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Keywords = HNRNPA2B1

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15 pages, 3592 KiB  
Article
Melatonin Regulates Osteoblast Differentiation through the m6A Reader hnRNPA2B1 under Simulated Microgravity
by Quan Sun, Liqun Xu, Zebing Hu, Jingchun Liu, Tingfei Yu, Meng Li, Shu Zhang and Fei Shi
Curr. Issues Mol. Biol. 2024, 46(9), 9624-9638; https://doi.org/10.3390/cimb46090572 - 1 Sep 2024
Viewed by 908
Abstract
Recent studies have confirmed that melatonin and N6-methyladenosine (m6A) modification can influence bone cell differentiation and bone formation. Melatonin can also regulate a variety of biological processes through m6A modification. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) serves as a reader of m6A modification. In [...] Read more.
Recent studies have confirmed that melatonin and N6-methyladenosine (m6A) modification can influence bone cell differentiation and bone formation. Melatonin can also regulate a variety of biological processes through m6A modification. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) serves as a reader of m6A modification. In this study, we used the hindlimb unloading model as an animal model of bone loss induced by simulated microgravity and used 2D clinorotation to simulate a microgravity environment for cells on the ground. We found that hnRNPA2B1 was downregulated both in vitro and in vivo during simulated microgravity. Further investigations showed that hnRNPA2B1 could promote osteoblast differentiation and that overexpression of hnRNPA2B1 attenuated the suppression of osteoblast differentiation induced by simulated microgravity. We also discovered that melatonin could promote the expression of hnRNPA2B1 under simulated microgravity. Moreover, we found that promotion of osteoblast differentiation by melatonin was partially dependent on hnRNPA2B1. Therefore, this research revealed, for the first time, the role of the melatonin/hnRNPA2B1 axis in osteoblast differentiation under simulated microgravity. Targeting this axis may be a potential protective strategy against microgravity-induced bone loss and osteoporosis. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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18 pages, 6265 KiB  
Article
RNA m6a Methylation Regulator Expression in Castration-Resistant Prostate Cancer Progression and Its Genetic Associations
by Chamikara Liyanage, Achala Fernando, Audrey Chamberlain, Afshin Moradi and Jyotsna Batra
Cancers 2024, 16(7), 1303; https://doi.org/10.3390/cancers16071303 - 27 Mar 2024
Cited by 2 | Viewed by 2083
Abstract
N6-methyladenosine (m6A) methylation, a prevalent epitranscriptomic modification, plays a crucial role in regulating mRNA expression, stability, and translation in mammals. M6A regulators have gained attention for their potential implications in tumorigenesis and clinical applications, such as cancer diagnosis and therapeutics. The existing literature [...] Read more.
N6-methyladenosine (m6A) methylation, a prevalent epitranscriptomic modification, plays a crucial role in regulating mRNA expression, stability, and translation in mammals. M6A regulators have gained attention for their potential implications in tumorigenesis and clinical applications, such as cancer diagnosis and therapeutics. The existing literature predominantly addresses m6A regulators in the context of primary prostate cancer (PCa). However, a notable gap in the knowledge emerges regarding the dynamic expression patterns of these regulators as PCa progresses towards the castration-resistant stage (CRPC). Employing sequential window acquisition of all theoretical mass spectra (SWATH-MS) and RNAseq analysis, we comprehensively profiled the expression of 27 m6A regulators in hormone/androgen-dependent and -independent PCa cell lines, revealing distinct clustering between tumor and adjacent normal prostate tissues. High-grade PCa tumors demonstrated the upregulation of METTL3, RBM15B, and HNRNAPA2B1 and the downregulation of ZC3H13, NUDT21, and FTO. Notably, we identified six m6A regulators associated with PCa survival. Additionally, association analysis of the PCa-associated risk loci in the cancer genome atlas program (TCGA) data unveiled genetic variations near the WTAP, HNRNPA2B1, and FTO genes as significant expression quantitative trait loci. In summary, our study unraveled abnormalities in m6A regulator expression in PCa progression, elucidating their association with PCa risk loci. Considering the heterogeneity within the PCa phenotypes and treatment responses, our findings suggest that prognostic stratification based on m6A regulator expression could enhance PCa diagnosis and prognosis. Full article
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13 pages, 2608 KiB  
Article
Genetic and Environmental Factors in Autoimmune Thyroid Disease: Exploring Associations with Selenium Levels and Novel Loci in a Latvian Cohort
by Sabine Upmale-Engela, Ieva Vaivode, Raitis Peculis, Helena Litvina, Tatjana Zake, Andrejs Skesters, Deniss Gogins, Vita Rovite and Ilze Konrade
Curr. Issues Mol. Biol. 2024, 46(3), 2553-2565; https://doi.org/10.3390/cimb46030162 - 17 Mar 2024
Viewed by 2010
Abstract
The interplay of genetic, immune and environmental factors strongly contributes to the development of autoimmune thyroid disease (AITD), which can be classified as Graves’ disease (GD) or Hashimoto thyroiditis (HT). One of the most studied exogenous factors in the pathogenesis of AITD is [...] Read more.
