DN.

背景:miRNA-146a和miRNA-223是toll样受体4(TLR4)/肿瘤坏死因子受体相关因子6(TRAF6)/NOD样受体家族含吡啶域3(NLRP3)炎性小体通路的关键表观遗传调节因子,而该通路参与了糖尿病肾病(DN)的发病机制。目前可用的口服抗糖尿病疗法不足以阻止 DN 的发生和发展。因此,本研究旨在评估天然化合物 6-姜酚(GR)单独或与二甲双胍(MET)联用对高脂饮食/链脲佐菌素诱导的大鼠 DN 的肾保护作用。此外,还对拟议的分子机制进行了研究:方法:每天给大鼠灌胃 6-姜酚(100 毫克/千克)和二甲双胍(300 毫克/千克),连续八周。采用实时 PCR 法检测 MiRNA-146a、miRNA-223、TLR4、TRAF6、核因子-kappa B(NF-κB)(p65)、NLRP3、caspase-1 和缺氧诱导因子-1 α(HIF-1α)mRNA 的表达。用酶联免疫吸附法测定 TLR4、TRAF6、NLRP3、caspase-1、肿瘤坏死因子-α(TNF-α)和白细胞介素-1-β(IL-1β)的肾组织水平。对肾组织进行组织病理学检查,并对纤维连接蛋白和 NF-κB (p65) 进行免疫组化检查:结果:6-姜酚治疗能明显减轻肾组织损伤和纤维化。6-姜酚上调了 miRNA-146a 和 miRNA-223,降低了 TLR4、TRAF6、NF-κB (p65)、NLRP3、caspase-1、TNF-α、IL-1β、HIF-1α 和纤维连接蛋白的肾脏表达。6 姜酚改善了血脂状况和肾功能,减轻了肾肥大,增加了还原型谷胱甘肽,降低了血糖和丙二醛水平。结论:6-姜酚通过诱导 miRNA-146a 和 miRNA-223 的表达以及抑制 TLR4/TRAF6/NLRP3 炎性体信号转导,对 DN 起着关键的保护作用。6-姜酚是一种安全、经济、丰富的天然化合物,有望与二甲双胍一起作为糖尿病患者的辅助疗法,以减轻肾损伤并阻止 DN 的进展。
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引用次数: 0
Unveiling a novel memory center in human brain: neurochemical identification of the nucleus incertus, a key pontine locus implicated in stress and neuropathology. 揭示人脑中的新型记忆中心:神经化学鉴定与压力和神经病理学有关的关键脑桥部位--incertus 核。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-16 DOI: 10.1186/s40659-024-00523-z
Camila de Ávila, Anna Gugula, Aleksandra Trenk, Anthony J Intorcia, Crystal Suazo, Jennifer Nolz, Julie Plamondon, Divyanshi Khatri, Lauren Tallant, Alexandre Caron, Anna Blasiak, Geidy E Serrano, Thomas G Beach, Andrew L Gundlach, Diego F Mastroeni

Background: The nucleus incertus (NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle of the human brain with an 'unknown' function. More than a century later, the neuroanatomy of the NI has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus.

Methods: Histochemical staining of serial, coronal sections of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal markers, microtubule-associated protein-2 (MAP2), glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin-releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in NI neurons in diverse species. RLN3 and vesicular GABA transporter 1 (vGAT1) mRNA were detected by fluorescent in situ hybridization. Pons sections containing the NI from an AD case were immunostained for phosphorylated-tau, to explore potential relevance to neurodegenerative diseases. Lastly, sections of the human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR.

Results: In the dorsal, anterior-medial region of the human pons, neurons containing RLN3- and MAP2-IR, and RLN3/vGAT1 mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67- and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3- and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3 and DG areas of the hippocampus, in the absence of RLN3 mRNA. In the DG, RLN3- and SST-IR were co-localized in a small population of neurons.

Conclusions: Aspects of the anatomy of the human NI are shared across species, including a population of stress-responsive, RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.

