Super enhancers (SEs) are a special type of enhancer with a unique shape and mechanism that allows them to regulate cellular processes by exhibiting a more significant gene transcription regulatory role than conventional enhancers. Tumorigenesis and metastasis may result from cancer cells exploiting SEs and developing a transcriptional addiction to them. Furthermore, tumor development may result from the translocation, creation, deletion, or duplication of SEs. According to reports, SEs closely control several carcinogenic chemicals and pathways. SE-targeting inhibitors can inhibit oncogene transcription and work in concert with chemotherapeutic drugs to overcome treatment resistance. In this work, we reviewed that SEs are essential players in the development of tumors, including the activation of oncogenes, the induction of tumor angiogenesis, the activation of invasion and metastasis, the control of immune checkpoint genes, cancer immune escape, cancer stem cells, and resistance to treatment. Additionally, we examined the therapeutic strategy and significant SE inhibitors that are helpful in cancer therapy in this research. The limits of SEs in malignancies, both present and prospective, have been covered last.

Four isoform peptides of the novel E3 ligase RNF220 have been identified in humans. However, all of previous studies have predominantly focused on isoform 1 (the full-length form), which consists of 566 amino acids (aa). Here, we show that a shorter isoform, which is 308 aa lacking most of the N-terminus (human isoform 4; mouse isoform 3; ΔN-RNF220), is the predominant and ubiquitously expressed variant that warrants functional investigation. Both isoform 1 and ΔN-RNF220 are expressed in the brain; however, ΔN-RNF220 is the major isoform expressed in all other tissues in mice. Consistently, H3K4me3 ChIP-seq data from ENCODE reveal that the transcription start site for ΔN-RNF220 demonstrates broader and stronger activity across human tissues than that of isoform 1. ΔN-RNF220 produces two peptides (4a and 4b) through alternative translation initiation, with isoform 4b displaying distinct subcellular localization, subnuclear structures and interaction with a nuclear protein WDR5. Notably, during embryonic stem cell differentiation into neural stem cells, isoform 1 expression increases, whereas ΔN-RNF220 expression decreases. In murine myoblasts, ΔN-RNF220 is the sole expressed isoform and is required for MyoD and myogenin expression, as well as for muscle differentiation. Our findings highlight ΔN-RNF220 as the ubiquitously and highly expressed variant, likely playing a fundamental role across tissues while exhibiting functional differences from isoform 1. These results emphasize the critical importance of ΔN-RNF220 in future studies investigating the biological functions of RNF220.

Human urine-derived stem cells (hUSCs) are a novel type of mesenchymal stem cells (MSCs) originating from the kidney, with promising potential for personalized therapies. However, it remains unclear whether hUSCs can be successfully isolated from individuals of different ages and disease states-including healthy young individuals, healthy elderly individuals, and patients with diabetic nephropathy (DN), as well as their therapeutic potential and mechanism in DN.

CD45 is the most abundant glycoprotein on the surface of all nucleated hematopoietic-lineage cells, comprising multiple isoforms generated by alternative splicing of three exons ("A", "B", "C") that are exquisitely restricted across hematopoietic development. Despite CD45's ubiquitous expression on hematopoietic cells, its function(s) remain rather obscure. Here, we report that discrete CD45 isoforms expressed uniquely by immature human hematopoietic cells are distinguished as functional glycoforms ("isoglycoforms") that bind E-selectin. Moreover, our studies indicate that "CD45RA", a marker of human acute myeloid leukemia (AML) cells, identifies a distinct isoglycoform of CD45 containing all splice exon-encoded peptides. This isoglycoform, "CD45RABC-E", is directly upregulated by AML cells and demarcates these malignant cells from mature human leukocytes and the native human hematopoietic stem cell. Further analyses revealed that treatment-resistant AML highly expresses CD45RABC-E. Our findings thus unveil heretofore unrecognized functions of CD45 and define a novel CD45 isoglycoform that delineates AML cells from life-sustaining human hematopoietic cells.

Optimal methods of alternative donor allogeneic transplant for pediatric patients with sickle cell disease (SCD) and beta thalassemia major (BTM) lacking matched related donors have remained elusive. Most studies demonstrate unacceptable rates of graft rejection, graft versus host disease, and/or organ toxicity in children. Ex vivo partial T cell depletion (pTCD) of unrelated donor peripheral stem cell (URD-PSC) grafts has the potential to facilitate durable engraftment while preventing GvHD.

