Breast cancer (BC) is the leading cause of cancer death among women worldwide. Women employed in shift jobs face heightened BC risk due to prolonged exposure to night shift work (NSW), classified as potentially carcinogenic by the International Agency for Research on Cancer (IARC). This risk is linked to disruptions in circadian rhythms governed by clock genes at the cellular level. However, the molecular mechanisms are unclear. This study aimed to assess clock genes as potential BC biomarkers among women exposed to long-term NSW. Clock gene expression was analysed in paired BC and normal breast tissues within Nurses’ Health Studies I and II GEO datasets. Validation was performed on additional gene expression datasets from healthy night shift workers and women with varying BC susceptibility, as well as single-cell sequencing datasets. Post-transcriptional regulators of clock genes were identified through miRNA analyses. Significant alterations in clock gene expression in BC compared to normal tissues were found. BHLHE40, CIART, CLOCK, PDPK1, and TIMELESS were over-expressed, while HLF, NFIL3, NPAS3, PER1, PER3, SIM1, and TEF were under-expressed. The downregulation of PER1 and TEF and upregulation of CLOCK correlated with increased BC risk in healthy women. Also, twenty-six miRNAs, including miR-10a, miR-21, miR-107, and miR-34, were identified as potential post-transcriptional regulators influenced by NSW. In conclusion, a panel of clock genes and circadian miRNAs are suggested as BC susceptibility biomarkers among night shift workers, supporting implications for risk stratification and early detection strategies.
乳腺癌（BC）是全球妇女癌症死亡的主要原因。由于长期从事夜班工作（NSW），从事轮班工作的妇女面临着更高的乳腺癌风险，国际癌症研究机构（IARC）将其归类为潜在致癌物。这种风险与细胞水平上由时钟基因控制的昼夜节律紊乱有关。然而，其分子机制尚不清楚。这项研究的目的是评估作为潜在 BC 生物标志物的时钟基因在长期暴露于新南威尔士州的女性中的作用。该研究分析了护士健康研究 I 和 II GEO 数据集中成对的 BC 和正常乳腺组织中的时钟基因表达。此外，还对来自健康夜班工人和具有不同乳腺癌易感性的女性的基因表达数据集以及单细胞测序数据集进行了验证。通过 miRNA 分析确定了时钟基因的转录后调控因子。与正常组织相比，发现 BC 中的时钟基因表达发生了显著变化。BHLHE40、CIART、CLOCK、PDPK1和TIMELESS过度表达，而HLF、NFIL3、NPAS3、PER1、PER3、SIM1和TEF表达不足。在健康女性中，PER1 和 TEF 的下调以及 CLOCK 的上调与 BC 风险的增加有关。此外，包括 miR-10a、miR-21、miR-107 和 miR-34 在内的 26 个 miRNA 被确定为受 NSW 影响的潜在转录后调节因子。总之，一组时钟基因和昼夜节律miRNA被认为是夜班工作者的BC易感性生物标志物，对风险分层和早期检测策略具有重要意义。
{"title":"Computational Analyses Reveal Deregulated Clock Genes Associated with Breast Cancer Development in Night Shift Workers","authors":"Silvia Vivarelli, Giovanna Spatari, Chiara Costa, Federica Giambò, Concettina Fenga","doi":"10.3390/ijms25168659","DOIUrl":"https://doi.org/10.3390/ijms25168659","url":null,"abstract":"Breast cancer (BC) is the leading cause of cancer death among women worldwide. Women employed in shift jobs face heightened BC risk due to prolonged exposure to night shift work (NSW), classified as potentially carcinogenic by the International Agency for Research on Cancer (IARC). This risk is linked to disruptions in circadian rhythms governed by clock genes at the cellular level. However, the molecular mechanisms are unclear. This study aimed to assess clock genes as potential BC biomarkers among women exposed to long-term NSW. Clock gene expression was analysed in paired BC and normal breast tissues within Nurses’ Health Studies I and II GEO datasets. Validation was performed on additional gene expression datasets from healthy night shift workers and women with varying BC susceptibility, as well as single-cell sequencing datasets. Post-transcriptional regulators of clock genes were identified through miRNA analyses. Significant alterations in clock gene expression in BC compared to normal tissues were found. BHLHE40, CIART, CLOCK, PDPK1, and TIMELESS were over-expressed, while HLF, NFIL3, NPAS3, PER1, PER3, SIM1, and TEF were under-expressed. The downregulation of PER1 and TEF and upregulation of CLOCK correlated with increased BC risk in healthy women. Also, twenty-six miRNAs, including miR-10a, miR-21, miR-107, and miR-34, were identified as potential post-transcriptional regulators influenced by NSW. In conclusion, a panel of clock genes and circadian miRNAs are suggested as BC susceptibility biomarkers among night shift workers, supporting implications for risk stratification and early detection strategies.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141928227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Randall Loaiza, F. Fattahi, M. Kalbitz, Jamison J. Grailer, Mark W. Russell, José Jalife, Héctor H. Valdivia, F. Zetoune, Peter A. Ward
In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone–TLR interactions and their mechanisms.
