Transcription factor 4 is a key mediator of oncogenesis in neuroblastoma by promoting MYC activity.

Super-enhancer-associated transcription factor networks define cell identity in neuroblastoma (NB). Dysregulation of these transcription factors contributes to the initiation and maintenance of NB by enforcing early developmental identity states. We report that the class I basic helix-loop-helix (bHLH) transcription factor 4 (TCF4; also known as E2-2) is a critical NB dependency gene that significantly contributes to these identity states through heterodimerization with cell-identity-specific bHLH transcription factors. Knockdown of TCF4 significantly induces apoptosis in vitro and inhibits tumorigenicity in vivo. We used genome-wide expression profiling, TCF4 chromatin immunoprecipitation sequencing (ChIP-seq) and TCF4 immunoprecipitation-mass spectrometry to determine the role of TCF4 in NB cells. Our results, along with recent findings in NB for the transcription factors T-box transcription factor TBX2, heart- and neural crest derivatives-expressed protein 2 (HAND2) and twist-related protein 1 (TWIST1), propose a role for TCF4 in regulating forkhead box protein M1 (FOXM1)/transcription factor E2F-driven gene regulatory networks that control cell cycle progression in cooperation with N-myc proto-oncogene protein (MYCN), TBX2, and the TCF4 dimerization partners HAND2 and TWIST1. Collectively, we showed that TCF4 promotes cell proliferation through direct transcriptional regulation of the c-MYC/MYCN oncogenic program that drives high-risk NB. Mechanistically, our data suggest the novel finding that TCF4 acts to support MYC activity by recruiting multiple factors known to regulate MYC function to sites of colocalization between critical NB transcription factors, TCF4 and MYC oncoproteins. Many of the TCF4-recruited factors are druggable, giving insight into potential therapies for high-risk NB. This study identifies a new function for class I bHLH transcription factors (e.g., TCF3, TCF4, and TCF12) that are important in cancer and development.

Mogroside V and mogrol: unveiling the neuroprotective and metabolic regulatory roles of Siraitia grosvenorii in Parkinson's disease.

Introduction: Siraitia grosvenorii (Swingle) C. Jeffrey, is an edible and traditional medicine widely used in China. Mogroside V (MGV) and mogrol (MG) are its main active ingredients, which have been found to be effective in the treatment of neurodegenerative diseases recently. However, whether they can effectively treat Parkinson's disease (PD) and their underlying mechanisms have not been sufficiently explored. In this study, we investigated the neuroprotective and metabolic regulatory effects of MGV and MG on PD. Materials and methods: Using SH-SY5Y cell models and an MPTP-induced mouse model of PD, we evaluated the compounds' efficacy in mitigating MPP+-induced neurotoxicity and ameliorating motor deficits and dopaminergic neuron loss. Employing widely targeted metabolomics and bioinformatics analysis to investigate the Metabolic imbalance rectification caused by MGV and MG treatment. The vivo experimental protocol encompassed a 14-day drug administration regimen with mice randomly allocated into six groups (n = 9) receiving distinct compound dosages including a control group, a model group, MGV-H (30 mg/kg/day), MGV-L (10 mg/kg/day), MG-H (15 mg/kg/day), and MG-L (3 mg/kg/day). Results: Our findings revealed that pre-treatment with MGV and MG significantly enhanced cell viability in SH-SY5Y cells exposed to MPP+, demonstrating a potent protective effect against neurotoxicity. In the MPTP mouse model, MGV-H, MGV-L, and MG-H significantly enhanced motor coordination as assessed by the rotarod test (p < 0.05); MGV-L and MG-H evidently inhibited dopaminergic neuronal loss in the substantia nigra pars compacta (p < 0.05). Furthermore, metabolomic analysis of the substantia nigra highlighted the restoration of metabolic balance, with MGV-L and MG-H impacting 160 differential metabolites and modulating key pathways disrupted in PD, including sphingolipid metabolism, fatty acid metabolism, and amino acid metabolism. Notably, treatment with MGV-L and MG-H led to the regulation of 106 metabolites, showing a recovery trend towards normal levels, which constitutes approximately 17.5% of the identified metabolites. Key metabolites such as n-acetyl-l-glutamate, hexadecanoic acid, and 9-octadecenal were significantly altered (p < 0.05), underscoring their broad-spectrum metabolic regulatory capacity. Conclusion: This study underscores the potential of natural compounds in developing comprehensive treatment strategies for neurodegenerative diseases, paving the way for future clinical research to validate the therapeutic efficacy of mogrosides in PD.

