CALR

本研究通过阐明Yaku A对兼性黑色素形成的抑制活性和机制，提出以MITF-M表达中的CREB和crtc磷酸化回路为靶点，作为预防皮肤色素沉着的基本原理。 阳光下的紫外线(UV)辐射会导致皮肤色素沉着、老化和致癌。黑色素的过量产生和异常分布是导致皮肤色素紊乱的原因，如黄褐斑、雀斑和老年性黄斑。在目前的研究中，研究者通过阐明yakuchinone A对兼性黑色素形成的抑制活性和机制，提出了靶向MITF-M表达中CREB和crtc的磷酸化回路作为抗黑色素生成的理论依据。 图片来源：https://pubmed.ncbi.nlm.nih.gov/38164184/ 近日，来自韩国忠北大学的研究者们在Int J Biol Sci.杂志上发表了题为“Targeting phosphorylation circuits on CREB and CRTCs as the strategy to prevent acquired skin hyperpigmentation”的文章，该研究表明在MITF-M的表达中靶向CREB和crtc的磷酸化回路可能是预防皮肤色素紊乱的合适策略。 cAMP反应元件结合蛋白(CREB)和CREB调控的转录共激活因子(crtc)共同参与小眼相关转录因子M亚型(MITF-M)的转录激活，而MITF-M是表皮黑色素细胞生物发生、色素沉着和黑色素小体转移的主要调节因子。 研究者采用人表皮黑素细胞、小鼠皮肤和小鼠黑色素瘤细胞，采用Western blotting、逆转录聚合酶链反应、免疫沉淀和共聚焦显微镜进行研究。 研究表：在MITF-M表达的crtc去磷酸化过程中，α-促黑素细胞激素(α-MSH)诱导的黑色素生成程序可能开启蛋白激酶a -盐诱导激酶(PKA-SIKs)的轴，而不是PKA-AMP激活的蛋白激酶(PKA-AMPK)的轴。在没有细胞外黑色素生成刺激的情况下，SIK抑制剂而不是AMPK抑制剂刺激了黑素细胞培养中的黑色素生成，其中SIK抑制剂增加了crtc的去磷酸化，但绕过了CREB的磷酸化以表达MITF-M。Yaku A可预防紫外线B (UV-B)照射下小鼠皮肤色素沉着，并抑制α-MSH或SIK抑制剂激活的黑素细胞培养物中黑色素的产生。 在机制上，Yaku A通过双重靶向抑制MITF-M的表达:1)PKA催化CREB磷酸化的上游PKA全酶的camp依赖解离，以及PKA- siks轴介导的α- msh诱导的crtc去磷酸化，以及ii) SIK抑制剂诱导的crtc去磷酸化后crtc的核输入。 Yaku A抗黑色素活性的分子机制图 图片来源：https://pubmed.ncbi.nlm.nih.gov/38164184/ 综上所述，本研究通过阐明Yaku A对兼性黑色素形成的抑制活性和机制，提出以MITF-M表达中的CREB和crtc磷酸化回路为靶点，作为预防皮肤色素沉着的基本原理。(生物谷 Bioon.com） 参考文献 Song-Hee Kim et al. Targeting phosphorylation circuits on CREB and CRTCs as the strategy to prevent acquired skin hyperpigmentation. Int J Biol Sci. 2024 Jan 1;20(1):312-330. doi: 10.7150/ijbs.86536.

本研究为理解剪接体的早期组装过程以及分支位点的识别和选择机制提供了重要的结构信息，同时也为与癌症相关的SF3B1突变的致病机制提供了新的见解。 西湖大学施一公团队在《自然结构与分子生物学》（Nature Structural and Molecular Biology）在线发表了题为“Structural Insights into Branch Site Proofreading by Human Spliceosome”的最新研究论文，报道了人源17S U2 snRNP复合物和剪接体pre-A复合物的高分辨率结构，并结合生化和功能实验，揭示了剪接体进行分支位点选择、校正的分子机理。