The interplay of genetic, immune and environmental factors strongly contributes to the development of autoimmune thyroid disease (AITD), which can be classified as Graves’ disease (GD) or Hashimoto thyroiditis (HT). One of the most studied exogenous factors in the pathogenesis of AITD is selenium, which, in the form of selenoproteins, strengthens the antioxidative defence system of thyroid cells against superoxide production. Furthermore, it modulates inflammatory cytokine release and autoantibody production. The aim of this study was to assess the associations of genetic factors with selenium levels in a cohort of adults with HT and GD and healthy controls from Latvia. A total of 148 GD patients, 102 HT patients and 2442 control participants were included in the study. The genotypes were determined using genome-wide genotyping; imputation was carried out using the TOPMed r2 imputation panel; and association analysis was performed with PLINK v1.90b7. We found three loci associated with GD (LSAMP, HNRNPA3P5, and NTN1) and one locus associated with HT (VAT1L); furthermore, one locus was associated with a serum selenium concentration > 80 µg/L (LINC01544/RNF152/PIGN). The detected associations could be attributed to population-specific effects or unknown stratification in our cohort, and further assessment of these results is required to explain the relationships of genetic traits with AITD and other phenotypes. Full article
(This article belongs to the Section Molecular Medicine)
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22 pages, 8754 KiB  
Article
Characteristics of ABCC4 and ABCG2 High Expression Subpopulations in CRC—A New Opportunity to Predict Therapy Response
by Jakub Kryczka and Joanna Boncela
Cancers 2023, 15(23), 5623; https://doi.org/10.3390/cancers15235623 - 28 Nov 2023
Viewed by 2014
Abstract
Background: Our previous findings proved that ABCC4 and ABCG2 proteins present much more complex roles in colorectal cancer (CRC) than typically cancer-associated functions as drug exporters. Our objective was to evaluate their predictive/diagnostic potential. Methods: CRC patients’ transcriptomic data from the Gene Expression [...] Read more.
Background: Our previous findings proved that ABCC4 and ABCG2 proteins present much more complex roles in colorectal cancer (CRC) than typically cancer-associated functions as drug exporters. Our objective was to evaluate their predictive/diagnostic potential. Methods: CRC patients’ transcriptomic data from the Gene Expression Omnibus database (GSE18105, GSE21510 and GSE41568) were discriminated into two subpopulations presenting either high expression levels of ABCC4 (ABCC4 High) or ABCG2 (ABCG2 High). Subpopulations were analysed using various bioinformatical tools and platforms (KEEG, Gene Ontology, FunRich v3.1.3, TIMER2.0 and STRING 12.0). Results: The analysed subpopulations present different gene expression patterns. The protein–protein interaction network of subpopulation-specific genes revealed the top hub proteins in ABCC4 High: RPS27A, SRSF1, DDX3X, BPTF, RBBP7, POLR1B, HNRNPA2B1, PSMD14, NOP58 and EIF2S3 and in ABCG2 High: MAPK3, HIST2H2BE, LMNA, HIST1H2BD, HIST1H2BK, HIST1H2AC, FYN, TLR4, FLNA and HIST1H2AJ. Additionally, our multi-omics analysis proved that the ABCC4 expression correlates with substantially increased tumour-associated macrophage infiltration and sensitivity to FOLFOX treatment. Conclusions: ABCC4 and ABCG2 may be used to distinguish CRC subpopulations that present different molecular and physiological functions. The ABCC4 High subpopulation demonstrates significant EMT reprogramming, RNA metabolism and high response to DNA damage stimuli. The ABCG2 High subpopulation may resist the anti-EGFR therapy, presenting higher proteolytical activity. Full article
(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)
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21 pages, 4481 KiB  
Article
Bta-miR-206 and a Novel lncRNA-lncA2B1 Promote Myogenesis of Skeletal Muscle Satellite Cells via Common Binding Protein HNRNPA2B1
by Junxing Zhang, Hui Sheng, Linlin Zhang, Xin Li, Yiwen Guo, Yimin Wang, Hong Guo and Xiangbin Ding
Cells 2023, 12(7), 1028; https://doi.org/10.3390/cells12071028 - 27 Mar 2023
Cited by 3 | Viewed by 1968
Abstract
Skeletal muscle satellite cells (MuSCs) can proliferate, differentiate, and self-renew, and can also participate in muscle formation and muscle injury repair. Long noncoding RNAs (lncRNAs) can play an important role with the RNA binding protein and microRNAs (miRNAs) to regulate the myogenesis of [...] Read more.