siRNA-loaded folic acid-modified TPGS alleviate MASH via targeting ER stress sensor XBP1 and reprogramming macrophages.

Macrophages show high plasticity and play a vital role in the progression of metabolic dysfunction-associated steatohepatitis (MASH). X-box binding protein 1 (XBP1), a key sensor of the unfolded protein response, can modulate macrophage-mediated pro-inflammatory responses in the pathogenesis of MASH. However, how XBP1 influences macrophage plasticity and promotes MASH progression remains unclear. Herein, we formulated an Xbp1 siRNA delivery system based on folic acid modified D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles (FT@XBP1) to explore the precise role of macrophage-specific Xbp1 deficiency in the progression of MASH. FT@XBP1 was specifically internalized into hepatic macrophages and subsequently inhibited the expression of spliced XBP1 both in vitro and in vivo. It promoted M1-phenotype macrophage repolarization to M2 macrophages, reduced the release of pro-inflammatory factors, and alleviated hepatic steatosis, liver injury, and fibrosis in mice with fat-, fructose- and cholesterol-rich diet-induced MASH. Mechanistically, FT@XBP1 promoted macrophage polarization toward the M2 phenotype and enhanced the release of exosomes that could inhibit the activation of hepatic stellate cells. A promising macrophage-targeted siRNA delivery system was revealed to pave a promising strategy in the treatment of MASH.

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation (HSCT) is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug (IND) application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+ HSPCs from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies towards clinical trials for treating SCD and other blood disorders.

Preoperative albumin-bilirubin score predicts short-term outcomes and long-term prognosis in colorectal cancer patients undergoing radical surgery.

BACKGROUND: The albumin-bilirubin (ALBI) score is a serum biochemical indicator of liver function and has been proven to have prognostic value in a variety of cancers. In colorectal cancer (CRC), a high ALBI score tends to be associated with poorer survival. AIM: To investigate the correlation between the preoperative ALBI score and outcomes in CRC patients who underwent radical surgery. METHODS: Patients who underwent radical CRC surgery between January 2011 and January 2020 at a single clinical center were included. The ALBI score was calculated by the formula (log10 bilirubin × 0.66) + (albumin × -0.085), and the cutoff value for grouping patients was -2.8. The short-term outcomes, overall survival (OS), and disease-free survival (DFS) were calculated. RESULTS: A total of 4025 CRC patients who underwent radical surgery were enrolled in this study, and there were 1908 patients in the low ALBI group and 2117 patients in the high ALBI group. Cox regression analysis revealed that age, tumor size, tumor stage, ALBI score, and overall complications were independent risk factors for OS; age, tumor stage, ALBI score, and overall complications were identified as independent risk factors for DFS. CONCLUSION: A high preoperative ALBI score is correlated with adverse short-term outcomes, and the ALBI score is an independent risk factor for OS and DFS in patients with CRC undergoing radical surgery.

Does one-stitch method of temporary ileostomy affect the stoma-related complications after laparoscopic low anterior resection in rectal cancer patients?

