Biochimica et biophysica acta. Molecular basis of disease最新文献_第2页

Severe dynein dysfunction in cholinergic neurons exacerbates ALS-like phenotypes in a new mouse model 在一种新的小鼠模型中，胆碱能神经元中严重的动力蛋白功能障碍会加剧类似渐冻人症的表型。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-18 DOI: 10.1016/j.bbadis.2024.167540

Cytoplasmic dynein 1, a motor protein essential for retrograde axonal transport, is increasingly implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this study, we developed a novel mouse model that combines the Legs at odd angles (Loa, F580Y) point mutation in the dynein heavy chain with a cholinergic neuron-specific knockout of the dynein heavy chain. This model, for the first time, allows us to investigate the impact of Loa allele exclusivity in these neurons into adulthood. Our findings reveal that this selective increase in dynein dysfunction exacerbated the phenotypes observed in heterozygous Loa mice including pre-wean survival, reduced body weight and grip strength. Additionally, it induced ALS-like pathology in neuromuscular junctions (NMJs) not seen in heterozygous Loa mice. Notably, we also found a previously unobserved significant increase in neurons displaying TDP-43 puncta in both Loa mutants, suggesting early TDP-43 mislocalisation – a hallmark of ALS. The novel model also exhibited a concurrent rise in p62 puncta that did not co-localise with TDP-43, indicating broader impairments in autophagic clearance mechanisms. Overall, this new model underscores the fact that dynein impairment alone can induce ALS-like pathology and provides a valuable platform to further explore the role of dynein in ALS.

细胞质动力蛋白 1 是一种对轴突逆行运输至关重要的运动蛋白，它与肌萎缩性脊髓侧索硬化症（ALS）等神经退行性疾病的发病机制有越来越密切的联系。在这项研究中，我们开发了一种新型小鼠模型，该模型结合了动力蛋白重链中的 Legs at odd angles（Loa，F580Y）点突变和胆碱能神经元特异性动力蛋白重链敲除。这一模型首次允许我们研究 Loa 等位基因排他性对这些神经元成年期的影响。我们的研究结果表明，这种选择性增加的动力蛋白功能障碍加剧了在杂合子 Loa 小鼠中观察到的表型，包括断奶前存活率、体重和握力下降。此外，它还诱导了神经肌肉接头（NMJ）出现类似 ALS 的病理变化，这在杂合子 Loa 小鼠中是看不到的。值得注意的是，我们还发现，在两种 Loa 突变体中，显示 TDP-43 点的神经元数量显著增加，这是以前未曾观察到的，这表明 TDP-43 早期错定位--这是 ALS 的一个特征。这种新型模型还表现出与 TDP-43 并不共定位的 p62 点同时增加，这表明自噬清除机制出现了更广泛的损伤。总之，这种新模型强调了这样一个事实，即单靠动力蛋白损伤就能诱发类似渐冻人症的病理变化，并为进一步探索动力蛋白在渐冻人症中的作用提供了一个宝贵的平台。

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引用次数: 0

Fatty acid β-oxidation in brain mitochondria: Insights from high-resolution respirometry in mouse, rat and Drosophila brain, ischemia and aging models 脑线粒体中的脂肪酸β氧化：从小鼠、大鼠和果蝇大脑、缺血和衰老模型的高分辨率呼吸测量中获得的启示。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-17 DOI: 10.1016/j.bbadis.2024.167544

Glucose is the main energy source of the brain, yet recent studies demonstrate that fatty acid oxidation (FAO) plays a relevant role in the pathogenesis of central nervous system disorders. We evaluated FAO in brain mitochondria under physiological conditions, in the aging brain, and after stroke. Using high-resolution respirometry we compared medium-chain (MC, octanoylcarnitine) and long-chain (LC, palmitoylcarnitine) acylcarnitines as substrates of β-oxidation in the brain. The protocols developed avoid FAO overestimation by malate-linked anaplerotic activity in brain mitochondria. The capacity of FA oxidative phosphorylation (F-OXPHOS) with palmitoylcarnitine was up to 4 times higher than respiration with octanoylcarnitine. The optimal concentration of palmitoylcarnitine was 10 μM which corresponds to the total concentration of LC acylcarnitines in the brain. Maximal respiration with octanoylcarnitine was reached at 20 μM, however, this concentration exceeds MC acylcarnitine concentrations in the brain 15 times. F-OXPHOS capacity was highest in mouse cerebellum, intermediate in cortex, prefrontal cortex, and hypothalamus, and hardly detectable in hippocampus. F-OXPHOS capacity was 2-fold lower and concentrations of LC acylcarnitines were 2-fold higher in brain of aged rats. A similar trend was observed in the rat model of endothelin-1-induced stroke, but reduction of OXPHOS capacity was not limited to FAO. In conclusion, although FAO is not a dominant pathway in brain bioenergetics, it deserves specific attention in studies of brain metabolism.