Skeletal muscle satellite cells (MuSCs) can proliferate, differentiate, and self-renew, and can also participate in muscle formation and muscle injury repair. Long noncoding RNAs (lncRNAs) can play an important role with the RNA binding protein and microRNAs (miRNAs) to regulate the myogenesis of bovine MuSCs, however, its molecular mechanism is still being explored. In this study, differentially expressed 301 lncRNAs were identified during the myogenic differentiation of cells based on an in vitro model of induced differentiation of bovine MuSCs using RNA sequencing (RNA-seq). Based on the ability of miR-206 to regulate myogenic cell differentiation, a new kind of lncRNA-lncA2B1 without protein-coding ability was found, which is expressed in the nucleus and cytoplasm. Subsequently, lncA2B1 inhibited cell proliferation by downregulating the expression of the proliferation marker Pax7 and promoted myogenic differentiation by upregulating the expression of the differentiation marker MyHC, whose regulatory function is closely related to miR-206. By RNA pulldown/LC-MS experiments, heterogeneous ribonucleoprotein A2/B1 (HNRNPA2B1), and DExH-Box Helicase 9 (DHX9) were identified as common binding proteins of lncA2B1 and miR-206. Overexpression of lncA2B1 and miR-206 significantly upregulated the expression level of HNRNPA2B1. Downregulation of HNRNPA2B1 expression significantly decreased the expression level of the differentiation marker MyHC, which indicates that miR-206 and lncA2B1 regulate myogenic differentiation of bovine MuSCs by acting on HNRNPA2B1. This study screened and identified a novel lncRNA-lncA2B1, which functions with miR-206 to regulate myogenesis via the common binding proteins HNRNPA2B1. The results of this study provide a new way to explore the molecular mechanisms by which lncRNAs and miRNAs regulate muscle growth and development. Full article
(This article belongs to the Collection Skeletal Muscle Differentiation and Epigenetics)
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17 pages, 4421 KiB  
Article
HnRNPA2B1 Aggravates Inflammation by Promoting M1 Macrophage Polarization
by Meiyao Meng, Yuxiang Cao, Yankang Zhang, Shuang Liu, Yinzhao Zhong, Dongmei Wang, Dali Li, Lingyan Xu and Xinran Ma
Nutrients 2023, 15(7), 1555; https://doi.org/10.3390/nu15071555 - 23 Mar 2023
Cited by 5 | Viewed by 2366
Abstract
Macrophages have critical contributions to both acute and chronic inflammatory diseases, for example, bowel disease and obesity, respectively. However, little is known about the post-transcriptional regulatory mechanisms in macrophage-mediated inflammatory diseases. hnRNPA2B1 (A2B1) is an RNA binding protein for mRNA fate determination. We [...] Read more.