PURPOSE: This current study attempted to investigate whether one-stitch method (OM) of temporary ileostomy influenced the stoma-related complications after laparoscopic low anterior resection (LLAR). METHODS: We searched for eligible studies in four databases including PubMed, Embase, Cochrane Library, and CNKI from inception to July 20, 2023. Both surgical outcomes and stoma-related complications were compared between the OM group and the traditional method (TM) group. The Newcastle-Ottawa Scale (NOS) was adopted for quality assessment. RevMan 5.4 was conducted for data analyzing. RESULTS: Totally 590 patients from six studies were enrolled in this study (272 patients in the OM group and 318 patients in the TM group). No significant difference was found in baseline information (P > 0.05). Patients in the OM group had shorter operative time in both the primary LLAR surgery (MD = - 17.73, 95%CI = - 25.65 to - 9.80, P < 0.01) and the stoma reversal surgery (MD = - 18.70, 95%CI = - 22.48 to -14.92, P < 0.01) than patients in the TM group. There was no significant difference in intraoperative blood loss of the primary LLAR surgery (MD = - 2.92, 95%CI = - 7.15 to 1.32, P = 0.18). Moreover, patients in the OM group had fewer stoma-related complications than patients in the TM group (OR = 0.55, 95%CI = 0.38 to 0.79, P < 0.01). CONCLUSION: The OM group had shorter operation time in both the primary LLAR surgery and the stoma reversal surgery than the TM group. Moreover, the OM group had less stoma-related complications.

New Ethylated Derivatives of Sulfur- and Nitrogen-Containing Artifacts from Tenodera sinensis Egg Pod and Their Anti-Renal Fibrosis.

Three pairs of enantiomers and one achiral molecule that are new ethylated derivatives of sulfur and nitrogen-containing compounds named mantidisamides E-H (1-4), along with twenty known ones (5-24), were derived from the ethanol extract of Tenodera sinensis Saussure. The structures of these new compounds and their absolute configurations were assigned on the basis of spectroscopic analyses and computational methods. The assessment of activities in NRK-52e cells induced by TGF-ß1 demonstrated that the previously undescribed compounds 1 and 2 exhibited a significant capacity to inhibit the expression of proteins (fibronectin, collagen I, and α-SMA). Moreover, the biological activity of these compounds was found to increase with rising concentrations. Notably, compounds 1-4 should be artifacts; however, undescribed compounds 1 and 2, which possessed obvious biological activity, might be attractive for chemists and biologists due to the potential for more detailed exploration of their properties. It is worth mentioning that compounds 1 and 2 remain novel structures even in the absence of the ethoxy group.

Revealing Roles of High-Electronegativity Fluorine Atoms in Boosting Redox Potential of Layered Sodium Cathodes.

The development of high-energy-density cathode materials is regarded as the ultimate goal of alkali metal-ion batteries energy storage. However, the strategy of regulating specific capacity is limited by the theoretical capacity, and meanwhile focusing on improving capacity will lead to structural destructions. Herein, a novel perspective is proposed that tuning the electronic band structure by introducing highly electronegative fluoride atoms in NaxTMO2-yFy (0 < x < 1, 0 < y < 2) model compounds to improve redox potential for developing high-energy-density layered oxides. Highly electronegative fluoride atoms is introduced into P2-type Na0.67Fe0.5Mn0.5O2 (NFM), and the thus fluoride NFM (F-NFM) cathode achieved high redox potential (3.0 V) and high energy density (446 Wh kg-1). Proved by structural characterizations, fluorine atoms are successfully incorporated into oxygen sites in NFM lattice. Ultraviolet photoelectron spectroscopy is applied to quantitatively analyze the improved redox potential of F-NFM, which is achieved by the decreased valence band energy in electronic band structure due to the strongly electrophilic fluoride ions. Moreover, fluoride atoms can stabilize the local environment of NFM and improve its redox potential. The work provides a perspective to improve redox potential by tuning the electronic band structure in layered oxides and developing high-energy-density alkali metal-ion batteries.

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state regulatory potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Five anti-inflammatory compounds from the resins of Liquidambar orientalis.