{"title":"The Impact of Extracellular Histones and Absence of Toll-like Receptors on Cardiac Functional and Electrical Disturbances in Mouse Hearts","authors":"Randall Loaiza, F. Fattahi, M. Kalbitz, Jamison J. Grailer, Mark W. Russell, José Jalife, Héctor H. Valdivia, F. Zetoune, Peter A. Ward","doi":"10.3390/ijms25168653","DOIUrl":"https://doi.org/10.3390/ijms25168653","url":null,"abstract":"In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone–TLR interactions and their mechanisms.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eleni Stamellou, Viktor Sterzer, Jessica Alam, Stefanos Roumeliotis, Vasillios Liakopoulos, E. Dounousi
Premenopausal women generally exhibit lower blood pressure and a lower prevalence of hypertension than men of the same age, but these differences reverse postmenopause due to estrogen withdrawal. Sexual dimorphism has been described in different components of kidney physiology and pathophysiology, including the renin–angiotensin–aldosterone system, endothelin system, and tubular transporters. This review explores the sex-specific differences in kidney function and blood pressure regulation. Understanding these differences provides insights into potential therapeutic targets for managing hypertension and kidney diseases, considering the patient’s sex and hormonal status.
{"title":"Sex-Specific Differences in Kidney Function and Blood Pressure Regulation","authors":"Eleni Stamellou, Viktor Sterzer, Jessica Alam, Stefanos Roumeliotis, Vasillios Liakopoulos, E. Dounousi","doi":"10.3390/ijms25168637","DOIUrl":"https://doi.org/10.3390/ijms25168637","url":null,"abstract":"Premenopausal women generally exhibit lower blood pressure and a lower prevalence of hypertension than men of the same age, but these differences reverse postmenopause due to estrogen withdrawal. Sexual dimorphism has been described in different components of kidney physiology and pathophysiology, including the renin–angiotensin–aldosterone system, endothelin system, and tubular transporters. This review explores the sex-specific differences in kidney function and blood pressure regulation. Understanding these differences provides insights into potential therapeutic targets for managing hypertension and kidney diseases, considering the patient’s sex and hormonal status.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Agata Kolecka-Bednarczyk, M. Frydrychowicz, B. Budny, M. Ruciński, Claudia Dompe, Piotr Gabryel, B. Płachno, M. Ruchała, K. Ziemnicka, Paweł Zieliński, Joanna Budna-Tukan
Non-small cell lung cancer (NSCLC) leads as a primary cause of cancer-related premature mortality in Western populations. This study leverages cutting-edge gene-expression-profiling technologies to perform an in-depth molecular characterization of NSCLC specimens, with the objective of uncovering tumor-specific genomic alterations. By employing DNA microarray analysis, our research aims to refine the classification of NSCLC for early detection, guide molecular-targeted treatment approaches, enhance prognostication, and broaden the scientific understanding of the disease’s biology. We identified widespread genomic abnormalities in our samples, including the recurrent loss of chromosomal regions 3p, 5q, 13q, and 21q and the gain of 12p. Furthermore, utilizing Metascape for bioinformatic analysis revealed critical biological pathways disrupted in NSCLC, offering promising leads for novel therapeutic interventions.