背景:无脑核(NI)最初由 Streeter 于 1903 年描述,是人脑第四脑室底部的一个中线区域,其功能 "未知"。一个多世纪后,NI 的神经解剖学在低等脊椎动物中得到了描述,但在人类中却没有。因此,我们使用包括神经肽松弛素-3(RLN3)在内的标记物研究了人类 NI 的神经化学解剖,并开始探索与 NI 相关的 RLN3 神经支配在海马中的分布。方法:通过检测神经元标记物微管相关蛋白-2(MAP2)、谷氨酸脱氢酶(GAD)-65/67、促肾上腺皮质激素释放激素受体 1(CRHR1)和 RLN3 的免疫反应性(IR)来揭示 NI 的存在。荧光原位杂交法检测了 RLN3 和囊泡 GABA 转运体 1 (vGAT1) mRNA。免疫染色法检测磷酸化-tau,以探索与神经退行性疾病的潜在相关性。最后,对人类海马的切片进行染色,以检测RLN3-IR和体生长抑素(SST)-IR:结果:在人类脑桥的背侧、前内侧区域,观察到含有RLN3-IR和MAP2-IR的神经元,以及RLN3/vGAT1 mRNA阳性神经元,其解剖模式与其他物种的NI一致。在这一区域还检测到了 GAD65/67- 和 CRHR1- 免疫阳性神经元。此外,RLN3- 和 AT8-IR 在一名 AD 受试者的 NI 神经元内共定位。最后,在海马CA1、CA2、CA3和DG区域的神经元中检测到了RLN3-IR,但没有RLN3 mRNA。在DG区,RLN3-和SST-IR共同定位在一小部分神经元中:结论:人类 NI 的解剖结构在物种间具有共通性,其中包括应激反应型 RLN3 表达神经元群和海马的 RLN3 神经支配。NI中磷酸化-tau的积累表明它可能与AD病理有关。对人类 NI 神经化学特性的进一步研究将加深我们对其在健康和疾病中的功能作用的了解。
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引用次数: 0
Chrysin-loaded PEGylated liposomes protect against alloxan-induced diabetic neuropathy in rats: the interplay between endoplasmic reticulum stress and autophagy. 含蛹虫草素的聚乙二醇脂质体对阿脲诱导的大鼠糖尿病神经病变有保护作用:内质网应激和自噬之间的相互作用
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-09 DOI: 10.1186/s40659-024-00521-1
Mahran Mohamed Abd El-Emam, Amany Behairy, Mahmoud Mostafa, Tarek Khamis, Noura M S Osman, Amira Ebrahim Alsemeh, Mohamed Fouad Mansour

Background: Diabetic neuropathy (DN) is recognized as a significant complication arising from diabetes mellitus (DM). Pathogenesis of DN is accelerated by endoplasmic reticulum (ER) stress, which inhibits autophagy and contributes to disease progression. Autophagy is a highly conserved mechanism crucial in mitigating cell death induced by ER stress. Chrysin, a naturally occurring flavonoid, can be found abundantly in honey, propolis, and various plant extracts. Despite possessing advantageous attributes such as being an antioxidant, anti-allergic, anti-inflammatory, anti-fibrotic, and anticancer agent, chrysin exhibits limited bioavailability. The current study aimed to produce a more bioavailable form of chrysin and discover how administering chrysin could alter the neuropathy induced by Alloxan in male rats.

Methods: Chrysin was formulated using PEGylated liposomes to boost its bioavailability and formulation. Chrysin PEGylated liposomes (Chr-PLs) were characterized for particle size diameter, zeta potential, polydispersity index, transmission electron microscopy, and in vitro drug release. Rats were divided into four groups: control, Alloxan, metformin, and Chr-PLs. In order to determine Chr- PLs' antidiabetic activity and, by extension, its capacity to ameliorate DN, several experiments were carried out. These included measuring acetylcholinesterase, fasting blood glucose, insulin, genes dependent on autophagy or stress in the endoplasmic reticulum, and histopathological analysis.

