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A Comprehensive Pan-Cancer Analysis of the Mitochondrial Uncoupling Protein UCP2, with a Focus on Sex and Gender-Related Aspects. 线粒体解偶联蛋白 UCP2 的泛癌症综合分析,重点关注与性别相关的方面。
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-10-27 DOI: 10.33594/000000735
Soha Sadeghi, Vanessa Checchetto, Tatiana Varanita

Background/aims: Mitochondrial uncoupling protein 2 (UCP2) plays a crucial role in regulating oxidative stress and cellular metabolism, positioning it as an important subject in oncological research. The involvement of UCP2 in cancer is complex and context-dependent, suggesting it as a potential therapeutic target. In this study, we aimed to perform a comprehensive pan-cancer analysis of UCP2, with a particular focus on gender-related malignancies such as breast (BRCA), prostate (PRAD), ovarian (OV), and testicular tumors (TGCT).

Methods: We analyzed UCP2 expression in The Cancer Genome Atlas (TCGA), examining correlations with prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), immune cell infiltration, immune checkpoint genes, genes involved in steroidogenesis, sex hormone receptor genes, and drug sensitivity.

Results: Significant variability in UCP2 expression was observed across cancer types. UCP2 levels were elevated in BRCA and OV but reduced in PRAD and TGCT. High UCP2 expression was associated with a better prognosis in OV and poorer overall survival in PRAD. Furthermore, UCP2 correlated with TMB and MSI in OV, TGCT, and BRCA. UCP2 expression was also linked to immune cell infiltration, immune checkpoint genes, steroidogenic genes, and sex hormone receptor genes, with variable effects depending on cancer type and gender. Additionally, UCP2 also demonstrated sensitivity to specific anticancer drugs.

Conclusion: Our findings highlight the interplay between UCP2, immune and hormonal pathways, and drug response and reveal potential opportunities for new therapeutic combinations, especially in gender-related cancers.