{"title":"Specific Deletions of Chromosomes 3p, 5q, 13q, and 21q among Patients with G2 Grade of Non-Small Cell Lung Cancer","authors":"Agata Kolecka-Bednarczyk, M. Frydrychowicz, B. Budny, M. Ruciński, Claudia Dompe, Piotr Gabryel, B. Płachno, M. Ruchała, K. Ziemnicka, Paweł Zieliński, Joanna Budna-Tukan","doi":"10.3390/ijms25168642","DOIUrl":"https://doi.org/10.3390/ijms25168642","url":null,"abstract":"Non-small cell lung cancer (NSCLC) leads as a primary cause of cancer-related premature mortality in Western populations. This study leverages cutting-edge gene-expression-profiling technologies to perform an in-depth molecular characterization of NSCLC specimens, with the objective of uncovering tumor-specific genomic alterations. By employing DNA microarray analysis, our research aims to refine the classification of NSCLC for early detection, guide molecular-targeted treatment approaches, enhance prognostication, and broaden the scientific understanding of the disease’s biology. We identified widespread genomic abnormalities in our samples, including the recurrent loss of chromosomal regions 3p, 5q, 13q, and 21q and the gain of 12p. Furthermore, utilizing Metascape for bioinformatic analysis revealed critical biological pathways disrupted in NSCLC, offering promising leads for novel therapeutic interventions.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peiting Li, Sharon Sze-Man Hon, M. S. Tsang, Lea Ling-Yu Kan, Andrea Yin-Tung Lai, B. Chan, P. Leung, Chun-Kwok Wong
Allergic rhinitis (AR) is a series of allergic reactions to allergens in the nasal mucosa and is one of the most common allergic diseases that affect both children and adults. Shi-Bi-Lin (SBL) is the modified formula of Cang Er Zi San (CEZS), a traditional Chinese herbal formula used for treating AR. Our study aims to elucidate the anti-inflammatory effects and mechanisms of SBL in house dust mite-induced AR by regulating gut microflora metabolism. In vivo studies showed that nasal allergies and the infiltration of inflammatory cells in the nasal epithelium were significantly suppressed by SBL. Moreover, SBL restored the impaired nasal epithelial barrier function with an increased tight junction protein expression and reduced the endothelial nitric oxide synthase (eNOS). Interestingly, SBL significantly reconstituted the abundance and composition of gut microbiota in AR mice; it increased the relative abundance of potentially beneficial genera and decreased the relative abundance of harmful genera. SBL also restored immune-related metabolisms, which were significantly increased and correlated with suppressing inflammatory cytokines. Furthermore, a network analysis and molecular docking indicated IL-6 was a possible target drug candidate for the SBL treatment. SBL dramatically reduced the IL-6 level in the nasal lavage fluid (NALF), suppressing the IL-6 downstream Erk1/2 and AKT/PI3K signaling pathways. In conclusion, our study integrates 16S rRNA sequencing, microflora metabolism, and network pharmacology to explain the immune mechanism of SBL in alleviating HDM-induced allergic rhinitis.