Macrophages have critical contributions to both acute and chronic inflammatory diseases, for example, bowel disease and obesity, respectively. However, little is known about the post-transcriptional regulatory mechanisms in macrophage-mediated inflammatory diseases. hnRNPA2B1 (A2B1) is an RNA binding protein for mRNA fate determination. We showed that hnRNPA2B1 mRNA levels were increased in colon in dextran sodium sulfate (DSS)-induced colitis mice and in epididymal white adipose tissue (eWAT) and spleen of high-fat-diet (HFD)-induced obese mice. Consistently, mice with haploinsufficiency of A2B1 (A2B1 HET) are protected against DSS-induced acute colitis and HFD-induced obesity, with decreased M1 macrophages polarization in colon, eWAT and spleen. Mechanistically, A2B1 mRNA and protein levels were increased in LPS-stimulated RAW 264.7 macrophages, and A2B1 enhanced RNA stability of pro-inflammatory genes Tnfα, Il-6 and Il-1β for the regulation of macrophages polarization. Interestingly, A2B1 HET mice exhibited reduced white fat expansion, which was influenced by macrophages, since conditioned medium from macrophages with A2B1 manipulation significantly changed preadipocyte proliferation. Our data demonstrate that A2B1 plays a vital role in macrophage-mediated inflammation via regulating mRNA stability, suggesting that A2B1 may be served as a promising target for the intervention of acute and chronic inflammatory diseases. Full article
(This article belongs to the Special Issue Adipose Tissue Metabolism and Exercise in Health and Disease)
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17 pages, 2867 KiB  
Article
HNRNPA2B1-Mediated MicroRNA-92a Upregulation and Section Acts as a Promising Noninvasive Diagnostic Biomarker in Colorectal Cancer
by Yiling Li, Kexin Li, Xiaoying Lou, Yue Wu, Samuel Seery, Danfei Xu, Yuqing Pei, Benheng Qian, Yuxin Wu, Shuang Liang, Kui Wu and Wei Cui
Cancers 2023, 15(4), 1367; https://doi.org/10.3390/cancers15051367 - 21 Feb 2023
Cited by 4 | Viewed by 2602
Abstract
MicroRNA-92a (miR-92a) may serve as a novel promising biomarker in multiple cancers, including colorectal cancer (CRC); however, the diagnostic accuracy and the underlying molecular mechanism of miR-92a in CRC is poorly understood. We first carried out meta-analysis and found that serum/plasma miR-92a yield [...] Read more.
MicroRNA-92a (miR-92a) may serve as a novel promising biomarker in multiple cancers, including colorectal cancer (CRC); however, the diagnostic accuracy and the underlying molecular mechanism of miR-92a in CRC is poorly understood. We first carried out meta-analysis and found that serum/plasma miR-92a yield better diagnostic efficacy when compared to stool samples and CRC tissues, and this finding was validated by our independent study through stool sample. Multiple bioinformatics assay indicated that miR-92a expression was positively correlated with heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) expression and closely related with the clinical characteristics of CRC. Experimental evidence showed that knockdown of HNRNPA2B1 could significantly decrease miR-92a expression and secretion in RKO cells. HNRNPA2B1 mediated miR-92a via m6A RNA modification. These findings indicate that HNRNPA2B1-m6A RNA modification-derived MicroRNA-92a upregulation and section from the local CRC acts a candidate noninvasive serum biomarker in colorectal cancer. Our study provides a novel insight into miR-92a mechanisms in relation to both expression and secretion for CRC diagnosis. Full article
(This article belongs to the Special Issue Advances in Blood-Based Screening for Cancer)
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13 pages, 2441 KiB  
Article
Alzheimer’s Disease-Associated Alternative Splicing of CD33 Is Regulated by the HNRNPA Family Proteins
by Riho Komuro, Yuka Honda, Motoaki Yanaizu, Masami Nagahama and Yoshihiro Kino
Cells 2023, 12(4), 602; https://doi.org/10.3390/cells12040602 - 13 Feb 2023
Cited by 1 | Viewed by 4570
Abstract
Genetic variations of CD33 have been implicated as a susceptibility factor of Alzheimer’s disease (AD). A polymorphism on exon 2 of CD33, rs12459419, affects the alternative splicing of this exon. The minor allele is associated with a reduced risk of AD and [...] Read more.