Moffitt’s preclinical findings strongly suggest PV-10 induces immunogenic cell death-associated immunogenicity in HPV-positive and HPV-negative HNSCC in vitro and in vivo KNOXVILLE, TN, March 07, 2024 (GLOBE NEWSWIRE) -- Provectus Biopharmaceuticals Inc. (“Provectus” or the “Company”) (OTCQB: PVCT) today announced that data from preclinical research on PV-10 (rose bengal sodium) for the treatments of human papillomavirus (“HPV”)-positive and HPV-negative head and neck squamous cell carcinoma (“HNSCC”) will be presented at the upcoming annual meeting of the American Association for Cancer Research (“AACR”), to be held April 5-10, 2024 in San Diego, California. The abstract, which was accepted for a poster presentation, is titled “PV 10 induces endoplasmic reticulum stress and autophagy, triggering immunogenic cell death and anti-tumor immunity in head and neck squamous cell carcinoma” (Abstract #6742, Topic Track: Immunology, Session: Vaccines, Antigens, and Antigen Presentation 2). The work underlying this poster presentation is part of research conducted by Christine Chung, M.D., Chair, Department of Head and Neck-Endocrine Oncology and Program Leader of Head and Neck Oncology and members of the Chung laboratory at Moffitt Cancer Center (“Moffitt”) in Tampa, Florida. According to Moffitt’s abstract, “…in vitro findings reveal that PV-10 induces cytotoxicity in both mEER and MTE-RAS cells. Notably, PV-10 promotes a significant increase in [reactive oxygen species], leading to an elevation in late apoptotic cells. Markers of immunogenic cell death (ICD), including a statistically significant increase in the release of damage-associated molecular pattern molecules HMGB1 and ATP, as well as enhanced surface expression of calreticulin, HSP-70, and HSP-90, were observed. At the molecular level, a remarkable activation of endoplasmic reticulum (ER) stress, pro-apoptotic protein, and autophagy markers were observed. Intratumoral PV-10 injection in vivo has shown significant tumor regression in both mEER and MTE-RAS tumors, and a complete response was noticed in some mice, indicating that PV-10 induces potent ICD in both mEER and MTE-RAS tumors.” About Provectus Provectus Biopharmaceuticals, Inc. is a clinical-stage biotechnology company developing immunotherapy medicines for different diseases that are based on a class of synthetic small molecule immuno-catalysts called halogenated xanthenes. Provectus’s lead HX molecule is named rose bengal sodium. Provectus’s medical science platform includes clinical development programs in oncology, dermatology, and ophthalmology; proof-of-concept in vivo development programs in oncology, hematology, full-thickness cutaneous wound healing, and canine cancers; and in vitro discovery programs in infectious diseases, tissue regeneration and repair, and proprietary targets. Information about the Company’s clinical trials can be found at the National Institutes of Health (NIH) registry, ClinicalTrials.gov. For additional information about Provectus, please visit the Company’s website at . FORWARD-LOOKING STATEMENTS: The information provided in this press release may include forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, relating to the business of Provectus and its affiliates, which are based on currently available information and current assumptions, expectations, and projections about future events and are subject to a variety of risks and uncertainties and other factors that could cause actual events or results to differ materially from those projected in the forward-looking statements. Such statements are made in reliance on the safe harbor provisions of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements are often, but not always, identified by the use of words such as “aim,” “likely,” “outlook,” “seek,” “anticipate,” “budget,” “plan,” “continue,” “estimate,” “expect,” “forecast,” “may,” “will,” “would,” “project,” “projection,” “predict,” “potential,” “targeting,” “intend,” “can,” “could,” “might,” “should,” “believe,” and similar words suggesting future outcomes or statements regarding an outlook. The safety and efficacy of Provectus’s drug agents and/or their uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated or that such agents as products will achieve any revenue levels. Due to the risks, uncertainties, and assumptions inherent in forward-looking statements, readers should not place undue reliance on these forward-looking statements. The forward-looking statements contained in this press release are made as of the date hereof or as of the date specifically specified herein, and the Company undertakes no obligation to update or revise any forward-looking statements, whether because of new information, future events, or otherwise, except in accordance with applicable securities laws. The forward-looking statements are expressly qualified by this cautionary statement. Risks, uncertainties, and assumptions include those discussed in the Company’s filings with the Securities and Exchange Commission, including those described in Item 1A of: The Company’s Annual Report on Form 10-K for the period ended December 31, 2022, and Provectus’s Quarterly Report on Form 10-Q for the period ended September 30, 2023. ##### Contact: Provectus Biopharmaceuticals, Inc. Heather Raines, CPA Chief Financial Officer Phone: (866) 594-5999