Recent advances in the reciprocal regulation of m6A modification with non-coding RNAs and its therapeutic application in acute myeloid leukemia.

N6-methyladenosine (m6A) is one of the most common modifications of RNA in eukaryotic cells and is involved in mRNA metabolism, including stability, translation, maturation, splicing, and export. m6A also participates in the modification of multiple types of non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, thereby affecting their metabolism and functions. Increasing evidence has revealed that m6A regulators, such as writers, erasers, and readers, perform m6A-dependent modification of ncRNAs, thus affecting cancer progression. Moreover, ncRNAs modulate m6A regulators to affect cancer development and progression. In this review, we summarize recent advances in understanding m6A modification and ncRNAs and provide insights into the interaction between m6A modification and ncRNAs in cancer. We also discuss the potential clinical applications of the mechanisms underlying the interplay between m6A modifications and ncRNAs in acute myeloid leukemia (AML). Therefore, clarifying the mutual regulation between m6A modifications and ncRNAs is of great significance to identify novel therapeutic targets for AML and has great clinical application prospects.

Minnelide exhibits antileukemic activity by targeting the Ars2/miR-190a-3p axis.

BACKGROUND: The identification of a novel and effective strategy for the clinical treatment of acute leukemia (AL) is a long-term goal. Minnelide, a water-soluble prodrug of triptolide, has recently been evaluated in phase I and II clinical trials in patients with multiple cancers and has shown promise as an antileukemic agent. However, the molecular mechanism underlying minnelide's antileukemic activity remains unclear. PURPOSE: To explore the molecular mechanisms by which minnelide exhibits antileukemic activity. METHODS: AL cells, primary human leukemia cells, and a xenograft mouse model were treated with triptolide and minnelide. The molecular mechanism was elucidated using western blotting, immunoprecipitation, flow cytometry, GSEA and liquid chromatography-mass spectrometry analysis. RESULTS: Minnelide was highly effective in inhibiting leukemogenesis and improving survival in two complementary AL mouse models. Triptolide, an active form of minnelide, causes cell cycle arrest in G1 phase and induces apoptosis in both human AL cell lines and primary AL cells. Mechanistically, we identified Ars2 as a new chemotherapeutic target of minnelide for AL treatment. We found that triptolide directly targeted Ars2, resulting in the downregulation of miR-190a-3p, which led to the disturbance of PTEN/Akt signaling and culminated in G1 cell cycle arrest and apoptosis. CONCLUSIONS: Our findings demonstrate that targeting Ars2/miR-190a-3p signaling using minnelide could represent a novel chemotherapeutic strategy for AL treatment and support the evaluation of minnelide for the treatment of AL in clinical trials.

Arenobufagin inhibits lung metastasis of colorectal cancer by targeting c-MYC/Nrf2 axis.

BACKGROUND: Colorectal cancer (CRC) is one of the commonest cancers worldwide. Metastasis is the most common cause of death in patients with CRC. Arenobufagin is an active component of bufadienolides, extracted from toad skin and parotid venom. Arenobufagin reportedly inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in various cancers. However, the mechanism through which arenobufagin inhibits CRC metastasis remains unclear. PURPOSE: This study aimed to elucidate the molecular mechanisms by which arenobufagin inhibits CRC metastasis. METHODS: Wound-healing and transwell assays were used to assess the migration and invasion of CRC cells. The expression of nuclear factor erythroid-2-related factor 2 (Nrf2) in the CRC tissues was assessed using immunohistochemistry. The protein expression levels of c-MYC and Nrf2 were detected by immunoblotting. A mouse model of lung metastasis was used to study the effects of arenobufagin on CRC lung metastasis in vivo. RESULTS: Arenobufagin observably inhibited the migration and invasion of CRC cells by downregulating c-MYC and inactivating the Nrf2 signaling pathway. Pretreatment with the Nrf2 inhibitor brusatol markedly enhanced arenobufagin-mediated inhibition of migration and invasion, whereas pretreatment with the Nrf2 agonist tert­butylhydroquinone significantly attenuated arenobufagin-mediated inhibition of migration and invasion of CRC cells. Furthermore, Nrf2 knockdown with short hairpin RNA enhanced the arenobufagin-induced inhibition of the migration and invasion of CRC cells. Importantly, c-MYC acts as an upstream modulator of Nrf2 in CRC cells. c-MYC knockdown markedly enhanced arenobufagin-mediated inhibition of the Nrf2 signaling pathway, cell migration, and invasion. Arenobufagin inhibited CRC lung metastasis in vivo. Together, these findings provide evidence that interruption of the c-MYC/Nrf2 signaling pathway is crucial for arenobufagin-inhibited cell metastasis in CRC. CONCLUSIONS: Collectively, our findings show that arenobufagin could be used as a potential anticancer agent against CRC metastasis. The arenobufagin-targeted c-MYC/Nrf2 signaling pathway may be a novel chemotherapeutic strategy for treating CRC.

