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WISH-BONE: Whole-mount in situ histology, to label osteocyte mRNA and protein in 3D adult mouse bones WISH-BONE:整装原位组织学,标记三维成年小鼠骨骼中的骨细胞 mRNA 和蛋白质。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-10 DOI: 10.1096/fj.202400635R
Quentin A. Meslier, Timothy J. Duerr, Webster Guan, Brian Nguyen, James R. Monaghan, Sandra J. Shefelbine

Bone is a three-dimensional (3D) highly dynamic tissue under constant remodeling. Commonly used tools to investigate bone biology require sample digestion for biomolecule extraction or provide only two-dimensional (2D) spatial information. There is a need for 3D tools to investigate spatially preserved biomarker expression in osteocytes. In this work, we present a new method, WISH-BONE, to label osteocyte messenger RNA (mRNA) and protein in whole-mount mouse bone. For mRNA labeling, we used hybridization chain reaction-fluorescence in situ hybridization (HCR-FISH) to label genes of interest in osteocytes. For protein labeling, samples were preserved using an epoxy-based solution that protects tissue structure and biomolecular components. Then an enzymatic matrix permeabilization step was performed to enable antibody penetration. Immunostaining was used to label various proteins involved in bone homeostasis. We also demonstrate the use of customized fluorescent nanobodies to target and label proteins in the cortical bone (CB). However, the relatively dim signal observed from nanobodies' staining limited detection. mRNA and protein labeling were performed in separate samples. In this study, we share protocols, highlight opportunities, and identify the challenges of this novel 3D labeling method. They are the first protocols for whole-mount osteocyte 3D labeling of mRNA and protein in mature mouse bones. WISH-BONE will allow the investigation of molecular signaling in bone cells in their 3D environment and could be applied to various bone-related fields of research.

骨骼是一种不断重塑的三维(3D)高度动态组织。研究骨生物学的常用工具需要消化样本以提取生物大分子,或者只能提供二维(2D)空间信息。我们需要三维工具来研究骨细胞中空间保存的生物标记表达。在这项工作中,我们提出了一种新方法--WISH-BONE,用于标记整块小鼠骨骼中的骨细胞信使 RNA(mRNA)和蛋白质。在标记 mRNA 时,我们使用杂交链反应-荧光原位杂交(HCR-FISH)来标记骨细胞中的相关基因。在蛋白质标记方面,我们使用环氧树脂溶液保存样本,以保护组织结构和生物分子成分。然后进行酶基质渗透步骤,使抗体渗透。免疫染色法用于标记参与骨平衡的各种蛋白质。我们还展示了使用定制的荧光纳米抗体来靶向和标记皮质骨(CB)中的蛋白质。然而,纳米抗体染色观察到的信号相对较暗,限制了检测。在本研究中,我们分享了这一新型三维标记方法的操作规程,强调了其机遇,并指出了其面临的挑战。它们是成熟小鼠骨骼中 mRNA 和蛋白质全贴片骨细胞三维标记的首个方案。WISH-BONE 将允许在三维环境中研究骨细胞的分子信号转导,并可应用于与骨相关的各种研究领域。
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引用次数: 0
Trophoblast-specific overexpression of adiponectin receptor 2 causes fetal growth restriction in pregnant mice 滋养层特异性过表达脂肪连蛋白受体 2 会导致妊娠小鼠胎儿生长受限
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-10 DOI: 10.1096/fj.202302143R
Jerad H. Dumolt, Fredrick J. Rosario, Kenneth Barentsen, Johann Urschitz, Theresa L. Powell, Thomas Jansson