{"title":"Integrating 16S rRNA Sequencing, Microflora Metabolism, and Network Pharmacology to Investigate the Mechanism of SBL in Alleviating HDM-Induced Allergic Rhinitis","authors":"Peiting Li, Sharon Sze-Man Hon, M. S. Tsang, Lea Ling-Yu Kan, Andrea Yin-Tung Lai, B. Chan, P. Leung, Chun-Kwok Wong","doi":"10.3390/ijms25168655","DOIUrl":"https://doi.org/10.3390/ijms25168655","url":null,"abstract":"Allergic rhinitis (AR) is a series of allergic reactions to allergens in the nasal mucosa and is one of the most common allergic diseases that affect both children and adults. Shi-Bi-Lin (SBL) is the modified formula of Cang Er Zi San (CEZS), a traditional Chinese herbal formula used for treating AR. Our study aims to elucidate the anti-inflammatory effects and mechanisms of SBL in house dust mite-induced AR by regulating gut microflora metabolism. In vivo studies showed that nasal allergies and the infiltration of inflammatory cells in the nasal epithelium were significantly suppressed by SBL. Moreover, SBL restored the impaired nasal epithelial barrier function with an increased tight junction protein expression and reduced the endothelial nitric oxide synthase (eNOS). Interestingly, SBL significantly reconstituted the abundance and composition of gut microbiota in AR mice; it increased the relative abundance of potentially beneficial genera and decreased the relative abundance of harmful genera. SBL also restored immune-related metabolisms, which were significantly increased and correlated with suppressing inflammatory cytokines. Furthermore, a network analysis and molecular docking indicated IL-6 was a possible target drug candidate for the SBL treatment. SBL dramatically reduced the IL-6 level in the nasal lavage fluid (NALF), suppressing the IL-6 downstream Erk1/2 and AKT/PI3K signaling pathways. In conclusion, our study integrates 16S rRNA sequencing, microflora metabolism, and network pharmacology to explain the immune mechanism of SBL in alleviating HDM-induced allergic rhinitis.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Wang, Ran Xiao, Shiqi Liu, Pengjie Wang, Yinhua Zhu, Tianjiao Niu, Han Chen
Milk thermal treatment, such as pasteurization, high-temperature short-time processing, and the emerging ultra-short-time processing (<0.5 s), are crucial for ensuring milk safety and extending its shelf life. Milk is a nutritive food matrix with various macro/micro-nutrients and other constituents that are possibly affected by thermal treatment for reasons associated with processing strength. Therefore, understanding the relationship between heating strength and milk quality is vital for the dairy industry. This review summarizes the impact of thermal treatment strength on milk’s nutritional and sensory properties, the synthesizing of the structural integrity and bioavailability of milk proteins, the profile and stability of fatty acids, the retention of macro/micro-nutrients, as well as the overall flavor profile. Additionally, it examines the formation of heat-induced markers, such as Maillard reaction products, lactulose, furosine, and alkaline phosphatase activity, which serve as indicators of heating intensity. Flavor and heating markers are commonly used to assess the quality of pasteurized milk. By examining former studies, we conclude that ultra-short-time-processing-treated milk is comparable to pasteurized milk in terms of specific parameters (such as whey protein behavior, furosine, and ALP contents). This review aims to better summarize how thermal treatments influence the milk matrix, guiding the dairy industry’s development and balancing milk products’ safety and nutritional value.
牛奶热处理，如巴氏杀菌、高温短时间加工和新兴的超短时间加工（<0.5 秒），对于确保牛奶安全和延长其保质期至关重要。牛奶是一种营养丰富的食品基质，含有各种宏/微量营养素和其他成分，热处理可能会影响这些成分，原因与加工强度有关。因此，了解加热强度与牛奶质量之间的关系对乳制品行业至关重要。本综述总结了热处理强度对牛奶营养和感官特性的影响、牛奶蛋白质结构完整性和生物利用率的合成、脂肪酸的特征和稳定性、宏/微量营养素的保留以及整体风味特征。此外，它还检查热诱导标记物的形成情况，如马氏反应产物、乳糖、糠酸和碱性磷酸酶活性，这些标记物可作为加热强度的指标。风味和加热标记通常用于评估巴氏杀菌奶的质量。通过考察以前的研究，我们得出结论，超短时间加工处理过的牛奶在特定参数（如乳清蛋白行为、糠酸和 ALP 含量）方面与巴氏杀菌奶相当。本综述旨在更好地总结热处理如何影响牛奶基质，从而指导乳制品行业的发展，平衡牛奶产品的安全性和营养价值。
{"title":"The Impact of Thermal Treatment Intensity on Proteins, Fatty Acids, Macro/Micro-Nutrients, Flavor, and Heating Markers of Milk—A Comprehensive Review","authors":"Yi Wang, Ran Xiao, Shiqi Liu, Pengjie Wang, Yinhua Zhu, Tianjiao Niu, Han Chen","doi":"10.3390/ijms25168670","DOIUrl":"https://doi.org/10.3390/ijms25168670","url":null,"abstract":"Milk thermal treatment, such as pasteurization, high-temperature short-time processing, and the emerging ultra-short-time processing (<0.5 s), are crucial for ensuring milk safety and extending its shelf life. Milk is a nutritive food matrix with various macro/micro-nutrients and other constituents that are possibly affected by thermal treatment for reasons associated with processing strength. Therefore, understanding the relationship between heating strength and milk quality is vital for the dairy industry. This review summarizes the impact of thermal treatment strength on milk’s nutritional and sensory properties, the synthesizing of the structural integrity and bioavailability of milk proteins, the profile and stability of fatty acids, the retention of macro/micro-nutrients, as well as the overall flavor profile. Additionally, it examines the formation of heat-induced markers, such as Maillard reaction products, lactulose, furosine, and alkaline phosphatase activity, which serve as indicators of heating intensity. Flavor and heating markers are commonly used to assess the quality of pasteurized milk. By examining former studies, we conclude that ultra-short-time-processing-treated milk is comparable to pasteurized milk in terms of specific parameters (such as whey protein behavior, furosine, and ALP contents). This review aims to better summarize how thermal treatments influence the milk matrix, guiding the dairy industry’s development and balancing milk products’ safety and nutritional value.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Resistance to first-generation somatostatin receptor ligand (fgSRL) treatment in acromegaly is common, making the identification of biomarkers that predict fgSRL response a desired goal. We conducted a retrospective analysis on 21 patients with acromegaly who underwent surgery and subsequent pharmacological treatment. Through immunohistochemistry (IHC), we assessed the expression of the somatostatin receptor subtypes SSTR2 and SSTR5, E-Cadherin, and cytokeratin granulation pattern (sparsely or densely). Patients were divided into responders and non-responders based on their biochemical response to fgSRL and/or the newer agent, Pasireotide, or the GH-blocker, Pegvisomant. Patients resistant to fgSRL (n = 12) exhibited lower SSTR2 and E-Cadherin expressions. Sparsely granulated tumors were more frequent in the non-responder group. SSTR2 (p = 0.024, r = 0.49) and E-Cadherin (p = 0.009, r = 0.64) positively correlated with the Insulin-like Growth Factor 1 (IGF-1) decrease after fgSRL, while SSTR5 (p = 0.107, r = −0.37) showed a trend towards negative correlation. SSTR5 positivity seemed to be associated with Pasireotide response, albeit the number of treated patients was too low (n = 4). No IHC markers correlated with Pegvisomant response. Our findings suggest that densely granulated tumors, with positive SSTR2 and E-Cadherin seem to be associated with favorable fgSRL responses. The strongest predictive value of the studied markers was found for E-Cadherin, which seems to surpass even SSTR2.
{"title":"Predicting Response to Medical Treatment in Acromegaly via Granulation Pattern, Expression of Somatostatin Receptors Type 2 and 5 and E-Cadherin","authors":"M. Gliga, L. Chinezu, I. M. Pascanu","doi":"10.3390/ijms25168663","DOIUrl":"https://doi.org/10.3390/ijms25168663","url":null,"abstract":"Resistance to first-generation somatostatin receptor ligand (fgSRL) treatment in acromegaly is common, making the identification of biomarkers that predict fgSRL response a desired goal. We conducted a retrospective analysis on 21 patients with acromegaly who underwent surgery and subsequent pharmacological treatment. Through immunohistochemistry (IHC), we assessed the expression of the somatostatin receptor subtypes SSTR2 and SSTR5, E-Cadherin, and cytokeratin granulation pattern (sparsely or densely). Patients were divided into responders and non-responders based on their biochemical response to fgSRL and/or the newer agent, Pasireotide, or the GH-blocker, Pegvisomant. Patients resistant to fgSRL (n = 12) exhibited lower SSTR2 and E-Cadherin expressions. Sparsely granulated tumors were more frequent in the non-responder group. SSTR2 (p = 0.024, r = 0.49) and E-Cadherin (p = 0.009, r = 0.64) positively correlated with the Insulin-like Growth Factor 1 (IGF-1) decrease after fgSRL, while SSTR5 (p = 0.107, r = −0.37) showed a trend towards negative correlation. SSTR5 positivity seemed to be associated with Pasireotide response, albeit the number of treated patients was too low (n = 4). No IHC markers correlated with Pegvisomant response. Our findings suggest that densely granulated tumors, with positive SSTR2 and E-Cadherin seem to be associated with favorable fgSRL responses. The strongest predictive value of the studied markers was found for E-Cadherin, which seems to surpass even SSTR2.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The fidelity of replication, especially in the presence of DNA damage, is essential for the proper function of cells. Mutations that inactivate genes involved in DNA damage repair or bypass are enriched in several types of cancer cells. Thus, it is important to further our understanding of the mechanisms governing replication fidelity. PCNA is a ring-shaped complex that encircles DNA at the front of the replication fork, at the double-stranded/single-stranded DNA junction. It serves as a processivity factor for the different DNA replication polymerases, allowing them to replicate longer stretches of DNA by physically tethering them to the DNA and preventing their detachment. In addition, PCNA also regulates and coordinates different DNA damage bypass pathways meant to allow DNA replication in the presence of DNA damage. Due to its essentiality and the numerous functions it has in the cell, much is still unclear about PCNA. Here, we utilize PCNA mutants that lower the stability of the PCNA complex on the chromatin, and thus tend to disassociate and fall from the DNA. Using these mutants, we show that PCNA’s physical presence on the DNA can prevent DNA misalignment at repetitive sequences, leading to increased mutation formation. We also show that PCNA-interacting proteins play an important role in strengthening the ring’s stability on the chromatin. Such repetitive sequence-induced mutations are common in several human diseases and it is important to study their formation and the mechanisms guarding against them.
复制的保真度，尤其是在 DNA 受损的情况下，对细胞的正常功能至关重要。在几种类型的癌细胞中，使参与 DNA 损伤修复或旁路的基因失活的突变很常见。因此，进一步了解制约复制保真度的机制非常重要。PCNA 是一种环形复合物，在复制叉的前端、双链/单链 DNA 交界处环绕 DNA。它是不同 DNA 复制聚合酶的加工因子，通过将聚合酶物理性地拴在 DNA 上并防止其脱离，使它们能够复制更长的 DNA 片段。此外，PCNA 还能调节和协调不同的 DNA 损伤旁路途径，以便在 DNA 受损时进行 DNA 复制。由于 PCNA 在细胞中的重要性和众多功能，人们对它仍有许多不清楚的地方。在这里，我们利用 PCNA 突变体，这些突变体会降低 PCNA 复合物在染色质上的稳定性，从而容易从 DNA 上分离和脱落。利用这些突变体，我们发现 PCNA 在 DNA 上的物理存在可以防止重复序列上的 DNA 错位，从而增加突变的形成。我们还发现，与 PCNA 相互作用的蛋白质在加强环在染色质上的稳定性方面发挥了重要作用。这种由重复序列诱发的突变在多种人类疾病中很常见，因此研究它们的形成和防范机制非常重要。
{"title":"Effects of PCNA Stability on the Formation of Mutations","authors":"Matan Arbel-Groissman, Batia Liefshitz, M. Kupiec","doi":"10.3390/ijms25168646","DOIUrl":"https://doi.org/10.3390/ijms25168646","url":null,"abstract":"The fidelity of replication, especially in the presence of DNA damage, is essential for the proper function of cells. Mutations that inactivate genes involved in DNA damage repair or bypass are enriched in several types of cancer cells. Thus, it is important to further our understanding of the mechanisms governing replication fidelity. PCNA is a ring-shaped complex that encircles DNA at the front of the replication fork, at the double-stranded/single-stranded DNA junction. It serves as a processivity