Results: According to the results, the prepared Chr-PLs exhibited an average particle size of approximately 134 nm. They displayed even distribution of particle sizes. The maximum entrapment efficiency of 90.48 ± 7.75% was achieved. Chr-PLs effectively decreased blood glucose levels by 67.7% and elevated serum acetylcholinesterase levels by 40% compared to diabetic rats. Additionally, Chr-PLs suppressed the expression of ER stress-related genes (ATF-6, CHOP, XBP-1, BiP, JNK, PI3K, Akt, and mTOR by 33%, 39.5%, 32.2%, 44.4%, 40.4%, 39.2%, 39%, and 35.9%, respectively). They also upregulated the miR-301a-5p expression levels by 513% and downregulated miR-301a-5p expression levels by 65%. They also boosted the expression of autophagic markers (AMPK, ULK1, Beclin 1, and LC3-II by 90.3%, 181%, 109%, and 78%, respectively) in the sciatic nerve. The histopathological analysis also showed that Chr-PLs inhibited sciatic nerve degeneration.

Conclusion: The findings suggest that Chr-PLs may be helpful in the protection against DN via regulation of ER stress and autophagy.

背景:糖尿病神经病变(DN)被认为是糖尿病(DM)引起的一种重要并发症。糖尿病神经病变的发病机制因内质网(ER)应激而加速,ER应激会抑制自噬并导致疾病进展。自噬是一种高度保守的机制,对减轻ER应激诱导的细胞死亡至关重要。蛹虫草素是一种天然黄酮类化合物,大量存在于蜂蜜、蜂胶和各种植物提取物中。尽管菊黄素具有抗氧化、抗过敏、抗炎、抗纤维化和抗癌等优点,但其生物利用度有限。目前的研究旨在生产一种生物利用度更高的菊黄素,并探索服用菊黄素如何改变阿脲诱导的雄性大鼠神经病变:方法:使用 PEG 化脂质体配制金丝桃素,以提高其生物利用度和配方。对蛹素 PEG 化脂质体(Chr-PLs)的粒径、ZETA 电位、多分散指数、透射电子显微镜和体外药物释放进行了表征。大鼠被分为四组:对照组、阿洛欣组、二甲双胍组和 Chr-PLs 组。为了确定 Chr-PLs 的抗糖尿病活性,并进而确定其改善 DN 的能力,进行了多项实验。这些实验包括测量乙酰胆碱酯酶、空腹血糖、胰岛素、依赖于自噬或内质网压力的基因以及组织病理学分析:结果表明,制备的 Chr-PLs 平均粒径约为 134 nm。它们的粒径分布均匀。最大夹带效率为 90.48 ± 7.75%。与糖尿病大鼠相比,Chr-PLs 能有效降低 67.7% 的血糖水平,提高 40% 的血清乙酰胆碱酯酶水平。此外,Chr-PLs 还抑制了 ER 应激相关基因的表达(ATF-6、CHOP、XBP-1、BiP、JNK、PI3K、Akt 和 mTOR 的表达分别为 33%、39.5%、32.2%、44.4%、40.4%、39.2%、39% 和 35.9%)。它们还将 miR-301a-5p 的表达水平上调了 513%,将 miR-301a-5p 的表达水平下调了 65%。它们还提高了坐骨神经中自噬标记物(AMPK、ULK1、Beclin 1 和 LC3-II)的表达,分别提高了 90.3%、181%、109% 和 78%。组织病理学分析也表明,Chr-PLs 可抑制坐骨神经变性:结论:研究结果表明,Chr-PLs可通过调节ER应激和自噬作用来预防DN。
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引用次数: 0
Lead and calcium crosstalk tempted acrosome damage and hyperpolarization of spermatozoa: signaling and ultra-structural evidences. 铅和钙的串扰诱导了顶体损伤和精子的超极化:信号和超结构证据。
IF 4.3 2区 生物学 Q1 BIOLOGY Pub Date : 2024-07-05 DOI: 10.1186/s40659-024-00517-x
Rajkumar Singh Yadav, Bhawna Kushawaha, Rahul Dhariya, Dilip Kumar Swain, Brijesh Yadav, Mukul Anand, Priyambada Kumari, Pradeep Kumar Rai, Dipty Singh, Sarvajeet Yadav, Satish Kumar Garg

