NCL

心肌梗死（Myocardial infarction, MI）是一种危害生命健康的临床疾病。成年哺乳动物心肌细胞（Cardiomyocytes, CMs）再生能力有限，是目前临床治疗心肌损伤的难题。通过提高CDK6和DNA含量来促进心肌细胞周期再进入的方式虽能促进CMs再生，但由于缺乏正确的细胞分裂导致产生双核CMs。因此寻找促进细胞分裂的关键通路有望促进MI修复。 2024年6月24日，苏州大心血管病研究所的李杨欣教授团队在Theranostics期刊上发表题为“The orchestration of cell-cycle reentry and ribosome biogenesis network is critical for cardiac repair”的文章。该项研究利用Ribo-Halo、Ribo-disome等实验方法发现核仁素（Nucleolin, Ncl）调控的核糖体新生是促进心肌修复的关键环节，并结合Rb1心肌特异性敲除小鼠模型，阐明了外泌体circASXL1参与心肌修复的CDK6/Rb1/cell-cycle reentry和Ncl/Ribo-bio/cytokinesis分子网络。 由于新生乳鼠CMs具有较强的再生潜能，因此该研究通过RNA/蛋白组测序比较了年轻和衰老心脏中相关的mRNA和蛋白的表达情况，确定了Rb1和Ncl可能在心肌再生中发挥重要作用。但二者在心肌再生中发挥的具体作用并不明确。此外，他们还通过RT-qPCR锁定了环状RNA circASXL1可能对于MI发展具有重要意义，并且通过外泌体递送circASXL1有利于MI后的心肌损伤修复。 该研究首先在细胞层面沉默Rb1，发现Rb1沉默后可促进H9C2细胞和原代心肌细胞增殖。进一步构建了Rb1心脏特异性敲除小鼠，与体外实验结果不同的是，虽然Rb1敲除可以促进CMs增殖，但对于MI小鼠的长期心功能恢复并没有显著益处。 为了进一步阐明外泌体中circASXL1促进心肌修复的机制，研究人员又将目光锁定在测序结果上，测序结果表明调控核糖体新生的Ncl在衰老心脏中表达下调，并且GO分析也表明核糖体新生和细胞周期途径可能参与了心肌再生的调控。因此他们通过circASXL1功能获得/缺失策略，结合银染、Ribo-disome、EU以及Ribo-Halo等多种研究方法，证实circASXL1可通过促进核糖体新生来促进心肌细胞增殖。机制上，RIP实验表明circASXL1结合在Ncl的5'UTR，稳定Ncl的表达，以促进核糖体新生和胞质分裂，修复受损心肌。 为了更加明确外泌体递送的circASXL1调控的核糖体新生途径，该研究中还使用了小分子抑制剂CX5461抑制核糖体新生，结果表明CX5461可显著减弱外泌体的治疗作用，具体表现在核糖体新生障碍、胞质分裂被抑制以及心功能受损等方面。 总之，这项研究发现circASXL1/Rb1和circASXL1/Ncl信号通路协调CMs细胞周期再进入。并且证明脐带间充质干细胞来源的外泌体可通过递送circASXL1刺激CMs细胞周期再进入和胞质分裂，促进MI修复。这一发现有望为基于circASXL1信号网络开发MI新疗法提供理论基础。 苏州大学心血管病研究所李杨欣教授为文章的通讯作者，课题组博士后王燕丽、硕士生涂均楚和吴伟亮为文章并列第一作者。通讯作者李杨欣教授(yangxin_li@yahoo.com)在招博士后。  参考文献： Wang Y, Tu J, Wu W, Xu Y, Li Y, Pan X, Liu B, Lu T, Han Q, Zhang H, Jiao L, Zhang Y, Yu XY, Shen Z, Li Y. The orchestration of cell-cycle reentry and ribosome biogenesis network is critical for cardiac repair. Theranostics. 2024, 14(10): 3927-3944. doi:10.7150/thno.96460 原文链接:  https://www.thno.org/v14p3927.htm Pubmed链接： https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/38994017/ 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

Generating specific cell lineages from induced pluripotent stem cells and embryonic stem cells is the holy grail of regenerative medicine. Guiding iPSCs toward a target cell line has garnered much attention, but the process remains challenging. Now, researchers from Japan have discovered that an anti-nucleolin DNA aptamer, iSN04, can determine a cell’s lineage during differentiation. By demonstrating the generation of cardiomyocytes from murine pluripotent stem cells, their concept shows promise as a regenerative therapy. Generating specific cell lineages from induced pluripotent stem cells and embryonic stem cells is the holy grail of regenerative medicine. Guiding iPSCs toward a target cell line has garnered much attention, but the process remains challenging. Now, researchers from Japan have discovered that an anti-nucleolin DNA aptamer, iSN04, can determine a cell's lineage during differentiation. By demonstrating the generation of cardiomyocytes from murine pluripotent stem cells, their concept shows promise as a regenerative therapy. Self-renewal and pluripotency-the capacity to form any cell lineage-are inherent characteristics of induced pluripotent stem cells (iPSCs). Furthermore, they are highly prized in regenerative therapies targeting cardiovascular, neurological, and metabolic diseases as they are immunologically suitable for transplantation back into a donor. Unfortunately, regenerative medicine is not yet feasible outside a laboratory setting as available protocols to generate target cells are complicated and expensive. This raises a pertinent question: Can regulating the fate of stem cells in clinical settings and at scale be made more economical? A team of researchers from Shinshu