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Background: Rosmarinic acid (RA), a natural phenolic acid, exhibits promising anti-cancer properties. The abnormal expression of microRNA (miRNA) regulates the gene expression and plays a role as an oncogenic or tumor suppressor in TNBC. However, the biological role of RA in miR-30a-5p on BCL2L11 during MDA-MB-231 induced breast cancer stem-like cells (BCSCs) progression and its regulatory mechanism have not been elucidated. Objective: To investigate whether RA inhibited the silencing effect of miR-30a- 5p on the BCL2L11 gene and promoted apoptosis in BCSCs. Materials and Methods: We assessed the migration, colony formation, proliferation, cell cycle, and apoptosis of BCSCs after RA treatment using the wound-healing assay, colony formation assay, CCK-8 assay, and flowcytometry, respectively. The expression of mRNA and protein levels of BCL-2, Bax, BCL2L11, and P53 genes in BCSCs after RA treatment was obtained by real-time polymerase chain reaction and Western blot. DifferentialmiRNA expression in BCSCswas analyzed by high-throughput sequencing. Targetscan was utilized to predict the targets of miR-30a-5p. The dual luciferase reporter system was used for validation of the miR-30a-5p target. Results:Wound-healing assay, colony formation assay,CCK-8 assay, and cell cycle assay results showed that RA inhibited migration, colony formation and viability of BCSCs, and cell cycle arrest in the G0-G1 phase. At the highest dose of RA, we noticed cell atrophy, while the arrest rate at 100 μg/mL RA surpassed that at 200 μg/mL RA. Apoptotic cells appeared early (Membrane Associated Protein V FITC+, PI-) or late (Membrane Associated Protein V FITC+, PI+) upon administration of 200 µg/mL RA, Using high-throughput sequencing to compare the differences in miRNA expression, we detected downregulation ofmiR-30a-5p expression, and the results of dual luciferase reporter gene analysis indicated that BCL2L11 was a direct target of miR-30a-5p. Conclusion: RA inhibited the silencing effect of miR-30a-5p on the BCL2L11 gene and enhanced apoptosis in BCSCs. [ABSTRACT FROM AUTHOR]

BackgroundRosmarinic acid (RA), a natural phenolic acid, exhibits promising anti-cancer properties. The abnormal expression of microRNA (miRNA) regulates the gene expression and plays a role as an oncogenic or tumor suppressor in TNBC. However, the biological role of RA in miR-30a-5p on BCL2L11 during MDA-MB-231 induced breast cancer stem-like cells (BCSCs) progression and its regulatory mechanism have not been elucidated.ObjectiveTo investigate whether RA inhibited the silencing effect of miR-30a-5p on the BCL2L11 gene and promoted apoptosis in BCSCs.Materials and MethodsWe assessed the migration, colony formation, proliferation, cell cycle, and apoptosis of BCSCs after RA treatment using the wound-healing assay, colony formation assay, CCK-8 assay, and flow cytometry, respectively. The expression of mRNA and protein levels of BCL-2, Bax, BCL2L11, and P53 genes in BCSCs after RA treatment was obtained by real-time polymerase chain reaction and Western blot. Differential miRNA expression in BCSCs was analyzed by high-throughput sequencing. Targetscan was utilized to predict the targets of miR-30a-5p. The dual luciferase reporter system was used for validation of the miR-30a-5p target.ResultsWound-healing assay, colony formation assay, CCK-8 assay, and cell cycle assay results showed that RA inhibited migration, colony formation and viability of BCSCs, and cell cycle arrest in the G0-G1 phase. At the highest dose of RA, we noticed cell atrophy, while the arrest rate at 100 μg/mL RA surpassed that at 200 μg/mL RA. Apoptotic cells appeared early (Membrane Associated Protein V FITC+, PI−) or late (Membrane Associated Protein V FITC+, PI+) upon administration of 200 μg/mL RA, Using high-throughput sequencing to compare the differences in miRNA expression, we detected downregulation of miR-30a-5p expression, and the results of dual luciferase reporter gene analysis indicated that BCL2L11 was a direct target of miR-30a-5p.ConclusionRA inhibited the silencing effect of miR-30a-5p on the BCL2L11 gene and enhanced apoptosis in BCSCs.

Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility. [ABSTRACT FROM AUTHOR]

Autoimmune Addison’s disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.