Background: Exposure of humans and animals to heavy metals is increasing day-by-day; thus, lead even today remains of significant public health concern. According to CDC, blood lead reference value (BLRV) ranges from 3.5 µg/dl to 5 μg/dl in adults. Recently, almost 2.6% decline in male fertility per year has been reported but the cause is not well established. Lead (Pb2+) affects the size of testis, semen quality, and secretory functions of prostate. But the molecular mechanism(s) of lead toxicity in sperm cells is not clear. Thus, present study was undertaken to evaluate the adverse effects of lead acetate at environmentally relevant exposure levels (0.5, 5, 10 and 20 ppm) on functional and molecular dynamics of spermatozoa of bucks following in vitro exposure for 15 min and 3 h.

Results: Lead significantly decreased motility, viable count, and motion kinematic patterns of spermatozoa like curvilinear velocity, straight-line velocity, average path velocity, beat cross frequency and maximum amplitude of head lateral displacement even at 5 ppm concentration. Pb2+ modulated intracellular cAMP and Ca2+ levels in sperm cells through L-type calcium channels and induced spontaneous or premature acrosome reaction (AR) by increasing tyrosine phosphorylation of sperm proteins and downregulated mitochondrial transmembrane potential. Lead significantly increased DNA damage and apoptosis as well. Electron microscopy studies revealed Pb2+ -induced deleterious effects on plasma membrane of head and acrosome including collapsed cristae in mitochondria.

Conclusions: Pb2+ not only mimics Ca2+ but also affects cellular targets involved in generation of cAMP, mitochondrial transmembrane potential, and ionic exchange. Lead seems to interact with Ca2+ channels because of charge similarity and probably enters the sperm cell through these channels and results in hyperpolarization. Our findings also indicate lead-induced TP and intracellular Ca2+ release in spermatozoa which in turn may be responsible for premature acrosome exocytosis which is essential feature of capacitation for fertilization. Thus, lead seems to reduce the fertilizing capacity of spermatozoa even at 0.5 ppm concentrations.

背景:人类和动物接触重金属的机会与日俱增,因此,即使在今天,铅仍然是公众健康的重大问题。根据美国疾病预防控制中心(CDC)的数据,成人血铅参考值(BLRV)为 3.5 µg/dl 至 5 μg/dl。最近有报道称,男性生育能力每年下降近 2.6%,但原因尚未明确。铅(Pb2+)会影响睾丸大小、精液质量和前列腺的分泌功能。但铅对精子细胞毒性的分子机制尚不清楚。因此,本研究评估了环境相关暴露水平(0.5、5、10 和 20 ppm)的醋酸铅在体外暴露 15 分钟和 3 小时后对雄鹿精子功能和分子动力学的不利影响:结果:铅明显降低了精子的运动能力、存活率和运动模式,如曲线速度、直线速度、平均路径速度、搏动交叉频率和头部横向位移的最大振幅,即使在百万分之 5 的浓度下也是如此。铅通过 L 型钙通道调节精子细胞内的 cAMP 和 Ca2+ 水平,并通过增加精子蛋白质的酪氨酸磷酸化和下调线粒体跨膜电位诱导自发或过早顶体反应(AR)。铅还会明显增加 DNA 损伤和细胞凋亡。电子显微镜研究显示,铅对精子头部和顶体的质膜产生有害影响,包括线粒体嵴的塌陷:结论:Pb2+不仅能模拟 Ca2+,还能影响细胞中参与产生 cAMP、线粒体跨膜电位和离子交换的靶点。由于电荷的相似性,铅似乎与 Ca2+ 通道相互作用,可能通过这些通道进入精子细胞并导致超极化。我们的研究结果还表明,铅诱导精子的 TP 和细胞内 Ca2+ 释放,这反过来又可能导致顶体过早外渗,而顶体外渗是获能受精的基本特征。因此,即使在 0.5 ppm 的浓度下,铅似乎也会降低精子的受精能力。
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引用次数: 0
Retraction Note: Tridax procumbens flavonoids promote osteoblast differentiation and bone formation. 撤稿说明:蒲公英黄酮类化合物可促进成骨细胞分化和骨形成。
IF 4.3 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-06-24 DOI: 10.1186/s40659-024-00525-x
Md Abdullah Al Mamun, Mohammad Jakir Hosen, Kamrul Islam, Amina Khatun, M Masihul Alam, Md Abdul Alim Al-Bari
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引用次数: 0
Molecular hydrogen promotes retinal vascular regeneration and attenuates neovascularization and neuroglial dysfunction in oxygen-induced retinopathy mice. 分子氢促进氧诱导视网膜病变小鼠的视网膜血管再生,并减轻新生血管和神经胶质细胞功能障碍。
IF 4.3 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-06-24 DOI: 10.1186/s40659-024-00515-z
Yatu Guo, Jiahui Qin, Ruiqiang Sun, Peng Hao, Zhixin Jiang, Yuchuan Wang, Zhiqi Gao, Huan Zhang, Keliang Xie, Wei Zhang