背景/目的:线粒体解偶联蛋白 2(UCP2)在调节氧化应激和细胞新陈代谢方面发挥着至关重要的作用,因此成为肿瘤学研究的一个重要课题。UCP2 在癌症中的参与是复杂的,且与环境有关,这表明它是一个潜在的治疗靶点。在本研究中,我们旨在对 UCP2 进行全面的泛癌症分析,尤其关注与性别相关的恶性肿瘤,如乳腺癌(BRCA)、前列腺癌(PRAD)、卵巢癌(OV)和睾丸癌(TGCT):我们分析了癌症基因组图谱(TCGA)中 UCP2 的表达,研究了其与预后、肿瘤突变负荷(TMB)、微卫星不稳定性(MSI)、免疫细胞浸润、免疫检查点基因、参与类固醇生成的基因、性激素受体基因和药物敏感性的相关性:结果:不同癌症类型的 UCP2 表达存在显著差异。在 BRCA 和 OV 中 UCP2 水平升高,而在 PRAD 和 TGCT 中则降低。UCP2 的高表达与 OV 的较好预后和 PRAD 的较差总生存率相关。此外,UCP2 与 OV、TGCT 和 BRCA 中的 TMB 和 MSI 相关。UCP2 的表达还与免疫细胞浸润、免疫检查点基因、类固醇生成基因和性激素受体基因有关,其影响因癌症类型和性别而异。此外,UCP2 还表现出对特定抗癌药物的敏感性:我们的研究结果突显了 UCP2、免疫和激素通路与药物反应之间的相互作用,并揭示了新疗法组合的潜在机会,尤其是在与性别相关的癌症中。
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引用次数: 0
Nitric Oxide-Dependent Regulation of Oxygen-Related Processes in a Rat Model of Lead Neurotoxicity: Influence of the Hypoxia Resistance Factor. 一氧化氮对铅神经毒性大鼠模型中氧相关过程的依赖性调节:缺氧抵抗因子的影响。
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-10-20 DOI: 10.33594/000000734
Natalia Kurhaluk, Piotr Kamiński, Oleksandr Lukash, Halina Tkaczenko
<p><strong>Background/aims: </strong>Lead exposure is known to induce oxidative stress and neurotoxicity. Nitric oxide (NO) plays an important role in modulating oxidative stress, with L-arginine as a precursor of NO and N<sup>ω</sup>-nitro-L-arginine (L-NNA) as an inhibitor of NO synthase, an enzyme that catalyses the production of nitric oxide (NO) from L-arginine.</p><p><strong>Methods: </strong>This study investigated the differential effects of L-arginine and L-NNA on markers of oxidative stress and biochemical changes in brain tissue from rats with different levels of resistance to hypoxia exposed to lead nitrate. Rats with either low or high resistance to hypoxia were exposed to lead nitrate (oral 3.6 mg lead nitrate/kg b.w. per day for 30 days) and treated with L-arginine (600 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate) or L-NNA (35 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate). Brain tissue samples were analysed for lipid peroxidation, oxidative modification of proteins, and activity of antioxidant enzymes, including superoxide dismutase, catalase, glutathione reductase, and peroxidase, and total antioxidant status (TAS). We also examined the biomarkers of biochemical pathways involving the activity of alanine and aspartate aminotransferases, succinate dehydrogenase (SDH), and α-ketoglutarate dehydrogenase (KGDH). In addition, the trend observed was supported by assessments of the acetylcholine levels and acetylcholinesterase activity (ACh-AChE system) in brain tissue.</p><p><strong>Results: </strong>In rats with low resistance to hypoxia, the L-arginine treatment significantly reduced lipid peroxidation and oxidative protein modification but increased antioxidant enzyme activity, suggesting a protective effect against lead-induced oxidative stress. Conversely, in rats with high resistance to hypoxia, L-NNA had a protective effect, reducing lead-induced oxidative damage and decreasing lipid peroxidation, whereas L-arginine exacerbated oxidative stress and impaired antioxidant defences. These findings were supported by corresponding changes in the acetylcholine-acetylcholinesterase system, reflecting the observed patterns of lead-induced oxidative stress and neurotoxicity. The study shows that L-arginine exerts a protective effect by reducing lead-induced oxidative damage via an improvement in TAS. Our study shows that lead nitrate exposure significantly increases ala-nine and aspartate aminotransferase activity in brain tissue, with L-arginine exacerbating and L-NNA reversing this effect. The lead nitrate exposure also affected the activities of SDH and KGDH, which are important for cellular energy production and hypoxia resistance, with L-arginine altering SDH activity depending on the level of resistance and L-NNA enhancing both SDH and KGDH activities. These trends were further validated by alterations in the ACh-AChE system, highlighting the differential role of NO-dependent mechanisms in
背景/目的:众所周知,铅暴露会诱发氧化应激和神经毒性。一氧化氮(NO)在调节氧化应激中起着重要作用,L-精氨酸是 NO 的前体,而 Nω-硝基-L-精氨酸(L-NNA)是 NO 合酶的抑制剂,NO 合酶是催化 L-精氨酸产生一氧化氮(NO)的酶:本研究调查了 L-精氨酸和 L-NNA 对不同耐缺氧程度的大鼠脑组织氧化应激标记物和生化变化的不同影响。低耐受性或高耐受性大鼠暴露于硝酸铅(每天口服 3.6 毫克硝酸铅/千克体重,持续 30 天),并在暴露于硝酸铅前后 30 分钟接受 L-精氨酸(600 毫克/千克体重,静注)或 L-NNA(35 毫克/千克体重,静注,在暴露于硝酸铅前后 30 分钟)治疗。对脑组织样本进行了脂质过氧化、蛋白质氧化修饰、抗氧化酶(包括超氧化物歧化酶、过氧化氢酶、谷胱甘肽还原酶和过氧化物酶)活性和总抗氧化状态(TAS)分析。我们还检测了涉及丙氨酸和天冬氨酸氨基转移酶、琥珀酸脱氢酶(SDH)和α-酮戊二酸脱氢酶(KGDH)活性的生化途径生物标志物。此外,对脑组织中乙酰胆碱水平和乙酰胆碱酯酶活性(ACh-AChE 系统)的评估也支持所观察到的趋势:结果:在耐缺氧能力低的大鼠中,L-精氨酸处理能显著降低脂质过氧化和氧化蛋白质修饰,但能提高抗氧化酶的活性,这表明它对铅诱导的氧化应激具有保护作用。相反,在耐缺氧能力较强的大鼠中,L-NNA 具有保护作用,可减少铅诱导的氧化损伤并降低脂质过氧化,而 L-精氨酸则会加剧氧化应激并损害抗氧化防御能力。这些发现得到了乙酰胆碱-乙酰胆碱酯酶系统相应变化的支持,反映了观察到的铅诱导氧化应激和神经毒性模式。研究表明,L-精氨酸通过改善 TAS,减少铅诱导的氧化损伤,从而发挥保护作用。我们的研究表明,接触硝酸铅会显著增加脑组织中的丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性,L-精氨酸会加剧这种效应,而 L-NNA 则会逆转这种效应。硝酸铅暴露还影响了 SDH 和 KGDH 的活性,而这两种物质对细胞能量生产和耐缺氧非常重要,L-精氨酸会根据耐缺氧程度改变 SDH 的活性,而 L-NNA 则会增强 SDH 和 KGDH 的活性。ACh-AChE 系统的改变进一步验证了这些趋势,凸显了 NO 依赖性机制在根据缺氧抵抗性调节铅诱导的神经毒性中的不同作用:这些发现提出了基于氧化应激特征的潜在靶向治疗策略,并强调了一氧化氮系统调节剂在抗衡铅诱导的生化改变和 ACh-AChE 系统动态方面的潜力,这取决于生物体的个体生理反应性。
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引用次数: 0
BMI-1 in Breast Cancer - Biological Role and Clinical Implications. 乳腺癌中的 BMI-1 - 生物学作用和临床意义。
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-10-15 DOI: 10.33594/000000733
Aleksandra Szustka, Anna Krześlak

