N6-methyladenosine (m6A) modification is a significant methylation alteration frequently observed in eukaryotic RNAs, garnering considerable attention in the field of breast cancer research in recent years. The m6A modification profoundly influences the onset, progression, and prognosis of breast cancer by regulating RNA stability, translation efficiency, and degradation processes. Numerous studies have demonstrated that m6A regulatory factors, including METTL3, METTL14, and ALKBH5, play pivotal roles in breast cancer cells, affecting cell proliferation, metastasis, and drug resistance. Furthermore, the interactions between m6A modification and non-coding RNAs, as well as its role in the tumor microenvironment, have increasingly attracted researchers' interest. Although numerous studies have elucidated the dual roles of m6A in breast cancer, its specific molecular mechanisms remain to be thoroughly investigated. Future research should explore various aspects, including the role of m6A in different subtypes of breast cancer, its involvement in chemotherapy resistance, and its interactions with the tumor microenvironment. This exploration will contribute to advancements in the diagnosis and treatment of breast cancer. The present article aims to systematically summarize the research progress on m6A modification in breast cancer, offering novel insights and strategies for future related research and clinical applications.
Missense mutations in the HSPB8 gene, encoding the small heat shock protein B8, cause distal hereditary motor neuropathy (dHMN) or an axonal form of Charcot–Marie–Tooth disease (CMT subtype 2L). Mice expressing mutant Hspb8 (Lys141Asn) mimic the human disease, whereas mice lacking Hspb8 show no overt phenotype. We aimed to design an RNA interference treatment strategy that rescues the mutant HSPB8 neuronal and muscle phenotype in patient-derived motor neurons and in a knock-in mouse model of CMT2L/dHMN.
We optimized RNA interference sequences targeting both human HSPB8 and mouse HspB8 transcripts with the aim to alleviate disease symptoms. We used human induced pluripotent stem cells and the Hspb8 knock-in mouse model. We designed lenti- and adeno-associated viral vectors that contained the short-hairpin RNA constructs. We performed expression and microscopy studies, magnetic resonance imaging, behaviour analysis and electrophysiology.
In CMT2L patient-derived induced pluripotent stem cells differentiated towards motor neurons, reducing the HSPB8 expression with a short-hairpin RNA (shRNA), directed towards the 3′ untranslated region (3′UTR), ameliorated the morphology and fragmentation of mitochondria. The AAV9-mediated treatment of the 3′UTR shRNA construct, under neuron-specific regulation, in Hspb8 knock-in mice showed inconclusive results towards functional improvement upon expression studies, magnetic resonance imaging and neuropathological findings.
Given the limited beneficial effect of the treatment, the RNA interference–mediated reduction of HSPB8/Hspb8 expression might not be the best therapeutic strategy to treat dHMN/CMT2L, unless a higher viral load and earlier treatment can be applied to the mouse model.
The forkhead box A (FOXA) family has been extensively studied in cancer research; however, the role of FOXA3 in malignant tumors, particularly esophageal squamous cell carcinoma (ESCC), is not well understood. This study explores the expression and function of FOXA3 in ESCC, assessing its potential as a prognostic marker and therapeutic target.
This study analyzed FOXA3 expression in ESCC tissues and its correlation with patient prognosis. The effects of FOXA3 overexpression on ESCC cell proliferation, migration, and invasion were examined in ESCC cell lines in vitro. Additionally, an in vivo tumorigenesis assay was performed using subcutaneous injection to assess the impact of FOXA3 overexpression on tumor growth. Statistical analyses were conducted to determine the significance of the results.
FOXA3 expression was significantly reduced in ESCC tissues compared with it in paired adjacent normal tissues, and low FOXA3 expression was significantly associated with poor prognosis in ESCC patients. FOXA3 overexpression markedly inhibited ESCC cell proliferation, migration, and invasion. In addition, overexpression of FOXA3 repressed tumor growth in mice.
These findings indicate that FOXA3 acts as a tumor suppressor in ESCC, and its low expression is linked to poor outcomes. FOXA3 may serve as a potential diagnostic and therapeutic target for ESCC.
Gliomas currently have a poor prognosis and limited therapy options. Betulinic acid (BA) has demonstrated antitumor activity in various cancers. This study is aimed at clarifying the underlying mechanisms by which BA inhibits gliomas.
