Cellular Physiology and Biochemistry最新文献

{"title":"A Comprehensive Pan-Cancer Analysis of the Mitochondrial Uncoupling Protein UCP2, with a Focus on Sex and Gender-Related Aspects.","authors":"Soha Sadeghi, Vanessa Checchetto, Tatiana Varanita","doi":"10.33594/000000735","DOIUrl":"10.33594/000000735","url":null,"abstract":"<p><strong>Background/aims: </strong>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).</p><p><strong>Methods: </strong>We analyzed <i>UCP2</i> 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.</p><p><strong>Results: </strong>Significant variability in UCP2 expression was observed across cancer types. <i>UCP2</i> levels were elevated in BRCA and OV but reduced in PRAD and TGCT. High <i>UCP2</i> expression was associated with a better prognosis in OV and poorer overall survival in PRAD. Furthermore, <i>UCP2</i> correlated with TMB and MSI in OV, TGCT, and BRCA. <i>UCP2</i> 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, <i>UCP2</i> also demonstrated sensitivity to specific anticancer drugs.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521115","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}

{"title":"Nitric Oxide-Dependent Regulation of Oxygen-Related Processes in a Rat Model of Lead Neurotoxicity: Influence of the Hypoxia Resistance Factor.","authors":"Natalia Kurhaluk, Piotr Kamiński, Oleksandr Lukash, Halina Tkaczenko","doi":"10.33594/000000734","DOIUrl":"https://doi.org/10.33594/000000734","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background/aims: &lt;/strong&gt;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&lt;sup&gt;ω&lt;/sup&gt;-nitro-L-arginine (L-NNA) as an inhibitor of NO synthase, an enzyme that catalyses the production of nitric oxide (NO) from L-arginine.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496045","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}

{"title":"BMI-1 in Breast Cancer - Biological Role and Clinical Implications.","authors":"Aleksandra Szustka, Anna Krześlak","doi":"10.33594/000000733","DOIUrl":"10.33594/000000733","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459218","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}

{"title":"The Effectiveness of Physical Exercise in Reducing Common Risk Factors of Atherosclerosis: A Systematic Review.","authors":"Nada Alhazmi","doi":"10.33594/000000732","DOIUrl":"10.33594/000000732","url":null,"abstract":"<p><strong>Background/aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459219","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}

{"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}

{"title":"Environmental Cues Facilitate Maturation and Patterning of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.","authors":"Enrique Coca, Scott Cho, Christopher Kauffman, Alonzo D Cook, Martin Tristani-Firouzi, Natalia S Torres","doi":"10.33594/000000730","DOIUrl":"https://doi.org/10.33594/000000730","url":null,"abstract":"<p><strong>Background/aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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 <i>in vitro</i> .</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380126","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}

{"title":"Peroxyredoxin 6 Protects RIN-M5F Pancreatic Beta Cells Against Streptozotocin-Induced Senescence.","authors":"Elena G Novoselova, Olga V Glushkova, Maxim O Khrenov, Sergey M Lunin, Tatyana V Novoselova, Mars G Sharapov, Svetlana B Parfenyuk","doi":"10.33594/000000729","DOIUrl":"https://doi.org/10.33594/000000729","url":null,"abstract":"<p><strong>Background/aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342605","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}

{"title":"GNAS, not a Highly Mutated Gene, Has Prognostic Significance and Carcinogenic Effects in Osteosarcoma.","authors":"Jin Qi, Yanjiao Huang, Yaogang Bian","doi":"10.33594/000000728","DOIUrl":"10.33594/000000728","url":null,"abstract":"<p><strong>Background/aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":9845,"journal":{"name":"Cellular Physiology and Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280988","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}

{"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}

{"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⁺ 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⁺ 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}