University, the National Institute of Advanced Industrial Science and Technology, and the University of Shizuoka in Japan set out to address this question by leveraging nucleic acid aptamers. Aptamers are single-stranded pieces of DNA that bind to target proteins and are able to modulate signaling cascades during cell differentiation when a stem cell commits to a specific functional role or phenotype. They hold promise in regenerative medicine as they are easily modified, can be synthesized economically, and are suitable for long-term storage. The team, led by Associate Professor Tomohide Takaya from the Department of Agricultural and Life Sciences at Shinshu University, recently discovered that an anti-nucleolin aptamer, myogenetic oligodeoxynucleotide iSN04, induced myocardial differentiation in embryonic stem cells (ESCs). The study was led by Mina Ishioka, a graduate student in Dr. Takaya's laboratory, and published in The International Journal of Molecular Sciences on 21 September 2023. "We had previously found that iSN04 promoted myogenic precursor cells (myoblasts) to differentiate into skeletal muscle cells and had hypothesized that the aptamer also enhanced differentiation of pluripotent stem cells. We were intrigued by the prospect of using iSN04 to promote iPSC differentiation into cardiomyocytes as this could lead to regenerating heart tissue," says Dr. Takaya, elaborating on the team's motivation to pursue the research. Using various assays like RNA sequencing, cell staining and imaging, and molecular interaction and pathway analysis, the researchers investigated iSN04's effect on murine ESCs and iPSCs. iSN04 treatment under differentiating conditions inhibited stem cell commitment to the cardiac lineage. However, when these pluripotent stem cells were treated after experiencing differentiating conditions for five days, specific marker genes were upregulated, and the cells committed to forming beating cardiomyocytes. "Ours is the first report to confirm a DNA aptamer that allows cardiomyocytes to develop from iPSCs," explains Dr. Takaya when asked about the significance of the work. "We uncovered two mechanisms of nucleolin interference with iSN04 at play whereby early treatment inhibits cardiomyogenesis, while treatment at a later stage enhances the generation of cardiac progenitors. First, iSN04 governs the translocation of nucleolin protein between the cytoplasm, plasma membrane, and nucleus. Second, it results in the modulation of the Wnt signaling pathway that governs cell differentiation." The immunostaining experiments revealed that nucleolin was retained in the nucleoli following iSN04 treatment. Nucleolar nucleolin has a role in chromatin remodeling and gene transcription, and interestingly enough, Wnt pathway genes were differentially expressed in the RNA-seq data following iSN04 suppression. The team postulates that the iSN04-anchored nucleolin alters gene expression and Wnt signaling. Ultimately, terminal cell differentiation commits to the cardiomyocyte lineage. And how could these findings impact regenerative medicine and patients' lives in the long term? Dr. Takaya provides insights into the broader implications of their work. "We believe there is a strong case to be made for further studies evaluating DNA aptamers in regenerative medicine. Aptamers are cost-effective and open up the possibility of producing specific cells from the patient's stem cells. But it doesn't end there! Since the aptamers can regulate stem cell fate, they can serve as therapeutic agents for many conditions linked to stem cell dysfunction," he concludes.

All cash deal with Chembio Diagnostics, a US Subsidiary of the French Diagnostics Company BIOSYNEX, SA, solidifies Qualigen’s strategic priority on therapeutics CARLSBAD, Calif., July 24, 2023 (GLOBE NEWSWIRE) -- Qualigen Therapeutics, Inc. (Nasdaq: QLGN), a therapeutics company focused on developing treatments for adult and pediatric cancers with potential for Orphan Drug Designation, announces today that it has sold its FastPack® diagnostics business to Chembio Diagnostics, Inc., an American subsidiary of French diagnostics provider BIOSYNEX Group, a leader in the design and distribution of rapid tests. The all cash transaction, which closed on July 20, 2023, enables the Company to further streamline operations and enhance its focus with additional capital on its therapeutics pipeline, in particular QN-302, its small molecule G-Quadruplex (G4) selective transcription inhibitor, and its pre-clinical pan-RAS inhibitor platform. QN-302 has strong binding affinity to G4s prevalent in cancer cells and is being developed for the potential treatment of solid tumors including pancreatic cancer, for which it was granted Orphan Drug Designation in January. Michael Poirier, Qualigen's Chairman and CEO, commented, “We are proud of the legacy our FastPack® rapid immunodiagnostics system has established by providing patients and doctors with quality laboratory solutions for over two decades. However, as we have transitioned our focus to cancer therapeutics, it is appropriate that we re-align our priorities and resources. BIOSYNEX, with their proven track record in rapid diagnostics, has the expertise and resources to further expand FastPack’s footprint throughout the in vitro diagnostics (IVD) market worldwide. In the meantime, we now have the ability to strengthen our efforts towards advancing our cancer therapeutics portfolio and look forward to reporting further developments soon.” AboutQualigenTherapeutics,Inc. Qualigen Therapeutics, Inc. is a therapeutics company focused on developing treatments for adult and pediatric cancer. Our investigational QN-302 compound is a small molecule selective transcription inhibitor with strong binding affinity to G4s prevalent in cancer cells; such binding could, by stabilizing the G4s against “unwinding”, help inhibit cancer cell proliferation. The investigational compounds within Qualigen’s family of pan-RAS oncogene protein-protein interaction inhibitor small molecules are believed to inhibit or block the binding of mutated RAS genes’ proteins to their effector proteins, thereby leaving the proteins from the mutated RAS unable to cause further harm. In theory, such mechanism of action may be effective in the treatment of about one quarter of all cancers, including certain forms of pancreatic, colorectal, and lung cancers. Our investigational QN-247 compound inhibits nucleolin, a key multi-functional regulatory protein that is overexpressed in cancer cells; QN-247 may thereby be able to inhibit the cells’ proliferation. QN-247 has shown promise in preclinical studies for the treatment of acute myeloid leukemia (AML). About BIOSYNEX Founded in 2005, French laboratory BIOSYNEX is a leading healthcare diagnostics group, specializing in rapid tests, monitoring of biotherapy and molecular diagnostics. As a key player in the medicine of the future, promoting improved access to healthcare, BIOSYNEX offers innovative healthcare solutions to a large range of users, including laboratories, hospitals, doctors and the general public, to improve overall patient care. For the general public: the BIOSYNEX Pharma division, specialized in self-diagnostics and family health products. It markets a complete range of well established brands in the fields of prevention, diagnosis and natural care to a large network of pharmacies and parapharmacies in Europe. For professionals: the BIOSYNEX Diagnostic division, a technology based business positioned in growing sectors, develops and offers in vitro diagnostic medical devices such as rapid diagnostic tests (RDTs), molecular biology tests and point-of-care (POC) tests for screening, and diagnosis to laboratories, hospitals, doctors and nursing homes. Headquartered in Illkirch-Graffenstaden, Alsace, the BIOSYNEX Group employs over 500 people and has a presence in 95 countries. The Group generated sales of €196.6 million in 2022. Listed on Euronext Growth (FR0011005933 ALBIO), BIOSYNEX is eligible for the French PEA PM scheme. Forward-Looking Statements This news release contains forward-looking statements by Qualigen that involve risks and uncertainties and reflect the Company's judgment as of the date of this release. These statements include those related to the Company's prospects and strategy for development of its therapeutic drug candidates. Actual events or results may differ from the Company's expectations. For example, there can be no assurance that the Company will be able to successfully develop any drugs (including QN-302, pan-RAS and QN-247); that preclinical development of the Company's drugs (including QN-302, pan-RAS and QN-247, and the deprioritized infectious-disease drug candidate QN-165) will be completed on any projected timeline or will be successful; that any clinical trials will be approved to begin by or will proceed as contemplated by any projected timeline, or at all; that any future clinical trial data will be favorable or that such trials will confirm any improvements over other products or lack negative impacts; that any drugs will receive required regulatory approvals (or Fast Track designation or Orphan Drug status) or that they will be commercially successful; that patents will issue on the Company's owned and in-licensed patent applications; that such patents, if any, and the Company's currently owned and in-licensed patents would prevent competition; or that the Company will be able to procure or earn sufficient working capital to complete the development, testing and launch of the Company's prospective therapeutic products (including QN-302, RAS and QN-247, and QN-165). The Company's stock price could be harmed if any of the events or trends contemplated by the forward-looking statements fail to occur or is delayed or if any actual future event otherwise differs from expectations. Additional information concerning these and other risk factors affecting the Company's business can be found in the Company's prior filings with the Securities and Exchange Commission, including its most recent annual report on Form 10-K, all of which are available at . The Company disclaims any intent or obligation to update these forward-looking statements beyond the date of this news release, except as required by law. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. For more information about Qualigen Therapeutics, Inc., please visit . Contact: Investor Relations 760-530-6487 ir@qualigeninc.com Source: Qualigen Therapeutics, Inc.