Background: Rosmarinic acid (RA), a natural phenolic acid, exhibits promising anti-cancer properties. The abnormal expression of microRNA (miRNA) regulates the gene expression and plays a role as an oncogenic or tumor suppressor in TNBC. However, the biological role of RA in miR-30a-5p on BCL2L11 during MDA-MB-231 induced breast cancer stem-like cells (BCSCs) progression and its regulatory mechanism have not been elucidated., Objective: To investigate whether RA inhibited the silencing effect of miR-30a-5p on the BCL2L11 gene and promoted apoptosis in BCSCs., Materials and Methods: We assessed the migration, colony formation, proliferation, cell cycle, and apoptosis of BCSCs after RA treatment using the wound-healing assay, colony formation assay, CCK-8 assay, and flow cytometry, respectively. The expression of mRNA and protein levels of BCL-2, Bax, BCL2L11, and P53 genes in BCSCs after RA treatment was obtained by real-time polymerase chain reaction and Western blot. Differential miRNA expression in BCSCs was analyzed by high-throughput sequencing. Targetscan was utilized to predict the targets of miR-30a-5p. The dual luciferase reporter system was used for validation of the miR-30a-5p target., Results: Wound-healing assay, colony formation assay, CCK-8 assay, and cell cycle assay results showed that RA inhibited migration, colony formation and viability of BCSCs, and cell cycle arrest in the G0-G1 phase. At the highest dose of RA, we noticed cell atrophy, while the arrest rate at 100 μg/mL RA surpassed that at 200 μg/mL RA. Apoptotic cells appeared early (Membrane Associated Protein V FITC + , PI - ) or late (Membrane Associated Protein V FITC + , PI + ) upon administration of 200 μg/mL RA, Using high-throughput sequencing to compare the differences in miRNA expression, we detected downregulation of miR-30a-5p expression, and the results of dual luciferase reporter gene analysis indicated that BCL2L11 was a direct target of miR-30a-5p., Conclusion: RA inhibited the silencing effect of miR-30a-5p on the BCL2L11 gene and enhanced apoptosis in BCSCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zhang, Huang, Li, Lin, Zhuang and Li.)

Introduction: Abnormalities in splicing factors, such as mutations or deregulated expression, can lead to aberrant splicing of target genes, potentially contributing to the pathogenesis of acute myeloid leukemia (AML). Despite this, the precise mechanism underlying the abnormal alternative splicing (AS) induced by SRSF1, a splicing factor associated with poor AML prognosis, remains elusive., Methods: Using strict splicing criteria, we globally screened for AS events in NPMc-positive and NPMc-negative AML samples from TCGA. An AS network associated with AML prognosis was then established. Functional assays, including CCK-8, flow cytometry, and Western blot, were conducted on K562 and THP-1 cells overexpressing SRSF1. Cell viability following 72-h Omipalisib treatment was also assessed. To explore the mechanism of SRSF1-induced AS, we created a BCL2L11 miniGene with a site-specific mutation at its branch point. The AS patterns of both wild-type and mutant miniGenes were analyzed following SRSF1 overexpression in HEK-293T, along with the subcellular localization of different spliceosomes., Results: SRSF1 was significantly associated with AML prognosis. Notably, its expression was markedly upregulated in refractory AML patients compared to those with a favorable chemotherapy response. Overexpression of SRSF1 promoted THP-1 cell proliferation, suppressed apoptosis, and reduced sensitivity to Omipalisib. Mechanistically, SRSF1 recognized an aberrant branch point within the BCL2L11 intron, promoting the inclusion of a cryptic exon 3, which in turn led to apoptosis arrest., Conclusion: Overexpression of SRSF1 and the resulting abnormal splicing of BCL2L11 are associated with drug resistance and poor prognosis in AML., (© 2024 S. Karger AG, Basel.)

Alzheimer's disease (AD) is a neurodegenerative illness characterized by intracellular tau-phosphorylation, β-amyloid (Aβ) plaques accumulation, neuroinflammation, and impaired behavioral ability. Owing to the lack of effective brain delivery approaches and the presence of the blood-brain barrier (BBB), current AD therapeutic endeavors are severely limited. Herein, a multifunctional delivery system (RVG-DDQ/PDP@siBACE1) is elaborately combined with a protein kinase B (AKT) agonist (SC79) for facilitating RVG-DDQ/PDP@siBACE1 to target and penetrate BBB, enter brain parenchyma, and further accumulate in AD brain lesion. Moreover, compared with the unitary dose of RVG-DDQ/PDP@siBACE1, this collaborative therapy strategy exhibits a distinctive synergistic function including scavenging reactive oxygen species (ROS), decreasing of Aβ production, alleviating neuroinflammation by promoting the polarized microglia into the anti-inflammatory M2-like phenotype and significantly enhancing the cognitive functions of AD mice. More strikingly, according to these results, an innovative signaling pathway "lncRNA MALAT1/miR-181c/BCL2L11" is found that can mediate the neuronal apoptosis of AD. Taken together, combining the brain targeted delivery system with noninvasive BBB opening can provide a promising strategy and platform for targeting treatment of AD and other neurodegenerative diseases., (© 2023 Wiley‐VCH GmbH.)