Genetic variations of CD33 have been implicated as a susceptibility factor of Alzheimer’s disease (AD). A polymorphism on exon 2 of CD33, rs12459419, affects the alternative splicing of this exon. The minor allele is associated with a reduced risk of AD and promotes the skipping of exon 2 to produce a shorter CD33 isoform lacking the extracellular ligand-binding domain, leading to decreased suppressive signaling on microglial activity. Therefore, factors that regulate the splicing of exon 2 may alter the disease-associated properties of CD33. Herein, we sought to identify the regulatory proteins of CD33 splicing. Using a panel of RNA-binding proteins and a human CD33 minigene, we found that exon 2 skipping of CD33 was promoted by HNRNPA1. Although the knockdown of HNRNPA1 alone did not reduce exon 2 skipping, simultaneous knockdown of HNRNPA1 together with that of HNRNPA2B1 and HNRNPA3 promoted exon 2 inclusion, suggesting functional redundancy among HNRNPA proteins. Similar redundant regulation by HNRNPA proteins was observed in endogenous CD33 of THP-1 and human microglia-like cells. Although mouse Cd33 showed a unique splicing pattern of exon 2, we confirmed that HNRNPA1 promoted the skipping of this exon. Collectively, our results revealed novel regulatory relationships between CD33 and HNRNPA proteins. Full article
(This article belongs to the Section Cell Nuclei: Function, Transport and Receptors)
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17 pages, 3190 KiB  
Article
Small Peptides Isolated from Enzymatic Hydrolyzate of Pneumatophorus japonicus Bone Promote Sleep by Regulating Circadian Rhythms
by Junbao Wang, Lu Zhang, Ningping Tao, Xichang Wang, Shanggui Deng, Mingyou Li, Yao Zu and Changhua Xu
Foods 2023, 12(3), 464; https://doi.org/10.3390/foods12030464 - 19 Jan 2023
Cited by 5 | Viewed by 2521
Abstract
Due to the high addiction and side effects of medicines, people have increasingly inclined to natural and healthy peptides to improve sleep. Herein, we isolated novel peptides with sleep-promoting ability from Pneumatophorus japonicus bone peptides (PBPs) and constructed an insomniac zebrafish model as [...] Read more.
Due to the high addiction and side effects of medicines, people have increasingly inclined to natural and healthy peptides to improve sleep. Herein, we isolated novel peptides with sleep-promoting ability from Pneumatophorus japonicus bone peptides (PBPs) and constructed an insomniac zebrafish model as a demonstration, incorporating behavioral and transcriptomic approaches to reveal the sleep-promoting effect and mechanism of PBPs. Specifically, a sequential targeting isolation approach was developed to refine and identify a peptide with remarkable sleep-promoting activity, namely TG7 (Tyr-Gly-Asn-Pro-Trp-Glu-Lys). TG7 shows comparable effects and a similar action pathway to melatonin in improving sleep. TG7 restores abnormal behavior of insomnia zebrafish to normal levels by upregulating the hnrnpa3 gene. The peptide downregulates per1b gene but upregulates cry1b, cry1ba and per2, improving the circadian rhythm. Furthermore, TG7 upregulates the genes gnb3b, arr3b and opn1mw1 to regulate the visual function. The above results indicate that TG7 improves circadian rhythms and attenuated abnormal alterations in visual function and motility induced by light, allowing for effective sleep promotion. This study isolated sleep-promoting peptides from PBPs, which provides a theoretical basis for the development of subsequent sleep-promoting products based on protein peptides. Full article
(This article belongs to the Section Food Nutrition)
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17 pages, 3016 KiB  
Article
SR Protein Kinase 1 Inhibition by TAF15
by Anastasia Koukiali, Makrina Daniilidou, Ilias Mylonis, Thomas Giannakouros and Eleni Nikolakaki
Cells 2023, 12(1), 126; https://doi.org/10.3390/cells12010126 - 28 Dec 2022
Cited by 2 | Viewed by 4877
Abstract
Although SRPKs were discovered nearly 30 years ago, our understanding of their mode of regulation is still limited. Regarded as constitutively active enzymes known to participate in diverse biological processes, their prominent mode of regulation mainly depends on their intracellular localization. Molecular chaperones [...] Read more.