葡萄糖是大脑的主要能量来源，但最近的研究表明，脂肪酸氧化（FAO）在中枢神经系统疾病的发病机制中发挥着重要作用。我们评估了生理条件下、衰老大脑和中风后大脑线粒体中的脂肪酸氧化。利用高分辨率呼吸测定法，我们比较了中链（MC，辛酰肉碱）和长链（LC，棕榈酰肉碱）酰基肉碱作为大脑中β氧化底物的情况。所开发的方案避免了脑线粒体中与苹果酸有关的无反应活性对 FAO 的高估。使用棕榈酰肉碱进行 FA 氧化磷酸化（F-OXPHOS）的能力比使用辛酰肉碱进行呼吸的能力高出 4 倍。棕榈酰肉碱的最佳浓度为 10 μM，这与大脑中低密度脂蛋白酰肉碱的总浓度相当。辛酰肉碱的最大呼吸作用在 20 μM 时达到，但这一浓度超过大脑中 MC酰基肉碱浓度的 15 倍。小鼠小脑的 F-OXPHOS 能力最高，皮层、前额叶皮层和下丘脑居中，海马几乎检测不到。老龄大鼠大脑中的 F-OXPHOS 能力低 2 倍，LC 乙酰肉碱浓度高 2 倍。在内皮素-1 诱导的中风大鼠模型中也观察到了类似的趋势，但 OXPHOS 能力的降低并不局限于 FAO。总之，虽然 FAO 并非大脑生物能的主要途径，但在大脑新陈代谢研究中值得特别关注。

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引用次数: 0

PFKP inhibition protects against pathological cardiac hypertrophy by regulating protein synthesis 抑制 PFKP 可通过调节蛋白质合成防止病理性心肌肥厚

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-15 DOI: 10.1016/j.bbadis.2024.167542

Metabolic reprogramming precedes most alterations during pathological cardiac hypertrophy and heart failure (HF). Recent studies have revealed that Phosphofructokinase, platelet (PFKP) has a wealth of metabolic and non-metabolic functions. In this study, we explored the role of PFKP in cardiac hypertrophic growth and HF. The expression level of PFKP was elevated both in pathological cardiac remodeling mouse model challenged by transverse aortic constriction (TAC) surgery and in the neonatal rat cardiomyocytes (NRCMs) stimulated by phenylephrine (PE). In global PFKP knockout (PFKP-KO) mice, cardiac hypertrophy was ameliorated under TAC surgery, while overexpression of PFKP by intravenous injection of adeno-associated virus 9 (AAV9) under the cardiac troponin T (cTnT) promoter worsened myocardial hypertrophy and fibrosis. In NRCMs, small interfering RNA (SiRNA) knockdown or adenovirus (Adv) overexpression of PFKP was employed and the intervention of PFKP showed a similar phenotype. Mechanistically, immunoprecipitation combined with liquid chromatography-tandem mass spectrometry (IP-MS/MS) analysis was used to identify the interacting proteins of PFKP. Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) was identified as the downstream target of PFKP. In the PE-stimulated NRCM hypertrophy model and mouse TAC model, knocking down EIF2S2 after PFKP overexpression reduced the synthesis of new proteins and alleviated the hypertrophy phenotype. Our findings illuminate that PFKP participates in pathological cardiac hypertrophy partly by regulating protein synthesis through EIF2S2, which provides a new clue for the involvement of metabolic intermediates in signal transduction.

