Chidamide induces cell cycle arrest via NR4A3/P21 axis upregulation to suppress relapsed and refractory acute myeloid leukemia.

(1) Currently, the survival prognosis for patients with relapsed and refractory acute myeloid leukemia (R/R AML) is extremely poor. Therefore, the exploration of novel drugs is imperative to enhance the prognosis of patients with R/R AML. The therapeutic efficacy and mechanism of Chidamide, a novel epigenetic regulatory drug, in the treatment of R/R AML remain unclear. METHODS: The mechanism of action of Chidamide has been explored in various AML cell lines through various methods such as cell apoptosis, cell cycle analysis, high-throughput transcriptome sequencing, gene silencing, and xenograft models. RESULTS: Here, we have discovered that chidamide potently induces apoptosis, G0/G1 phase arrest, and mitochondrial membrane potential depolarization in R/R AML cells, encompassing both primary cells and cell lines. Through RNA-seq analysis, we further revealed that chidamide epigenetically regulates the upregulation of differentiation-related pathways while suppressing those associated with cell replication and cell cycle progression. Notably, our screening identified NR4A3 as a key suppressor gene whose upregulation by chidamide leads to P21-dependent cell cycle arrest in the G0/G1 phase. CONCLUSIONS: We have discovered a novel epigenetic regulatory mechanism of chidamide in the treatment of relapsed and refractory acute myeloid leukemia (R/R AML).

Extraction of Uranium by a Pyrazole-Based Porous Organic Polymer.

In this work, we report a pyrazole-based porous organic polymer (namely, ECUT-POP-2) for extraction of uranium. ECUT-POP-2 affords a high uranium extraction capacity of up to 1851 mg/g, excellent selectivity, and good reusability, suggesting its superior application in treating uranium-containing wastewater and acquring nuclear fuel.

An imidazole-based covalent-organic framework enabling a super-efficiency in sunlight-driven uranium extraction from seawater.

Uranium extraction from seawater represents an effective way to solve the difficulty of the insufficient uranium supply chain. However, this route is still restricted by the low extraction efficiency of reported adsorbents. Here, we find that reversing the donor-acceptor in imidazole-based COFs (covalent-organic frameworks) would be effective for enhancing the extraction efficiency of uranium. As a result, the TI-COF is found to enable a uranium extraction efficiency up to 8.8 mg g-1 day-1 from seawater under visible light irradiation, exceeding all established adsorbents for such use, and an unprecedented uranium extraction efficiency up to 6.9 mg g-1 day-1 from seawater under natural sunlight.

Identification of drug targets for Sjögren's syndrome: multi-omics Mendelian randomization and colocalization analyses.

Background: Targeted therapy for Sjögren's syndrome (SS) has become an important focus for clinicians. Multi-omics-wide Mendelian randomization (MR) analyses have provided new ideas for identifying potential drug targets. Methods: We conducted summary-data-based Mendelian randomization (SMR) analysis to evaluate therapeutic targets associated with SS by integrating DNA methylation, gene expression and protein quantitative trait loci (mQTL, eQTL, and pQTL, respectively). Genetic associations with SS were derived from the FinnGen study (discovery) and the GWAS catalog (replication). Colocalization analyses were employed to determine whether two potentially relevant phenotypes share the same genetic factors in a given region. Moreover, to delve deeper into potential regulation among DNA methylation, gene expression, and protein abundance, we conducted MR analysis to explore the causal relationship between candidate gene methylation and expression, as well as between gene expression and protein abundance. Drug prediction and molecular docking were further employed to validate the pharmacological activity of the candidate drug targets. Results: Upon integrating the multi-omics data, we identified three genes associated with SS risk: TNFAIP3, BTN3A1, and PLAU. The methylation of cg22068371 in BTN3A1 was positively associated with protein levels, consistent with the negative effect of cg22068371 methylation on the risk of SS. Additionally, positive correlations were observed between the gene methylation of PLAU (cg04939496) and expression, as well as between expression and protein levels. This consistency elucidates the promotional effects of PLAU on SS risk at the DNA methylation, gene expression, and protein levels. At the protein level, genetically predicted TNFAIP3 (OR 2.47, 95% CI 1.56-3.92) was positively associated with SS risk, while BTN3A1 (OR 2.96E-03, 95% CI 2.63E-04-3.33E-02) was negatively associated with SS risk. Molecular docking showed stable binding for candidate drugs and target proteins. Conclusion: Our study reveals promising therapeutic targets for the treatment of SS, providing valuable insights into targeted therapy for SS. However, further validation through future experiments is warranted.