Optic neuropathies significantly contribute to permanent vision loss, frequently characterized by the deterioration of retinal ganglion cells (RGCs) and axonal loss. Current therapeutic strategies remain insufficient. Induced pluripotent stem cell-derived extracellular vesicles (iPSC-EVs) have surfaced as a compelling substitute for stem cell therapies. Our study evaluates the neuroprotective effects of iPSC-EVs in a rat optic nerve crush (ONC) model. iPSC-EVs were isolated and characterized. The intravitreal (IVT) injections of iPSC-EVs or PBS were performed. RGCs survival was assessed at 7 and 14 days post-injury. Axonal regeneration was evaluated via anterograde labeling. Apoptosis of RGCs was detected using TUNEL assay. Retinal morphological changes and visual function recovery were assessed. Transcriptomic changes in the retina were analyzed by RNA sequencing to investigate potential underlying mechanisms. Additionally, Western blot was conducted to evaluate the expression levels of components in the phosphatidylinositol 3-kinases/protein kinase B (PI3K/AKT) pathway. The IVT injections of iPSC-EVs significantly improved RGCs survival and reduced neuronal apoptosis. Optical coherence tomography (OCT) revealed preservation of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness, alongside reduced optic nerve atrophy. Functional recovery was evidenced by F-VEP and axonal regeneration was detected. Mechanistically, RNA sequencing and Western blot implicated the stimulation of the PI3K/AKT pathway. Our study shows that iPSC-EVs exert significant neuroprotective and regenerative effects in a rat ONC model, underscoring their promise as a novel treatment candidate for optic neuropathies.

In this study, we investigated the effects of cytochrome P450 46A1 (CYP46A1)-overexpressing mesenchymal stem cells (MSCs) on neuroinflammation and lipid metabolism in N9 microglial cells. Secretory proteomic analysis of CYP46A1-MSCs revealed 261 upregulated and 87 downregulated proteins, with involvement in pathways related to neurodegenerative diseases and cholesterol metabolism. Compared with control MSCs, CYP46A1-MSCs significantly inhibited the lipopolysaccharide-induced decrease in cell viability, nitric oxide production, and release of pro-inflammatory factors in N9 microglial cells. Furthermore, CYP46A1-MSCs reduced lipid droplet formation and the accumulation of cholesterol and triglycerides in lipopolysaccharide-stimulated microglial cells. Lipidomics analysis revealed that the differentially expressed lipids primarily included sphingolipids, glycerolipids, sterol lipids, and glycerophospholipids. Additionally, CYP46A1-MSCs reversed the LPS-induced changes in the expression of glycerophospholipid-metabolizing enzymes, including diacylglycerol kinase γ (Dgkg), glycerol-3-phosphate acyltransferase 3 (Gpat3), phosphatidate phosphatase (Lpin1), and phospholipid phosphatase 3 (Plpp3). These findings suggest that CYP46A1-MSCs have a potent anti-inflammatory effect and can modulate lipid metabolism in microglia, highlighting their potential as a therapeutic strategy for neuroinflammatory diseases.

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives medulloblastoma leptomeningeal dissemination, whereas premedication with corticosteroids prevents both inflammation and the pro-metastatic effect of radiation. In murine model systems, inflammation in the tumor microenvironment secondary to external beam radiation is both sufficient and necessary to drive leptomeningeal metastases.

Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.

Hematopoietic stem cell transplantation is an important treatment for many benign and malignant diseases. Factors affecting the donor response to mobilization and thus hematopoietic progenitor cell yield have been investigated, but studies on donor body mass index are limited and contradictory. Our aim in our study was to investigate this situation.

SIX2-positive urine-derived renal progenitor cells (UdRPCs) were isolated from an 18-year-old Bartter syndrome type 3 (BS3) patient within a homozygous CLCNKB gene deletion. Two episomal-based plasmids expressing OCT4, SOX2, NANOG, KLF4, c-MYC and LIN28 we were able to generate an integration-free induced pluripotent stem cell line (iPSC). Pluripotency was confirmed by fluorescence-activated cell sorting analysis and immunocytochemistry for the markers-OCT4, SOX2, NANOG, TRA-1-60, TRA-1-81 and SSEA4. Embryoid body-based differentiation into the three germ layers was the conducted and confirmed by immunocytochemistry. Pluritest analysis revealed a Pearson correlation of 0,93. Short tandem repeat DNA fingerprinting and karyotype analyses were performed.

Drug resistance prominently hampers the effects of sorafenib in hepatocellular carcinoma (HCC). Epigenetics play important roles in drug resistance. However, the contributions of SET And MYND Domain Containing 2 (SMYD2) to sorafenib resistance in HCC remain unknown. This study is aimed at elucidating the role and mechanism of SMYD2 in sorafenib resistance of HCC.

B lymphocytes have been implicated in the inhibition of osteogenesis, but their role in osteoporosis (OP) remains unclear. This study investigates the association between B lymphocytes and impaired osteogenesis in OP patients and explores the underlying mechanisms.