在病理性心肌肥厚和心力衰竭（HF）过程中，代谢重编程先于大多数改变。最近的研究发现，血小板磷酸果激酶（PFKP）具有丰富的代谢和非代谢功能。在本研究中，我们探讨了 PFKP 在心脏肥大生长和 HF 中的作用。在横主动脉缩窄（TAC）手术挑战的病理性心脏重塑小鼠模型和苯肾上腺素（PE）刺激的新生大鼠心肌细胞（NRCMs）中，PFKP的表达水平均升高。在全基因 PFKP 敲除（PFKP-KO）小鼠中，TAC 手术可改善心肌肥厚，而通过静脉注射腺相关病毒 9（AAV9）在心肌肌钙蛋白 T（cTnT）启动子下过表达 PFKP 则会加重心肌肥厚和纤维化。在 NRCMs 中，采用小干扰 RNA（SiRNA）敲除或腺病毒（Adv）过表达 PFKP，对 PFKP 的干预显示出相似的表型。从机理上讲，免疫沉淀结合液相色谱-串联质谱（IP-MS/MS）分析被用来鉴定与PFKP相互作用的蛋白。真核翻译起始因子 2 亚基 beta（EIF2S2）被确定为 PFKP 的下游靶标。在 PE 刺激的 NRCM 肥大模型和小鼠 TAC 模型中，过表达 PFKP 后敲除 EIF2S2 可减少新蛋白质的合成并减轻肥大表型。我们的研究结果表明，PFKP 部分通过 EIF2S2 调节蛋白质合成参与病理性心肌肥厚，这为代谢中间产物参与信号转导提供了新的线索。

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引用次数: 0

Metabolic alterations in fibroblasts of patients presenting with the MPAN subtype of neurodegeneration with brain iron accumulation (NBIA) 脑铁积聚性神经变性 MPAN 亚型（NBIA）患者成纤维细胞中的代谢变化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-15 DOI: 10.1016/j.bbadis.2024.167541

Mutations in the following genes: PANK2, PLA2G6, C19orf12, WDR45, CP, FA2H, ATP13A2, FTL, DCAF17, and CoASY are associated with the development of different subtypes of inherited rare disease Neurodegeneration with Brain Iron Accumulation (NBIA). Additionally, recently described mutations in FTH1, AP4M1, REPS1, SCP2, CRAT and GTPBP2 affecting iron and lipid metabolism also are thought to be involved in NBIA development. Four main subtypes, pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and beta-propeller protein-associated neurodegeneration (BPAN), are responsible for up to 82 % of all NBIA cases. Here we studied fibroblasts from 11 patients with pathogenic mutations in C19orf12, and demonstrate various cellular aberrations. Differences between fibroblasts from healthy individuals and MPAN patients were potentiated when cells were grown under oxidative phosphorylation (OXPHOS) promoting condition suggesting an impaired metabolic flexibility. The extent of some of the cellular aberrations quantitatively correlated with disease severity, suggesting their involvement in the NBIA pathomechanism.

以下基因的突变PANK2、PLA2G6、C19orf12、WDR45、CP、FA2H、ATP13A2、FTL、DCAF17、CoASY 与不同亚型的遗传性罕见病脑铁蓄积性神经变性（NBIA）的发病有关。此外，最近描述的影响铁和脂代谢的基因 FTH1、AP4M1、REPS1、SCP2、CRAT 和 GTPBP2 的突变也被认为与 NBIA 的发病有关。泛酸激酶相关神经变性（PKAN）、PLA2G6相关神经变性（PLAN）、线粒体膜蛋白相关神经变性（MPAN）和β-螺旋桨蛋白相关神经变性（BPAN）这四种主要亚型是所有 NBIA 病例中高达 82% 的病因。在这里，我们研究了来自 11 位 C19orf12 致病突变患者的成纤维细胞，结果显示了各种细胞畸变。当细胞在促进氧化磷酸化（OXPHOS）的条件下生长时，健康人的成纤维细胞和 MPAN 患者的成纤维细胞之间的差异会加剧，这表明新陈代谢的灵活性受损。一些细胞畸变的程度与疾病的严重程度存在定量相关性，这表明它们参与了 NBIA 的病理机制。

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引用次数: 0

Nuclear localization of APLF facilitates breast cancer metastasis APLF 的核定位促进了乳腺癌的转移。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-09 DOI: 10.1016/j.bbadis.2024.167537

Most breast cancer deaths result from metastases. We previously reported that DNA repair factor and histone chaperone Aprataxin PNK-like Factor (APLF) is involved in EMT-associated metastasis of triple negative breast cancer (TNBC) cells. However, non-metastatic cells also expressed APLF, the implications of which in disease advancement remain uncertain. Here, we demonstrate that the metastatic prognosis of breast cancer cells may be determined by the cellular localization of APLF. Using TNBC patient samples and cell lines, we discovered that APLF was localized in the nucleus and cytoplasm, whereas other subtypes of breast cancer had cytosolic or perinuclear localization. To investigate metastatic properties in vitro and in vivo, we modeled APLF differential localization by stably producing APLF-tagged nuclear localization signal (NLS) in the luminal subtype MCF7 cells in the absence of putative APLF NLS. Nuclear APLF in non-metastatic MCF7 cells demonstrated pronounced migration, invasion and metastatic potential. We obtained the mechanistic insight from molecular studies that PARP1 could facilitate the transport of APLF from the cytosol to the nucleus, assisting in the metastasis of TNBC cells linked with EMT. Inhibition of PARP1 enzymatic activity with olaparib abrogated the nuclear expression of APLF with loss in expression of genes associated with EMT. Thus, our findings reveal that cellular localization of APLF may predict the risk of breast cancer to metastasize and hence could be exploited to determine the disease progression. We anticipate that the inhibition of cytosolic PARP1-APLF interaction may potentially aid in the prevention of breast cancer metastasis in TNBC patients.

大多数乳腺癌患者死于转移。我们以前曾报道过，DNA 修复因子和组蛋白合子 Aprataxin PNK-like Factor（APLF）参与了三阴性乳腺癌（TNBC）细胞与 EMT 相关的转移。然而，非转移细胞也表达 APLF，其对疾病进展的影响仍不确定。在这里，我们证明乳腺癌细胞的转移预后可能由 APLF 的细胞定位决定。利用 TNBC 患者样本和细胞系，我们发现 APLF 定位于细胞核和细胞质中，而其他亚型乳腺癌则定位于细胞膜或核周。为了研究体外和体内的转移特性，我们通过在腔内亚型 MCF7 细胞中稳定生产 APLF 标记的核定位信号（NLS）来模拟 APLF 的不同定位。非转移性 MCF7 细胞的核 APLF 表现出明显的迁移、侵袭和转移潜力。通过分子研究，我们从机理上认识到，PARP1 可促进 APLF 从细胞质到细胞核的转运，有助于与 EMT 相关的 TNBC 细胞的转移。用奥拉帕利抑制PARP1酶的活性，可抑制APLF的核表达，同时抑制与EMT相关基因的表达。因此，我们的研究结果表明，APLF 的细胞定位可能预示着乳腺癌转移的风险，因此可以利用它来判断疾病的进展。我们预计，抑制细胞膜 PARP1 与 APLF 的相互作用可能有助于预防 TNBC 患者的乳腺癌转移。

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引用次数: 0

Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway 转谷氨酰胺酶2通过MEK/ERK信号通路调节结直肠癌细胞中基质金属蛋白酶7的表达，从而促进上皮细胞向间质转化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-09 DOI: 10.1016/j.bbadis.2024.167538

Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells.

TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling.

TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7.

TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.

组织转谷氨酰胺酶 2（TGM2）和基质金属蛋白酶 7（MMP7）被认为参与了癌症的发生和发展，但它们在结肠癌中的具体作用仍不明确。本研究探讨了 TGM2 和 MMP7 是否会影响结肠癌细胞的上皮-间质转化（EMT）过程。在 SW480 和 HCT-116 细胞中过表达或敲除 TGM2，并分析 MMP7 的表达和活性。反之，则对 MMP7 进行沉默，并检测其与 TGM2 表达和活性的相关性。共免疫沉淀用于评估 TGM2 与 MMP7 的相互作用。TGM2和MMP7的表达与侵袭、迁移、EMT标记物（E-cadherin、N-cadherin、Slug、Snail）的表达以及ERK/MEK信号转导相关。TGM2的过表达增强了MMP7的表达和活性，促进了细胞的侵袭、迁移和EMT，其特征是N-adherin和Snail/Slug的表达增加。而敲除 TGM2 则会产生相反的效果。敲除 MMP7 与 TGM2 蛋白表达、细胞侵袭和迁移减少有关。下调 MMP7 会减少 ERK/MEK 信号传导，而上调则会激活这一途径。ERK抑制剂GDC-0994阻断了MEK/ERK的磷酸化，抑制了TGM2和MMP7。TGM2 与结肠癌细胞中的 MMP7 通过 MEK/ERK 信号通路进行交流，迫使细胞迁移和侵袭，并引发 EMT。因此，抑制 TGM2 可为治疗结肠癌患者提供新的治疗方案，尤其是防止转移进展。