Maternal obesity in pregnancy is strongly associated with complications such as fetal overgrowth and infants of obese mothers have an increased risk to develop obesity, diabetes, and cardiovascular disease later in life. However, the underlying mechanisms are not well established. Circulating levels of adiponectin are low in obese pregnant women and maternal circulating adiponectin is negatively associated with birth weight. We have reported that normalizing maternal adiponectin in obese pregnant mice prevents placental dysfunction, fetal overgrowth, and programming of offspring cardio-metabolic disease. However, the mechanistic link between maternal adiponectin, placental function, and fetal growth remains to be established. We hypothesized that trophoblast-specific overexpression of the adiponectin receptor 2 (Adipor2) in healthy pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Using lentiviral transduction of blastocysts with a mammalian gene expression lentiviral vector for up-regulation of Adipor2 (Adipor2-OX), we achieved a ~ 3-fold increase in placenta Adipor2 mRNA levels and a 2-fold increase of the ADIPOR2 protein in the trophoblast plasma membrane. Placenta-specific Adipor2-OX increased placental peroxisome proliferator-activated receptor-α phosphorylation, ceramide synthase expression and ceramide concentrations. Furthermore, Adipor2-OX inhibited placental mTORC1 signaling and reduced in vivo placental transport of glucose and amino acids. Lastly, Adipor2-OX reduced fetal weight by 11%. These data provide mechanistic evidence that placental Adipor2 signaling directly affects fetal growth. We propose that low circulating adiponectin in maternal obesity causes fetal overgrowth and programs the offspring for cardio-metabolic disease mediated by a direct effect on placental function.

孕妇肥胖与胎儿发育过快等并发症密切相关,肥胖母亲的婴儿日后患肥胖症、糖尿病和心血管疾病的风险也会增加。然而,其潜在机制尚未得到很好的证实。肥胖孕妇循环中的脂肪连通素水平较低,而母体循环中的脂肪连通素与出生体重呈负相关。我们曾报道,使肥胖妊娠小鼠的母体脂肪连素正常化可防止胎盘功能障碍、胎儿过度生长和后代心血管代谢疾病的发生。然而,母体脂肪连素、胎盘功能和胎儿生长之间的机理联系仍有待确定。我们假设,在健康的怀孕小鼠中,滋养层特异性过表达的脂肪粘连素受体 2(Adipor2)会抑制胎盘 mTORC1 信号传导和营养物质运输,从而导致胎儿生长受限。利用哺乳动物基因表达慢病毒载体转导囊胚以上调 Adipor2(Adipor2-OX),我们发现胎盘 Adipor2 mRNA 水平增加了约 3 倍,滋养细胞质膜中的 ADIPOR2 蛋白增加了 2 倍。胎盘特异性 Adipor2-OX 增加了胎盘过氧化物酶体增殖激活受体-α 磷酸化、神经酰胺合成酶表达和神经酰胺浓度。此外,Adipor2-OX 还抑制了胎盘 mTORC1 信号传导,减少了体内胎盘葡萄糖和氨基酸的转运。最后,Adipor2-OX 使胎儿体重降低了 11%。这些数据提供了胎盘 Adipor2 信号直接影响胎儿生长的机理证据。我们认为,母体肥胖时循环中的低脂连素会导致胎儿过度生长,并通过直接影响胎盘功能使后代患上心血管代谢疾病。
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引用次数: 0
Therapeutic potential of Astragalus membranaceus—Pueraria lobata decoction for the treatment of chemotherapy bowel injury 黄芪-葛根水煎剂治疗化疗性肠损伤的治疗潜力
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-09 DOI: 10.1096/fj.202401677R
Yixuan Wang, Yujie Qin, Qian Kang, Huinan Wang, Shihong Zhou, Yifan Wu, Yongqi Liu, Yun Su, Yaqiong Guo, Minghui Xiu, Jianzheng He

Intestinal mucositis (IM) is one of the most serious side effects of the chemotherapeutic agent irinotecan (CPT-11). Astragalus membranaceus-Pueraria lobata decoction is from the ancient medical book Zhengzhihuibu, has been reported to be used for the treatment of diabetes and hypertension. However, the beneficial effect and mechanism of AP on chemotherapy intestinal mucositis (CIM) remain largely unknown. This study aimed to investigate the efficacy and mechanism of Astragalus membranaceus-Pueraria lobata decoction (AP) in treating CIM. The beneficial effect and mechanism of AP on chemotherapy intestinal mucositis (CIM) were detected using Drosophila model, and combination with RT qPCR, transcriptomics. AP supplementation could significantly alleviate the CPT-11-induced body injury in Drosophila, such as increasing the survival rate, recovering the impaired digestion, improving the movement, and repairing the reproduction and developmental processes. Administration of AP remarkably alleviated the IM caused by CPT-11, including inhibiting the excretion, repairing the intestinal atrophy, improving the acid–base homeostasis imbalance, and inhibiting the disruption of intestinal structure. Mechanistic studies revealed that the protective role of AP against CPT-11 induced intestinal injury was regulated mainly by inhibiting immune-related Toll and Imd pathways, and enhancing the antioxidant capacity. Taken together, these results suggest that AP may be a novel agent to relieve CIM.

肠粘膜炎(IM)是化疗药物伊立替康(CPT-11)最严重的副作用之一。黄芪葛根汤出自古代医书《证治必备》,曾被报道用于治疗糖尿病和高血压。然而,AP 对化疗性肠粘膜炎(CIM)的有益作用和机制仍不清楚。本研究旨在探讨黄芪葛根汤(AP)治疗化疗性肠粘膜炎的疗效和机制。研究采用果蝇模型,并结合 RT qPCR、转录组学等方法,检测了黄芪葛根汤对化疗性肠黏膜炎(CIM)的作用及机制。补充 AP 能明显缓解 CPT-11 引起的果蝇机体损伤,如提高存活率、恢复受损的消化功能、改善运动能力、修复生殖和发育过程等。服用 AP 能显著缓解 CPT-11 引起的 IM,包括抑制排泄、修复肠道萎缩、改善酸碱平衡失调和抑制肠道结构破坏。机理研究发现,AP 对 CPT-11 引起的肠道损伤的保护作用主要通过抑制免疫相关的 Toll 和 Imd 通路以及增强抗氧化能力来调节。综上所述,这些结果表明 AP 可能是一种缓解 CIM 的新型药物。
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引用次数: 0
Unveiling shared diagnostic biomarkers and molecular mechanisms between T2DM and sepsis: Insights from bioinformatics to experimental assays 揭示 T2DM 和败血症之间共同的诊断生物标志物和分子机制:从生物信息学到实验测定的启示。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-09 DOI: 10.1096/fj.202401872R
Danlei Weng, Wei Shi, Yue Hu, Ying Chen, Shuxing Wei, Andong Li, Shubin Guo

Septic patients with T2DM were prone to prolonged recovery and unfavorable prognoses. Thus, this study aimed to pinpoint potential genes related to sepsis with T2DM and develop a predictive model for the disease. The candidate genes were screened using protein–protein interaction networks (PPI) and machine learning algorithms. The nomogram and receiver operating characteristic curve were developed to assess the diagnostic efficiency of the biomarkers. The relationship between sepsis and immune cells was analyzed using the CIBERSORT algorithm. The biomarkers were validated by qPCR and western blotting in basic experiments, and differences in organ damage in mice were studied. Three genes (MMP8, CD177, and S100A12) were identified using PPI and machine learning algorithms, demonstrating strong predictive capabilities. These biomarkers presented significant differences in gene expression patterns between diseased and healthy conditions. Additionally, the expression levels of biomarkers in mouse models and blood samples were consistent with the findings of the bioinformatics analysis. The study elucidated the common molecular mechanisms associated with the pathogenesis of T2DM and sepsis and developed a gene signature-based prediction model for sepsis. These findings provide new targets for the diagnosis and intervention of sepsis complicated with T2DM.

患有 T2DM 的败血症患者容易出现恢复期延长和预后不良的情况。因此,本研究旨在找出与T2DM败血症相关的潜在基因,并建立该疾病的预测模型。研究人员利用蛋白质-蛋白质相互作用网络(PPI)和机器学习算法对候选基因进行了筛选。通过建立提名图和接收者操作特征曲线来评估生物标志物的诊断效率。利用 CIBERSORT 算法分析了败血症与免疫细胞之间的关系。在基础实验中通过 qPCR 和 Western 印迹对生物标志物进行了验证,并研究了小鼠器官损伤的差异。使用 PPI 和机器学习算法确定了三个基因(MMP8、CD177 和 S100A12),显示出很强的预测能力。这些生物标志物的基因表达模式在患病和健康状态之间存在显著差异。此外,生物标志物在小鼠模型和血液样本中的表达水平与生物信息学分析的结果一致。该研究阐明了与 T2DM 和败血症发病机制相关的共同分子机制,并建立了基于基因特征的败血症预测模型。这些发现为诊断和干预 T2DM 并发败血症提供了新的目标。
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引用次数: 0
Targeting hypoxia and thrombospondin-2 in diabetic wound healing 针对糖尿病伤口愈合中的缺氧和血栓软骨素-2。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-09 DOI: 10.1096/fj.202302429RRR
Yaqing Huang, Hao Xing, Sophie Naud, Themis R. Kyriakides

Impaired wound healing in diabetic patients is the leading cause of diabetes-associated hospitalizations and approximately 50% of lower limb amputations. This is due to multiple factors, including elevated glucose, sustained hypoxia, and cell dysfunction. Previously, diabetic wounds were found to contain excessive levels of the matricellular protein thrombospondin-2 (TSP2) and genetic ablation of TSP2 in diabetic mice or treatment of wounds with a hydrogel derived from TSP2-null mouse skin improved healing. Previously, TSP2 has been shown to be repressed by hypoxia, but in the present study we observed sustained hypoxia and overlapping TSP2 deposition in diabetic wounds. We determined this observation was due to the insufficient HIF-1α activation verified by western blot and immunofluorescent analysis of wound tissues and in vitro hypoxia experiments. Application of Dimethyloxalylglycine (DMOG), which can stabilize HIF-1α, inhibited TSP2 expression in diabetic fibroblasts in hypoxic conditions. Therefore, we prepared DMOG-containing TSP2KO hydrogel and applied it to the wounds of diabetic mice. In comparison to empty TSP2KO hydrogel or DMOG treatment, we observed improved wound healing associated with a reduction of TSP2, reduced hypoxia, and increased neovascularization. Overall, our findings shed light on the intricate interplay between hyperglycemia, hypoxia, and TSP2 in the complex environment of diabetic wounds.

糖尿病患者伤口愈合受损是导致糖尿病相关住院治疗和约 50% 下肢截肢的主要原因。这是由多种因素造成的,包括血糖升高、持续缺氧和细胞功能障碍。以前曾发现糖尿病伤口含有过量的母细胞蛋白血栓软骨素-2(TSP2),对糖尿病小鼠进行 TSP2 基因消融或用 TSP2 基因无效小鼠皮肤制成的水凝胶处理伤口可改善伤口愈合。以前的研究表明,TSP2 受缺氧抑制,但在本研究中,我们观察到糖尿病伤口中存在持续缺氧和重叠的 TSP2 沉积。通过对伤口组织进行 Western 印迹和免疫荧光分析以及体外缺氧实验,我们确定这一观察结果是由于 HIF-1α 激活不足所致。二甲基羟乙基甘氨酸(DMOG)能稳定 HIF-1α,在缺氧条件下可抑制糖尿病成纤维细胞中 TSP2 的表达。因此,我们制备了含 DMOG 的 TSP2KO 水凝胶,并将其应用于糖尿病小鼠的伤口。与空 TSP2KO 水凝胶或 DMOG 处理相比,我们观察到伤口愈合的改善与 TSP2 的减少、缺氧的降低和新生血管的增加有关。总之,我们的研究结果揭示了糖尿病伤口复杂环境中高血糖、缺氧和 TSP2 之间错综复杂的相互作用。
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引用次数: 0
Advances in natural products modulating autophagy influenced by cellular stress conditions and their anticancer roles in the treatment of ovarian cancer 受细胞应激条件影响的自噬调节天然产品的研究进展及其在治疗卵巢癌中的抗癌作用。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-09 DOI: 10.1096/fj.202401409R
Dongxiao Li, Danbo Geng, Min Wang

Autophagy is a conservative catabolic process that typically serves a cell-protective function. Under stress conditions, when the cellular environment becomes unstable, autophagy is activated as an adaptive response for self-protection. Autophagy delivers damaged cellular components to lysosomes for degradation and recycling, thereby providing essential nutrients for cell survival. However, this function of promoting cell survival under stress conditions often leads to malignant progression and chemotherapy resistance in cancer. Consequently, autophagy is considered a potential target for cancer therapy. Herein, we aim to review how natural products act as key modulators of autophagy by regulating cellular stress conditions. We revisit various stressors, including starvation, hypoxia, endoplasmic reticulum stress, and oxidative stress, and their regulatory relationship with autophagy, focusing on recent advances in ovarian cancer research. Additionally, we explore how polyphenolic compounds, flavonoids, alkaloids, terpenoids, and other natural products modulate autophagy mediated by stress responses, affecting the malignant biological behavior of cancer. Furthermore, we discuss their roles in ovarian cancer therapy. This review emphasizes the importance of natural products as valuable resources in cancer therapeutics, highlighting the need for further exploration of their potential in regulating autophagy. Moreover, it provides novel insights and potential therapeutic strategies in ovarian cancer by utilizing natural products to modulate autophagy.

自噬是一种保守的分解代谢过程,通常具有保护细胞的功能。在压力条件下,当细胞环境变得不稳定时,自噬作为一种自我保护的适应性反应就会被激活。自噬将受损的细胞成分送到溶酶体进行降解和再循环,从而为细胞存活提供必要的营养物质。然而,这种在压力条件下促进细胞存活的功能往往会导致癌症的恶性发展和化疗抗药性。因此,自噬被认为是癌症治疗的潜在靶点。在此,我们旨在回顾天然产物如何通过调节细胞应激条件来充当自噬的关键调节剂。我们重新审视了各种应激源,包括饥饿、缺氧、内质网应激和氧化应激,以及它们与自噬的调控关系,重点关注卵巢癌研究的最新进展。此外,我们还探讨了多酚类化合物、黄酮类化合物、生物碱、萜类化合物和其他天然产物如何调节应激反应介导的自噬,从而影响癌症的恶性生物学行为。此外,我们还讨论了它们在卵巢癌治疗中的作用。这篇综述强调了天然产物作为癌症疗法中宝贵资源的重要性,突出了进一步探索它们在调节自噬方面潜力的必要性。此外,它还提供了利用天然产物调节自噬的新见解和潜在的卵巢癌治疗策略。
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引用次数: 0
Overexpression of CPT1A disrupts the maintenance and regenerative function of muscle stem cells 过表达 CPT1A 会破坏肌肉干细胞的维持和再生功能。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-09 DOI: 10.1096/fj.202400947R
Jiamin Qiu, Feng Yue, Kun Ho Kim, Xiyue Chen, Mennatallah A. Khedr, Jingjuan Chen, Lijie Gu, Junxiao Ren, Christina R. Ferreira, Jessica Ellis, Shihuan Kuang

The skeletal muscle satellite cells (SCs) mediate regeneration of myofibers upon injury. As they switch from maintenance (quiescence) to regeneration, their relative reliance on glucose and fatty acid metabolism alters. To explore the contribution of mitochondrial fatty acid oxidation (FAO) pathway to SCs and myogenesis, we examined the role of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO. CPT1A is highly expressed in quiescent SCs (QSCs) compared with activated and proliferating SCs, and its expression level decreases during myogenic differentiation. Myod1Cre-driven overexpression (OE) of Cpt1a in embryonic myoblasts (Cpt1aMTG) reduces muscle weight, grip strength, and contractile force without affecting treadmill endurance of adult mice. Adult Cpt1aMTG mice have reduced number of SC, impairing muscle regeneration and promoting lipid infiltration. Similarly, Pax7CreER-driven, tamoxifen-inducible Cpt1a-OE in QSCs of adult muscles (Cpt1aPTG) leads to depletion of SCs and compromises muscle regeneration. The reduced proliferation of Cpt1a-OE SCs is associated with elevated level of acyl-carnitine, and acyl-carnitine treatment impedes proliferation of wildtype SCs. These findings indicate that aberrant level of CPT1A elevates acyl-carnitine to impair the maintenance, proliferation and regenerative function of SCs.

骨骼肌卫星细胞(SC)在肌纤维受伤后介导其再生。当卫星细胞从维持(静止)状态转入再生状态时,它们对葡萄糖和脂肪酸代谢的相对依赖性会发生变化。为了探索线粒体脂肪酸氧化(FAO)途径对 SCs 和肌生成的贡献,我们研究了肉碱棕榈酰基转移酶 1A(CPT1A)的作用,它是 FAO 的限速酶。与活化和增殖的SCs相比,CPT1A在静止SCs(QSCs)中高表达,其表达水平在成肌分化过程中降低。Myod1Cre 驱动的 Cpt1a 在胚胎肌母细胞(Cpt1aMTG)中的过表达(OE)会降低肌肉重量、握力和收缩力,但不会影响成年小鼠的跑步机耐力。成年 Cpt1aMTG 小鼠的 SC 数量减少,影响肌肉再生并促进脂质浸润。同样,Pax7CreER 驱动、他莫昔芬诱导的成体肌肉 QSCs 中的 Cpt1a-OE (Cpt1aPTG)也会导致 SC 数量减少并影响肌肉再生。Cpt1a-OE SCs 的增殖减少与酰基肉碱水平升高有关,而酰基肉碱处理会阻碍野生型 SCs 的增殖。这些研究结果表明,CPT1A 的异常水平会使酰基肉碱升高,从而损害 SCs 的维持、增殖和再生功能。
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引用次数: 0
Selective depletion of kisspeptin neurons in the hypothalamic arcuate nucleus in early juvenile life reduces pubertal LH secretion and delays puberty onset in mice 在小鼠幼年时期选择性消耗下丘脑弓状核中的吻肽素神经元可减少青春期LH分泌并延迟青春期的到来。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-08 DOI: 10.1096/fj.202401696R
Eulalia A. Coutinho, Lourdes A. Esparza, Paige H. Steffen, Reanna Liaw, Shreyana Bolleddu, Alexander S. Kauffman

Puberty is the critical developmental transition to reproductive capability driven by the activation of gonadotropin-releasing hormone (GnRH) neurons. The complex neural mechanisms underlying pubertal activation of GnRH secretion still remain unknown, yet likely include kisspeptin neurons. However, kisspeptin neurons reside in several hypothalamic areas and the specific kisspeptin population timing pubertal onset remains undetermined. To investigate this, we strategically capitalized on the differential ontological expression of the Kiss1 gene in different hypothalamic nuclei to selectively ablate just arcuate kisspeptin neurons (aka KNDy neurons) during the early juvenile period, well before puberty, while sparing RP3V kisspeptin neurons. Both male and female transgenic mice with a majority of their KNDy neurons ablated (KNDyABL) by diphtheria toxin treatment in juvenile life demonstrated significantly delayed puberty onset and lower peripubertal LH secretion than controls. In adulthood, KNDyABL mice demonstrated normal in vivo LH pulse frequency with lower basal and peak LH levels, suggesting that only a small subset of KNDy neurons is sufficient for normal GnRH pulse timing but more KNDy cells are needed to secrete normal LH concentrations. Unlike prior KNDy ablation studies in rats, there was no alteration in the occurrence or magnitude of estradiol-induced LH surges in KNDyABL female mice, indicating that a complete KNDy neuronal population is not essential for normal LH surge generation. This study teases apart the contributions of different kisspeptin neural populations to the control of puberty onset, demonstrating that a majority of KNDy neurons in the arcuate nucleus are necessary for the proper timing of puberty in both sexes.

青春期是由促性腺激素释放激素(GnRH)神经元激活驱动的向生殖能力过渡的关键发育阶段。青春期激活促性腺激素释放激素(GnRH)分泌的复杂神经机制仍然未知,但很可能包括吻肽(kisspeptin)神经元。然而,kisspeptin神经元分布在下丘脑的多个区域,而青春期开始时的特定kisspeptin群体仍未确定。为了研究这个问题,我们战略性地利用 Kiss1 基因在下丘脑不同核团中的不同本体表达,在青春期之前的幼年时期选择性地消减弧形吻肽素神经元(又称 KNDy 神经元),同时保留 RP3V 吻肽素神经元。与对照组相比,在幼年时期通过白喉毒素处理消减了大部分 KNDy 神经元(KNDyABL)的雄性和雌性转基因小鼠的青春期开始时间明显推迟,围青春期 LH 分泌也较低。成年后,KNDyABL小鼠体内LH脉冲频率正常,但基础和峰值LH水平较低,这表明只有一小部分KNDy神经元足以维持正常的GnRH脉冲时间,但需要更多的KNDy细胞才能分泌正常浓度的LH。与之前在大鼠中进行的 KNDy 消融研究不同,KNDyABL 雌性小鼠中雌二醇诱导的 LH 激增的发生或幅度没有发生改变,这表明完整的 KNDy 神经元群对正常 LH 激增的产生并不重要。这项研究揭示了不同的Kisspeptin神经元群对控制青春期开始的贡献,证明了弓状核中的大多数KNDy神经元对两性青春期的适当时间都是必要的。
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引用次数: 0
Targeting KRAS in gynecological malignancies 针对妇科恶性肿瘤中的 KRAS。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-08 DOI: 10.1096/fj.202401734R
Yuanyuan Peng, Qing Yang

Cervical, endometrial, and ovarian cancers stand prominently as the leading gynecological malignancies of the female reproductive system. The conventional therapeutic modalities for gynecological malignancies have predominantly encompassed surgery, chemotherapy, and radiotherapy. However, efficacy of these approaches remains limited in cases of relapse or drug resistance. KRAS is one of the most frequently mutated oncogenes in human cancers. The KRAS gene encodes a small guanosine triphosphatase protein that acts as a molecular switch for crucial intracellular signaling pathways. KRAS mutations are deeply involved in the occurrence and development of gynecological malignancies. The present review aims to expound upon the role of oncogenic KRAS as a biomarker, elucidating various therapeutic approaches under investigation targeting the KRAS pathway in gynecological tumors.

宫颈癌、子宫内膜癌和卵巢癌是女性生殖系统中最主要的妇科恶性肿瘤。妇科恶性肿瘤的传统治疗方法主要包括手术、化疗和放疗。然而,在复发或耐药的情况下,这些方法的疗效仍然有限。KRAS 是人类癌症中最常发生突变的致癌基因之一。KRAS 基因编码一种小型鸟苷三磷酸酶蛋白,是细胞内重要信号通路的分子开关。KRAS 基因突变与妇科恶性肿瘤的发生和发展密切相关。本综述旨在阐述致癌 KRAS 作为生物标志物的作用,阐明针对妇科肿瘤中 KRAS 通路的各种正在研究的治疗方法。
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引用次数: 0
MREDTA: A BERT and transformer-based molecular representation encoder for predicting drug-target binding affinity MREDTA:基于 BERT 和变换器的分子表征编码器,用于预测药物与目标的结合亲和力。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 DOI: 10.1096/fj.202401254R
Xu Sun, Juanjuan Huang, Yabo Fang, Yixuan Jin, Jiageng Wu, Guoqing Wang, Jiwei Jia

Drug-target binding affinity (DTA) prediction is vital for drug repositioning. The accuracy and generalizability of DTA models remain a major challenge. Here, we develop a model composed of BERT-Trans Block, Multi-Trans Block, and DTI Learning modules, referred to as Molecular Representation Encoder-based DTA prediction (MREDTA). MREDTA has three advantages: (1) extraction of both local and global molecular features simultaneously through skip connections; (2) improved sensitivity to molecular structures through the Multi-Trans Block; (3) enhanced generalizability through the introduction of BERT. Compared with 12 advanced models, benchmark testing of KIBA and Davis datasets demonstrated optimal performance of MREDTA. In case study, we applied MREDTA to 2034 FDA-approved drugs for treating non-small-cell lung cancer (NSCLC), all of which act on mutant EGFRT790M protein. The corresponding molecular docking results demonstrated the robustness of MREDTA.

药物-靶点结合亲和力(DTA)预测对药物重新定位至关重要。DTA 模型的准确性和通用性仍是一大挑战。在此,我们开发了一种由 BERT-Trans Block、Multi-Trans Block 和 DTI 学习模块组成的模型,称为基于分子表征编码器的 DTA 预测(MREDTA)。MREDTA有三个优点:(1)通过跳转连接同时提取局部和全局分子特征;(2)通过Multi-Trans Block提高对分子结构的敏感性;(3)通过引入BERT增强通用性。与 12 个高级模型相比,KIBA 和 Davis 数据集的基准测试表明 MREDTA 具有最佳性能。在案例研究中,我们将 MREDTA 应用于 2034 种 FDA 批准的治疗非小细胞肺癌(NSCLC)的药物,这些药物都作用于突变的 EGFRT790M 蛋白。相应的分子对接结果证明了 MREDTA 的稳健性。
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