factor for the different DNA replication polymerases, allowing them to replicate longer stretches of DNA by physically tethering them to the DNA and preventing their detachment. In addition, PCNA also regulates and coordinates different DNA damage bypass pathways meant to allow DNA replication in the presence of DNA damage. Due to its essentiality and the numerous functions it has in the cell, much is still unclear about PCNA. Here, we utilize PCNA mutants that lower the stability of the PCNA complex on the chromatin, and thus tend to disassociate and fall from the DNA. Using these mutants, we show that PCNA’s physical presence on the DNA can prevent DNA misalignment at repetitive sequences, leading to increased mutation formation. We also show that PCNA-interacting proteins play an important role in strengthening the ring’s stability on the chromatin. Such repetitive sequence-induced mutations are common in several human diseases and it is important to study their formation and the mechanisms guarding against them.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141925475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This comprehensive review critically examines the current state of research on the biological effects of millimeter-wave (MMW) therapy and its potential implications for disease treatment. By investigating both the thermal and non-thermal impacts of MMWs, we elucidate cellular-level alterations, including changes in ion channels and signaling pathways. Our analysis encompasses MMW’s therapeutic prospects in oncology, such as inducing apoptosis, managing pain, and modulating immunity through cytokine regulation and immune cell activation. By employing a rigorous methodology involving an extensive database search and stringent inclusion criteria, we emphasize the need for standardized protocols to enhance the reliability of future research. Although MMWs exhibit promising therapeutic potential, our findings highlight the urgent need for further elucidation of non-thermal mechanisms and rigorous safety assessments, considering the intricate nature of MMW interactions and inconsistent study outcomes. This review underscores the importance of focused research on the biological mechanisms of MMWs and the identification of optimal frequencies to fully harness their therapeutic capabilities. However, we acknowledge the challenges of variable study quality and the necessity for advanced quality control measures to ensure the reproducibility and comparability of future investigations. In conclusion, while MMW therapy holds promise as a novel therapeutic modality, further research is imperative to unravel its complex biological effects, establish safety profiles, and optimize treatment protocols before widespread clinical application.
{"title":"Advances in Millimeter-Wave Treatment and Its Biological Effects Development","authors":"Rui Jing, Zhenqi Jiang, Xiaoying Tang","doi":"10.3390/ijms25168638","DOIUrl":"https://doi.org/10.3390/ijms25168638","url":null,"abstract":"This comprehensive review critically examines the current state of research on the biological effects of millimeter-wave (MMW) therapy and its potential implications for disease treatment. By investigating both the thermal and non-thermal impacts of MMWs, we elucidate cellular-level alterations, including changes in ion channels and signaling pathways. Our analysis encompasses MMW’s therapeutic prospects in oncology, such as inducing apoptosis, managing pain, and modulating immunity through cytokine regulation and immune cell activation. By employing a rigorous methodology involving an extensive database search and stringent inclusion criteria, we emphasize the need for standardized protocols to enhance the reliability of future research. Although MMWs exhibit promising therapeutic potential, our findings highlight the urgent need for further elucidation of non-thermal mechanisms and rigorous safety assessments, considering the intricate nature of MMW interactions and inconsistent study outcomes. This review underscores the importance of focused research on the biological mechanisms of MMWs and the identification of optimal frequencies to fully harness their therapeutic capabilities. However, we acknowledge the challenges of variable study quality and the necessity for advanced quality control measures to ensure the reproducibility and comparability of future investigations. In conclusion, while MMW therapy holds promise as a novel therapeutic modality, further research is imperative to unravel its complex biological effects, establish safety profiles, and optimize treatment protocols before widespread clinical application.