Breast cancer is the most frequent cancer among women. Despite extensive research in recent years the molecular basis of breast cancer development, growth and metastasis remains unclear. Numerous studies highlight the involvement of BMI-1 in tumorigenesis. BMI-1 protein is a key component of Polycomb Repressive Complex 1, which by ubiquitinylation of histone H2A, regulates expression of genes involved in various cellular processes including cell cycle, proliferation and programmed cell death. Overexpression of BMI-1 has been often associated with breast cancer development and progression. This review summarizes the current state of knowledge of BMI-1's role in breast cancer biology and its potential significance as prognostic marker and potential target of new anticancer therapy.

乳腺癌是女性最常见的癌症。尽管近年来进行了大量研究,但乳腺癌发生、生长和转移的分子基础仍不清楚。大量研究强调了 BMI-1 在肿瘤发生过程中的参与作用。BMI-1 蛋白是多聚核抑制复合体 1 的一个重要组成部分,它通过泛素化组蛋白 H2A,调节参与细胞周期、增殖和细胞程序性死亡等各种细胞过程的基因的表达。BMI-1 的过表达往往与乳腺癌的发生和发展有关。本综述总结了 BMI-1 在乳腺癌生物学中的作用及其作为预后标志物和新抗癌疗法潜在靶点的潜在意义。
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引用次数: 0
The Effectiveness of Physical Exercise in Reducing Common Risk Factors of Atherosclerosis: A Systematic Review. 体育锻炼对减少动脉粥样硬化常见风险因素的效果:系统回顾
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-10-13 DOI: 10.33594/000000732
Nada Alhazmi

Background/aims: Atherosclerotic cardiovascular disease (ASCVD) or atherosclerosis is a chronic condition that is incurable and a leading contributor to morbidity and mortality. However, it is easy to prevent ASCVD by managing or preventing risk factors like hyperlipidemia, obesity/overweight, hypertension, and diabetes. This systematic review summarizes and presents current evidence on whether physical exercise could help in reducing ASCVD risk factors.

Methods: A comprehensive search was performed on PubMed, CINAHAL, ProQuest and Google Scholar. The sources were assessed based on their peer-review status, description of methods, unavailability of full texts, publication date (less than seven years), and publication in the English Language. The final search results constituted 19 peer-reviewed articles.

Results: Physical exercise is effective in improving the lipid profile, reducing waist circumference, reducing blood pressure, and lowering blood glucose levels. All types of physical exercise with intensity varying from low to high yield positive outcomes, although there is no consensus on whether the physical exercise program should be implemented for three months or less or on a long-term basis.

Conclusion: Physical exercise prevents and improves the management of hyperlipidemia, obesity/overweight, hypertension, and diabetes, which makes it a good intervention for reducing the risk of ASCVD. However, further studies should be performed to determine the duration within which the intervention should be sustained for optimal results.

背景/目的:动脉粥样硬化性心血管疾病(ASCVD)或动脉粥样硬化是一种无法治愈的慢性疾病,也是导致发病和死亡的主要因素。然而,通过控制或预防高脂血症、肥胖/超重、高血压和糖尿病等危险因素,预防动脉粥样硬化性心血管疾病是很容易的。本系统性综述总结并介绍了目前有关体育锻炼是否有助于减少急性心血管疾病风险因素的证据:方法:在 PubMed、CINAHAL、ProQuest 和 Google Scholar 上进行了全面检索。根据同行评议状态、方法描述、无法获得全文、出版日期(少于 7 年)和以英语出版等因素对资料来源进行了评估。最终的搜索结果包括 19 篇经同行评审的文章:体育锻炼能有效改善血脂状况、减少腰围、降低血压和血糖水平。各种类型、强度从低到高的体育锻炼都能产生积极的效果,但对于体育锻炼计划应实施三个月或更短时间,还是长期实施,还没有达成共识:结论:体育锻炼可以预防和改善高脂血症、肥胖/超重、高血压和糖尿病,因此是降低急性心血管疾病风险的良好干预措施。然而,应开展进一步研究,以确定应在多长时间内持续进行干预,从而达到最佳效果。
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引用次数: 0
Change in Nfkb/Nrf2/Bax Levels by High Monomeric Polyphenols Berries Extract (HMPBE) in Acute and Chronic Secondary Brain Damage. 高单体多酚浆果提取物(HMPBE)对急性和慢性继发性脑损伤中 Nfkb/Nrf2/Bax 水平的影响。
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-10-06 DOI: 10.33594/000000731
Sergio Modafferi, Francesco Molinari, Livia Interdonato, Roberta Fusco, Daniela Impellizzeri, Rosalba Siracusa, Ramona D'Amico, Ali S Abdelhameed, Uwe Wenzel, Ursula Jacobs, Tilman Fritsch, Naomi Osakabe, Salvatore Cuzzocrea, Vittorio Calabrese, Rosanna Di Paola, Marika Cordaro

Background/aims: High Monomeric Polyphenols Berries Extract (HMPBE) is a formula highly rich in polyphenols clinically proven to enhance learning and memory. It is currently used to enhances cognitive performance including accuracy, working memory and concentration.