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引用次数: 0

Maternal heart exhibits metabolic and redox adaptations post-uncomplicated pregnancy Biochimica et biophysica acta：非并发妊娠后母体心脏出现新陈代谢和氧化还原适应性疾病的分子基础。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-06 DOI: 10.1016/j.bbadis.2024.167539

Pregnancy may be a challenging period for the maternal systems and has been regarded as a stress test, as imperceptible/mild dysfunctions eventually present may be exacerbated during this period. The cardiovascular system is no exception, and several morphological and functional adaptations accompanying pregnancy have been described. However, long-term pregnancy-induced cardiac molecular alterations remain highly unexplored. The postpartum is marked by reverse remodeling of the pregnancy-induced cardiovascular adaptations, representing a possible critical period for assessing future maternal cardiovascular health. The current study explored the molecular and metabolic alterations in the cardiac tissue eight weeks after a physiological uncomplicated pregnancy. Female Sprague-Dawley rats were fed a chow diet through pregnancy, lactation, and weaning and compared to their non-pregnant counterparts. Eight weeks postpartum, increased levels of the phosphorylated form of AMPKα (Thr172) and its ratio to total AMPKα indicated possible alterations in cardiac metabolic flexibility, accompanied by increased Pparα and Hif1α transcripts levels. Additionally, postpartum hearts exhibited higher mitochondrial ATP and NADH levels without major changes in mitochondrial respiratory function. Elevated Nrf2 levels in the cardiac tissue suggested potential implications for cardiac redox balance, further supported by increased levels or activity of proteins directly regulated by Nrf2. The findings herein reported suggest that at eight weeks postpartum, molecular alterations induced by pregnancy, especially regarding redox balance, are still observed in the mothers' heart. These alterations present at late postpartum may open new avenues to understand the different risk for cardiovascular complications development after normal pregnancies.

妊娠期对母体系统来说是一个充满挑战的时期，被认为是一种压力测试，因为在此期间，最终存在的不易察觉/轻微的功能障碍可能会加剧。心血管系统也不例外，已经描述了伴随妊娠出现的几种形态和功能适应性变化。然而，长期妊娠诱导的心脏分子改变仍是一个尚未探索的领域。产后妊娠诱导的心血管适应性会发生反向重塑，这可能是评估孕产妇未来心血管健康的关键时期。本研究探讨了生理性无并发症妊娠八周后心脏组织的分子和代谢变化。雌性 Sprague-Dawley 大鼠在整个孕期、哺乳期和断奶期都以饲料喂养，并与未怀孕的大鼠进行比较。产后八周，AMPKα的磷酸化形式（Thr172）水平及其与总AMPKα的比率升高，表明心脏代谢灵活性可能发生了改变，同时Pparα和Hif1α转录物水平升高。此外，产后心脏的线粒体 ATP 和 NADH 水平较高，但线粒体呼吸功能没有发生重大变化。心脏组织中 Nrf2 水平的升高表明了对心脏氧化还原平衡的潜在影响，而 Nrf2 直接调控的蛋白质水平或活性的升高也进一步证实了这一点。本文报告的研究结果表明，在产后八周，仍可在母亲的心脏中观察到妊娠引起的分子变化，尤其是氧化还原平衡方面的变化。产后晚期出现的这些变化可能为了解正常妊娠后心血管并发症的不同风险开辟了新的途径。

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引用次数: 0

VEGFB promotes adipose tissue thermogenesis by inhibiting norepinephrine clearance in macrophages 血管内皮生长因子B通过抑制巨噬细胞中去甲肾上腺素的清除来促进脂肪组织产热。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-06 DOI: 10.1016/j.bbadis.2024.167536

