bims-caglex 2025-05-25 papers

Adv Healthc Mater. 2025 May 21. e2501030

Intracellular In Situ Assembled DNA Networks Targeting Mitochondria Enable Selective Elimination of Senescent Cells and Improve Cell Viability.

Zhi-Qi Dai, Sha Lu, Zhen-Tong Shen, Qing-Nan Li, Gui-Mei Han, Jin-Ming Liu, Yan Huang, Hao Zheng, Yi Zhang, Guo Chen, Quan Chen, Yun-Xi Cui, Li-Na Zhu, De-Ming Kong.

Mitochondria play crucial roles in energy production, metabolism regulation, and cell death. Mitochondrial dysfunction is associated with many diseases, including cancers, aging, and neurodegenerative disorders. Consequently, developing methods for mitochondrial regulation and treating related diseases has garnered significant interest in biological and medical research. Here, a smart framework nucleic acid (FNA) strategy is presented for mitochondrial interference and targeted cell elimination. Our approach involves the design of tetrahedral DNA nanostructures (TDNs) modified with triphenylphosphine and single-stranded DNA sequences responding to specific nucleic acid biomarkers (e.g., microRNAs) presented in target cells. The interlinked DNA networks, formed in situ responding to specific biomarkers, enable targeting and enveloping of the mitochondria, leading to mitochondrial fragmentation and dysfunction. It is demonstrated that TDN-based FNAs targeted the cancer-associated microRNA (miR-21) may enhance the efficacy of cancer therapy by disrupting mitochondrial function, while also serving as carriers of anti-cancer drugs to reduce the side effects. Additionally, FNAs targeting the senescence-associated microRNA (miR-34a) specifically eliminate senescent cells in both cell and Caenorhabditis elegans models, thereby improving overall cell viability within mixed cell populations. This programmable and functionalized TDN-based platform opens new avenues for advancing anti-aging research and treating various diseases by achieving targeted cell elimination through mitochondrial interference.

Keywords: DNA network; framework nucleic acid; mitochondria; senescence; targeted cell elimination

DOI: https://doi.org/10.1002/adhm.202501030

Biomed J. 2025 May 20. pii: S2319-4170(25)00048-4. [Epub ahead of print] 100874

Overview: PAI-1 inhibitors and clinical applications.

Toshio Miyata.

Plasminogen activator inhibitor-1 (PAI-1) is a protein involved in the fibrinolytic system and has been reported to be involved in various pathologies such as fibrosis and inflammation. We have developed small molecule inhibitors of human PAI-1 for clinical applications. A clinical candidate compound (TM5509) was finally identified among over 1,400 derivatives of a hit compound (TM5275) searched by the X-ray crystal structure information of human PAI-1 and the in silico approach on a big virtual chemical library. From pre-clinical studies using our PAI-1 inhibitors, new therapeutic concepts for clinical applications, such as anti-cancer and anti-aging, have been conceived, some oh which have been tested in various investigator-initiated clinical trials.

DOI: https://doi.org/10.1016/j.bj.2025.100874

Front Bioeng Biotechnol. 2025 ;13 1562412

Harnessing CRISPR potential for intervertebral disc regeneration strategies.

Catarina Milheiro, Maria L Moura, Mario Amendola, Mário A Barbosa, Joana Caldeira.

Genome editing technologies, particularly CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), have broadened the possibilities of genetic research and molecular biology by enabling precise modifications of the genome, offering novel therapeutic potential for various disorders. Herein, we present an overview of traditional genome editing techniques and delve deeper into the CRISPR toolbox, with particular attention given to epigenetic and transcriptional regulation. In the context of the intervertebral disc (IVD), CRISPR offers an unprecedented approach to address the mechanisms underlying tissue degeneration, advancing the development of revolutionary therapies for Low Back Pain (LBP). As so, we showcase how to leverage CRISPR systems for IVD. This cutting-edge technology has been successfully used to improve our understanding of IVD biology through functional studies and disease modeling. Most relevant research prioritizes new targets associated with the extracellular matrix (ECM), pain sensing or inflammatory pathways. Promising CRISPR applications encompass IVD regeneration by recapitulation of a regenerative environment or by targeting important degenerative catalysts. In the future, priority should be given to fetal gene reactivation, multiple healthy gene expression enhancement and disease-associated polymorphisms' correction. Despite several challenges such as effective delivery, off-target effects, as well as ethical and safety concerns, exciting clinical trials are anticipated in the years to come, providing more effective and long-lasting solutions for IVD degeneration.

Keywords: CRISPR/Cas9; degenerative disc disease; genome editing tools; intervertebral disc; low back pain

DOI: https://doi.org/10.3389/fbioe.2025.1562412

Nat Aging. 2025 May 19.

Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis.

Chuantao Tu, Cheng Qian, Shuyu Li, De-Ying Lin, Zhi-Yang Liu, Wan-Gan Ouyang, Xin-Lei Kang, Fangyuan Chen, Shu Song, Shi-Qing Cai.