Methods: Here, we investigated for the first time the beneficial effects of HMPBE in a mouse model of acute and chronic traumatic brain injury (TBI).

Results: HMPBE, at the dose of 15 mg/kg was able to reduce histological alteration as well as inflammation and lipid peroxidation. HMPBE ameliorate TBI by improving Nrf-2 pathway, reducing Nf-kb nuclear translocation and apoptosis, and ameliorating behavioral alteration such as anxiety and depression. Moreover, in the chronic model of TBI, HMPBE administration restored the decline of Tyrosine Hydroxylase (TH) and dopamine transporter (DAT) and the accumulation of a-synuclein into the midbrain region. This finding correlates the beneficial effect of HMPBE administration with the onset of parkinsonism related to traumatic brain damage.

Conclusion: The data may open a window for developing new support strategies to limit the neuroinflammation event of acute and chronic TBI.

背景/目的:高单体多酚浆果提取物(HMPBE)是一种富含多酚的配方,临床证明可增强学习和记忆能力。方法:在此,我们首次研究了高单体多酚浆果提取物对急性和慢性创伤性脑损伤(TBI)小鼠模型的有益影响:结果:剂量为15毫克/千克的羟丙基丁酸能够减轻组织学改变,并减少炎症和脂质过氧化反应。通过改善 Nrf-2 通路、减少 Nf-kb 核转位和细胞凋亡,以及改善焦虑和抑郁等行为改变,HMPBE 可改善创伤性脑损伤。此外,在慢性创伤性脑损伤模型中,服用 HMPBE 可抑制酪氨酸羟化酶(TH)和多巴胺转运体(DAT)的下降以及 a-突触核蛋白在中脑区域的聚集。这一发现将HMPBE的有益作用与创伤性脑损伤导致的帕金森病的发生联系起来:这些数据为开发新的支持策略以限制急性和慢性创伤性脑损伤的神经炎症事件打开了一扇窗。
{"title":"Change in Nfkb/Nrf2/Bax Levels by High Monomeric Polyphenols Berries Extract (HMPBE) in Acute and Chronic Secondary Brain Damage.","authors":"Sergio Modafferi, Francesco Molinari, Livia Interdonato, Roberta Fusco, Daniela Impellizzeri, Rosalba Siracusa, Ramona D'Amico, Ali S Abdelhameed, Uwe Wenzel, Ursula Jacobs, Tilman Fritsch, Naomi Osakabe, Salvatore Cuzzocrea, Vittorio Calabrese, Rosanna Di Paola, Marika Cordaro","doi":"10.33594/000000731","DOIUrl":"10.33594/000000731","url":null,"abstract":"<p><strong>Background/aims: </strong>High Monomeric Polyphenols Berries Extract (HMPBE) is a formula highly rich in polyphenols clinically proven to enhance learning and memory. It is currently used to enhances cognitive performance including accuracy, working memory and concentration.</p><p><strong>Methods: </strong>Here, we investigated for the first time the beneficial effects of HMPBE in a mouse model of acute and chronic traumatic brain injury (TBI).</p><p><strong>Results: </strong>HMPBE, at the dose of 15 mg/kg was able to reduce histological alteration as well as inflammation and lipid peroxidation. HMPBE ameliorate TBI by improving Nrf-2 pathway, reducing Nf-kb nuclear translocation and apoptosis, and ameliorating behavioral alteration such as anxiety and depression. Moreover, in the chronic model of TBI, HMPBE administration restored the decline of Tyrosine Hydroxylase (TH) and dopamine transporter (DAT) and the accumulation of a-synuclein into the midbrain region. This finding correlates the beneficial effect of HMPBE administration with the onset of parkinsonism related to traumatic brain damage.</p><p><strong>Conclusion: </strong>The data may open a window for developing new support strategies to limit the neuroinflammation event of acute and chronic TBI.</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Environmental Cues Facilitate Maturation and Patterning of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. 环境线索促进人类诱导多能干细胞衍生心肌细胞的成熟和分型
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-10-04 DOI: 10.33594/000000730
Enrique Coca, Scott Cho, Christopher Kauffman, Alonzo D Cook, Martin Tristani-Firouzi, Natalia S Torres

Background/aims: Advances in induced pluripotent stem cell (iPSC) technology allow for reprogramming of adult somatic cells into stem cells from which patient- and disease-specific cardiomyocytes (CMs) can be derived. Yet, the potential of iPSC technology to revolutionize cardiovascular research is limited, in part, by the embryonic nature of these cells. Here, we test the hypothesis that decellularized porcine left ventricular extracellular cardiac matrix (ECM) provides environmental cues that promote transcriptional maturation and patterning of iPSC-CMs in culture.