Adipokines play key roles in adaptive thermogenesis of beige adipocytes, though its detailed regulatory mechanisms are not fully understood. In the present study, we identify a critical function of vascular endothelial growth factor B (VEGFB)/vascular endothelial growth factor receptor 1 (VEGFR1) signaling in improving thermogenesis in white adipose tissue (WAT). In mouse subcutaneous WAT (scWAT), thermogenesis activation leads to the up-regulation of VEGFB in adipocytes and its receptor VEGFR1 in macrophages. Ablation of adipocyte VEGFB results in deficiency in murine WAT browning. Meanwhile, supplementation of VEGFB promotes WAT thermogenesis, but this effect is blocked by knockout of macrophage VEGFR1. Mechanistic studies show that the VEGFB-activated VEGFR1 inhibits p38 MAPK signaling through its dissociation with receptor for activated C kinase 1, thereby preventing norepinephrine transporter (solute carrier family 6 member 2) and norepinephrine-degrative monoamine oxidase a mediated norepinephrine clearance in macrophages. Our findings demonstrate that VEGFB/VEGFR1 circuit contributes to the WAT thermogenesis.

脂肪因子在米色脂肪细胞的适应性产热过程中发挥着关键作用，但其详细的调控机制尚不完全清楚。在本研究中，我们发现了血管内皮生长因子 B（VEGFB）/血管内皮生长因子受体 1（VEGFR1）信号在改善白色脂肪组织（WAT）产热过程中的关键功能。在小鼠皮下脂肪组织（scWAT）中，产热激活会导致脂肪细胞中的血管内皮生长因子B和巨噬细胞中的血管内皮生长因子受体VEGFR1上调。消融脂肪细胞中的 VEGFB 会导致小鼠 WAT 褐化不足。同时，补充 VEGFB 可促进脂肪细胞的产热，但巨噬细胞 VEGFR1 的基因敲除会阻断这种效应。机理研究表明，VEGFB激活的VEGFR1通过与活化C激酶1受体分离抑制p38 MAPK信号转导，从而阻止巨噬细胞中去甲肾上腺素转运体（溶质运载家族6成员2）和去甲肾上腺素降解单胺氧化酶a介导的去甲肾上腺素清除。我们的研究结果表明，血管内皮生长因子B/血管内皮生长因子受体1回路有助于脂肪热生成。

引用次数: 0

Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells 激酶库筛选确定 IGF-1R 是肝内胆管癌干样细胞的致癌弱点。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-05 DOI: 10.1016/j.bbadis.2024.167521

Background

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive.

Methods

The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated.

Results

Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top ‘hit’ inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations.

Conclusions

IGF-1R plays a critical role in maintaining iCCA-stem like cell populations.

General significance

Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.

背景：肝内胆管癌（iCCA）是一种侵袭性极强的外周胆管癌，其特征是肿瘤组织中存在大量癌症干样细胞（CSC）。虽然 iCCA 中的 CSC 标记已明确定义，但这一亚群的分子弱点仍然难以捉摸：方法：96孔三维（3D）瘤球培养是从一个成熟的CSC模型改良而来，通过基因表达分析验证了CSC标记物。然后进行激酶库筛选，以揭示潜在的致癌脆弱通路。利用RNA干扰在三个iCCA细胞系中稳定沉默候选基因，并评估其对iCCA细胞增殖和瘤球形成效率（TFE）的影响：结果：激酶抑制剂库筛选出了对肿瘤球活力至关重要的前50种激酶抑制剂，其中11种抑制剂靶向IGF-1R/PI3K/AKT轴。对 "热门 "抑制剂的进一步剂量依赖性分析证实了IGF-1R是候选分子。稳定沉默IGF-1R后，所有三种iCCA细胞系都表现出AKT活化减少、增殖受阻和TFE降低，表明CSC亚群减少：结论：IGF-1R 在维持 iCCA 干样细胞群中发挥着关键作用：我们的数据强调了 IGF-1R 作为 iCCA 预后标志物和消除其 CSC 亚群治疗靶点的潜在作用。