Background: Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H2) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H2 provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H2 on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice.

Methods: In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H2) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H2 under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining.

Results: Our results indicate that 3-4% H2 does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H2 prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H2 inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H2 plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H2 promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreove

背景:早产儿视网膜病变(ROP早产儿视网膜病变(ROP)是一种发生在早产儿视网膜上的增生性视网膜血管疾病,是导致儿童失明的主要原因。目前,抗血管内皮生长因子(VEGF)和视网膜光凝是治疗早产儿视网膜病变的主流方法,但它们会产生各种并发症。氢气(H2)被广泛认为是一种有效的神经保护和抗氧化治疗方法,可治疗缺氧缺血性疾病,且无毒副作用。本研究旨在探讨氢气对氧致视网膜病变(OIR)小鼠视网膜血管生成、新生血管形成和神经胶质功能障碍的影响:在这项研究中,将7天大的野生型(WT)或Nrf2缺陷型(Nrf2-/-)小鼠暴露于75%的氧气中5天,然后放回正常空气条件下。在不同阶段吸入氢气(H2)。对血管阻塞、新生血管和血管渗漏进行分析和比较。为了计算新生血管内皮细胞核的数量,对视网膜切片进行了常规 HE 染色。使用 DyLight 594 标记的 GSL I-isolectin B4(IB4)以及增殖细胞核抗原(PCNA)、神经胶质纤维酸性蛋白(GFAP)和 Iba-1 的一抗进行免疫组化。Western 印迹用于测量 NF-E2 相关因子 2 (Nrf2)、血管内皮生长因子 (VEGF)、Notch1、Dll4 和 HIF-1α 的表达。此外,还测量了 NQO1、HO-1、Notch1、Hey1、Hey2 和 Dll4 等靶基因的表达。以缺氧条件下用 H2 处理的人脐静脉内皮细胞(HUVECs)为体外模型。采用 RT-PCR 技术评估 Nrf2、Notch/Dll4 和靶基因的 mRNA 表达。使用免疫荧光染色法观察活性氧(ROS)的表达:结果:我们的研究结果表明,3-4% 的 H2 不会干扰视网膜生理性血管生成,但会改善 OIR 小鼠的血管闭塞和新生血管形成。此外,H2 还能防止氧损伤引起的视网膜星形胶质细胞密度下降,并逆转其形态和功能变化。此外,吸入 H2 还能减少小胶质细胞的活化,尤其是在 OIR 小鼠的新生血管区域。H2 在体内通过促进 Nrf2 激活和抑制 Dll4 诱导的 Notch 信号通路,对血管再生起到保护作用。此外,视网膜氧传感机制(HIF-1α/VEGF)也参与了氢介导的视网膜血管再通和新生血管抑制:总之,我们的研究结果表明,氢气可能是一种治疗 POR 的有效药物,它对人类 ROP 的有益作用可能涉及 Nrf2-Notch 轴和 HIF-1α/VEGF 通路的激活。
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引用次数: 0
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