Although SRPKs were discovered nearly 30 years ago, our understanding of their mode of regulation is still limited. Regarded as constitutively active enzymes known to participate in diverse biological processes, their prominent mode of regulation mainly depends on their intracellular localization. Molecular chaperones associate with a large internal spacer sequence that separates the bipartite kinase catalytic core and modulates the kinases’ partitioning between the cytoplasm and nucleus. Besides molecular chaperones that function as anchoring proteins, a few other proteins were shown to interact directly with SRPK1, the most-studied member of SRPKs, and alter its activity. In this study, we identified TAF15, which has been involved in transcription initiation, splicing, DNA repair, and RNA maturation, as a novel SRPK1-interacting protein. The C-terminal RGG domain of TAF15 was able to associate with SRPK1 and downregulate its activity. Furthermore, overexpression of this domain partially relocalized SRPK1 to the nucleus and resulted in hypophosphorylation of SR proteins, inhibition of splicing of a reporter minigene, and inhibition of Lamin B receptor phosphorylation. We further demonstrated that peptides comprising the RGG repeats of nucleolin, HNRPU, and HNRNPA2B1, were also able to inhibit SRPK1 activity, suggesting that negative regulation of SRPK1 activity might be a key biochemical property of RGG motif-containing proteins. Full article
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15 pages, 4519 KiB  
Article
Identification and Validation of Three m6A Regulators: FTO, HNRNPC, and HNRNPA2B1 as Potential Biomarkers for Endometriosis
by Jiani Sun, Lei Gan and Jing Sun
Genes 2023, 14(1), 86; https://doi.org/10.3390/genes14010086 - 28 Dec 2022
Cited by 5 | Viewed by 2650
Abstract
Background: N6-methyladenosine is involved in numerous biological processes. However, the significance of m6A regulators in endometriosis is still unclear. Methods: We extracted three significant m6A regulators between non-endometriosis and endometriosis patients from GSE6364 and then we used the random forest model to obtain [...] Read more.
Background: N6-methyladenosine is involved in numerous biological processes. However, the significance of m6A regulators in endometriosis is still unclear. Methods: We extracted three significant m6A regulators between non-endometriosis and endometriosis patients from GSE6364 and then we used the random forest model to obtain significant m6A regulators. In addition, we used the nomogram model to evaluate the prevalence of endometriosis. The predictive ability of the candidate genes was evaluated through the receiver operating characteristic curves, while the expression of candidate biomarkers was validated via Western blotting. Additionally, according to candidate genes, we identified m6A subtypes based on which functional enrichment analysis and immune infiltration were performed. Results: Three significant m6A regulators (fat mass and obesity-associated protein, heterogeneous nuclear ribonucleoprotein A2/B1, and heterogeneous nuclear ribonucleoprotein C) were discovered. We identified three m6A subtypes, including clusterA, clusterB, and clusterC. ClusterB was demonstrated to be correlated with significantly overexpressed VEGF and notably downregulated ESR1 and PGR, which are convincing biomarkers of endometriosis. Furthermore, we discovered that patients in clusterB were associated with high levels of neutrophil infiltration, a reduced Treg/Th17 ratio, and overexpressed pyroptosis-related genes, which also indicated that clusterB was highly linked to endometriosis. Conclusion: In conclusion, m6A regulators are of great significance for the occurrence and process of endometriosis. The findings of our study provide novel insights into the underlying molecular mechanism of endometriosis. The novel investigation of m6A patterns and their correlation with immunity may also help to guide the clinical diagnosis, provide prognostic significance, and develop immunotherapy strategies for endometriosis patients. Full article
(This article belongs to the Special Issue Bioinformatics and Machine Learning in Disease Research)
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15 pages, 2273 KiB  
Article
Preclinical Evaluation of hnRNPA2B1 Antibody in Human Triple-Negative Breast Cancer MDA-MB-231 Cells via PET Imaging
by Abhinav Bhise, Hyun Park, Woonghee Lee, Swarbhanu Sarkar, Yeong Su Ha, Subramani Rajkumar, Bora Nam, Jeong Eun Lim, Phuong Tu Huynh, Kiwoong Lee, Ji-Yoon Son, Jung Young Kim, Kyo Chul Lee and Jeongsoo Yoo
Pharmaceutics 2022, 14(8), 1677; https://doi.org/10.3390/pharmaceutics14081677 - 12 Aug 2022
Cited by 2 | Viewed by 2849
Abstract
Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Because TNBC lacks the expression of commonly targeted receptors, it is challenging to develop a new imaging agent for this cancer subtype. Heterogeneous nuclear ribonucleoproteins [...] Read more.
Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Because TNBC lacks the expression of commonly targeted receptors, it is challenging to develop a new imaging agent for this cancer subtype. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA–protein complexes that have been linked to tumor development and progression. Considering the high expression of hnRNPA2B1, an hnRNP subtype, in TNBC MDA-MB-231 cells, this study aimed to develop a novel hnRNPA2B1 antibody-based nuclear imaging agent. The hnRNPA2B1-specific antibody was radiolabeled with 64Cu and evaluated in vitro and in vivo. The trans-cyclooctene (TCO) was functionalized on the antibody to obtain hnRNP-PEG4-TCO and reactive tetrazine (Tz) on the ultrastable bifunctional chelator PCB-TE2A-alkyne to yield PCB-TE2A-Tz for the inverse electron demand Diels–Alder reaction. The 64Cu-radiolabeled antibody was administered and imaged at 1–18 h time points for conventional imaging. Alternatively, the unlabeled antibody conjugate was administered, and 48 h later radiolabeled 64Cu-PCB-TE2A-Tz was administered to the same mice for the pretargeting strategy and imaged at the same time intervals for direct comparison. The tumor was successfully visualized in both strategies, and comparatively, pretargeting showed superior results. The 64Cu-PCB-TE2A-Tz was successfully clicked at the tumor site with hnRNP-PEG4-TCO and the non-clicked were concurrently eliminated. This led to increase the tumor uptake with extremely high tumor-to-background ratio manifested by positron emission tomography (PET) imaging and biodistribution studies. Full article
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16 pages, 2712 KiB  
Article
Citicoline Modifies the Expression of Specific miRNAs Related to Cardioprotection in Patients with ST-Segment Elevation Myocardial Infarction Subjected to Coronary Angioplasty
by Alejandro Silva-Palacios, Miguel Arroyo-Campuzano, Mirthala Flores-García, Mariana Patlán, Adrián Hernández-Díazcouder, Diego Alcántara, Ixchel Ramírez-Camacho, Dana Arana-Hidalgo, Elizabeth Soria-Castro, Fausto Sánchez, Héctor González-Pacheco and Cecilia Zazueta
Pharmaceuticals 2022, 15(8), 925; https://doi.org/10.3390/ph15080925 - 27 Jul 2022
Cited by 11 | Viewed by 2433
Abstract
Extracellular vesicles are recognized as signaling mediators between cells both in physiological and pathological communication. In this work, we explored the potential effect of citicoline to modify relevant proteins or miRNAs for cardioprotection in the smallest population of such microvesicles; i.e., in exosomes [...] Read more.
Extracellular vesicles are recognized as signaling mediators between cells both in physiological and pathological communication. In this work, we explored the potential effect of citicoline to modify relevant proteins or miRNAs for cardioprotection in the smallest population of such microvesicles; i.e., in exosomes from patients diagnosed with ST-segment elevation myocardial infarction (STEMI) undergoing coronary angioplasty. The plasma-exosome-enriched fraction from these patients was characterized. Their cellular origin was assessed by flow cytometry and Western blot, whereas miRNA expression was evaluated by real-time polymerase chain reaction (qRT-PCR). The content of caveolin-1, caveolin-3, and hnRNPA2B1, which play a relevant role in selective transport of miRNAs into microvesicles, along with the effect on cell viability of the exosomes obtained from citicoline-treated and untreated groups were also analyzed. Our results showed that hypoxic stress increases exosome release into the circulation. Moreover, we found that CD146+ increased in exosomes from citicoline-treated patients, while CD142+ decreased in these patients compared to the placebo group. No changes were detected in the protein levels of caveolin-1, caveolin-3, and hnRNPA2B1. Citicoline administration modified the expression of miR233-3p, miR92, and miR21-5p in exosomes. Cell viability decreased in the presence of exosomes from infarcted patients, while incubation of H9c2 cells with exosomes from patients reperfused with citicoline did not affect cell viability. In conclusion, citicoline administration modifies the expression of specific miRNAs related to cardioprotection in exosomes. Full article
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18 pages, 889 KiB  
Review
Cytogenetic and Genetic Abnormalities with Diagnostic Value in Myelodysplastic Syndromes (MDS): Focus on the Pre-Messenger RNA Splicing Process
by Nathalie Douet-Guilbert, Benoît Soubise, Delphine G. Bernard and Marie-Bérengère Troadec
Diagnostics 2022, 12(7), 1658; https://doi.org/10.3390/diagnostics12071658 - 7 Jul 2022
Cited by 6 | Viewed by 4219
Abstract
Myelodysplastic syndromes (MDS) are considered to be diseases associated with splicing defects. A large number of genes involved in the pre-messenger RNA splicing process are mutated in MDS. Deletion of 5q and 7q are of diagnostic value, and those chromosome regions bear the [...] Read more.
Myelodysplastic syndromes (MDS) are considered to be diseases associated with splicing defects. A large number of genes involved in the pre-messenger RNA splicing process are mutated in MDS. Deletion of 5q and 7q are of diagnostic value, and those chromosome regions bear the numbers of splicing genes potentially deleted in del(5q) and del(7q)/-7 MDS. In this review, we present the splicing genes already known or suspected to be implicated in MDS pathogenesis. First, we focus on the splicing genes located on chromosome 5 (HNRNPA0, RBM27, RBM22, SLU7, DDX41), chromosome 7 (LUC7L2), and on the SF3B1 gene since both chromosome aberrations and the SF3B1 mutation are the only genetic abnormalities in splicing genes with clear diagnostic values. Then, we present and discuss other splicing genes that are showing a prognostic interest (SRSF2, U2AF1, ZRSR2, U2AF2, and PRPF8). Finally, we discuss the haploinsufficiency of splicing genes, especially from chromosomes 5 and 7, the important amplifier process of splicing defects, and the cumulative and synergistic effect of splicing genes defects in the MDS pathogenesis. At the time, when many authors suggest including the sequencing of some splicing genes to improve the diagnosis and the prognosis of MDS, a better understanding of these cooperative defects is needed. Full article
(This article belongs to the Special Issue Myelodysplastic Syndrome: Diagnosis and Screening)
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11 pages, 7531 KiB  
Communication
Comprehensive Analysis of N6-Methyladenosine (m6A) Writers, Erasers, and Readers in Cervical Cancer
by Mateja Condic, Damian J. Ralser, Niklas Klümper, Jörg Ellinger, Maryam Qureischi, Eva K. Egger, Glen Kristiansen, Alexander Mustea and Thore Thiesler
Int. J. Mol. Sci. 2022, 23(13), 7165; https://doi.org/10.3390/ijms23137165 - 28 Jun 2022
Cited by 18 | Viewed by 3352
Abstract
There is growing scientific evidence for the crucial role of post-transcriptional RNA modifications in carcinogenesis, progression, metastasis, and drug resistance across various cancer entities. N6-methyladenosine (m6A) is the most abundant type of RNA modification. m6A is coordinated by a dynamic interplay of ‘writers’ [...] Read more.
There is growing scientific evidence for the crucial role of post-transcriptional RNA modifications in carcinogenesis, progression, metastasis, and drug resistance across various cancer entities. N6-methyladenosine (m6A) is the most abundant type of RNA modification. m6A is coordinated by a dynamic interplay of ‘writers’ (METTL3, METTL4, METTL14, WTAP, KIAA1429), ‘erasers’ (FTO, ALKBH5), and ‘readers’ (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In this study, we comprehensively examined protein and mRNA expression levels of m6A writers, readers, and erasers in two cervical cancer (CC) cohorts (UHB CC cohort, N = 118; TCGA CC cohort, N = 307) with regard to clinical outcomes. In the UHB CC cohort, high protein expression levels of METTL14 (p = 0.016), WTAP (p = 0.007), KIAA1439 (p < 0.001), ALKBH5 (p < 0.001), HNRNPC (p = 0.012), YTHDC1 (p < 0.001), and YTHDF3 (p = 0.004) were significantly associated with a shorter overall survival (OS). In the TCGA CC cohort, mRNA expression levels of METTL14 (p = 0.012), WTAP (p = 0.041), KIAA1429 (p = 0.016), and YTHDC1 (p = 0.026) showed prognostic values. However, after correction for multiple testing, statistical significance remained only for m6A protein expression levels (q < 0.1). Our study points towards dysregulated m6A modification in CC. Hence, m6A might serve as a promising prognostic biomarker and therapeutical target in CC. Full article
(This article belongs to the Special Issue Altered RNA Processing in Tumor Pathogenesis and Therapy)
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