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引用次数: 0

Bulk integrated single-cell-spatial transcriptomics reveals the impact of preoperative chemotherapy on cancer-associated fibroblasts and tumor cells in colorectal cancer, and construction of related predictive models using machine learning 批量整合的单细胞空间转录组学揭示了结直肠癌术前化疗对癌症相关成纤维细胞和肿瘤细胞的影响，并利用机器学习构建了相关预测模型。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2024-10-05 DOI: 10.1016/j.bbadis.2024.167535

Background

Preoperative chemotherapy (PC) is an important component of Colorectal cancer (CRC) treatment, but its effects on the biological functions of fibroblasts and epithelial cells in CRC are unclear.

Methods

This study utilized bulk, single-cell, and spatial transcriptomic sequencing data from 22 independent cohorts of CRC. Through bioinformatics analysis and in vitro experiments, the research investigated the impact of PC on fibroblast and epithelial cells in CRC. Subpopulations associated with PC and CRC prognosis were identified, and a predictive model was constructed using machine learning.

Results

PC significantly attenuated the pathways related to tumor progression in fibroblasts and epithelial cells. NOTCH3 + Fibroblast (NOTCH3 + Fib), TNNT1 + Epithelial (TNNT1 + Epi), and HSPA1A + Epithelial (HSPA1A + Epi) subpopulations were identified in the adjacent spatial region and were associated with poor prognosis in CRC. PC effectively diminished the presence of these subpopulations, concurrently inhibiting pathway activity and intercellular crosstalk. A risk signature model, named the Preoperative Chemotherapy Risk Signature Model (PCRSM), was constructed using machine learning. PCRSM emerged as an independent prognostic indicator for CRC, impacting both overall survival (OS) and recurrence-free survival (RFS), surpassing the performance of 89 previously published CRC risk signatures. Additionally, patients with a high PCRSM risk score showed sensitivity to fluorouracil-based adjuvant chemotherapy (FOLFOX) but resistance to single chemotherapy drugs (such as Bevacizumab and Oxaliplatin). Furthermore, this study predicted that patients with high PCRSM were resistant to anti-PD1therapy.

Conclusion

In conclusion, this study identified three cell subpopulations (NOTCH3 + Fib, TNNT1 + Epi, and HSPA1A + Epi) associated with PC, which can be targeted to improve the prognosis of CRC patients. The PCRSM model shows promise in enhancing the survival and treatment of CRC patients.

背景：术前化疗（PC）是结直肠癌（CRC）治疗的重要组成部分，但其对 CRC 中成纤维细胞和上皮细胞生物功能的影响尚不清楚：本研究利用了来自 22 个独立队列的 CRC 的大量、单细胞和空间转录组测序数据。通过生物信息学分析和体外实验，该研究调查了 PC 对 CRC 中成纤维细胞和上皮细胞的影响。研究发现了与PC和CRC预后相关的亚群，并利用机器学习构建了一个预测模型：结果：PC能明显减弱成纤维细胞和上皮细胞中与肿瘤进展相关的通路。在邻近空间区域发现了NOTCH3 +成纤维细胞（NOTCH3 + Fib）、TNNT1 +上皮细胞（TNNT1 + Epi）和HSPA1A +上皮细胞（HSPA1A + Epi）亚群，它们与CRC的不良预后有关。PC 能有效减少这些亚群的存在，同时抑制通路活性和细胞间串扰。研究人员利用机器学习构建了一个风险特征模型，命名为术前化疗风险特征模型（PCRSM）。PCRSM成为独立的CRC预后指标，对总生存期（OS）和无复发生存期（RFS）都有影响，超过了之前发表的89个CRC风险特征模型。此外，PCRSM风险评分高的患者对以氟尿嘧啶为基础的辅助化疗（FOLFOX）敏感，但对单一化疗药物（如贝伐单抗和奥沙利铂）耐药。此外，本研究还预测 PCRSM 分值高的患者对抗 PD1 治疗具有耐药性：总之，这项研究发现了与 PC 相关的三种细胞亚群（NOTCH3 + Fib、TNNT1 + Epi 和 HSPA1A + Epi），可以针对这些亚群改善 CRC 患者的预后。PCRSM 模型有望提高 CRC 患者的生存率和治疗效果。

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