Five undescribed compounds, including a triterpenoid (1), three phenylpropanoids [(±)-2 and 4], and an aromatic compound (3), as well as six known analogues (5-10), were isolated from the resins of Liquidambar orientalis Mill. Their structures, including absolute configurations, were determined by using spectroscopic and computational methods, and the five new compounds displayed anti-inflammatory activities in LPS-induced RAW264.7 cells.

Effect of spin-lock frequency on quantitative myocardial T1ρ mapping.

OBJECTIVES: To use T1ρ mapping to assess myocardial fibrosis and to provide a reference for future clinical application, it is necessary to understand the factors influencing T1ρ values. This study explored the influence of different spin-locking frequencies on T1ρ values under a 3.0-T MR system. METHODS: Fifty-seven healthy subjects were prospectively and consecutively included in this study, and T1ρ mapping was performed on them in 3 short-axis slices with three spin-lock frequencies at the amplitude of 300 Hz, 400 Hz, and 500 Hz, then nine T1ρ images were acquired per subject. Four T1ρ-weighted images were acquired using a spin-lock preparation pulse with varying durations (0 msec, 13.3 msec, 26.6 msec, 40 msec). T1ρ relaxation times were quantified for each slice and each myocardial segment. The results were analyzed using Student's t-test and one-way analysis of variance (ANOVA) methods. RESULTS: Mean T1ρ relaxation times were 43.5 ± 2.8 msec at 300 Hz, 44.9 ± 3.6 msec at 400 Hz, and 46.2 ± 3.1 msec at 500 Hz, showing a significant progressive increase from low to high spin-lock frequency (300 Hz vs. 400 Hz, p = 0.046; 300 Hz vs. 500 Hz, p < 0.001; 400 Hz vs. 500 Hz, p = 0.043). In addition, The T1ρ values of females were significantly higher than those of males (300 Hz, p = 0.049; 400 Hz, p = 0.01; 500 Hz, p = 0.002). CONCLUSION: In this prospective study, myocardial T1ρ values for the specific CMR setting are provided, and we found that gender and spin-lock frequency can affect the T1ρ values. CRITICAL RELEVANCE STATEMENT: T1ρ mapping could supersede late gadolinium enhancement for detection of myocardial fibrosis. Establishing reference mean values that take key technical elements into account will facilitate interpretation of data in disease states. KEY POINTS: This study established myocardial T1ρ reference values for different spin-lock frequencies. T1ρ values increased with spin-lock frequency, but numerical differences were minimal. Females had higher T1ρ values than males at all frequencies.

Use of Period Analysis to Timely Assess Five-Year Relative Survival for the Patients With Bone Cancer.

Background: While timely assessment of long-term survival for patients with bone cancer is essential for evaluation on early detection and prognosis level of treatment of bone cancer, those data are extremely scarce in China. We aimed to timely and accurately assess long-term survival for patients with bone cancer in Eastern China. Methods: Patients diagnosed with bone cancer during 2004 - 2018 from four cancer registries with high-quality data from Taizhou, Eastern China were included. Five-year relative survival (RS) of bone cancer patients was calculated by period analysis for overall and the stratification. We further predicted 5-year RS during upcoming 2019 - 2023 using a model-based period analysis and survival data during 2004 - 2018. Results: Overall, 5-year RS for patients with bone cancer during 2014 - 2018 reached 46.6%, being 40.8% for male and 51.0% for female. Five-year RS declined along with aging, decreasing from 58.9% for age < 45 years to 41.5% for age > 60 years, while 5-year RS for urban area was higher compared to rural area (59.1% vs. 44.3%). The 5-year RS during upcoming 2019 - 2023 reached 48.3%. We found a clear upward trend in 5-year RS during 2004 - 2023 for overall and the stratification by sex, age at diagnosis, and region. Conclusions: We found that, for first time in China using period analysis, most up-to-date 5-year RS for patients with bone cancer reached 46.6% during 2014 - 2018, and is projected to reach 48.3% for the period 2019 - 2023, which has important implications for timely evaluation on early detection and prognosis level of treatment for patients with bone cancer in Eastern China.