We assessed how BA affected the migration, apoptosis, invasion, proliferation, and viability of U251 glioma cells. The genes that were differentially expressed after BA treatment were identified via RNA sequencing. Utilizing Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes, research was done to determine the affected pathways. Molecular docking was applied to explore the interaction of BA with key pathway molecules. Experimental assays were conducted to confirm the impact of BA on these pathways and targets.
In U251 cells, BA reduced viability; inhibited colony formation, migration, and invasion; and triggered apoptosis. Through RNA sequencing, 923 up- and 1469 downregulated genes were found, with notable enrichment in the TNF, PI3K-Akt, and ferroptosis pathways. BA can stably bind to TNF and PI3K-Akt pathway molecules, especially AKT1 (binding energy = −10.2 kcal/mol). BA administration decreased the levels of phosphorylated PI3K and AKT. Moreover, BA-induced ferroptosis and HO-1 and NRF2 levels were increased. Ferrostatin-1 and zinc protoporphyrin pretreatment decreased intracellular iron and lipid peroxidation and decreased the decrease in cell viability caused by BA.
BA controls the PI3K/Akt and NRF2/HO-1 pathways, which results in glioma ferroptosis. Understanding BA's multipathway mechanism may inform its therapeutic potential in glioma treatment.
Mitochondria are key organelles that perform and coordinate various metabolic processes in the cell, and their homeostasis is essential for the maintenance of eukaryotic life. To maintain mitochondrial homeostasis and cellular health, close communication between noncoding RNAs (ncRNAs) and proteins is required. For example, there are numerous crosstalk between ncRNAs and the sirtuin (SIRT1–7) family, which is a group of nicotinamide adenine dinucleotides (NAD(+))–dependent Type III deacetylases. NcRNAs are involved in the regulation of gene expression of sirtuin family members, and deacetylation of sirtuin family members can also influence the generation of ncRNAs. This review focuses on the relationship between the two mentioned above and summarizes the impact of their interactions on mitochondrial metabolism, oxidative stress, mitochondrial apoptotic pathways, mitochondrial biogenesis, mitochondrial dynamics, and other mitochondria-related pathophysiological processes. Finally, the review also describes targeted and appropriate treatment strategies. In conclusion, we provide an overview of the ncRNA-sirtuins/mitochondria relationship that could provide a reference for related research in the mitochondrial field and help the future development of new biomedical applications in this area.
Postmenopausal osteoporosis (PMO) is mainly concerned with the imbalance of bone resorption and bone formation. Icariin (ICA) plays a vital role in bone protection. This study investigated the mechanism of ICA in PMO rats.
The rats were treated with ovariectomy (OVX) and ICA. Bone structure parameters were measured by Micro-CT. BMSCs were obtained from normal rats, OVX rats, and ICA-treated rats. BMSCs were infected with SOST overexpression lentivirus, and TWS119, an activator of Wnt pathway, was introduced for joint experiment. The binding of ERα to SOST promoter was verified. OVX/ICA rats were injected with DNA methyltransferase inhibitor 5-Aza-dC.
ICA increased bone mass and decreased bone marrow fat content in OVX rats. ICA facilitated osteogenic differentiation and repressed adipogenic differentiation of BMSCs. Overexpressing SOST antagonized the effect of ICA, whereas TWS119 rescued the effect of overexpressing SOST. ICA reduced SOST expression by attenuating the effect of ERα. Methylation of SOST inhibited ERα binding to SOST promoter. In vivo experiments confirmed that ICA improved bone mass and reduced bone marrow fat content by enhancing SOST methylation.
Overall, ICA upregulated SOST methylation and inhibited the binding of ERα to SOST promoter, thereby promoting osteogenic differentiation and repressing adipogenic differentiation of BMSCs.
The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear; previous studies revealed the underlying connection between IPF and diabetes, but there is no consensual opinion. This study is aimed at examining the association between Type 1 diabetes (T1D) and IPF using Mendelian randomization (MR).
In our two-sample MR study, we selected single nucleotide polymorphisms (SNPs) that are strongly associated with T1D in a genome-wide association study (GWAS) from IEU (dataset: ebi-a-GCST005536) and obtained their corresponding effect estimates on T1D risk in an IPF GWAS from IEU (dataset: finn-b-IPF). We conducted a multivariable Mendelian randomization (MVMR) analysis to eliminate the interference of aging.