With increased age, the liver becomes more vulnerable to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Deciphering the complex interplay between aging, the emergence of senescent cells in the liver and MASH fibrosis is critical for developing treatments. Here we report an epigenetic mechanism that links liver aging to MASH fibrosis. We find that upregulation of the chromatin remodeler BAZ2B in a subpopulation of hepatocytes (HEPs) is linked to MASH pathology in patients. Genetic ablation or hepatocyte-specific knockdown of Baz2b in mice attenuates HEP senescence and MASH fibrosis by preserving peroxisome proliferator-activated receptor α (PPARα)-mediated lipid metabolism, which was impaired in both naturally aged and MASH mouse livers. Mechanistically, Baz2b downregulates the expression of genes related to the PPARα signaling pathway by directly binding their promoter regions and reducing chromatin accessibility. Thus, our study unravels the BAZ2B-PPARα-lipid metabolism axis as a link from liver aging to MASH fibrosis, suggesting that BAZ2B is a potential therapeutic target for HEP senescence and fibrosis.

DOI: https://doi.org/10.1038/s43587-025-00862-w

Adv Sci (Weinh). 2025 May 23. e01612

Inhibition and Rescue of Hyperglycemia-Induced Cellular Senescence by Mitochondrial Transfer from Enucleated Mesenchymal Stem Cell-Derived Microvesicles for Chronic Wound Healing.

Zixuan Dong, Xiaobing Liu, Shichun Li, Xiaoling Fu.

The aberrant cellular senescence in chronic wounds presents a significant barrier to healing. Mitochondrial dysfunction is critical in initiating and maintaining cellular senescence, underscoring therapeutic potential in restoring mitochondrial function by delivering healthy mitochondria to wound cells. However, approaches for delivering mitochondria to achieve optimized wound repair remain lacking. Herein, enucleated MSCs-derived microvesicles containing functional mitochondria (Mito@euMVs) via simple extrusion are developed. By controlling the size of microvesicles within a small micron-scale range, the mitochondrial encapsulation efficiency is optimized. Mito@euMVs effectively delivered mitochondria into fibroblasts and HUVECs, inhibiting and rejuvenating hyperglycemia-induced cellular senescence. To enhance the clinical applicability, soluble PVA microneedle patches for the transdermal Mito@euMVs delivery are utilized. In diabetic rats with pressure sores, the senescence-inhibiting and -rescuing properties of Mito@euMVs are further validated, along with their therapeutic efficacy, demonstrating their potential for chronic wound repair. Moreover, as a versatile delivery vehicle for mitochondria, Mito@euMVs hold promising for treating mitochondrial dysfunction and aging-related conditions.

Keywords: cellular senescence; diabetic pressure sore; enucleated mesenchymal stem cells; mitochondrial transfer

DOI: https://doi.org/10.1002/advs.202501612

J Dent. 2025 May 20. pii: S0300-5712(25)00276-3. [Epub ahead of print] 105832

Photobiomodulation for Stem Cell Modulation and Regenerative Medicine -WALT position paper 2025.

Mohadese Azarsina, Praveen Arany, Marcia Martins Marques, Heidi Abrahamse, Nima Dehghani, Saeed Azarsina, Reza Fekrazad.

This position paper reviews the various effects of combination therapy by photobiomodulation therapy (PBMT) and stem cells, on different parts of the body. The aim of this paper is to reach consensus on recommendations for the parameters of PBMT regarding its application on stem cells. A significant number of studies involving PBMT, and stem cells have been published. The advantages of this combination therapy on tissue regeneration, cell differentiation and proliferation, and healing have been reported in many studies. Due to the diverse nature of study designs used with respect to light parameters, as well as a lack of well designed, ethically approved clinical trials, clinicians may benefit from suggested guidelines for clinical application based on data obtained from previous studies. These guidelines would also help researchers in designing future studies. An in-depth review of literature on the effect of PBMT on stem cells at a molecular, cellular and tissue specific level was performed, using experts in each field of PBMT. Depending on the number of studies in each field, recommendations are presented which can suggest further studies on stem cells and PBMT. PBMT has diverse applications on stem cells. Both in-vivo and in-vitro studies represent the effectiveness of PBMT in conjunction with stem cell therapy in cell proliferation, differentiation, tissue regeneration, wound healing, angiogenesis, and treatment of different diseases. However, there is a considerable lack of clinical studies in all the reviewed fields. In each category, we attempted to recommend a PBMT protocol based on information from literature, experience, and expertise. Protocols for PBMT on stem cells were reviewed in each field of medicine, and recommendations were made for further clinical studies. Not surprising, the main wavelengths used in PBMT studies in relation to stem cells, were in the range of 630-660 nm, and 800-890 nm. However, other laser parameters are in a very wide range of difference, depending on the tissue that PBMT was applied or the aim of its application.

Keywords: Low Level Laser Therapies; Photobiomodulation Therapy; Stem Cells

DOI: https://doi.org/10.1016/j.jdent.2025.105832