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Monkeypox virus (MPXV) is a cross-kingdom pathogen infecting both humans and wildlife, which poses a significant health risk to the public. Although MPXV attracts broad attention, there is a lack of adequate studies to elucidate pathogenic mechanisms associated with viral infections. In this study, a high-throughput RNA sequencing (RNA-seq) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) approach was used to explore the transcriptional and metabolic responses of MPXV A23 protein to HEK293T cells. The protein–protein interactions and signaling pathways were conducted by GO and KEGG analyses. The localization of A23 protein in HEK293T cells was detected by immunofluorescence. A total of 648 differentially expressed genes (DEGs) were identified in cells by RNA-Seq, including 314 upregulated genes and 334 downregulated genes. Additionally, liquid chromatography–tandem mass spectrometry (LC-MS/MS) detected 115 cellular proteins that interact with the A23 proteins. Transcriptomic sequencing analysis revealed that transfection of MPXV A23 protein modulated genes primarily associated with cellular apoptosis and DNA damage repair. Proteomic analysis indicated that this protein primarily interacted with host ribosomal proteins and histones. Following the identification of the nuclear localization sequence RKKR within the A23 protein, a truncated mutant A23ΔRKKR was constructed to investigate the subcellular localization of A23 protein. The wild-type A23 protein exhibits a significantly higher nuclear-to-cytoplasmic ratio, exceeding 1.5, in contrast to the mutant A23ΔRKKR, which has a ratio of approximately 1. Immunofluorescence assays showed that the A23 protein was mainly localized in the nucleus. The integration of transcriptomics and proteomics analysis provides a comprehensive understanding of the interaction between MPXV A23 protein and the host. Our findings highlight the potential role of this enzyme in suppressing host antiviral immune responses and modulating host gene expression.
{"title":"A Combined Transcriptomic and Proteomic Analysis of Monkeypox Virus A23 Protein on HEK293T Cells","authors":"Yihao Wang, Yihan Li, Mingzhi Li, Keyi Wang, Jiaqi Xiong, Ting Wang, Yu Wang, Yunli Guo, Lingbao Kong, Meifeng Li","doi":"10.3390/ijms25168678","DOIUrl":"https://doi.org/10.3390/ijms25168678","url":null,"abstract":"Monkeypox virus (MPXV) is a cross-kingdom pathogen infecting both humans and wildlife, which poses a significant health risk to the public. Although MPXV attracts broad attention, there is a lack of adequate studies to elucidate pathogenic mechanisms associated with viral infections. In this study, a high-throughput RNA sequencing (RNA-seq) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) approach was used to explore the transcriptional and metabolic responses of MPXV A23 protein to HEK293T cells. The protein–protein interactions and signaling pathways were conducted by GO and KEGG analyses. The localization of A23 protein in HEK293T cells was detected by immunofluorescence. A total of 648 differentially expressed genes (DEGs) were identified in cells by RNA-Seq, including 314 upregulated genes and 334 downregulated genes. Additionally, liquid chromatography–tandem mass spectrometry (LC-MS/MS) detected 115 cellular proteins that interact with the A23 proteins. Transcriptomic sequencing analysis revealed that transfection of MPXV A23 protein modulated genes primarily associated with cellular apoptosis and DNA damage repair. Proteomic analysis indicated that this protein primarily interacted with host ribosomal proteins and histones. Following the identification of the nuclear localization sequence RKKR within the A23 protein, a truncated mutant A23ΔRKKR was constructed to investigate the subcellular localization of A23 protein. The wild-type A23 protein exhibits a significantly higher nuclear-to-cytoplasmic ratio, exceeding 1.5, in contrast to the mutant A23ΔRKKR, which has a ratio of approximately 1. Immunofluorescence assays showed that the A23 protein was mainly localized in the nucleus. The integration of transcriptomics and proteomics analysis provides a comprehensive understanding of the interaction between MPXV A23 protein and the host. Our findings highlight the potential role of this enzyme in suppressing host antiviral immune responses and modulating host gene expression.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141925794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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