In the outcome of inverse-variance weighted (IVW) method, T1D showed a promoting effect on IPF (odds ratio (OR): 1.132, p = 0.005). The statistics passed the MR-PRESSO test, and no outliers were observed (global test p = 0.238). MVMR study was performed, and the aging-adjusted result remains almost the same (OR = 1.132, OR_95% CI: 1.034–1.239, p = 0.007).
Our study shows a causal relation between T1D and IPF; further investigation should be conducted.
Cardiac dysfunction and adverse consequences induced by cardiac fibrosis have been well documented. However, the cardiac fibrosis pathway in chronic heart failure (CHF) remains unclear, and it is therefore necessary to conduct further research for the sake of developing more effective therapeutic strategies for CHF. Some recent studies suggest that Pericarpium Trichosanthis (PT) may help improve the progression of fibrotic diseases. To validate this possibility, we conducted an experiment to evaluate the effect of PT on cardiac fibrosis and explore the hidden mechanism. In the experiment, we induced cardiac fibrosis in rats by left anterior descending (LAD) coronary artery ligation. The findings revealed that PT reduced myocardial fibrosis and increased cardiac activity in CHF rats receiving LAD ligation. In addition, the TGF-β1 level was decreased, and the miR-29b expression was increased in CHF rats after PT treatment. Our in vitro experiment also demonstrated that PT treatment suppressed fibroblast activation and collagen synthesis in cardiac fibroblasts stimulated by TGF-β1， and at the same time decreased the TGF-β1 level and increased the miR-29b expression. We further verified that this action was correlated with the TGF-β/Smad3 signaling pathway. We also observe that miR-29b could suppress the TGF-β1 expression, and the suppression of miR-29b weakened the anti-fibrotic effect of PT. This suggests that PT could cure cardiac fibrosis and dysfunction both in vitro and in vivo via the TGF-β/Smad3 signaling pathway, while miR-29b may participate in this action.
Osteoarthritis (OA) is characterized by progressive cartilage degeneration mediated by various molecular pathways, including inflammatory and autophagic processes. SET domain-containing lysine methyltransferase 7 (SETD7), a methyltransferase, has been implicated in OA pathology. This study investigates the expression pattern of SETD7 in OA and its role in promoting interleukin-1 beta (IL-1β)-induced chondrocyte injury through modulation of autophagy and inflammation.
The expression of SETD7 in cartilage tissues from OA patients and healthy controls was quantified using quantitative reverse transcription PCR and Western blot analysis. Small interfering RNA targeting SETD7 (si-SETD7) was transfected into human articular chondrocytes (HACs) treated with IL-1β to examine its impact on cellular viability, apoptosis, inflammatory responses, and autophagy. Functional assays including Cell Counting Kit-8, flow cytometry, enzyme-linked immunosorbent assay, and commercial kits were employed to assess biochemical changes. Interaction between YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) and SETD7 was explored using RNA immunoprecipitation and co-immunoprecipitation assays.
SETD7 was overexpressed in OA cartilage compared with controls and increased further upon IL-1β treatment. Knockdown of SETD7 in IL-1β-treated HACs improved cellular viability, decreased apoptosis, and reversed the adverse effects on lactate dehydrogenase release and inflammatory markers (tumor necrosis factor-alpha and interleukin-6) while enhancing antioxidant enzymes (catalase, malondialdehyde, and superoxide dismutase). Additionally, autophagy was restored, as evidenced by changes in the levels of autophagy related 5, Beclin1, and sequestosome 1. Interfering with autophagy using chloroquine negated the protective effects of SETD7 knockdown. Furthermore, YTHDF2 was found to stabilize SETD7 mRNA, influencing its expression and enhancing IL-1β-induced chondrocyte injury.
SETD7 plays a critical role in the pathogenesis of OA by modulating chondrocyte survival, apoptosis, inflammation, and autophagy. The interaction between YTHDF2 and SETD7 exacerbates chondrocyte injury under inflammatory conditions, highlighting potential therapeutic targets for OA treatment. The YTHDF2/SETD7 axis offers a novel insight into the molecular mechanisms governing cartilage degeneration in OA.
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