Treating ischemic stroke by improving vascular structure and promoting angiogenesis using Taohong Siwu Decoction: An integrative pharmacology strategy.

ETHNOPHARMACOLOGICAL RELEVANCE: Neovessels represent a crucial therapeutic target and strategy for repairing ischemic tissue. Taohong Siwu Decoction (THSWD) exhibits potential in promoting angiogenesis to address ischemic stroke (IS). However, its impact on neovessel structure and function, alongside the underlying molecular mechanisms, remains elusive. AIM OF THE STUDY: Our aim is to investigate the protective effects of THSWD on neovessel structure and function, as well as the associated molecular mechanisms, utilizing an integrative pharmacological approach. MATERIALS AND METHODS: We initially employed behavioral tests, 2,3,5-triphenyltetrazolium chloride (TTC) staining, Haematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), Laser Doppler flowmetry (LDF), Evans blue staining, and immunofluorescence to evaluate the protective effects of THSWD on neovascular structure and function in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Subsequently, we utilized network pharmacology, metabolomics, and experimental validation to elucidate the underlying molecular mechanisms of THSWD in enhancing neovascular structure and function. RESULT: In addition to significantly reducing neurological deficits and cerebral infarct volume, THSWD mitigated pathological damage, blood-brain barrier (BBB) leakage, and cerebral blood flow disruption. Moreover, it preserved neovascular structure and stimulated angiogenesis. THSWD demonstrated potential in ameliorating cerebral microvascular metabolic disturbances including lipoic acid metabolism, fructose and mannose metabolism, purine metabolism, and ether lipid metabolism. Consequently, it exhibited multifaceted therapeutic effects, encompassing anti-inflammatory, antioxidant, energy metabolism modulation, and antiplatelet aggregation properties. CONCLUSION: THSWD exhibited protective effects on cerebral vascular structure and function and facilitated angiogenesis by rectifying cerebral microvascular metabolic disturbances in MCAO/R rats. Furthermore, integrated pharmacology offers a promising approach for studying the intricate traditional Chinese medicine (TCM) system in IS treatment.

Long non-coding RNA small nucleolar RNA host gene 29 drives chronic myeloid leukemia progression via microRNA-483-3p/Casitas B-lineage Lymphoma axis-mediated activation of the phosphoinositide 3-kinase/Akt pathway.

The aberrant expression of the long non-coding RNA (lncRNA) Small Nucleolar RNA Host Gene 29 (SNHG29) has been associated with various human cancers. However, the role of SNHG29 in chronic myeloid leukemia (CML) remains elusive. Therefore, this study aimed to investigate the function of SNHG29 in CML and unveil its potential underlying mechanisms. Herein, peripheral blood samples from 44 CML patients and 17 healthy subjects were collected. The expressions of SNHG29, microRNA-483-3p (miR-483-3p), and Casitas B-lineage Lymphoma (CBL) were measured using quantitative polymerase chain reaction (qPCR) or Western Blot. Cell viability, apoptosis, and cell cycle progression were evaluated using the Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine incorporation, and flow cytometry, respectively. Western Blot analysis was employed to assess protein expressions related to cellular proliferation, apoptosis, and oncogenesis. RNA immunoprecipitation and dual-luciferase reporter assays were utilized to verify the interactions among SNHG29, miR-483-3p, and CBL. SNHG29 was significantly overexpressed in both blood samples of CML patients and CML cell lines. In CML, increased expression of SNHG29 was positively correlated with clinical staging, and patients with high SNHG29 expression had poorer survival outcomes. Functionally, knocking down SNHG29 effectively inhibited CML cell proliferation and promoted apoptosis. Mechanistically, SNHG29 acted as a competing endogenous RNA for miR-483-3p to modulate CBL expression, thereby activating the Phosphoinositide 3-Kinase/Akt signaling pathway and mediating CML progression. In summary, these findings reveal that SNHG29 promotes tumorigenesis in CML, offering a potential therapeutic strategy for CML treatment.

Prognostic implication and immunotherapy response prediction of a novel ubiquitination-related gene signature in liver cancer.

HCC, also known as hepatocellular carcinoma, is a frequently occurring form of cancer with an unfavorable prognosis. This research constructed a prognostic signature related to ubiquitination and investigated its correlation with the response to immunotherapy in HCC. The Molecular Signatures Database provided a compilation of genes associated with ubiquitination. A gene signature related to ubiquitination was obtained through Cox regression using the Least Absolute Shrinkage and Selection Operator method. The genetic factors CPY26B1, MCM10, SPINK4, and TRIM54 notably impacted the outcomes of HCC. The patients were divided into two groups: one group had a high risk of poor survival while the other had a low risk but a greater chance of controlling HCC progression. Both univariate and multivariate analyses using Cox regression found the risk score to be an independent predictor of HCC prognosis. Gene set enrichment analysis (GSEA) indicated enrichment in cell cycle and cancer-related microRNAs in high-risk groups. The tumor microenvironment (TME), response to immunotherapy, and effectiveness of chemotherapy medications positively correlated with the risk score. In the high-risk group, erlotinib showed higher IC50 values compared to the low-risk group which exhibited higher IC50 values for VX-11e, AKT inhibitor VIII, AT-7519, BMS345541, Bortezomib, CP466722, FMK, and JNK-9L. The results of RT-qPCR revealed that the expression of four UEGs was higher in tumor tissue as compared to normal tissue. Based on the genes that were expressed differently and associated with ubiquitination-related tumor categorization, we have developed a pattern of four genes and a strong nomogram that can predict the prognosis of HCC, which could be useful in identifying and managing HCC.

In vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment.

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drugs. It is caused by mutations in CYP4V2 gene, and about 80% of BCD patients carry mutations in exon 7 to 11. Here, we apply CRISPR/Cas9 mediated homology-independent targeted integration (HITI)-based gene editing therapy in HEK293T cells, BCD patient derived iPSCs, and humanized Cyp4v3 mouse model (h-Cyp4v3mut/mut) using two rAAV2/8 vectors via sub-retinal administration. We find that sgRNA-guided Cas9 generates double-strand cleavage on intron 6 of the CYP4V2 gene, and the HITI donor inserts the carried sequence, part of intron 6, exon 7-11, and a stop codon into the DNA break, achieving precise integration, effective transcription and translation both in vitro and in vivo. HITI-based editing restores the viability of iPSC-RPE cells from BCD patient, improves the morphology, number and metabolism of RPE and photoreceptors in h-Cyp4v3mut/mut mice. These results suggest that HITI-based editing could be a promising therapeutic strategy for those BCD patients carrying mutations in exon 7 to 11, and one injection will achieve lifelong effectiveness.

Forum: COVID-19 Dispatches.

COVID-19 pandemic is the first truly global crisis in the digital age. With death count worldwide reaching 586,000 merely 7 months after its first outbreak in China in late December 2019 and 13.6 million cases reported in 188 countries and territories as of July 2020, this ongoing pandemic has spread far beyond domain of world health problem to become an unprecedented challenge facing humanity at every level. In addition to causing social and economic disruptions on a scale unseen before, it has turned the world into a site of biopolitical agon where science and reason are forced to betray their impotence against cultish thinking in the planetary endgame depicted in so many dystopian science fictions. It is in this context that this forum offers a set of modest reflections on the current impacts incurred by the COVID-19 virus. Blending ethnographic observations with theory-driven reflections, the five authors address issues made manifest by the crisis across different regions, while keeping their sight on the sociopolitical problems plaguing our life both individually and collectively. Taken together, they provide a grounded documentary for the archive that the COVID-19 virus is making us to construct.