The connectome-based prediction of trust propensity in older adults: A resting-state functional magnetic resonance imaging study.

A recent neuropsychoeconomic model of trust propensity argues that an individual uses economic (executive functions) and social (social cognition) rationality strategies to transform the risk of treachery (affect) into positive expectations of reciprocity, promoting trust in another person. Previous studies have shown that the trust of older adults is associated with affect and social cognition. However, little is known about the intrinsic functional connectivity correlated with trust propensity or whether trust propensity is associated with executive functions in older adults. In this study, we examined the association between trust propensity (measured by a one-shot trust game [TG]), social preference (measured by a one-shot dictator game), and executive functions (measured by a battery of neuropsychological tests). We also performed connectome-based predictive modeling (CPM) and computational lesion analysis to identify the key large-scale resting-state functional connectivity (RSFC) underlying the prediction of trust propensity. Our behavioral results showed a lower trust propensity in older adults in our study than in younger adults in a previous meta-analysis. Furthermore, trust propensity was associated with social preference, but there was no significant relationship between trust propensity and executive functions. The neuroimaging results showed that the cingulo-opercular network (CON) and the default mode network (DMN), rather than the frontoparietal network (FPN), significantly contributed to the prediction of trust propensity in older adults. Our findings suggest that older adults rely less on economic rationality (executive functions, associated with FPN) in trust games. Rather, they are likely to depend more on social rationality (social cognition, associated with social preference and DMN) to resolve the risk of treachery (affect, associated with CON) in trust dilemmas. This study contributes to a better understanding of the neural underpinnings of older adults' trust propensity.

Age-related intrinsic functional connectivity underlying emotion utilization.

Previous studies investigated the age-related positivity effect in terms of emotion perception and management, whereas little is known about whether the positivity effect is shown in emotion utilization (EU). If yes, the EU-related intrinsic functional connectivity and its age-associated alterations remain to be elucidated. In this study, we collected resting-state functional magnetic resonance imaging data from 62 healthy older adults and 72 undergraduates as well as their self-ratings of EU. By using the connectome-based predictive modeling (CPM) method, we constructed a predictive model of the positive relationship between EU self-ratings and resting-state functional connectivity. Lesion simulation analyses revealed that the medial-frontal network, default mode network, frontoparietal network, and subcortical regions played key roles in the EU-related CPM. Older subjects showed significantly higher EU self-ratings than undergraduates, which was associated with strengthened connectivity between the left dorsolateral prefrontal cortex and bilateral frontal poles, and between the left frontal pole and thalamus. A mediation analysis indicated that the age-related EU network mediated the age effect on EU self-ratings. Our findings extend previous research on the age-related "positivity effect" to the EU domain, suggesting that the positivity effect on the self-evaluation of EU is probably associated with emotion knowledge which accumulates with age.