YZL-51N functions as a selective inhibitor of SIRT7 by NAD+ competition to impede DNA damage repair.

The NAD+-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited progress has been made in SIRT7 modulator discovery. Here, we applied peptide-based deacetylase platforms for SIRT7 enzymatic evaluation and successfully identified a potent SIRT7 inhibitor YZL-51N. We initially isolated bioactive YZL-51N from cockroach (Periplaneta americana) extracts and then developed the de novo synthesis of this compound. Further investigation revealed that YZL-51N impaired SIRT7 enzymatic activities through occupation of the NAD+ binding pocket. YZL-51N attenuated DNA damage repair induced by ionizing radiation (IR) in colorectal cancer cells and exhibited a synergistic anticancer effect when used in combination with etoposide. Overall, our study not only identified YZL-51N as a selective SIRT7 inhibitor from insect resources, but also confirmed its potential use in combined chemo-radiotherapy by interfering in the DNA damage repair process.

Long non-coding RNA LBX2-AS1 activates IL4R to promote glioblastoma metastasis and angiogenesis by binding to the transcription factor NFKB1.

INTRODUCTION: LncRNA LBX2-AS1 drives the development of various cancers, but the exact mechanism whereby LBX2-AS1 affects glioblastoma (GBM) progression is unaddressed. This study intended to delineate the regulatory mechanism of LBX2-AS1 in GBM metastasis and angiogenesis. MATERIAL AND METHODS: LBX2-AS1 level in GBM was assessed by bioinformatics methods. The lncRNA-transcription factor (TF)-mRNA trios were predicted using the lncMAP database. Correlation between genes was predicted by Pearson analysis. The binding relationship was predicted by JASPAR. Levels of LBX2-AS1 and its downstream genes were assayed via qRT-PCR. Changes in expressions of VEGF-A, IL4R, and epithelial-mesenchymal transition (EMT)-associated proteins were assessed through western blot. GBM cell proliferation, migration, and invasion were assayed through CCK8, colony formation, and Transwell experiments. In vitro angiogenesis capacity was evaluated via a HUVEC tube formation experiment. The regulatory relationship between various genes was verified through radioimmunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and dual-luciferase assays. RESULTS: LBX2-AS1 was elevated in GBM, and in vitro experiments demonstrated the stimulatory effect of LBX2-AS1 on GBM cell proliferation, invasion, migration, and angiogenesis. We observed that LBX2-AS1 activated IL4R expression by binding the transcription factor NFKB1, thus promoting the progression of GBM. Rescue experiments illustrated that silencing IL4R or NFKB1 reversed the impact of forced LBX2-AS1 expression on GBM cells. CONCLUSIONS: This study revealed the mechanism of the LBX2-AS1/NFKB1/IL4R axis in driving GBM metastasis and angiogenesis, which may help to improve the regulatory network of GBM malignant progression and provide potential targets for GBM treatment.

Stereochemical Control of Redox CoII/CoIII-Cages with Switchable Cotton Effects Based on Labile-Static States.