A deeper understanding of how teriparatide exerts its anabolic effects on bone tissue may open new avenues for osteoanabolic treatment. Our study aimed to identify long non-coding RNAs and messenger RNAs (mRNAs) regulated by teriparatide. Bone marrow mesenchymal stem cells (MSCs) were treated with teriparatide during osteogenic differentiation, and long RNA sequencing was performed. We identified 7 622 differentially expressed lncRNAs in both continuous and intermittent treatment groups compared to untreated MSCs. In intermittent treatment, the most upregulated lncRNAs were VCP, EMP1, OXA1L, LPP, and SCARB2, while in continuous treatment, they were XLOC_055533, SCARB2, HNRNPC, VCP, and CALM3. The most downregulated lncRNAs in intermittent treatment were KRTAP4-11, DUBR, MEG3, DIABLO, and ABI3BP, while in continuous treatment, they were XLOC_055164, SLC2A3, COPG1, and SMTN. Among mRNAs, the most upregulated in intermittent treatment were DNAJC25-GNG10, ZBTB4, SLC2A6, TMEM189-UBE2V1, and BDP1, whereas SLC2A6, ZBTB4, MX1, BDP1, and RSAD2 were the most upregulated in continuous treatment. The most downregulated mRNAs in intermittent treatment were PIP4K2B, GFI1B, ISY1-RAB43, AC010422.5, SESN2 and ISY1-RAB43, whereas ZDBF2, KLKB1, RPS10-NUDT3, and XLOC_055092 were the most downregulated mRNAs in continuous treatment. AC008622.2, MED17, and RNF213 emerged as the most critical lncRNAs for elucidating the mechanism of intermittent teriparatide therapy, while XLOC_055533, SPG7, and HOOK3 were highlighted as the most important lncRNAs in the continuous treatment. Additionally, we identified novel lncRNAs (KRTAP4-11, CEBPZOS, and CDC42SE2) that may have a role in teriparatide effects on MSCs. Identified lncRNAs and mRNAs could serve as therapeutic targets or diagnostic markers to improve osteoanabolic treatments.

Cow urine has been utilized in traditional Indian medicine for the treatment of various ailments such as wounds, oxidative stress, and the management of various metabolic disorders with limited toxicity. However, there is a scarcity of scientific evidence confirming its exact mode of action.

Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell activity. Here, we expand on this work and demonstrate that in aged mice, (1) 15-PGDH expression and activity remain conserved in the bone marrow and spleen, suggesting it remains a viable therapeutic target in aging, (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function, (3) PGDHi-treated bone marrow enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution, and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline.

Transcriptome analyses identify neural progenitor cells in the adult human hippocampus.

Continuous adult hippocampal neurogenesis is involved in memory formation and mood regulation but is challenging to study in humans. Difficulties finding proliferating progenitor cells called into question whether and how new neurons may be generated. We analyzed the human hippocampus from birth through adulthood by single-nucleus RNA sequencing. We identified all neural progenitor cell stages in early childhood. In adults, using antibodies against the proliferation marker Ki67 and machine learning algorithms, we found proliferating neural progenitor cells. Furthermore, transcriptomic data showed that neural progenitors were localized within the dentate gyrus. The results contribute to understanding neurogenesis in adult humans.

TP53-Y220C is a recurrent hotspot mutation in cancers and leukemias. It is observed predominantly in acute myeloid leukemia (AML)/myelodysplastic syndromes among hematological malignancies and is associated with poor outcome. The mutation creates a structural pocket in the p53 protein. PC14586 (rezatapopt) is a small molecule designed to bind to this pocket and thus restore a p53-wild type (p53-WT) conformation. We demonstrate that PC14586 converts p53-Y220C into a p53-WT conformation and activates p53 transcriptional targets, but surprisingly induces limited/no apoptosis in TP53-Y220C AML. Mechanistically, MDM2 induced by PC14586-activated conformational p53-WT and the nuclear exporter XPO1 reduce the transcriptional activities of p53, which are fully restored by inhibition of MDM2 and/or XPO1. Importantly, p53-WT protein can bind to BCL-2, competing with BAX in the BH3 binding pocket of BCL-2 and also binds to BCL-xL and MCL-1. However, such binding by PC14586-activated conformational p53-WT is not detected. Pharmacological inhibition of the BCL-2/BAX interaction with venetoclax fully compensates for this deficiency, induces massive cell death in AML cells and stem/progenitor cells in vitro and prolongs survival of TP53-Y220C AML xenografts in vivo. Collectively, we identified transcription-dependent and -independent mechanisms that limit the apoptogenic activities of reactivated conformational p53-WT and suggest approaches to optimize apoptosis induction in TP53-mutant leukemia. A clinical trial of PC14586 in TP53-Y220C AML/myelodysplastic syndromes has recently been initiated (NCT06616636).

Viruses, including picornaviruses, modulate cellular metabolism to generate sufficient building blocks for virus replication and dissemination. Previously, we showed that two picornaviruses, coxsackievirus B3 (CVB3) and EMCV, remodel nucleotide metabolism during infection. Here, we investigated whether this modulation is attributable to specific viral proteins. For this, we studied the modulation of metabolism by several recombinant CVB3 and EMCV viruses in HeLa cells. Using isotope tracing metabolomics with three distinct labels, 13C6-glucose or 13C5/15N2-glutamine, we reveal that the 2A protease of CVB3 and the Leader protein of EMCV inhibit de novo nucleotide synthesis. Furthermore, we show that nucleotide metabolism is also reprogrammed by CVB3 and EMCV in human induced pluripotent stem cell-derived cardiomyocytes. Our insights are important to increase understanding of picornavirus-host interactions and may lead to novel therapeutic strategies.