Methods: Cardiac progenitor cells were plated on ECM or standard tissue plates (2D monolayer) for 30 days, after which CM orientation and single cell transcriptomics were evaluated using confocal imaging and singe cell RNA-sequencing, respectively.

Results: Cardiac progenitors differentiated on left ventricular ECM formed longitudinal fibers that differed quantitatively from progenitors differentiated in standard 2D conditions. Unsupervised clustering of single cell transcriptomics identified a CM cluster expressing a higher level of genes related to CM maturation. CMs differentiated on ECM were overrepresented in this cluster, indicating a bias toward CM maturation, compared to cells differentiated in standard 2D monolayer conditions.

Conclusion: Our data suggest that environmental cues related to the left ventricular ECM may promote differentiation to a more mature CM state compared to cells differentiated on a standard 2D monolayer, while facilitating organization into longitudinal micro-fibers. Our study highlights the utility of ECM as a differentiation substrate to promote CM maturation and fiber orientation in vitro .

背景/目的:诱导多能干细胞(iPSC)技术的进步可将成人体细胞重编程为干细胞,并从中衍生出患者和疾病特异性心肌细胞(CM)。然而,iPSC 技术彻底改变心血管研究的潜力部分受限于这些细胞的胚胎性质。在这里,我们验证了这样一个假设:脱细胞猪左心室细胞外基质(ECM)提供环境线索,促进 iPSC-CMs 在培养过程中的转录成熟和模式化:方法:将心脏祖细胞在 ECM 或标准组织板(二维单层)上培养 30 天,然后分别使用共焦成像和单细胞 RNA 序列对 CM 定向和单细胞转录组学进行评估:结果:在左心室 ECM 上分化的心脏祖细胞形成的纵向纤维在数量上与在标准二维条件下分化的祖细胞不同。单细胞转录组学的无监督聚类确定了一个表达与CM成熟相关的高水平基因的CM集群。与在标准二维单层条件下分化的细胞相比,在ECM上分化的CM在该集群中的比例过高,这表明CM偏向于成熟:我们的数据表明,与在标准二维单层上分化的细胞相比,与左心室 ECM 相关的环境线索可促进 CM 向更成熟的状态分化,同时有利于组织成纵向微纤维。我们的研究强调了 ECM 作为分化基质在体外促进 CM 成熟和纤维定向的效用。
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引用次数: 0
Peroxyredoxin 6 Protects RIN-M5F Pancreatic Beta Cells Against Streptozotocin-Induced Senescence. 过氧化还原酶 6 可保护 RIN-M5F 胰腺β细胞免受链脲佐菌素诱导的衰老。
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-09-23 DOI: 10.33594/000000729
Elena G Novoselova, Olga V Glushkova, Maxim O Khrenov, Sergey M Lunin, Tatyana V Novoselova, Mars G Sharapov, Svetlana B Parfenyuk

Background/aims: There are evidences that a decrease in the functional activity of pancreatic β-cells under type 2 diabetes conditions may be associated with their senescence, therefore, senotherapy may be a prospective strategy for the diabetes treatment.

Methods: The senotherapeutic potential of peroxiredoxin 6 (PRDX6) was studied in RIN-m5F pancreatic β-cells with streptozotocin-induced senescence by measuring markers, associated with senescence.

Results: Exposure to streptozotocin (STZ) resulted in the senescence of the β-cells. The addition of PRDX6 to the culture medium of RIN-m5F β-cells before treatment with STZ decreased the levels of the following senescence markers: the percentage of SA-β-Gal-positive cells, the phosphorylation of histone H2AX and p21 proteins, and the secretion of the proinflammatory cytokine IL-6 but not the anti-inflammatory cytokine IL-10. These effects were accompanied by a decrease in the production of reactive oxygen species (ROS) and the restoration of impaired NF-κB activation. In addition, PRDX6 altered the production of the heat shock protein HSP90: the production of the constitutive form of HSP90-beta decreased, while the level of inducible HSP90-alpha increased.

Conclusion: PRDX6 prevented the senescence of RIN-m5F cells in response to the DNA damage-inducing agent streptozotocin, indicating a potential protective role of PRDX6 in type 2 diabetes mellitus.

背景/目的:有证据表明,在2型糖尿病条件下,胰腺β细胞功能活性的降低可能与其衰老有关,因此,衰老疗法可能是糖尿病治疗的一种前瞻性策略:方法:在链脲佐菌素诱导衰老的RIN-m5F胰腺β细胞中,通过测量与衰老相关的标记物,研究过氧化物歧化酶6(PRDX6)的衰老治疗潜力:结果:接触链脲佐菌素(STZ)会导致β细胞衰老。在用 STZ 处理 RIN-m5F β 细胞之前向其培养液中添加 PRDX6 可降低以下衰老标记物的水平:SA-β-Gal 阳性细胞的百分比、组蛋白 H2AX 和 p21 蛋白的磷酸化、促炎细胞因子 IL-6 的分泌,但不包括抗炎细胞因子 IL-10。在产生这些影响的同时,活性氧(ROS)的产生也有所减少,受损的 NF-κB 激活也得到了恢复。此外,PRDX6 还改变了热休克蛋白 HSP90 的产生:组成型 HSP90-beta 的产生减少,而诱导型 HSP90-α 的水平增加:结论:PRDX6能防止RIN-m5F细胞在DNA损伤诱导剂链脲佐菌素作用下衰老,这表明PRDX6在2型糖尿病中具有潜在的保护作用。
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引用次数: 0
GNAS, not a Highly Mutated Gene, Has Prognostic Significance and Carcinogenic Effects in Osteosarcoma. GNAS并非高度突变基因,但在骨肉瘤中具有预后意义和致癌作用。
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-09-15 DOI: 10.33594/000000728
Jin Qi, Yanjiao Huang, Yaogang Bian

Background/aims: Osteosarcoma is a prevalent and aggressive primary malignant bone tumor affecting children and adolescents. Despite advancements in sequencing technologies, there remains a lack of reliable prognostic biomarkers and effective targeted therapies for osteosarcoma. This study focuses on identifying key prognostic genes, particularly the role of GNAS, in osteosarcoma progression.

Methods: Bioinformatics analyses were performed on osteosarcoma datasets from the Gene Expression Omnibus (GEO). Differential gene expression analysis, weighted correlation network analysis (WGCNA), and survival analysis identified potential prognostic hub genes. The expression and function of these genes were validated through immunohistochemistry and animal experiments. Specifically, the role of GNAS was investigated through siRNA-mediated knockdown in osteosarcoma cell lines and nude mice models.

Results: Five hub genes (PROP1, GNAS, CYP4F2, LHX3, CNGB1) were identified as significantly related to osteosarcoma prognosis. Among these, GNAS was found to be highly expressed in osteosarcoma tissues compared to normal tissues. Immunohistochemical analysis confirmed the elevated expression of GNAS in osteosarcoma samples. GNAS mutation analysis revealed a low mutation rate in osteosarcoma, suggesting its oncogenic role is independent of mutational status. Animal experiments demonstrated that knocking down GNAS significantly inhibited tumor growth and induced apoptosis in osteosarcoma cells.

Conclusion: GNAS is highly expressed in osteosarcoma and associated with poor prognosis, acting as an oncogene in osteosarcoma progression. Targeting GNAS could be a potential therapeutic strategy for osteosarcoma. Further studies on GNAS-related signaling pathways may provide deeper insights into the molecular mechanisms driving osteosarcoma malignancy.

背景/目的:骨肉瘤是一种常见的侵袭性原发性恶性骨肿瘤,多发于儿童和青少年。尽管测序技术不断进步,但骨肉瘤仍缺乏可靠的预后生物标志物和有效的靶向治疗。本研究的重点是确定关键预后基因,特别是 GNAS 在骨肉瘤进展中的作用:方法:对基因表达总库(GEO)中的骨肉瘤数据集进行生物信息学分析。差异基因表达分析、加权相关网络分析(WGCNA)和生存分析确定了潜在的预后枢纽基因。通过免疫组化和动物实验验证了这些基因的表达和功能。特别是,通过 siRNA 介导的骨肉瘤细胞系和裸鼠模型敲除,研究了 GNAS 的作用:结果:五个枢纽基因(PROP1、GNAS、CYP4F2、LHX3、CNGB1)与骨肉瘤预后显著相关。其中,与正常组织相比,GNAS在骨肉瘤组织中高表达。免疫组化分析证实了骨肉瘤样本中GNAS的高表达。GNAS突变分析显示,骨肉瘤中的突变率较低,表明其致癌作用与突变状态无关。动物实验表明,敲除 GNAS 能显著抑制肿瘤生长并诱导骨肉瘤细胞凋亡:结论:GNAS在骨肉瘤中高表达,与预后不良有关,是骨肉瘤发展过程中的致癌基因。靶向 GNAS 可能是骨肉瘤的一种潜在治疗策略。对GNAS相关信号通路的进一步研究可能会让人们对骨肉瘤恶性发展的分子机制有更深入的了解。
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引用次数: 0
Analysis of Erythrocyte Parameters in Multiple and Long-Term Blood Donors from Northern Pomerania (Poland). 北波美拉尼亚(波兰)多次和长期献血者的红细胞参数分析。
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-09-14 DOI: 10.33594/000000727
Natalia Kurhaluk, Małgorzata Gradziuk, Piotr Kamiński, Halina Tkaczenko

Background/aims: Assessment of the levels of vital blood parameters in donors is essential to evaluate their health status, ensure their suitability for donation, preserve the integrity of the circulatory system, and facilitate comprehensive health monitoring. The aim of our study was to analyse the levels of haemoglobin, haematocrit, erythrocyte count, MCV, MCH, and MCHC in 12 groups of first-time donors and experienced donors of both sexes at the John Paul II Regional Blood Donation and Treatment Centre in Słupsk, northern Poland. The donors were divided into three age groups (18-30 years, 31-45 years, and 46-65 years).

Methods: Using MANOVA multivariate significance tests, we examined the main effects of donor-related factors (age, sex, donor stage) on morphological blood parameters to evaluate different haematological parameters, such as Hb, Ht, RBC, MCV, MCH, and MCHC, and identified statistically significant relationships between all variables.

Results: The multivariate analysis of these three main factors showed that the variation in haemoglobin (Hb) levels accounted for 46% of the explained dependence in this statistical model. In particular, approximately half of the variability in the multivariate statistical analysis was attributed to the role of Hb and haematocrit (Ht). In addition, the β-coefficient values for Hb and Ht were statistically higher in relation to donor sex and donor type (single versus repeat). These β-coefficient values from our data represent the strength and direction of the relationship between the haematological parameters (Hb and Ht) and the specific donor characteristics. A higher β-coefficient indicates a stronger influence of donor sex and donor type on these parameters, suggesting that these factors contribute significantly to the variation in the Hb and Ht levels. Based on our results, the comprehensive analysis of the entire statistical model of metabolic biomarkers revealed the following hierarchy: Hb > Ht > MCHC > MCV > RBC > MCH. The results obtained showed strong statistical relationships, as indicated by the high values of the key statistical indicators in our analysis. The coefficient of determination (R²) showed that the model explained a significant proportion of the variance in the data, while the F-test statistic confirmed the significance of the predictors.

Conclusion: These strong statistical dependencies provided a clear justification for selecting this model over others, as it effectively represented the underlying relationships within the data. These statistics help to assess how well the model matches the actual data, thereby helping to reduce the risks associated with blood donation, optimise donor safety, and maintain the quality and efficiency of blood transfusion services.

背景/目的:评估捐献者的重要血液参数水平对于评估其健康状况、确保其适合捐献、保护循环系统的完整性以及促进全面健康监测至关重要。我们的研究旨在分析波兰北部斯武普斯克市约翰-保罗二世地区献血和治疗中心的 12 组首次献血者和经验丰富的男女献血者的血红蛋白、血细胞比容、红细胞计数、MCV、MCH 和 MCHC 水平。献血者分为三个年龄组(18-30 岁、31-45 岁和 46-65 岁):使用 MANOVA 多变量显著性检验,我们研究了捐献者相关因素(年龄、性别、捐献者阶段)对血液形态学参数的主要影响,以评估不同的血液学参数,如 Hb、Ht、RBC、MCV、MCH 和 MCHC,并确定了所有变量之间具有统计学意义的关系:对这三个主要因素进行的多变量分析表明,在该统计模型中,血红蛋白(Hb)水平的变化占解释依存度的 46%。特别是,在多变量统计分析中,约有一半的变异归因于 Hb 和血细胞比容(Ht)的作用。此外,从统计学角度看,Hb 和 Ht 的 β 系数值与捐献者性别和捐献者类型(单一捐献者与重复捐献者)有关。我们数据中的这些 β 系数值代表了血液学参数(Hb 和 Ht)与特定供体特征之间关系的强度和方向。β系数越高,表明供体性别和供体类型对这些参数的影响越大,说明这些因素对 Hb 和 Ht 水平的变化有显著影响。根据我们的研究结果,对整个代谢生物标志物统计模型的综合分析显示出以下层次结构:Hb > Ht > MCHC > MCV > RBC > MCH。所得结果显示出很强的统计关系,这一点从我们分析中关键统计指标的高值可以看出。判定系数(R²)表明,模型解释了数据中相当大比例的方差,而 F 检验统计量则证实了预测因子的显著性:这些强大的统计依赖性为选择该模型而非其他模型提供了明确的理由,因为该模型有效地代表了数据中的潜在关系。这些统计数据有助于评估模型与实际数据的匹配程度,从而帮助降低献血相关风险,优化献血者安全,保持输血服务的质量和效率。
{"title":"Analysis of Erythrocyte Parameters in Multiple and Long-Term Blood Donors from Northern Pomerania (Poland).","authors":"Natalia Kurhaluk, Małgorzata Gradziuk, Piotr Kamiński, Halina Tkaczenko","doi":"10.33594/000000727","DOIUrl":"https://doi.org/10.33594/000000727","url":null,"abstract":"<p><strong>Background/aims: </strong>Assessment of the levels of vital blood parameters in donors is essential to evaluate their health status, ensure their suitability for donation, preserve the integrity of the circulatory system, and facilitate comprehensive health monitoring. The aim of our study was to analyse the levels of haemoglobin, haematocrit, erythrocyte count, MCV, MCH, and MCHC in 12 groups of first-time donors and experienced donors of both sexes at the John Paul II Regional Blood Donation and Treatment Centre in Słupsk, northern Poland. The donors were divided into three age groups (18-30 years, 31-45 years, and 46-65 years).</p><p><strong>Methods: </strong>Using MANOVA multivariate significance tests, we examined the main effects of donor-related factors (age, sex, donor stage) on morphological blood parameters to evaluate different haematological parameters, such as Hb, Ht, RBC, MCV, MCH, and MCHC, and identified statistically significant relationships between all variables.</p><p><strong>Results: </strong>The multivariate analysis of these three main factors showed that the variation in haemoglobin (Hb) levels accounted for 46% of the explained dependence in this statistical model. In particular, approximately half of the variability in the multivariate statistical analysis was attributed to the role of Hb and haematocrit (Ht). In addition, the β-coefficient values for Hb and Ht were statistically higher in relation to donor sex and donor type (single versus repeat). These β-coefficient values from our data represent the strength and direction of the relationship between the haematological parameters (Hb and Ht) and the specific donor characteristics. A higher β-coefficient indicates a stronger influence of donor sex and donor type on these parameters, suggesting that these factors contribute significantly to the variation in the Hb and Ht levels. Based on our results, the comprehensive analysis of the entire statistical model of metabolic biomarkers revealed the following hierarchy: Hb > Ht > MCHC > MCV > RBC > MCH. The results obtained showed strong statistical relationships, as indicated by the high values of the key statistical indicators in our analysis. The coefficient of determination (R²) showed that the model explained a significant proportion of the variance in the data, while the F-test statistic confirmed the significance of the predictors.</p><p><strong>Conclusion: </strong>These strong statistical dependencies provided a clear justification for selecting this model over others, as it effectively represented the underlying relationships within the data. These statistics help to assess how well the model matches the actual data, thereby helping to reduce the risks associated with blood donation, optimise donor safety, and maintain the quality and efficiency of blood transfusion services.</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ASMase is Essential for the Immune Response to Partial-Tumor Radiation Exposure. ASMase对部分肿瘤辐射的免疫反应至关重要
IF 2.5 Q3 CELL BIOLOGY Pub Date : 2024-09-08 DOI: 10.33594/000000726
Mickael Mathieu, Prerna R Nepali, James Russell, Hadi Askarifirouzjaei, Melis Baltaci, Simon N Powell, John Humm, Joseph O Deasy, Adriana Haimovitz-Friedman

Background/aims: Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings.

Methods: We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8+ T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts.

Results: We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8+ T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice.

Conclusion: ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response via STING activation.

背景/目的:肿瘤对辐射的反应被认为取决于对肿瘤细胞的直接杀伤。我们的实验室对此提出了质疑。首先,我们证明了宿主的生物学特性,特别是酸性鞘磷脂酶(ASMase)的内皮表达,是决定肿瘤放射可逆性的关键。其次,我们证明了免疫系统可以增强辐射反应,使半辐射肿瘤得到完全控制。在本文中,我们将重点讨论这两项发现的整合:我们使用刘易斯肺癌(LLC)细胞,在(i) ASMase基因敲除小鼠或(ii) 匹配背景的 WT(sv129xBl/6)或(iii) C57Bl/6小鼠的腹部注射。对LLC肿瘤体积的50%或100%进行放射治疗(RT)。测量肿瘤反应、免疫浸润(CD8+ T 细胞)、ICAM-1 和 STING 活化。放疗还与甲基环糊精联合使用,以抑制 ASMase 介导的神经酰胺富集脂质筏的形成:结果:我们再现了之前的发现,即在 LLC/C57Bl/6 模型中,肿瘤半照射足以控制肿瘤。然而,在 ASMase KO 小鼠中,半照射是无效的。同样,药理抑制 ASMase 也会显著降低肿瘤对半照射的反应。此外,我们还发现,在 C57Bl/6 小鼠和 ASMase WT 株系中生长的肿瘤中,ICAM-1 表达升高,CD8+ T 细胞、ICAM-1 和 STING 激活水平升高。然而,在 ASMase KO 小鼠体内生长的肿瘤中却未见此类变化:结论:ASMase和神经酰胺的生成是通过STING激活辐射诱导抗肿瘤免疫反应的必要条件。
{"title":"ASMase is Essential for the Immune Response to Partial-Tumor Radiation Exposure.","authors":"Mickael Mathieu, Prerna R Nepali, James Russell, Hadi Askarifirouzjaei, Melis Baltaci, Simon N Powell, John Humm, Joseph O Deasy, Adriana Haimovitz-Friedman","doi":"10.33594/000000726","DOIUrl":"https://doi.org/10.33594/000000726","url":null,"abstract":"<p><strong>Background/aims: </strong>Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings.</p><p><strong>Methods: </strong>We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8<sup>+</sup> T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts.</p><p><strong>Results: </strong>We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8<sup>+</sup> T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice.</p><p><strong>Conclusion: </strong>ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response <i>via</i> STING activation.</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Cellular Physiology and Biochemistry
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