The structural dynamics of artificial assemblies, in aspects such as molecular recognition and structural transformation, provide us with a blueprint to achieve bioinspired applications. Here, we describe the assembly of redox-switchable chiral metal-organic cages Λ8/Δ8-[Pd6(CoIIL3)8]28+ and Λ8/Δ8-[Pd6(CoIIIL3)8]36+. These isomeric cages demonstrate an on-off chirality logic gate controlled by their chemical and stereostructural dynamics tunable through redox transitions between the labile CoII-state and static CoIII-state with a distinct Cotton effect. The transition between different states is enabled by a reversible redox process and chiral recognition originating in the tris-chelate Co-centers. All cages in two states are thoroughly characterized by NMR, ESI-MS, CV, CD, and X-ray crystallographic analysis, which clarify their redox-switching behaviors upon chemical reduction/oxidation. The stereochemical lability of the CoII-center endows the Λ8/Δ8-CoII-cages with efficient chiral-induction by enantiomeric guests, leading to enantiomeric isomerization to switch between Λ8/Δ8-CoII-cages, which can be stabilized by oxidation to their chemically inert forms of Λ8/Δ8-CoIII-cages. Kinetic studies reveal that the isomerization rate of the Δ8-CoIII-cage is at least an order of magnitude slower than that of the Δ8-CoII-cage even at an elevated temperature, while its activation energy is 16 kcal mol-1 higher than that of the CoII-cage.

Multipocket Cage Enables the Binding of High-Order Bulky and Drug Guests Uncovered by MS Methodology.

Achieving high guest loading and multiguest-binding capacity holds crucial significance for advancement in separation, catalysis, and drug delivery with synthetic receptors; however, it remains a challenging bottleneck in characterization of high-stoichiometry guest-binding events. Herein, we describe a large-sized coordination cage (MOC-70-Zn8Pd6) possessing 12 peripheral pockets capable of accommodating multiple guests and a high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)-based method to understand the solution host-guest chemistry. A diverse range of bulky guests, varying from drug molecules to rigid fullerenes as well as flexible host molecules of crown ethers and calixarenes, could be loaded into open pockets with high capacities. Notably, these hollow cage pockets provide multisites to capture different guests, showing heteroguest coloading behavior to capture binary, ternary, or even quaternary guests. Moreover, a pair of commercially applied drugs for the combination therapy of chronic lymphocytic leukemia (CLL) has been tested, highlighting its potential in multidrug delivery for combined treatment.

Epitaxy of Monoclinic VO2 on Large-Misfit 3m Template Enabled by a Metastable Interfacial Layer.

We report the epitaxial growth of a monoclinic VO2 thin film on the CoFe2O4(111) template, assisted by an interfacial layer of the metastable orthorhombic phase. The interface between orthorhombic VO2 and CoFe2O4 is atomically sharp without noticeable interfacial diffusion. The (010)-faceted orthorhombic VO2 layer is lattice-matched to both the CoFe2O4(111) template and the monoclinic phase, although they have different surface symmetries. The occurrence of an orthorhombic VO2 thin layer significantly lowers the in-plane misfit strains of the monoclinic VO2 epilayer, along both the [100] and [001] axes. Our first-principles calculations confirm that the low-misfit orthorhombic VO2 is preferred on CoFe2O4(111) over the large-misfit monoclinic phase, at the initial growth stage. Additionally, upon increasing the film thickness to ∼8 nm, the orthorhombic phase is no longer favored, and the bulk stable monoclinic VO2 appears to minimize the free energy of the system. Moreover, we show that the metal-to-insulator transition of our VO2 epilayer can be efficiently triggered by both the temperature and Joule self-heating effect.

Ganospirones A-G, seven undescribed spiro-meroterpenoids from Ganoderma lucidum and their biological activities.

Ganoderma lucidum, a medicinal mushroom with a long history in traditional Chinese medicine, is widely used for chronic diseases. Ganospirones A-G (1-7), seven pairs of undescribed spiro-meroterpenoids, were isolated from the fruiting bodies of G. lucidum. Their structures including absolute configurations were characterized by using NMR spectroscopic data, ECD computational and X-ray diffraction methods. The anti-inflammatory and anti-renal fibrosis activities of the meroterpenoids 1-7 were tested, and the results revealed that (-)-2 and (+)-2 could inhibit iNOS expression in lipopolysaccharide-induced RAW264.7 cells at 20 µM.

Integrin-α9 overexpression underlies the niche-independent maintenance of leukemia stem cells in acute myeloid leukemia.

Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML.