bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–09–22
fifty-four papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Reversing Pdgfrβ signaling restores metabolically active beige adipocytes by alleviating ILC2 suppression in aged and obese mice.
  2. Lipid remodeling in context of cellular senescence.
  3. Senoinflammation as the underlying mechanism of aging and its modulation by calorie restriction.
  4. Elimination of physiological senescent cutaneous cells in a novel p16-dependent senolytic mouse model impacts lipid metabolism in skin aging.
  5. Resistance training suppresses accumulation of senescent fibro-adipogenic progenitors and senescence-associated secretory phenotype in aging rat skeletal muscle.
  6. Molecular Mechanisms of Healthy Aging: The Role of Caloric Restriction, Intermittent Fasting, Mediterranean Diet, and Ketogenic Diet-A Scoping Review.
  7. Calorie restriction and rapamycin distinctly restore non-canonical ORF translation in the muscles of aging mice.
  8. Uncertainty quantification in epigenetic clocks via conformalized quantile regression.
  9. The genetic advantage of healthy centenarians: unraveling the central role of NLRP3 in exceptional healthspan.
  10. Simple and highly specific targeting of resident microglia with adeno-associated virus.
  11. Dose-response relationship of dietary Omega-3 fatty acids on slowing phenotypic age acceleration: a cross-sectional study.
  12. A cellular identity crisis? Plasticity changes during aging and rejuvenation.
  13. Age-Related Decline in Pancreas Regeneration Is Associated With an Increased Proinflammatory Response to Injury.
  14. α-Klotho: the hidden link between dietary inflammatory index and accelerated ageing.
  15. Metformin acts on miR-181a-5p/PAI-1 axis in stem cells providing new strategies for improving age-related osteogenic differentiation decline.
  16. Can stable introns and noncoding RNAs be harnessed to improve health through activation of mitohormesis?
  17. Troxerutin Delays Skin Keratinocyte Senescence Induced by Ionizing Radiation Both In Vitro and In Vivo.
  18. Multifaceted roles of SUMO in DNA metabolism.
  19. Association between plant and animal protein and biological aging: findings from the UK Biobank.
  20. Role of Agrin in tissue repair and regeneration: From mechanisms to therapeutic opportunities (Review).
  21. Jingle Cell Rock: Steering Cellular Activity With Low-Intensity Pulsed Ultrasound (LIPUS) to Engineer Functional Tissues in Regenerative Medicine.
  22. Compact RNA editors with natural miniature Cas13j nucleases.
  23. The role of mitofusin 2 in regulating endothelial cell senescence: Implications for vascular aging.
  24. Characterization of a natural model of adult mice with different rate of aging.
  25. Genome-Wide Mapping of RNA-Protein Associations via Sequencing.
  26. Aneuploidy of Specific Chromosomes is Beneficial to Cells Lacking Spindle Checkpoint Protein Bub3.
  27. Photobiomodulation ameliorates ovarian aging by alleviating oxidative stress and inflammation damage and improving mitochondrial function.
  28. Extended replicative lifespan of primary resting T cells by CRISPR/dCas9-based epigenetic modifiers and transcriptional activators.
  29. Exploring the vitamin biosynthesis landscape of the human gut microbiota.
  30. A comprehensive review on physiological and biological activities of carnosine: turning from preclinical facts to potential clinical applications.
  31. Increased DNA damage of adipose tissue-derived mesenchymal stem cells under inflammatory conditions.
  32. CASIN exerts anti-aging effects through RPL4 on the skin of naturally aging mice.
  33. High-Intensity Interval Training Mitigates Sarcopenia and Suppresses the Myoblast Senescence Regulator EEF1E1.
  34. Tailoring biomaterials for skin anti-aging.
  35. IGFBP2 Functions as an Endogenous Protector against Hepatic Steatosis via Suppression of the EGFR-STAT3 Pathway.
  36. NucleoCraft: The Art of Stimuli-Responsive Precision in DNA and RNA Bioengineering.
  37. Iron regulatory protein 2 facilitates ferritinophagy and DNA damage/repair through guiding ATG9A trafficking.
  38. Inflammasome activity regulation by PUFA metabolites.
  39. Targeting hepatic macrophages for non-alcoholic fatty liver disease therapy.
  40. Dietary omega-3 intake and cognitive function in older adults.
  41. iPLA2β loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy.
  42. Small molecules help misplaced proteins hitchhike around cells.
  43. Oleanolic acid improves 5-fluorouracil-induced intestinal damage and inflammation by alleviating intestinal senescence.
  44. A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study.
  45. Effects of Different Exercises Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis.
  46. A point-of-research decision in synovial tissue engineering: Mesenchymal stromal cells, tissue derived fibroblast or CTGF-mediated mesenchymal-to-fibroblast transition.
  47. EphA4 Targeting Peptide-Conjugated Extracellular Vesicles Rejuvenates Adult Neural Stem Cells and Exerts Therapeutic Benefits in Aging Rats.
  48. The production, function, and clinical applications of IL-33 in type 2 inflammation-related respiratory diseases.
  49. An anti-neoplastic tale of metformin through its transport.
  50. Regulation of TGF-β1-induced fibroblast differentiation of human periodontal ligament stem cells through the mutually antagonistic action of ectonucleotide pyrophosphatase/phosphodiesterase 1 and 2.
  51. New method to induce neurotrophin gene expression in human adipose-derived stem cells in vitro.
  52. Freeze-dried porous collagen scaffolds for the repair of volumetric muscle loss injuries.
  53. RNA-Binding Small Molecules in Drug Discovery and Delivery: An Overview from Fundamentals.
  54. Machine learning-assisted rapid determination for traditional Chinese Medicine Constitution.
  1. Mol Metab. 2024 Sep 13. pii: S2212-8778(24)00159-5. [Epub ahead of print] 102028
    Reversing Pdgfrβ signaling restores metabolically active beige adipocytes by alleviating ILC2 suppression in aged and obese mice.
    Abigail M Benvie, Daniel C Berry.
       OBJECTIVE: Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline.
    METHODS: We employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity.
    RESULTS: Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism.
    CONCLUSIONS: This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.
    Keywords:  Aging; Beige fat; Immune cell; Obesity; Pdgfrb; Thermogenesis
    DOI:  https://doi.org/10.1016/j.molmet.2024.102028
  2. Biochimie. 2024 Sep 17. pii: S0300-9084(24)00213-X. [Epub ahead of print]
    Lipid remodeling in context of cellular senescence.
    Khaled Tighanimine.
      Cellular senescence is a response that irreversibly arrests stressed cells thus providing a potent tumor suppressor mechanism. In parallel, senescent cells exhibit an immunogenic secretome called SASP (senescence-associated secretory phenotype) that impairs tissue homeostasis and is involved in numerous age-related diseases. Senescence establishment is achieved through the unfolding of a profound transcriptional reprogramming together with morphological changes. These alterations are accompanied by important metabolic adaptations characterized by biosynthetic pathways reshuffling and lipid remodeling. In this mini-review we highlight the intricate links between lipid metabolism and the senescence program and we discuss the potential interventions on lipid pathways that can alleviate the senescence burden.
    Keywords:  SASP; Senescence; cell cycle; lipids
    DOI:  https://doi.org/10.1016/j.biochi.2024.09.003
  3. Ageing Res Rev. 2024 Sep 14. pii: S1568-1637(24)00321-0. [Epub ahead of print]101 102503
    Senoinflammation as the underlying mechanism of aging and its modulation by calorie restriction.
    Sang Gyun Noh, Hyun Woo Kim, Seungwoo Kim, Ki Wung Chung, Young-Suk Jung, Jeong-Hyun Yoon, Byung Pal Yu, Jaewon Lee, Hae Young Chung.
      Senoinflammation is characterized by an unresolved low-grade inflammatory process that affects multiple organs and systemic functions. This review begins with a brief overview of the fundamental concepts and frameworks of senoinflammation. It is widely involved in the aging of various organs and ultimately leads to progressive systemic degeneration. Senoinflammation underlying age-related inflammation, is causally related to metabolic dysregulation and the formation of senescence-associated secretory phenotype (SASP) during aging and age-related diseases. This review discusses the biochemical evidence and molecular biology data supporting the concept of senoinflammation and its regulatory processes, highlighting the anti-aging and anti-inflammatory effects of calorie restriction (CR). Experimental data from CR studies demonstrated effective suppression of various pro-inflammatory cytokines and chemokines, lipid accumulation, and SASP during aging. In conclusion, senoinflammation represents the basic mechanism that creates a microenvironment conducive to aging and age-related diseases. Furthermore, it serves as a potential therapeutic target for mitigating aging and age-related diseases.
    Keywords:  Age-related diseases; Aging; Calorie restriction; Metabolic dysregulation; SASP; Senoinflammation
    DOI:  https://doi.org/10.1016/j.arr.2024.102503
  4. Genes Cells. 2024 Sep 16.
    Elimination of physiological senescent cutaneous cells in a novel p16-dependent senolytic mouse model impacts lipid metabolism in skin aging.
    Yuma Sugiyama, Yoichiro Kawabe, Tanenobu Harada, Yu Aoki, Keiko Tsuji, Daijiro Sugiyama, Mitsuo Maruyama.
      The evidence of the correlation between cellular senescence and aging has increased in research with animal models. These models have been intentionally generated to target and regulate cellular senescent cells with the promoter activity of p16Ink4a or p19Arf, genes that are highly expressed in aging cells. However, the senolytic efficiency in various organs and cells from these models represents unexpected variation and diversity in some cases. We have generated a novel knock-in model, p16tdT-hDTR mice, which possess tdTomato and human diphtheria toxin receptor (hDTR) downstream of Cdkn2a, an endogenous p16Ink4a gene. We successfully demonstrated that p16-derived tdTomato and hDTR expressions are observed in these mouse embryo fibroblasts and following treatment with diphtheria toxin (DT) eliminates those cells. Furthermore, we demonstrated the efficacy of eliminating p16-positive cells in vivo, and also observed a tendency to decrease their cutaneous SA-β-gal activity after subcutaneous DT injection into p16tdT-hDTR mice. In particular, comprehensive gene expression analysis in skin revealed that upregulated genes related to lipid metabolisms with aging exhibited remarkable expressions under the senolysis. These results clearly unveiled p16-positive senescent cells contribute to age-related changes in skin.
    Keywords:  cellular senescence; lipid metabolism; p16ink4a; senolytic mouse model; skin aging
    DOI:  https://doi.org/10.1111/gtc.13163
  5. Geroscience. 2024 Sep 19.
    Resistance training suppresses accumulation of senescent fibro-adipogenic progenitors and senescence-associated secretory phenotype in aging rat skeletal muscle.
    Yung-Li Hung, Ayami Sato, Yuka Takino, Akihito Ishigami, Shuichi Machida.
      Accumulation of senescent cells in tissues contributes to multiple aging-related pathologies. Senescent fibro-adipogenic progenitors (FAPs) contribute to aging-related muscle atrophy. Resistance training can help to maintain skeletal muscle mass, improve mobility, and reduce certain health risks commonly associated with aging. We investigated, using rat model, the impact of resistance training on FAPs in aging skeletal muscle, which remains unclear. Twenty-two-month-old female rats were divided into sedentary and training groups. The training group rodents were trained to climb a ladder while bearing a load for 20 training sessions over 2 months, after which, the flexor hallucis longus muscles were collected and analyzed. Senescent cells were identified using a senescence-associated β-galactosidase stain and p21 immunohistochemistry (IHC), and FAPs were identified using platelet-derived growth factor receptor alpha IHC. The results indicate that resistance training in rats prevented aging-associated skeletal muscle atrophy and suppressed M2 polarization of macrophages. The number of senescent cells was significantly reduced in the 24-month-old training group, with most of them being FAPs. Conversely, the number of senescent FAPs increased significantly in the 24-month-old sedentary group compared with that in the 18-month-old sedentary group. The number of senescent FAPs in the 24-month-old training group decreased significantly. Resistance training also suppressed the senescence-associated secretory phenotype (SASP). The killer T cell-specific marker, CD8α, was elevated in the skeletal muscles of the aging rats following resistance training, indicating upregulation of recognition and elimination of senescent cells. Overall, resistance training suppressed the accumulation of senescent FAPs and acquisition of SASP in aging skeletal muscles.
    Keywords:  Fibro-adipogenic progenitors; Resistance training; Sarcopenia; Senescent cells
    DOI:  https://doi.org/10.1007/s11357-024-01338-2
  6. Nutrients. 2024 Aug 28. pii: 2878. [Epub ahead of print]16(17):
    Molecular Mechanisms of Healthy Aging: The Role of Caloric Restriction, Intermittent Fasting, Mediterranean Diet, and Ketogenic Diet-A Scoping Review.
    Roxana Surugiu, Mihaela Adela Iancu, Ștefănița Bianca Vintilescu, Mioara Desdemona Stepan, Daiana Burdusel, Amelia Valentina Genunche-Dumitrescu, Carmen-Adriana Dogaru, Gheorghe Gindrovel Dumitra.
      As the population ages, promoting healthy aging through targeted interventions becomes increasingly crucial. Growing evidence suggests that dietary interventions can significantly impact this process by modulating fundamental molecular pathways. This review focuses on the potential of targeted dietary strategies in promoting healthy aging and the mechanisms by which specific nutrients and dietary patterns influence key pathways involved in cellular repair, inflammation, and metabolic regulation. Caloric restriction, intermittent fasting, the Mediterranean diet, as well as the ketogenic diet showed promising effects on promoting healthy aging, possibly by modulating mTORC1 AMPK, an insulin signaling pathway. By understanding the intricate interplay between diet and molecular pathways, we can develop personalized dietary strategies that not only prevent age-related diseases, but also promote overall health and well-being throughout the aging process.
    Keywords:  caloric restriction; dietary interventions; healthy aging; intermittent fasting; ketogenic diet; longevity; mediterranean diet
    DOI:  https://doi.org/10.3390/nu16172878
  7. NPJ Regen Med. 2024 Sep 19. 9(1): 23
    Calorie restriction and rapamycin distinctly restore non-canonical ORF translation in the muscles of aging mice.
    Nitish Mittal, Meric Ataman, Lionel Tintignac, Daniel J Ham, Lena Jörin, Alexander Schmidt, Michael Sinnreich, Markus A Ruegg, Mihaela Zavolan.
      Loss of protein homeostasis is one of the hallmarks of aging. As such, interventions that restore proteostasis should slow down the aging process and improve healthspan. Two of the most broadly used anti-aging interventions that are effective in organisms from yeast to mammals are calorie restriction (CR) and rapamycin (RM) treatment. To identify the regulatory mechanisms by which these interventions improve the protein homeostasis, we carried out ribosome footprinting in the muscle of mice aged under standard conditions, or under long-term treatment with CR or RM. We found that the treatments distinctly impact the non-canonical translation, RM primarily remodeling the translation of upstream open reading frames (uORFs), while CR restores stop codon readthrough and the translation of downstream ORFs. Proteomics analysis revealed the expression of numerous non-canonical ORFs at the protein level. The corresponding peptides may provide entry points for therapies aiming to maintain muscle function and extend health span.
    DOI:  https://doi.org/10.1038/s41536-024-00369-9
  8. medRxiv. 2024 Sep 06. pii: 2024.09.06.24313192. [Epub ahead of print]
    Uncertainty quantification in epigenetic clocks via conformalized quantile regression.
    Yanping Li, Jaclyn M Goodrich, Karen E Peterson, Peter X-K Song, Lan Luo.
      DNA methylation (DNAm) is a chemical modification of DNA that can be influenced by various factors, including age, environment, and lifestyle. An epigenetic clock is a predictive tool that measures biological age based on DNAm levels. It can provide insights into an individual's biological age, which may differ from their chronological age. This difference, known as the epigenetic age acceleration, may indicate the state of one's health and risk for age-related diseases. Moreover, epigenetic clocks are used in studies of aging to assess the effectiveness of anti-aging interventions and to understand the underlying mechanisms of aging and disease. Various epigenetic clocks have been developed using samples from different populations, tissues, and cell types, typically by training high-dimensional linear regression models with an elastic net penalty. While these models can predict mean biological age with high precision, there is a lack of uncertainty quantification which is important for interpreting the precision of age estimations and for clinical decision-making. To understand the distribution of a biological age clock beyond its mean, we propose a general pipeline for training epigenetic clocks, based on an integration of high-dimensional quantile regression and conformal prediction, to effectively reveal population heterogeneity and construct prediction intervals. Our approach produces adaptive prediction intervals not only achieving nominal coverage but also accounting for the inherent variability across individuals. By using the data collected from 728 blood samples in 11 DNAm datasets from children, we find that our quantile regression-based prediction intervals are narrower than those derived from conventional mean regression-based epigenetic clocks. This observation demonstrates an improved statistical efficiency over the existing pipeline for training epigenetic clocks. In addition, the resulting intervals have a synchronized varying pattern to age acceleration, effectively revealing cellular evolutionary heterogeneity in age patterns in different developmental stages during individual childhoods and adolescent cohort. Our findings suggest that conformalized high-dimensional quantile regression can produce valid prediction intervals and uncover underlying population heterogeneity. Although our methodology focuses on the distribution of aging in children, it is applicable to a broader range of populations to improve understanding of epigenetic age beyond the mean. This inference-based toolbox could provide valuable insights for future applications of epigenetic interventions for age-related diseases.
    DOI:  https://doi.org/10.1101/2024.09.06.24313192
  9. Front Aging. 2024 ;5 1452453
    The genetic advantage of healthy centenarians: unraveling the central role of NLRP3 in exceptional healthspan.
    Stef F Verlinden.
      Despite extensive research into extending human healthspan (HS) and compressing morbidity, the mechanisms underlying aging remain elusive. However, a better understanding of the genetic advantages responsible for the exceptional HS of healthy centenarians (HC), who live in good physical and mental health for one hundred or more years, could lead to innovative health-extending strategies. This review explores the role of NLRP3, a critical component of innate immunity that significantly impacts aging. It is activated by pathogen-associated signals and self-derived signals that increase with age, leading to low-grade inflammation implicated in age-related diseases. Furthermore, NLRP3 functions upstream in several molecular aging pathways, regulates cellular senescence, and may underlie the robust health observed in HC. By targeting NLRP3, mice exhibit a phenotype akin to that of HC, the HS of monkeys is extended, and aging symptoms are reversed in humans. Thus, targeting NLRP3 could offer a promising approach to extend HS. Additionally, a paradigm shift is proposed. Given that the HS of the broader population is 30 years shorter than that of HC, it is postulated that they suffer from a form of accelerated aging. The term 'auto-aging' is suggested to describe accelerated aging driven by NLRP3.
    Keywords:  NLRP3; accelerated aging; aging; auto-aging; health extension; healthy centenarians; senescence
    DOI:  https://doi.org/10.3389/fragi.2024.1452453
  10. iScience. 2024 Sep 20. 27(9): 110706
    Simple and highly specific targeting of resident microglia with adeno-associated virus.
    Carolina Serrano, Sergio Cananzi, Tianjin Shen, Lei-Lei Wang, Chun-Li Zhang.
      Microglia, as the immune cells of the central nervous system (CNS), play dynamic roles in both healthy and diseased conditions. The ability to genetically target microglia using viruses is crucial for understanding their functions and advancing microglia-based treatments. We here show that resident microglia can be simply and specifically targeted using adeno-associated virus (AAV) vectors containing a 466-bp DNA fragment from the human IBA1 (hIBA1) promoter. This targeting approach is applicable to both resting and reactive microglia. When combining the short hIBA1 promoter with the target sequence of miR124, up to 98% of transduced cells are identified as microglia. Such a simple and highly specific microglia-targeting strategy may be further optimized for research and therapeutics.
    Keywords:  Genetics; Immunology; Molecular Genetics
    DOI:  https://doi.org/10.1016/j.isci.2024.110706
  11. Front Nutr. 2024 ;11 1424156
    Dose-response relationship of dietary Omega-3 fatty acids on slowing phenotypic age acceleration: a cross-sectional study.
    Dongzhe Wu, Yishuai Jia, Yujia Liu, Mingyu Shang.
       Purpose: This study investigates the association between dietary Omega-3 fatty acid intake and accelerated phenotypic aging, referred to as PhenoAgeAccel. PhenoAgeAccel is defined as the difference between phenotypic biological age, calculated using blood biochemical markers, and chronological age. This study assesses the potential of Omega-3 intake to slow biological aging and its implications for public health.
    Methods: Utilizing data from the NHANES from 1999 to 2018, this cross-sectional study included 20,337 adult participants. Through a nationally representative sample combined with comprehensive phenotypic age calculation methods, a cross-sectional analysis of Omega-3 fatty acid intake and accelerated phenotypic aging was conducted. Weighted generalized linear regression models and restricted cubic spline analyses were applied to explore the potential non-linear relationships between them. Threshold effects were further clarified through piecewise regression models, and the impact of different demographic and health characteristics was evaluated through interaction effect tests.
    Results: After adjusting for various potential confounding factors, a significant negative correlation was found between Omega-3 fatty acid intake and PhenoAgeAccel (β = -0.071; 95% CI: -0.119, -0.024; p = 0.004), indicating that an increase in Omega-3 intake is associated with a slowdown in PhenoAgeAccel. Specifically, for each unit increase in Omega-3 intake, the accelerated phenotypic aging decreased by an average of 0.071 units, revealing a significant linear negative correlation between Omega-3 intake and PhenoAgeAccel. Moreover, threshold effect analysis identified an Omega-3 fatty acid intake threshold (1.103 grams/day), beyond which the impact of Omega-3 intake on accelerated phenotypic aging tends to stabilize. Additionally, factors such as gender, age, race, and hypertension may influence the relationship between Omega-3 intake and PhenoAgeAccel, suggesting individual dietary guidance needs in different populations.
    Conclusion: This study highlights the potential role of dietary Omega-3 fatty acids in regulating PhenoAgeAccel and supports the strategy of delaying the aging process through dietary interventions to increase Omega-3 intake. The findings of this study contributes to the development of precise nutritional intervention strategies for different populations to optimize healthy longevity.
    Keywords:  Omega-3; aging; nutritional health; phenotypic age; phenotypic age acceleration
    DOI:  https://doi.org/10.3389/fnut.2024.1424156
  12. Genes Dev. 2024 Sep 18.
    A cellular identity crisis? Plasticity changes during aging and rejuvenation.
    Rebecca Gorelov, Konrad Hochedlinger.
      Cellular plasticity in adult multicellular organisms is a protective mechanism that allows certain tissues to regenerate in response to injury. Considering that aging involves exposure to repeated injuries over a lifetime, it is conceivable that cell identity itself is more malleable-and potentially erroneous-with age. In this review, we summarize and critically discuss the available evidence that cells undergo age-related shifts in identity, with an emphasis on those that contribute to age-associated pathologies, including neurodegeneration and cancer. Specifically, we focus on reported instances of programs associated with dedifferentiation, biased differentiation, acquisition of features from alternative lineages, and entry into a preneoplastic state. As some of the most promising approaches to rejuvenate cells reportedly also elicit transient changes to cell identity, we further discuss whether cell state change and rejuvenation can be uncoupled to yield more tractable therapeutic strategies.
    Keywords:  aging; cellular plasticity; epigenetics; rejuvenation; reprogramming; stem cells
    DOI:  https://doi.org/10.1101/gad.351728.124
  13. Gastro Hep Adv. 2024 ;3(7): 973-985
    Age-Related Decline in Pancreas Regeneration Is Associated With an Increased Proinflammatory Response to Injury.
    Kristina Høj, Jonathan Baldan, Philip Allan Seymour, Charlotte Vestrup Rift, Jane Preuss Hasselby, Albin Sandelin, Luis Arnes.
       Background and Aims: The regenerative capacity of the pancreas diminishes with age. Understanding acinar cell responses to injury and the resolution of regenerative processes is crucial for tissue homeostasis. However, knowledge about the impact of aging on these processes remains limited.
    Methods: To investigate the influence of aging on pancreas regeneration, we established a cohort of young (7-14 weeks) and old (18 months) C57bl/6 mice. Experimental pancreatitis was induced using caerulein, and pancreas samples were collected at various time points after induction, covering acute damage response, inflammation, peak proliferation, and inflammation resolution. Our analysis involved immunohistochemistry, quantitative imaging, and gene expression analyses.
    Results: Our study revealed a significant decline in the regenerative capacity of the pancreas in old mice. Despite similar morphology and transcriptional profiles between the pancreas of young and old mice under homeostasis, the aged pancreas is primed to generate an exacerbated proinflammatory reaction in response to injury. Specifically, we observed notable upregulation of Junb expression in acinar cells and aberrant myofibroblast activation in the aged pancreas.
    Conclusion: The response of acinar cells to injury in the pancreas of aged mice is characterized by an increased susceptibility to inflammation and stromal reactions. Our findings uncover a pre-existing proinflammatory state in aged acinar cells, offering insights into potential strategies to prevent the onset of pancreatic insufficiency and the development of inflammatory conditions. These insights hold implications for preventing conditions such as chronic pancreatitis and pancreatic ductal adenocarcinoma.
    Keywords:  ADM; Aging; Junb; Plasticity
    DOI:  https://doi.org/10.1016/j.gastha.2024.07.002
  14. Br J Nutr. 2024 Sep 20. 1-7
    α-Klotho: the hidden link between dietary inflammatory index and accelerated ageing.
    Ruiqiang Li, Baijing Zhou, Xueqing Deng, Wenbo Tian, Yingyue Huang, Jiao Wang, Lin Xu.
      Recent studies suggest an association between greater dietary inflammatory index (DII) and higher biological ageing. As α-Klotho has been considered as a longevity protein, we examined whether α-Klotho plays a role in the association between DII and ageing. We included 3054 participants from the National Health and Nutrition Examination Survey. The associations of DII with biological and phenotypic age were assessed by multivariable linear regression, and the mediating role of α-Klotho was evaluated by mediation analyses. Participants' mean age was 58·0 years (sd 11·0), with a median DII score of 1·85 and interquartile range from 0·44 to 2·79. After adjusting for age, sex, race/ethnicity, BMI, education, marital status, poverty income ratio, serum cotinine, alcohol, physical activity, a higher DII was associated with both older biological age and phenotypic age, with per DII score increment being associated with a 1·01-year increase in biological age (1·01 (95 % CI: 1·005, 1·02)) and 1·01-year increase in phenotypic age (1·01 (1·001, 1·02)). Negative associations of DII with α-Klotho (β = -1·01 pg/ml, 95 % CI: -1·02, -1·006) and α-Klotho with biological age (β= -1·07 years, 95 % CI: -1·13, -1·02) and phenotypic age (β= -1·03 years, 95 % CI: -1·05, -1·01) were found. Furthermore, α-Klotho mediated 10·13 % (P < 0·001) and 9·61 % (P < 0·001) of the association of DII with biological and phenotypic age, respectively. Higher DII was associated with older biological and phenotypic age, and the potential detrimental effects could be partly mediated through α-Klotho.
    Keywords:  Biological age; Dietary inflammatory index; Phenotypic age; α-Klotho
    DOI:  https://doi.org/10.1017/S0007114524001417
  15. Stem Cells. 2024 Sep 16. pii: sxae057. [Epub ahead of print]
    Metformin acts on miR-181a-5p/PAI-1 axis in stem cells providing new strategies for improving age-related osteogenic differentiation decline.
    Guanhao Hong, Yulan Zhou, Shukai Yang, Shouquan Yan, Jiaxu Lu, Bo Xu, Zeyu Zhan, Huasheng Jiang, Bo Wei, Jiafeng Wang.
      A general decline in the osteogenic differentiation capacity of human bone marrow mesenchymal stem cells (hBMSCs) in the elderly is a clinical consensus, with diverse opinions on the mechanisms. Many studies have demonstrated that metformin (MF) significantly protects against osteoporosis and reduces fracture risk. However, the exact mechanism of this effect remains unclear. In this study, we found that the decreased miR-181a-5p expression triggered by MF treatment plays a critical role in recovering the osteogenic ability of aging hBMSCs (derived from elderly individuals). Notably, the miR-181a-5p expression in hBMSCs was significantly decreased with prolonged MF (1000 μM) treatment. Further investigation revealed that miR-181a-5p overexpression markedly impairs the osteogenic ability of hBMSCs, while miR-181a-5p inhibition reveals the opposite result. We also found that miR-181a-5p could suppress the protein translation process of plasminogen activator inhibitor-1 (PAI-1), as evidenced by luciferase assays and western blots. Additionally, low PAI-1 levels were associated with diminished osteogenic ability, whereas high levels promoted it. These findings were further validated in human umbilical cord mesenchymal stem cells (hUCMSCs). Finally, our in vivo experiment with a bone defects rat model confirmed that the agomiR-181a-5p (long-lasting miR-181a-5p mimic) undermined bone defects recovery, while the antagomiR-181a-5p (long-lasting miR-181a-5p inhibitor) significantly promoted the bone defects recovery. In conclusion, we found that MF promotes bone tissue regeneration through the miR-181a-5p/PAI-1 axis by affecting MSC osteogenic ability, providing new strategies for the treatment of age-related bone regeneration disorders.
    Keywords:  BMSC; Metformin; Osteogenic differentiation; PAI-1; UCMSC; miR-181a-5p
    DOI:  https://doi.org/10.1093/stmcls/sxae057
  16. Bioessays. 2024 Sep 20. e2400143
    Can stable introns and noncoding RNAs be harnessed to improve health through activation of mitohormesis?
    Seow Neng Chan, Jun Wei Pek.
      Ever since their introduction a decade ago, stable introns, a type of noncoding (nc)RNAs, are found to be key players in different important cellular processes acting through regulation of gene expression and feedback loops to maintain cellular homeostasis. Despite being commonly regarded as useless byproducts, recent studies in yeast suggested that stable introns are essential for cell survivability under starvation. In Drosophila, we found that a stable intron, sisR-1, has a direct effect in regulating mitochondrial dynamics during short-term fasting and subsequently improved overall oocyte quality. We speculated that the beneficial effects implicated by sisR-1 is through the activation of mitohormesis, an interesting phenomenon in mitochondrial biology. Mitohormesis is suggested to improve health span and lifespan of cells and organisms, but the involvement of ncRNAs is not well-documented. Here, we discuss the potential role of sisR-1 and other ncRNAs in activating mitohormesis and the possible applications in improving cellular and organismal health.
    Keywords:  fasting; fertility; health span; mitochondria; mitohormesis; noncoding RNAs; stable introns
    DOI:  https://doi.org/10.1002/bies.202400143
  17. J Cosmet Dermatol. 2024 Sep 18.
    Troxerutin Delays Skin Keratinocyte Senescence Induced by Ionizing Radiation Both In Vitro and In Vivo.
    Juping Chen, Jinghui Yang, Jiang Ma, Xiaoming Sun, Yuxuan Wang, Changjiao Luan, Jiaxiao Chen, Weili Liu, Qing Shan, Xingjie Ma.
       BACKGROUNDS: With the increasing demand for beauty and a healthy lifespan, studies regarding anti-skin aging have drawn much more attention than ever before. Skin cellular senescence, the primary cause of skin aging, is characterized by a cell cycle arrest in proliferating cells along with a senescence-associated secretory phenotype (SASP), which can be triggered by various internal or external stimuli.
    AIMS: Recent studies have made significant progress in the fields of anti-senescence and anti-aging. However, little is known about the roles and functions of natural compounds, particularly flavonoids, in skin cellular senescence studies.
    METHODS: In this study, using strategies including ionizing radiation (IR), senescence-associated β galactosidase assay (SA-β-Gal), immunofluorescence (IF), flow cytometry, PCR array, as well as in vivo experiments, we investigated the effects and roles of troxerutin (Trx), a natural flavonoid, in skin keratinocyte senescence.
    RESULTS: We found that Trx delays skin keratinocyte senescence induced by IR. Mechanistically, Trx protects the skin keratinocyte cells from senescence by alleviating reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and DNA damage caused by IR. In addition, Trx was also proved to relieve skin senescence and SASP secretion in vivo induced by IR stimulation.
    CONCLUSIONS: Altogether, our findings pointed to a new function of Trx in delaying stress-induced skin keratinocyte senescence, and should thus provide theoretical foundations for exploring novel strategies against skin aging.
    Keywords:  DNA damage; Trx; age; aging skin; cell signaling; keratinocyte; mitochondria dysfunction; skin cellular senescence
    DOI:  https://doi.org/10.1111/jocd.16584
  18. Nucleus. 2024 Dec;15(1): 2398450
    Multifaceted roles of SUMO in DNA metabolism.
    Yee Mon Thu.
      Sumoylation, a process in which SUMO (small ubiquitin like modifier) is conjugated to target proteins, emerges as a post-translational modification that mediates protein-protein interactions, protein complex assembly, and localization of target proteins. The coordinated actions of SUMO ligases, proteases, and SUMO-targeted ubiquitin ligases determine the net result of sumoylation. It is well established that sumoylation can somewhat promiscuously target proteins in groups as well as selectively target individual proteins. Through changing protein dynamics, sumoylation orchestrates multi-step processes in chromatin biology. Sumoylation influences various steps of mitosis, DNA replication, DNA damage repair, and pathways protecting chromosome integrity. This review highlights examples of SUMO-regulated nuclear processes to provide mechanistic views of sumoylation in DNA metabolism.
    Keywords:  Chromatin regulation; DNA damage; SUMO; genome instability; post-translational modification
    DOI:  https://doi.org/10.1080/19491034.2024.2398450
  19. Eur J Nutr. 2024 Sep 18.
    Association between plant and animal protein and biological aging: findings from the UK Biobank.
    Xiaoqing Xu, Jinxia Hu, Xibo Pang, Xuanyang Wang, Huan Xu, Xuemin Yan, Jia Zhang, Sijia Pan, Wei Wei, Ying Li.
       PURPOSE: This study aimed to evaluate the relationship between plant protein, animal protein and biological aging through different dimensions of biological aging indices. Then explore the effects of substitution of plant protein, animal protein, and their food sources on biological aging.
    METHODS: The data came from 79,294 participants in the UK Biobank who completed at least two 24-h dietary assessments. Higher Klemera-Doubal Method Biological Age (HKDM-BA), higher PhenoAge (HPA), higher allostatic load (HAL), and longer telomere length (LTL) were estimated to assess biological aging. Logistic regression was used to estimate protein-biological aging associations. Substitution model was performed to assess the effect of dietary protein substitutions.
    RESULTS: Plant protein intake was inversely associated with HKDM-BA, HPA, HAL, and positively associated with LTL (odds ratios after fully adjusting and comparing the highest to the lowest quartile: 0.83 (0.79-0.88) for HKDM-BA, 0.86 (0.72-0.94) for HPA, 0.90 (0.85-0.95) for HAL, 1.06 (1.01-1.12) for LTL), while animal protein was not correlated with the four indices. Substituting 5% of energy intake from animal protein with plant protein, replacing red meat or poultry with whole grains, and replacing red or processed meat with nuts, were negatively associated with HKDM-BA, HPA, HAL and positively associated with LTL. However, an inverse association was found when legumes were substituted for yogurt. Gamma glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase mediated the relationship between plant protein and HKDM-BA, HPA, HAL, and LTL (mediation proportion 11.5-24.5%; 1.9-6.7%; 2.8-4.5%, respectively).
    CONCLUSION: Higher plant protein intake is inversely associated with biological aging. Although there is no association with animal protein, food with animal proteins displayed a varied correlation.
    Keywords:  Animal protein; Biological aging; Dietary protein food sources; Plant protein; Substitution; UK Biobank
    DOI:  https://doi.org/10.1007/s00394-024-03494-9
  20. Int J Mol Med. 2024 Nov;pii: 98. [Epub ahead of print]54(5):
    Role of Agrin in tissue repair and regeneration: From mechanisms to therapeutic opportunities (Review).
    Xiang Li, Yuan Xu, Jing-Xing Si, Fang Gu, Ying-Yu Ma.
      Tissue regeneration is a complex process that involves the recruitment of various types of cells for healing after injury; it is mediated by numerous precise interactions. However, the identification of effective targets for improving tissue regeneration remains a challenge. As an extracellular matrix protein, Agrin plays a critical role in neuromuscular junction formation. Furthermore, recent studies have revealed the role of Agrin in regulating tissue proliferation and regeneration, which contributes to the repair process of injured tissues. An in‑depth understanding of the role of Agrin will therefore be of value. Given that repair and regeneration processes occur in various parts of the human body, the present systematic review focuses on the role of Agrin in typical tissue and highlights the potential signaling pathways that are involved in Agrin‑induced repair and regeneration. This review offers important insight into novel strategies for the future clinical applications of Agrin‑based therapies, which may represent a feasible treatment option for patients who require organ replacement or repair.
    Keywords:  Agrin; mechanism; regeneration; repair
    DOI:  https://doi.org/10.3892/ijmm.2024.5422
  21. Ultrasound Med Biol. 2024 Sep 16. pii: S0301-5629(24)00327-2. [Epub ahead of print]
    Jingle Cell Rock: Steering Cellular Activity With Low-Intensity Pulsed Ultrasound (LIPUS) to Engineer Functional Tissues in Regenerative Medicine.
    Martina Marcotulli, Andrea Barbetta, Edoardo Scarpa, Fabiano Bini, Franco Marinozzi, Giancarlo Ruocco, Carlo Massimo Casciola, Chiara Scognamiglio, Dario Carugo, Gianluca Cidonio.
      Acoustic manipulation or perturbation of biological soft matter has emerged as a promising clinical treatment for a number of applications within regenerative medicine, ranging from bone fracture repair to neuromodulation. The potential of ultrasound (US) endures in imparting mechanical stimuli that are able to trigger a cascade of molecular signals within unscathed cells. Particularly, low-intensity pulsed ultrasound (LIPUS) has been associated with bio-effects such as activation of specific cellular pathways and alteration of cell morphology and gene expression, the extent of which can be modulated by fine tuning of LIPUS parameters including intensity, frequency and exposure time. Although the molecular mechanisms underlying LIPUS are not yet fully elucidated, a number of studies clearly define the modulation of specific ultrasonic parameters as a means to guide the differentiation of a specific set of stem cells towards adult and fully differentiated cell types. Herein, we outline the applications of LIPUS in regenerative medicine and the in vivo and in vitro studies that have confirmed the unbounded clinical potential of this platform. We highlight the latest developments aimed at investigating the physical and biological mechanisms of action of LIPUS, outlining the most recent efforts in using this technology to aid tissue engineering strategies for repairing tissue or modelling specific diseases. Ultimately, we detail tissue-specific applications harnessing LIPUS stimuli, offering insights over the engineering of new constructs and therapeutic modalities. Overall, we aim to lay the foundation for a deeper understanding of the mechanisms governing LIPUS-based therapy, to inform the development of safer and more effective tissue regeneration strategies in the field of regenerative medicine.
    Keywords:  LIPUS; biomaterials; differentiation; regenerative medicine; stem cells; ultrasound
    DOI:  https://doi.org/10.1016/j.ultrasmedbio.2024.08.016
  22. Nat Chem Biol. 2024 Sep 19.
    Compact RNA editors with natural miniature Cas13j nucleases.
    Guo Li, Yaxian Cheng, Jingwen Yu, Yunfei Zhu, Hongru Ma, Yuqiao Zhou, Zhongji Pu, Guanglin Zhu, Yichen Yuan, Ziyue Zhang, Xinzhi Zhou, Kairen Tian, Jianjun Qiao, Xiaoxiang Hu, Xue-Xin Chen, Quanjiang Ji, Xingxu Huang, Bin Ma, Yuan Yao.
      Clustered regularly interspaced short palindromic repeats-Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as APOC3D65N and SCN9AR896Q, to the wild-type forms. In addition, we developed an optimized system, Chi-RESCUE-S-mini3, which pioneered efficient in vivo C-to-U RNA editing of PCSK9 in mice through single-AAV delivery, resulting in reduced total cholesterol levels. These results highlight the potential of Cas13j to treat human diseases.
    DOI:  https://doi.org/10.1038/s41589-024-01729-8
  23. iScience. 2024 Sep 20. 27(9): 110809
    The role of mitofusin 2 in regulating endothelial cell senescence: Implications for vascular aging.
    Jiayin Li, Zheming Yang, Haixu Song, Lin Yang, Kun Na, Zhu Mei, Shuli Zhang, Jing Liu, Kai Xu, Chenghui Yan, Xiaozeng Wang.
      Endothelial cell dysfunction contributes to age-related vascular diseases. Analyzing public databases and mouse tissues, we found decreased MFN2 expression in senescent endothelial cells and angiotensin II-treated mouse aortas. In human endothelial cells, Ang II reduced MFN2 expression while increasing senescence markers P21 and P53. siMFN2 treatment worsened Ang II-induced senescence, while MFN2 overexpression alleviated it. siMFN2 or Ang II treatment caused mitochondrial dysfunction and morphological abnormalities, including increased ROS production and reduced respiration, mitigated by ovMFN2 treatment. Further study revealed that BCL6, a negative regulator of MFN2, significantly contributes to Ang II-induced endothelial senescence. In vivo, Ang II infusion decreased MFN2 expression and increased BCL6, P21, and P53 expression in vascular endothelial cells. The shMfn2+Ang II group showed elevated senescence markers in vascular tissues. These findings highlight MFN2's regulatory role in endothelial cell senescence, emphasizing its importance in maintaining endothelial homeostasis and preventing age-related vascular diseases.
    Keywords:  Biochemistry; Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110809
  24. Mech Ageing Dev. 2024 Sep 14. pii: S0047-6374(24)00091-5. [Epub ahead of print]222 111991
    Characterization of a natural model of adult mice with different rate of aging.
    Judith Félix, Estefanía Díaz-Del Cerro, Antonio Garrido, Mónica De La Fuente.
      Aging is a heterogeneous process, so individuals of the same age may be aging at a different rate. A natural model of premature aging in mice have been proposed based on the poor response to the T-maze. Those that take longer to cross the intersection are known as Prematurely Aging Mice (PAM), while those that show an exceptional response are known as Exceptional non-PAM (E-NPAM), being the rest non-PAM (NPAM). Although many aspects of PAM and E-NPAM have been described, some aspects of their brain aging have not been studied. Similarly, it is known that PAM, NPAM and E-NPAM show a different rate of aging and longevity, but the differences between these three groups in behavior, immune function and oxidative-inflammatory state are unknown. The present study aims to deepen the study of brain aging in PAM and E-NPAM, and to study the differences in behavior, immunity, and oxidative-inflammatory state of peritoneal leukocytes between PAM, NPAM and E-NPAM. Results show deteriorated brains in PAM. Moreover, NPAM show an oxidative state similar to E-NPAM, an anxiety similar to PAM, and an intermediate immunity and lifespan between PAM and E-NPAM. In conclusion, immune function seems to be more associated with the longevity achieved.
    Keywords:  Behavior; Brain; Immune function; Longevity; Premature aging; Redox state
    DOI:  https://doi.org/10.1016/j.mad.2024.111991
  25. bioRxiv. 2024 Sep 04. pii: 2024.09.04.611288. [Epub ahead of print]
    Genome-Wide Mapping of RNA-Protein Associations via Sequencing.
    Zhijie Qi, Shuanghong Xue, Junchen Chen, Wenxin Zhao, Kara Johnson, Xingzhao Wen, John Lalith Charles Richard, Sheng Zhong.
      RNA-protein interactions are crucial for regulating gene expression and cellular functions, with their dysregulation potentially impacting disease progression. Systematically mapping these interactions is resource-intensive due to the vast number of potential RNA and protein interactions. Here, we introduce PRIM-seq ( P rotein- R NA Interaction M apping by sequencing), a method for the concurrent de novo identification of RNA-binding proteins (RBPs) and the elucidation of their associated RNAs. PRIM-seq works by converting each RNA-protein pair into a unique chimeric DNA sequence, which is then decoded through DNA sequencing. Applied to two human cell types, PRIM-seq generated a comprehensive human RNA-protein association network (HuRPA), consisting of more than 350,000 RNA-proteins pairs involving approximately 7,000 RNAs and 11,000 proteins. The data revealed an enrichment of previously reported RBPs and RNA-protein interactions within HuRPA. We also identified LINC00339 as a protein-associating non-coding RNA and PHGDH as an RNA-associating protein. Notably, PHGDH interacts with BECN1 and ATF4 mRNAs, suppressing their protein expression and consequently inhibiting autophagy, apoptosis, and neurite outgrowth while promoting cell proliferation. PRIM-seq offers a powerful tool for discovering RBPs and RNA-protein associations, contributing to more comprehensive functional genome annotations.
    DOI:  https://doi.org/10.1101/2024.09.04.611288
  26. bioRxiv. 2024 Sep 03. pii: 2024.09.02.610809. [Epub ahead of print]
    Aneuploidy of Specific Chromosomes is Beneficial to Cells Lacking Spindle Checkpoint Protein Bub3.
    Pallavi Gadgil, Olivia Ballew, Timothy J Sullivan, Soni Lacefield.
      Aneuploidy typically poses challenges for cell survival and growth. However, recent studies have identified exceptions where aneuploidy is beneficial for cells with mutations in certain regulatory genes. Our research reveals that cells lacking the spindle checkpoint gene BUB3 exhibit aneuploidy of select chromosomes. While the spindle checkpoint is not essential in budding yeast, the loss of BUB3 and BUB1 increases the probability of chromosome missegregation compared to wildtype cells. Contrary to the prevailing assumption that the aneuploid cells would be outcompeted due to growth defects, our findings demonstrate that bub3 Δ cells consistently maintained aneuploidy of specific chromosomes over many generations. We investigated whether the persistence of these additional chromosomes in bub3 Δ cells resulted from the beneficial elevated expression of certain genes, or mere tolerance. We identified several genes involved in chromosome segregation and cell cycle regulation that confer an advantage to Bub3-depleted cells. Overall, our results suggest that the upregulation of specific genes through aneuploidy may provide a survival and growth advantage to strains with poor chromosome segregation fidelity.
    AUTHOR SUMMARY: Accurate chromosome segregation is crucial for the proper development of all living organisms. Errors in chromosome segregation can lead to aneuploidy, characterized by an abnormal number of chromosomes, which generally impairs cell survival and growth. However, under certain stress conditions, such as in various cancers, cells with specific mutations and extra copies of advantageous chromosomes exhibit improved survival and proliferation. In our study, we discovered that cells lacking the spindle checkpoint protein Bub3 became aneuploid, retaining specific chromosomes. This finding was unexpected because although bub3 Δ cells have a higher rate of chromosome mis-segregation, they were not thought to maintain an aneuploid karyotype. We investigated whether the increased copy number of specific genes on these acquired chromosomes offered a benefit to Bub3-deficient cells. Our results revealed that several genes involved in chromosome segregation and cell cycle regulation prevented the gain of chromosomes upon Bub3-depletion, suggesting that these genes confer a survival advantage. Overall, our study demonstrates that cells lacking Bub3 selectively retain specific chromosomes to increase the copy number of genes that promote proper chromosome segregation.
    DOI:  https://doi.org/10.1101/2024.09.02.610809
  27. J Photochem Photobiol B. 2024 Aug 30. pii: S1011-1344(24)00184-2. [Epub ahead of print]260 113024
    Photobiomodulation ameliorates ovarian aging by alleviating oxidative stress and inflammation damage and improving mitochondrial function.
    Yu He, Rongan Ye, Yinbo Peng, Qing Pei, Lei Wu, Caixia Wang, Wei Ni, Ming Li, Yiqiu Zhang, Min Yao.
      Ovarian aging is a serious clinical concern. Few safe and effective methods are currently available to improve ovarian functions. Photobiomodulation (PBM) is a safe and noninvasive physical therapy that can modulate a series of biological processes. Recently, several studies have noted its potential to improve the function of ovary and reproductive cells. However, the effects of PBM treatment on natural ovarian aging remain unclear. In this study, we used a naturally reproductive aging mouse model to observe the effect of PBM on ovarian function. Young and aged female ICR mice were treated with or without PBM for 2 months. PBM was performed using a semiconductor InGaAlP laser emitting at 650 nm (80 mW, 6.7 mW/cm2 for 5 or 10 min, resulting in a dose of 2 or 4 J/cm2, respectively). After treatment, the effects of PBM and its role in oxidative stress, inflammation, and mitochondrial function were investigated. We found that PBM (4 J/cm2) effectively recovered the levels of sex hormones, increased the number of primordial and growing follicles, improved angiogenesis, and decreased cell apoptosis in naturally aged mice. Moreover, PBM reduced oxidative stress, inhibited chronic ovarian inflammation, and improved mitochondrial function in aged ovaries. Similar protective effects of PBM were observed in a hydrogen peroxide-induced oxidative stress model of human granulosa cell line (KGN) in vitro. Increased cell viability, cell proliferation, hormone secretion, mitochondrial membrane potential, and adenosine triphosphate levels and decreased apoptosis and oxidative stress were detected in KGN cells after PBM treatment. Collectively, this study suggest that PBM treatment is beneficial for restoring ovarian function in naturally reproductive aging mice and has a significant protective effect against oxidative stress damage in KGN cells. The mechanisms underlying the benefits of PBM in ovarian aging include antioxidant stress, reduction of inflammation, and preservation of mitochondrial function. Therefore, this study emphasizes the potential of PBM as a therapeutic intervention to ameliorate ovarian aging.
    Keywords:  Inflammation; Mitochondrial function; Ovarian aging; Oxidative stress; Photobiomodulation
    DOI:  https://doi.org/10.1016/j.jphotobiol.2024.113024
  28. Cell Mol Life Sci. 2024 Sep 17. 81(1): 407
    Extended replicative lifespan of primary resting T cells by CRISPR/dCas9-based epigenetic modifiers and transcriptional activators.
    Siping Huang, Cia-Hin Lau, Chung Tin, Raymond H W Lam.
      Extension of the replicative lifespan of primary cells can be achieved by activating human telomerase reverse transcriptase (hTERT) to maintain sufficient telomere lengths. In this work, we utilize CRISPR/dCas9-based epigenetic modifiers (p300 histone acetyltransferase and TET1 DNA demethylase) and transcriptional activators (VPH and VPR) to reactivate the endogenous TERT gene in unstimulated T cells in the peripheral blood mononuclear cells (PBMCs) by rewiring the epigenetic marks of the TERT promoter. Importantly, we have successfully expanded resting T cells and delayed their cellular senescence for at least three months through TERT reactivation, without affecting the expression of a T-cell marker (CD3) or inducing an accelerated cell division rate. We have also demonstrated the effectiveness of these CRISPR tools in HEK293FT and THP-1-derived macrophages. TERT reactivation and replicative senescence delay were achieved without inducing malignancy transformation, as shown in various cellular senescence assays, cell cycle state, proliferation rate, cell viability, and karyotype analyses. Our chromatin immunoprecipitation (ChIP)-qPCR data together with TERT mRNA and protein expression analyses confirmed the specificity of CRISPR-based transcription activators in modulating epigenetic marks of the TERT promoter, and induced telomerase expression. Therefore, the strategy of cell immortalization described here can be potentially adopted and generalized to delay cell death or even immortalize any other cell types.
    Keywords:  CRISPRa; Epigenome editing; Immortalization; Lifespan extension; Longevity; Replicative senescence
    DOI:  https://doi.org/10.1007/s00018-024-05415-9
  29. mSystems. 2024 Sep 17. e0092924
    Exploring the vitamin biosynthesis landscape of the human gut microbiota.
    Chiara Tarracchini, Gabriele Andrea Lugli, Leonardo Mancabelli, Douwe van Sinderen, Francesca Turroni, Marco Ventura, Christian Milani.
      The human gut microbiota possesses the capacity to synthesize vitamins, especially B group vitamins, which are recognized as indispensable for various biological processes both among members of these bacterial communities and host cells. Accordingly, vitamin production by intestinal commensals has attracted significant interest. Nevertheless, our current understanding of bacterial vitamin synthesis is primarily based on individual genomic and monoculture investigations, therefore not providing an overall view of the biosynthetic potential of complex microbial communities. In the current study, we utilized over 100 bacterial genes known to be involved in the biosynthesis of B group and K vitamins to assess the corresponding vitamin biosynthetic potential of approximately 8,000 human gut microbiomes. Our analyses reveal that host-associated factors, such as age and geographical origin, appear to influence the diversity and abundance of vitamin biosynthetic pathways. Furthermore, we identify gut microbiota members that substantially contribute to these biosynthetic functions at each stage of human life. Interestingly, inference of microbial co-associations and network relationships uncovered the apparent key role played by folate and cobalamin in equilibrium establishment of the infant and adult gut microbial communities, respectively.IMPORTANCEOverall, this study expands our understanding of microbe-mediated vitamin biosynthesis in the human gut and may provide potential novel targets to improve availability of these essential micronutrients in the host.
    Keywords:  bacteria; microbiome; micronutrients
    DOI:  https://doi.org/10.1128/msystems.00929-24
  30. Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep 20.
    A comprehensive review on physiological and biological activities of carnosine: turning from preclinical facts to potential clinical applications.
    Akshita Kumar, Geetha Suryakumar, Som Nath Singh, Richa Rathor.
      Carnosine, a compound with plethora of benefits, was originally discovered in 1900 and is formed by the amide linkage of β-alanine and L-histidine. Carnosine production is limited by β-alanine whereas the imidazole ring of histidine moiety makes it a suitable buffer in physiological pH range. It is reported to be found in the skeletal muscle, brain, heart, and gastrointestinal tissues of humans. This review focuses on the biological properties of carnosine including pH buffering ability, antioxidant activity, anti-inflammatory activity, anti-aging effect, enhancement of cognitive function, and immunomodulation. The relevance of carnosine in muscle function attributing to enhancement of physical performance has also been highlighted. Studies spanning several years have proved the preclinical effectiveness of carnosine in treating diverse pathological diseases. A complete summary of all key activities of carnosine from in vivo investigations and clinical trials has been compiled. Considering its numerous advantages, carnosine may be a promising option for the development of a nutraceutical.
    Keywords:  Antioxidant; Carnosine; Clinical trials; Muscle function; PH buffering capacity
    DOI:  https://doi.org/10.1007/s00210-024-03427-7
  31. Heliyon. 2024 Sep 15. 10(17): e36275
    Increased DNA damage of adipose tissue-derived mesenchymal stem cells under inflammatory conditions.
    Zoltán G Páhi, Diána Szűcs, Vanda Miklós, Nóra Ördög, Tamás Monostori, János Varga, Lajos Kemény, Zoltán Veréb, Tibor Pankotai.
      Cells have evolved various DNA repair mechanisms to prevent DNA damage from building up. Malfunctions during DNA repair can influence cellular homeostasis because they can bring on genomic instability through the improper recognition of DNA damage or dysregulation of the repair process. Maintaining proper DNA repair is also essential for stem cells (SCs), as they provide a differentiated cell population to the living organism. SCs are regularly used in personalized stem cell therapy. Patients must be treated with specific activators to produce these SCs effectively. This report investigated the impact of treating mesenchymal stem cells (MSC) with lipopolysaccharide, tumor necrosis factor, interferon-gamma, polyinosinic acid, interleukin 1 beta, while monitoring their transcription-related response using next-generation sequencing. RNA sequencing revealed robust gene expression changes, including those of specific genes encoding proteins implicated in DNA damage response. Stem cells can effectively repair specific DNA damages; moreover, they fail to undergo senescence or cell death when genetic lesions accumulate. Here, we draw attention to an elevated DNA repair activation following MSC induction, which may be the main reason for the ineffective stem cell transplantation and may also contribute to the genetic drift that can initiate tumor formation.
    Keywords:  ADMSC; DNA repair; NHEJ; RNAseq; Stem cells
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e36275
  32. Aging Cell. 2024 Sep 17. e14333
    CASIN exerts anti-aging effects through RPL4 on the skin of naturally aging mice.
    Yijia Zhang, Xueer Wang, Jianyuan Huang, Xinyue Zhang, Lingwei Bu, Yarui Zhang, Fengting Liang, Shenhua Wu, Min Zhang, Lu Zhang, Lin Zhang.
      Skin aging has been associated with the onset of various skin issues, and recent studies have identified an increase in Cdc42 activity in naturally aging mice. While previous literature has suggested that CASIN, a specific inhibitor of Cdc42 activity, may possess anti-aging properties, its specific effects on the epidermis and dermis, as well as the underlying mechanisms in naturally aging mice, remain unclear. Our study revealed that CASIN demonstrated the ability to increase epidermal and dermal thickness, enhance dermal-epidermal junction, and stimulate collagen and elastic fiber synthesis in 9-, 15-, and 24-month-old C57BL/6 mice in vivo. Moreover, CASIN was found to enhance the proliferation, differentiation, and colony formation and restore the cytoskeletal morphology of primary keratinocytes in naturally aging skin in vitro. Furthermore, the anti-aging properties of CASIN on primary fibroblasts in aging mice were mediated by the ribosomal protein RPL4 using proteomic sequencing, influencing collagen synthesis and cytoskeletal morphology both in vitro and in vivo. Meanwhile, both subcutaneous injection and topical application exhibited anti-aging effects for a duration of 21 days. Additionally, CASIN exhibited anti-inflammatory properties, while reduced expression of RPL4 was associated with increased inflammation in the skin of naturally aging mice. Taken together, our results unveil a novel function of RPL4 in skin aging, providing a foundational basis for future investigations into ribosomal proteins. And CASIN shows promise as a potential anti-aging agent for naturally aging mouse skin, suggesting potential applications in the field.
    Keywords:  CASIN; Cdc42; fibroblast; keratinocyte; ribosome; skin aging
    DOI:  https://doi.org/10.1111/acel.14333
  33. J Cachexia Sarcopenia Muscle. 2024 Sep 14.
    High-Intensity Interval Training Mitigates Sarcopenia and Suppresses the Myoblast Senescence Regulator EEF1E1.
    Yaoshan Dun, Wenliang Zhang, Yang Du, Kangling Xie, Yuan Liu, Cui Li, Ling Qiu, Siqian Fu, Thomas P Olson, Yuqiong Long, Baiyang You, Suixin Liu.
       BACKGROUND: The optimal exercise regimen for alleviating sarcopenia remains uncertain. This study aimed to investigate the efficacy of high-intensity interval training (HIIT) over moderate-intensity continuous training (MICT) in ameliorating sarcopenia.
    METHODS: We conducted a randomized crossover trial to evaluate plasma proteomic reactions to acute HIIT (four 4-min high-intensity intervals at 70% maximal capacity alternating with 4 min at 30%) versus MICT (constant 50% maximal capacity) in inactive adults. We explored the relationship between a HIIT-specific protein relative to MICT, identified via comparative proteomic analysis, eukaryotic translation elongation factor 1 epsilon 1 (EEF1E1) and sarcopenia in a paired case-control study of elderly individuals (aged over 65). Young (3 months old) and aged (20 months old) mice were randomized to sedentary, HIIT and MICT groups (five sessions/week for 4 weeks; n = 8 for each group). Measurements included skeletal muscle index, hand grip strength, expression of atrophic markers Atrogin1 and MuRF1 and differentiation markers MyoD, myogenin and MyHC-II via western blotting. We examined the impact of EEF1E1 siRNA and recombinant protein on D-galactose-induced myoblast senescence, measuring senescence-associated β-galactosidase and markers like p21 and p53.
    RESULTS: The crossover trial, including 10 sedentary adults (32 years old, IQR 31-32) demonstrated significant alterations in the abundance of 21 plasma proteins after HIIT compared with MICT. In the paired case-control study of 84 older adults (84 years old, IQR 69-81; 52% female), EEF1E1 was significantly increased in those with sarcopenia compared to those without (14.68 [95%CI, 2.02-27.34] pg/mL, p = 0.03) and was associated with skeletal muscle index (R2 = 0.51, p < 0.001) and hand grip strength (R2 = 0.54, p < 0.001). In the preclinical study, aged mice exhibited higher EEF1E1 mRNA and protein levels in skeletal muscle compared to young mice, accompanied by a lower muscle mass and strength, increased cellular senescence and protein degradation markers and reduced muscle differentiation efficiency (all p < 0.05). HIIT reduced EEF1E1 expression and mitigated age-related muscle decline and atrophy in aged mice more effectively than MICT. Notably, EEF1E1 downregulation via siRNA significantly counteracted D-galactose-induced myoblast senescence as evidenced by reduced markers of muscle protein degradation and improved muscle differentiation efficiency (all p < 0.05). Conversely, treatments that increased EEF1E1 levels accelerated the senescence process (p < 0.05). Further exploration indicated that the decrease in EEF1E1 was associated with increased SIRT1 level and enhanced autophagy.
    CONCLUSIONS: This study highlights the potential of HIIT as a promising approach to prevent and treat sarcopenia while also highlighting EEF1E1 as a potential intervention target.
    Keywords:  EEF1E1; autophagy; high‐intensity interval training; sarcopenia; senescence
    DOI:  https://doi.org/10.1002/jcsm.13600
  34. Mater Today Bio. 2024 Oct;28 101210
    Tailoring biomaterials for skin anti-aging.
    Xin Dan, Songjie Li, Han Chen, Ping Xue, Bo Liu, Yikun Ju, Lanjie Lei, Yang Li, Xing Fan.
      Skin aging is the phenomenon of degenerative changes in the structure and function of skin tissues over time and is manifested by a gradual loss of skin elasticity and firmness, an increased number of wrinkles, and hyperpigmentation. Skin anti-aging refers to a reduction in the skin aging phenomenon through medical cosmetic technologies. In recent years, new biomaterials have been continuously developed for improving the appearance of the skin through mechanical tissue filling, regulating collagen synthesis and degradation, inhibiting pigmentation, and repairing the skin barrier. This review summarizes the mechanisms associated with skin aging, describes the biomaterials that are commonly used in medical aesthetics and their possible modes of action, and discusses the application strategies of biomaterials in this area. Moreover, the synergistic effects of such biomaterials and other active ingredients, such as stem cells, exosomes, growth factors, and antioxidants, on tissue regeneration and anti-aging are evaluated. Finally, the possible challenges and development prospects of biomaterials in the field of anti-aging are discussed, and novel ideas for future innovations in this area are summarized.
    Keywords:  Biomaterials; Medical aesthetics; Plastic surgery; Skin anti-aging; Tissue regeneration
    DOI:  https://doi.org/10.1016/j.mtbio.2024.101210
  35. Mol Metab. 2024 Sep 17. pii: S2212-8778(24)00157-1. [Epub ahead of print] 102026
    IGFBP2 Functions as an Endogenous Protector against Hepatic Steatosis via Suppression of the EGFR-STAT3 Pathway.
    Tianyu Zhai, Liang Cai, Xi Jia, Mingfeng Xia, Hua Bian, Xin Gao, Chenling Pan, Xiaoying Li, Pu Xia.
       BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is deemed as an emerging global epidemic, whereas the underlying pathogenic mechanism remains to be clarified. We aimed to systemically analyze all the NAFLD-related gene expression datasets from published human-based studies, by which exploring potential key factors and mechanisms accounting for the pathogenesis of NAFLD.
    APPROACH & RESULTS: By using Robust rank aggregation method to integrate all public datasets of human NAFLD transcriptome, the present study identified IGFBP2 (Insulin-like growth factor binding protein 2) being the most significantly down-regulated gene in all NAFLD subjects. The decreased IGFBP2 expression was further confirmed in the liver tissues from patients and animal models of NAFLD. IGFBP2 deficiency aggravated hepatic steatosis and NASH phenotypes and promoted lipogenic gene expression both in vivo and in vitro. Mechanistically, IGFBP2 directly binds to and regulates EGFR, whereas blockage of the IGFBP2-EGFR complex by knockdown of IGFBP2 resulted in the EGFR-STAT3 pathway activation, which in turn promoted the promoter activity of Srebf1. By using molecular docking simulation and protein-protein interaction analysis, the sequence of 233-257 amino acids in IGFBP2 was characterized as a key motif responding for its specific binding to EGFR and the protective effect against hepatic steatosis.
    CONCLUSIONS: The current study has, for the first time, identified IGFBP2 as a novel protector against hepatosteatosis. The protective effect is mediated by its specific interaction with EGFR and thereby suppressing the EGFR-STAT3 pathway. Therefore, pharmaceutically targeting the IGFBP2-EGFR-STAT3 axis may provide a theoretical basis for for the treatment of NAFLD/NASH and the associated diseases.
    Keywords:  Non-alcoholic fatty liver disease; epidermal growth factor receptor; hepatic steatosis; insulin-like growth factor binding protein 2; robust rank aggregation; signal transducer and activator of transcription 3
    DOI:  https://doi.org/10.1016/j.molmet.2024.102026
  36. BME Front. 2024 ;5 0050
    NucleoCraft: The Art of Stimuli-Responsive Precision in DNA and RNA Bioengineering.
    Lu Yu, Liangxiao Chen, Deeksha Satyabola, Abhay Prasad, Hao Yan.
      Recent advancements in DNA and RNA bioengineering have paved the way for developing stimuli-responsive nanostructures with remarkable potential across various applications. These nanostructures, crafted through sophisticated bioengineering techniques, can dynamically and precisely respond to both physiological and physical stimuli, including nucleic acids (DNA/RNA), adenosine triphosphate, proteins, ions, small molecules, pH, light, and temperature. They offer high sensitivity and specificity, making them ideal for applications such as biomarker detection, gene therapy, and controlled targeted drug delivery. In this review, we summarize the bioengineering methods used to assemble versatile stimuli-responsive DNA/RNA nanostructures and discuss their emerging applications in structural biology and biomedicine, including biosensing, targeted drug delivery, and therapeutics. Finally, we highlight the challenges and opportunities in the rational design of these intelligent bioengineered nanostructures.
    DOI:  https://doi.org/10.34133/bmef.0050
  37. J Biol Chem. 2024 Sep 12. pii: S0021-9258(24)02268-3. [Epub ahead of print] 107767
    Iron regulatory protein 2 facilitates ferritinophagy and DNA damage/repair through guiding ATG9A trafficking.
    Ting Zhang, Qian Liu, Quan Chen, Hao Wu.
      Trace elemental iron is an essential nutrient that participates in diverse metabolic processes. Dysregulation of cellular iron homeostasis, both iron deficiency and iron overload, is detrimental and tightly associated with diseases pathogenesis. IRPs-IREs system locates at the center for iron homeostasis regulation. Additionally, ferritinophagy, the autophagy-dependent ferritin catabolism for iron recycle, is emerging as a novel mechanism for iron homeostasis regulation. It is still unclear whether IRPs-IREs system and ferritinophagy are synergistic or redundant in determining iron homeostasis. Here we report that IRP2, but not IRP1, is indispensable for ferritinophagy in response to iron depletion. Mechanistically, IRP2 ablation results in compromised AMPK activation and defective ATG9A endosomal trafficking, leading to the decreased engulfment of NCOA4-ferritin complex by endosomes and the subsequent dysregulated endosomal microferritinophagy. Moreover, this defective endosomal microferritinophagy exacerbates DNA damage and reduces colony formation in IRP2 depleted cells. Collectively, this study expands the physiological function of IRP2 in endosomal microferritinophagy and highlights a potential crosstalk between IRPs-IREs and ferritinophagy in manipulating iron homeostasis.
    Keywords:  AMPK; ATG9A; Ferritinophagy; IRP2; Iron
    DOI:  https://doi.org/10.1016/j.jbc.2024.107767
  38. Front Immunol. 2024 ;15 1452749
    Inflammasome activity regulation by PUFA metabolites.
    Sinemyiz Atalay Ekiner, Agnieszka Gęgotek, Elżbieta Skrzydlewska.
      Oxidative stress and the accompanying chronic inflammation constitute an important metabolic problem that may lead to pathology, especially when the body is exposed to physicochemical and biological factors, including UV radiation, pathogens, drugs, as well as endogenous metabolic disorders. The cellular response is associated, among others, with changes in lipid metabolism, mainly due to the oxidation and the action of lipolytic enzymes. Products of oxidative fragmentation/cyclization of polyunsaturated fatty acids (PUFAs) [4-HNE, MDA, 8-isoprostanes, neuroprostanes] and eicosanoids generated as a result of the enzymatic metabolism of PUFAs significantly modify cellular metabolism, including inflammation and the functioning of the immune system by interfering with intracellular molecular signaling. The key regulators of inflammation, the effectiveness of which can be regulated by interacting with the products of lipid metabolism under oxidative stress, are inflammasome complexes. An example is both negative or positive regulation of NLRP3 inflammasome activity by 4-HNE depending on the severity of oxidative stress. 4-HNE modifies NLRP3 activity by both direct interaction with NLRP3 and alteration of NF-κB signaling. Furthermore, prostaglandin E2 is known to be positively correlated with both NLRP3 and NLRC4 activity, while its potential interference with AIM2 or NLRP1 activity is unproven. Therefore, the influence of PUFA metabolites on the activity of well-characterized inflammasome complexes is reviewed.
    Keywords:  PUFA metabolites; eicosanoids; inflammasome complexes; inflammation; lipid mediators; oxidative stress
    DOI:  https://doi.org/10.3389/fimmu.2024.1452749
  39. Front Cell Dev Biol. 2024 ;12 1444198
    Targeting hepatic macrophages for non-alcoholic fatty liver disease therapy.
    Yingxin Tian, Yiming Ni, Ting Zhang, Yemin Cao, Mingmei Zhou, Cheng Zhao.
      Non-alcoholic fatty liver disease (NAFLD) and its more advanced form, non-alcoholic steatohepatitis (NASH), have become global health challenges with significant morbidity and mortality rates. NAFLD encompasses several liver diseases, ranging from simple steatosis to more severe inflammatory and fibrotic forms. Ultimately, this can lead to liver cirrhosis and hepatocellular carcinoma. The intricate role of hepatic macrophages, particularly Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), in the pathogenesis of NAFLD and NASH, has received increasing attention. Hepatic macrophages can interact with hepatocytes, hepatic stellate cells, and endothelial cells, playing a crucial role in maintaining homeostasis. Paradoxically, they also participate in the pathogenesis of some liver diseases. This review highlights the fundamental role of hepatic macrophages in the pathogenesis of NAFLD and NASH, emphasizing their plasticity and contribution to inflammation and fibrosis, and hopes to provide ideas for subsequent experimental research and clinical treatment.
    Keywords:  Kupffer cells (KCs); NASH; macrophages; monocyte-derived macrophages (MoMFs); non-alcoholic fatty liver disease (NAFLD)
    DOI:  https://doi.org/10.3389/fcell.2024.1444198
  40. Int J Psychiatry Med. 2024 Sep 15. 912174241284925
    Dietary omega-3 intake and cognitive function in older adults.
    Bingdian Wang, Deqin Li, Cuicui Peng, Jingfang Hong, Yonggui Wu.
       OBJECTIVE: Dietary habits have long been known to be a critical factor influencing cognitive health, especially among older adults. Despite extensive research on various dietary components, the impact of omega-3 polyunsaturated fatty acids (PUFAs) on cognitive function has not yet been thoroughly investigated. This research seeks to determine whether more intake of omega-3 PUFAs correlates with improved cognitive function in older adults.
    METHODS: Data were analyzed from the National Health and Nutrition Examination Survey (NHANES), which included 2430 elderly participants aged 60 and above. The association between omega-3 consumption and cognitive outcomes was evaluated using linear regression models. Smoothing curves and threshold effect analysis were employed to examine nonlinear associations. Subgroup studies were conducted to demonstrate the strength and reliability of the correlation and factors affecting them.
    RESULTS: The fully adjusted model demonstrated significant positive correlations between omega-3 intake and scores on all 3 cognitive assessments performed. Specifically, in the final model, the beta coefficients for the CERAD Word Learning test, Animal Fluency Test, and Digit Symbol Substitution Test were 0.53 (95% CI: 0.33-0.72; P < 0.0001), 0.29 (95% CI: 0.12-0.47; P = 0.001), and 0.61 (95% CI: 0.19-1.03; P = 0.0045), respectively.
    CONCLUSION: Increased intake of omega-3 was positively and independently associated with cognitive function in older adults, suggesting that consumption of omega-3 PUFAs may help to prevent cognitive decline with aging. Prospective studies are needed to determine the direct of effect in this association.
    Keywords:  NHANES; PUFAs; cognitive function; omega-3
    DOI:  https://doi.org/10.1177/00912174241284925
  41. J Neuroinflammation. 2024 Sep 18. 21(1): 228
    iPLA2β loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy.
    Li Jiao, Wenxin Shao, Wenqi Quan, Longjiang Xu, Penghui Liu, Jinling Yang, Xiaozhong Peng.
       BACKGROUND: During brain aging, disturbances in neuronal phospholipid metabolism result in impaired cognitive function and dysregulation of neurological processes. Mutations in iPLA2β are associated with neurodegenerative conditions that significantly impact brain phospholipids. iPLA2β deficiency exacerbates mitochondrial dysfunction and abnormal mitochondrial accumulation. We hypothesized that iPLA2β contributes to age-related cognitive decline by disrupting neuronal mitophagy.
    METHODOLOGY: We used aged wild-type (WT) mice and iPLA2β-/- mice as natural aging models to assess cognitive performance, iPLA2β expression in the cortex, levels of chemokines and inflammatory cytokines, and mitochondrial dysfunction, with a specific focus on mitophagy and the mitochondrial phospholipid profile. To further elucidate the role of iPLA2β, we employed adeno-associated virus (AAV)-mediated iPLA2β overexpression in aged mice and re-evaluated these parameters.
    RESULTS: Our findings revealed a significant reduction in iPLA2β levels in the prefrontal cortex of aged brains. Notably, iPLA2β-deficient mice exhibited impaired learning and memory. Loss of iPLA2β in the PFC of aged mice led to increased levels of chemokines and inflammatory cytokines. This damage was associated with altered mitochondrial morphology, reduced ATP levels due to dysregulation of the parkin-independent mitophagy pathway, and changes in the mitochondrial phospholipid profile. AAV-mediated overexpression of iPLA2β alleviated age-related parkin-independent mitophagy pathway dysregulation in primary neurons and the PFC of aged mice, reduced inflammation, and improved cognitive function.
    CONCLUSIONS: Our study suggests that age-related iPLA2β loss in the PFC leads to cognitive decline through the disruption of mitophagy. These findings highlight the potential of targeting iPLA2β to ameliorate age-related neurocognitive disorders.
    DOI:  https://doi.org/10.1186/s12974-024-03219-z
  42. Nature. 2024 Sep 18.
    Small molecules help misplaced proteins hitchhike around cells.
    Robert Yvon, Christina M Woo.
      
    Keywords:  Chemical biology
    DOI:  https://doi.org/10.1038/d41586-024-02802-x
  43. Sci Rep. 2024 09 19. 14(1): 21852
    Oleanolic acid improves 5-fluorouracil-induced intestinal damage and inflammation by alleviating intestinal senescence.
    Shi-Rui Bai, Bing-Xiang Zhao, Qi Zhao, Yu-Chen Ge, Man Li, Cheng-Gang Zhao, Xiao-Jian Wu, Xiao-Bo Wang.
      5-Fluorouracil (5-FU) is used as a standard first-line drug for colorectal cancer malignancy (CRC), but it brings a series of side effects such as severe diarrhea and intestinal damage. Our previous study found that a large number of senescent cells increased while 5-Fu induced intestinal damage, and anti-senescence drugs can alleviate its side effects of inflammatory damage. Oleanolic acid (OA) is a common pentacyclic triterpenoid mainly derived from food fungi and medicinal plants, and studies have shown that it mainly possesses hepatoprotective, enzyme-lowering, anti-inflammatory, and anti-tumor effects. But its role in senescence is still unclear. In the present study, we demonstrated for the first time that OA ameliorated 5-Fu-induced human umbilical vein endothelial cells (HUVECs) and human normal intestinal epithelial cells (NCM460) in a 5-Fu-induced cellular senescence model by decreasing the activity of SA-β-gal-positive cells, and the expression of senescence-associated proteins (p16), senescence-associated genes (p53 and p21), and senescence-associated secretory phenotypes (SASPs: IL-1β, IL-6, IL-8, IFN-γ and TNF-α). Meanwhile, in this study, in a BALB/c mouse model, we demonstrated that 5-FU induced intestinal inflammatory response and injury, which was also found to be closely related to the increase of senescent cells, and that OA treatment was effective in ameliorating these adverse phenomena. Furthermore, our in vivo and in vitro studies showed that OA could alleviate senescence by inhibiting mTOR. In colon cancer cell models, OA also enhanced the ability of 5-FU to kill HCT116 cells and SW480 cells. Overall, this study demonstrates for the first time the potential role of OA in counteracting the side effects of 5-FU chemotherapy, providing a new option for the treatment of colorectal cancer to progressively achieve the goal of high efficacy and low toxicity of chemotherapy.
    Keywords:  5-Fluorouracil; Foodborne fungus; Intestinal damage; Oleanolic acid; mTOR
    DOI:  https://doi.org/10.1038/s41598-024-72536-3
  44. Nutrients. 2024 Sep 03. pii: 2963. [Epub ahead of print]16(17):
    A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study.
    Christophe de Jaeger, Saskia Kruiskamp, Elena Voronska, Carla Lamberti, Hani Baramki, Jean Louis Beaudeux, Patrick Cherin.
      Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, maintaining genomic integrity during the cell cycle. A decrease in average telomere length is associated with with age and with aging-related diseases such as cancer and cardiovascular disease. In this study, we conducted a randomized, double-blind, placebo-controlled trial over six months to compare the effects of the Astragalus-based supplement versus a placebo on telomere length (TL) in 40 healthy volunteers (mean age 56.1 ± 6.0 years). Twenty subjects received the supplement, and 20 received placebo capsules. All participants completed the study, and no adverse side effects were reported at six months. Subjects taking the Astragalus-based supplement exhibited significantly longer median TL (p = 0.01) and short TL (p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement's intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging.
    Keywords:  Astragalus; aging; cardiovascular health; randomized controlled trial; telomerase activator; telomere length
    DOI:  https://doi.org/10.3390/nu16172963
  45. Nutrients. 2024 Sep 05. pii: 3007. [Epub ahead of print]16(17):
    Effects of Different Exercises Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis.
    Yongchao Xie, Yu Gu, Zhen Li, Bingchen He, Lei Zhang.
       BACKGROUND: Exercise and dietary interventions are essential for maintaining weight and reducing fat accumulation. With the growing popularity of various dietary strategies, evidence suggests that combining exercise with dietary interventions offers greater benefits than either approach alone. Consequently, this combined strategy has become a preferred method for many individuals aiming to maintain health. Calorie restriction, 5/2 intermittent fasting, time-restricted feeding, and the ketogenic diet are among the most popular dietary interventions today. Aerobic exercise, resistance training, and mixed exercise are the most widely practiced forms of physical activity. Exploring the best combinations of these approaches to determine which yields the most effective results is both meaningful and valuable. Despite this trend, a comparative analysis of the effects of different exercise and diet combinations is lacking. This study uses network meta-analysis to evaluate the impact of various combined interventions on body composition and to compare their efficacy.
    METHODS: We systematically reviewed literature from database inception through May 2024, searching PubMed, Web of Science, Embase, and the Cochrane Library. The study was registered in PROSPERO under the title: "Effects of Exercise Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis" (identifier: CRD42024542184). Studies were meticulously selected based on specific inclusion and exclusion criteria (The included studies must be randomized controlled trials involving healthy adults aged 18 to 65 years. Articles were rigorously screened according to the specified inclusion and exclusion criteria.), and their risk of bias was assessed using the Cochrane risk of bias tool. Data were aggregated and analyzed using network meta-analysis, with intervention efficacy ranked by Surface Under the Cumulative Ranking (SUCRA) curves.
    RESULTS: The network meta-analysis included 78 randomized controlled trials with 5219 participants, comparing the effects of four combined interventions: exercise with calorie restriction (CR+EX), exercise with time-restricted eating (TRF+EX), exercise with 5/2 intermittent fasting (5/2F+EX), and exercise with a ketogenic diet (KD+EX) on body composition. Intervention efficacy ranking was as follows: (1) Weight Reduction: CR+EX > KD+EX > TRF+EX > 5/2F+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 2.94 (-3.64, 9.52); 2.37 (-0.40, 5.15); 1.80 (-1.75, 5.34)). (2) BMI: CR+EX > KD+EX > 5/2F+EX > TRF+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 1.95 (-0.49, 4.39); 2.20 (1.08, 3.32); 1.23 (-0.26, 2.71)). (3) Body Fat Percentage: CR+EX > 5/2F+EX > TRF+EX > KD+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 2.66 (-1.56, 6.89); 2.84 (0.56, 5.13); 3.14 (0.52, 5.75).). (4) Lean Body Mass in Male: CR+EX > TRF+EX > KD+EX (Relative to CR+EX, the effect sizes of TRF+EX and KD+EX are -1.60 (-6.98, 3.78); -2.76 (-7.93, 2.40)). (5) Lean Body Mass in Female: TRF+EX > CR+EX > 5/2F+EX > KD+EX (Relative to TRF+EX, the effect sizes of CR+EX, 5/2F+EX and KD+EX are -0.52 (-2.58, 1.55); -1.83 (-4.71, 1.04); -2.46 (-5.69,0.76).).
    CONCLUSION: Calorie restriction combined with exercise emerged as the most effective strategy for reducing weight and fat percentage while maintaining lean body mass. For women, combining exercise with time-restricted eating proved optimal for preserving muscle mass. While combining exercise with a ketogenic diet effectively reduces weight, it is comparatively less effective at decreasing fat percentage and preserving lean body mass. Hence, the ketogenic diet combined with exercise is considered suboptimal.
    Keywords:  BMI; aerobic exercise; body fat percentage; caloric restriction; intermittent fasting; ketogenic diet; lean body mass; resistance exercise; weight
    DOI:  https://doi.org/10.3390/nu16173007
  46. Eur J Cell Biol. 2024 Sep 10. pii: S0171-9335(24)00072-4. [Epub ahead of print]103(4): 151455
    A point-of-research decision in synovial tissue engineering: Mesenchymal stromal cells, tissue derived fibroblast or CTGF-mediated mesenchymal-to-fibroblast transition.
    Alexandra Damerau, Marieluise Kirchner, Philipp Mertins, Frank Buttgereit, Timo Gaber.
      Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent inflammatory joint diseases characterized by synovitis, cartilage, and bone destruction. Fibroblast-like synoviocytes (FLSs) of the synovial membrane are a decisive factor in arthritis, making them a target for future therapies. Developing novel strategies targeting FLSs requires advanced in vitro joint models that accurately replicate non-diseased joint tissue. This study aims to identify a cell source reflecting physiological synovial fibroblasts. Therefore, we newly compared the phenotype and metabolism of "healthy" knee-derived FLSs from patients with ligament injuries (trauma-FLSs) to mesenchymal stromal cells (MSCs), their native precursors. We differentiated MSCs into fibroblasts using connective tissue growth factor (CTGF) and compared selected protein and gene expression patterns to those obtained from trauma-FLSs and OA-FLSs. Based on these findings, we explored the potential of an MSC-derived synovial tissue model to simulate a chronic inflammatory response akin to that seen in arthritis. We have identified MSCs as a suitable cell source for synovial tissue engineering because, despite metabolic differences, they closely resemble human trauma-derived FLSs. CTGF-mediated differentiation of MSCs increased HAS2 expression, essential for hyaluronan synthesis. It showed protein expression patterns akin to OA-FLSs, including markers of ECM components and fibrosis, and enzymes leading to a shift in metabolism towards increased fatty acid oxidation. In general, cytokine stimulation of MSCs in a synovial tissue model induced pro-inflammatory and pro-angiogenic gene expression, hyperproliferation, and increased glucose consumption, reflecting cellular response in human arthritis. We conclude that MSCs can serve as a proxy to study physiological synovial processes and inflammatory responses. In addition, CTGF-mediated mesenchymal-to-fibroblast transition resembles OA-FLSs. Thus, we emphasize MSCs as a valuable cell source for tools in preclinical drug screening and their application in tissue engineering.
    Keywords:  Cytokines; Metabolism; Osteoarthritis; Synovial membrane model; Trauma-fibroblast
    DOI:  https://doi.org/10.1016/j.ejcb.2024.151455
  47. ACS Chem Neurosci. 2024 Sep 17.
    EphA4 Targeting Peptide-Conjugated Extracellular Vesicles Rejuvenates Adult Neural Stem Cells and Exerts Therapeutic Benefits in Aging Rats.
    Satyajit Ghosh, Rajsekhar Roy, Nabanita Mukherjee, Surojit Ghosh, Moumita Jash, Aniket Jana, Surajit Ghosh.
      Aging and various neurodegenerative diseases cause significant reduction in adult neurogenesis and simultaneous increase in quiescent neural stem cells (NSCs), which impact the brain's regenerative capabilities. To deal with this challenging issue, current treatments involve stem cell transplants or prevention of neurodegeneration; however, the efficacy or success of this process remains limited. Therefore, extensive and focused investigation is highly demanding to overcome this challenging task. Here, we have designed an efficient peptide-based EphA4 receptor-targeted ligand through an in silico approach. Further, this strategy involves chemical conjugation of the peptide with adipose tissue stem cell-derived EV (Exo-pep-11). Interestingly, our newly designed engineered EV, Exo-pep-11, targets NSC through EphA4 receptors, which offers promising therapeutic advantages by stimulating NSC proliferation and subsequent differentiation. Our result demonstrates that NSC successfully internalized Exo-pep-11 in both in vitro culture conditions as well as in the in vivo aging rats. We found that the uptake of Exo-pep-11 decreased by ∼2.3-fold when NSC was treated with EphA4 antibody before Exo-pep-11 incubation, which confirms the receptor-specific uptake of Exo-pep-11. Exo-pep-11 treatment also increases NSC proliferation by ∼1.9-fold and also shows ∼1.6- and ∼2.4-fold increase in expressions of Nestin and ID1, respectively. Exo-pep-11 also has the potential to increase neurogenesis in aging rats, which is confirmed by ∼1.6- and ∼1.5-fold increases in expressions of TH and Tuj1, respectively, in rat olfactory bulb. Overall, our findings highlight the potential role of Exo-pep-11 for prospective applications in combating age-related declines in NSC activity and neurogenesis.
    Keywords:  adult neurogenesis; engineered extracellular vesicle; neural stem cell; neural stem cell targeting and rejuvenation
    DOI:  https://doi.org/10.1021/acschemneuro.4c00331
  48. Front Immunol. 2024 ;15 1436437
    The production, function, and clinical applications of IL-33 in type 2 inflammation-related respiratory diseases.
    Shiyao Gu, Ruixuan Wang, Wantian Zhang, Cen Wen, Chunhua Chen, Su Liu, Qian Lei, Peng Zhang, Si Zeng.
      Epithelial-derived IL-33 (Interleukin-33), as a member of alarm signals, is a chemical substance produced under harmful stimuli that can promote innate immunity and activate adaptive immune responses. Type 2 inflammation refers to inflammation primarily mediated by Type 2 helper T cells (Th2), Type 2 innate lymphoid cells (ILC2), and related cytokines. Type 2 inflammation manifests in various forms in the lungs, with diseases such as asthma and chronic obstructive pulmonary disease chronic obstructive pulmonary disease (COPD) closely associated with Type 2 inflammation. Recent research suggests that IL-33 has a promoting effect on Type 2 inflammation in the lungs and can be regarded as an alarm signal for Type 2 inflammation. This article provides an overview of the mechanisms and related targets of IL-33 in the development of lung diseases caused by Type 2 inflammation, and summarizes the associated treatment methods. Analyzing lung diseases from a new perspective through the alarm of Type 2 inflammation helps to gain a deeper understanding of the pathogenesis of these related lung diseases. This, in turn, facilitates a better understanding of the latest treatment methods and potential therapeutic targets for diseases, with the expectation that targeting lL-33 can propose new strategies for disease prevention.
    Keywords:  IL-33; alarmin; asthma; respiratory diseases; type 2 inflammation
    DOI:  https://doi.org/10.3389/fimmu.2024.1436437
  49. Life Sci. 2024 Sep 13. pii: S0024-3205(24)00650-7. [Epub ahead of print] 123060
    An anti-neoplastic tale of metformin through its transport.
    Firoz Khan Bhati, Manoj Kumar Bhat.
      Metformin is an attractive candidate drug among all the repurposed drugs for cancer. Extensive preclinical and clinical research has evaluated its efficacy in cancer therapy, revealing a mixed outcome in clinical settings. To fully exploit metformin's therapeutic potential, understanding cellular factors relevant to its transport and accumulation in cancer cells needs to be understood. This review highlights the relevance of metformin transporter status towards its anti-cancer potential. Metformin transporters are regulated at pre-transcriptional, transcriptional, and post-translational levels. Moreover, the tumour microenvironment can also influence metformin accumulation in cancer cells. Also, Metformin treatment can regulate its transporters by altering global DNA methylation, protein acetylation, and transcription factors. Importantly, metformin transporters not only influence chemotherapeutic drug toxicity but are also associated with the prognosis and survival of individuals having cancer. Strategic decisions based on the expression and regulation of metformin transporters holds promise for its therapeutic implications and relevance.
    Keywords:  Cancer; Chemotherapeutic drugs; Metformin; Transporter
    DOI:  https://doi.org/10.1016/j.lfs.2024.123060
  50. Front Cell Dev Biol. 2024 ;12 1426762
    Regulation of TGF-β1-induced fibroblast differentiation of human periodontal ligament stem cells through the mutually antagonistic action of ectonucleotide pyrophosphatase/phosphodiesterase 1 and 2.
    Onyou Ju, Seon-Yle Ko, Young-Joo Jang.
      Human periodontal ligament stem cells (hPDLSCs) differentiate into periodontal ligament (PDL) fibroblasts, osteoblasts, and cementoblasts. To identify inducers of PDL fibroblastic differentiation, monoclonal antibody series were developed a series of against membrane/extracellular matrix (ECM) molecules through decoy immunization. The anti-PDL13 antibody targets ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), renowned for regulating skeletal and soft tissue mineralization. ENPP1 accumulates in the periodontal ligament region of tooth roots, and specifically localizes to the cell boundaries and elongated processes of the fibroblastic cells. As ENPP1 expression increases during fibroblastic differentiation, mineralization induced by tissue-nonspecific alkaline phosphatase (TNAP), a pyrophosphate-degrading enzyme, is completely inhibited. This is consistent with ENPP1 and TNAP acting in opposition, and TGF-β1-induced ENPP1 expression creates an essential environment for PDL fibroblast differentiation. Representative fibroblastic differentiation markers decrease with endogenous ENPP1 inhibition by siRNA and antibody blocking. ENPP2 generates lipid signaling molecules. In contrast to ENPP1, ENPP2 disappears in TGF-β1-induced PDL fibroblasts. Ectopic expression of ENPP2 hinders TGF-β1-induced PDL fibroblastic differentiation. Suppression of ENPP1 and ENPP2 leads to severe defects in undifferentiated and differentiated cells, demonstrating that these two factors play opposing roles in soft and hard tissue differentiation but can complement each other for cell survival. In conclusion, increased ENPP1 is crucial for TGF-β1-induced PDL differentiation, while ENPP2 and TNAP can inhibit ENPP1. ENPP1 and ENPP2 exhibit complementary functions in the cell survival.
    Keywords:  ENPP1; ENPP2; TGF-β1; fibroblastic differentiation; periodontal ligament stem cells (PDLSC)
    DOI:  https://doi.org/10.3389/fcell.2024.1426762
  51. J Adv Pharm Technol Res. 2024 Jul-Sep;15(3):15(3): 214-219
    New method to induce neurotrophin gene expression in human adipose-derived stem cells in vitro.
    Dhiya Altememy, Maryam Haji Ghasem Kashani, Amirahmadi Fateme, Pegah Khosravian.
      Rosemary leaf extract, a well-known medicinal plant, can induce neurotrophin gene expression and proliferation in stem cells. Human adipose-derived stem cells (hASCs) with high proliferation and differentiation capacity are easily accessible and can be extracted with the least damage. This study evaluated the effect of rosemary extract (RE) on neurotrophin gene expression at 48 h postinduction in hASCs. hASCs were isolated from healthy female donors, aged 28-35 years, who had undergone abdominal liposuction. Passage-4 stem cells were cultured and treated with different doses of RE (from 30 to 70 µg/ml) containing 40% carnosic acid for 48 h. Reverse transcription-polymerase chain reaction was used to check the expression of neurotrophin genes. The expression of NTF3, NTF4, and nerve growth factor genes in cells treated with 40-60 µg/ml and the expression of GDNF in cells treated with 50-70 µg/ml of RE for 48 h showed a significant increase compared to cells cultured in serum-containing medium. However, different doses of RE showed no effect on brain-derived neurotrophic factor gene expression in the treated cells. RE (50, 60 µg/ml) leads to an increase of neurotrophin gene expression in hASCs as compared to routine cell culture. Hence, this protocol can be used to prepare ideal cell sources for cell therapy.
    Keywords:  In vitro culture; neurotrophins; reverse transcription-polymerase chain reaction; rosemary extract
    DOI:  https://doi.org/10.4103/JAPTR.JAPTR_390_23
  52. bioRxiv. 2024 Sep 03. pii: 2024.08.30.610194. [Epub ahead of print]
    Freeze-dried porous collagen scaffolds for the repair of volumetric muscle loss injuries.
    Ivan M Basurto, Ryann D Boudreau, Geshani C Bandara, Samir A Muhammad, George J Christ, Steven R Caliari.
      Volumetric muscle loss (VML) injuries are characterized by the traumatic loss of skeletal muscle resulting in permanent damage to both tissue architecture and electrical excitability. To address this challenge, we previously developed a 3D aligned collagen-glycosaminoglycan (CG) scaffold platform that supported in vitro myotube alignment and maturation. In this work, we assessed the ability of CG scaffolds to facilitate functional muscle recovery in a rat tibialis anterior (TA) model of VML. Functional muscle recovery was assessed following implantation of either non-conductive CG or electrically conductive CG-polypyrrole (PPy) scaffolds at 4, 8, and 12 weeks post-injury by in vivo electrical stimulation of the peroneal nerve. After 12 weeks, scaffold-treated muscles produced maximum isometric torque that was significantly greater than non-treated tissues. Histological analysis further supported these reparative outcomes with evidence of regenerating muscle fibers at the material-tissue interface in scaffold-treated tissues that was not observed in non-repaired muscles. Scaffold-treated muscles possessed higher numbers of M1 and M2 macrophages at the injury while conductive CG-PPy scaffold-treated muscles showed significantly higher levels of neovascularization as indicated by the presence of pericytes and endothelial cells, suggesting a persistent wound repair response not observed in non-treated tissues. Finally, only tissues treated with non-conductive CG scaffolds displayed neurofilament staining similar to native muscle, further corroborating isometric contraction data. Together, these findings show that CG scaffolds can facilitate improved skeletal muscle function and endogenous cellular repair, highlighting their potential use as therapeutics for VML injuries.
    DOI:  https://doi.org/10.1101/2024.08.30.610194
  53. J Med Chem. 2024 Sep 17.
    RNA-Binding Small Molecules in Drug Discovery and Delivery: An Overview from Fundamentals.
    Siyi Chen, Qi Mao, Hong Cheng, Wanyi Tai.
      RNA molecules, similar to proteins, fold into complex structures to confer diverse functions in cells. The intertwining of functions with RNA structures offers a new therapeutic opportunity for small molecules to bind and manipulate disease-relevant RNA pathways, thus creating a therapeutic realm of RNA-binding small molecules. The ongoing interest in RNA targeting and subsequent screening campaigns have led to the identification of numerous compounds that can regulate RNAs from splicing, degradation to malfunctions, with therapeutic benefits for a variety of diseases. Moreover, along with the rise of RNA-based therapeutics, RNA-binding small molecules have expanded their application to the modification, regulation, and delivery of RNA drugs, leading to the burgeoning interest in this field. This Perspective overviews the emerging roles of RNA-binding small molecules in drug discovery and delivery, covering aspects from their action fundamentals to therapeutic applications, which may inspire researchers to advance the field.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c01330
  54. Chin Med. 2024 Sep 15. 19(1): 127
    Machine learning-assisted rapid determination for traditional Chinese Medicine Constitution.
    Wen Sun, Minghua Bai, Ji Wang, Bei Wang, Yixing Liu, Qi Wang, Dongran Han.
      The aim of this study was to develop a machine learning-assisted rapid determination methodology for traditional Chinese Medicine Constitution. Based on the Constitution in Chinese Medicine Questionnaire (CCMQ), the most applied diagnostic instrument for assessing individuals' constitutions, we employed automated supervised machine learning algorithms (i.e., Tree-based Pipeline Optimization Tool; TPOT) on all the possible item combinations for each subscale and an unsupervised machine learning algorithm (i.e., variable clustering; varclus) on the whole scale to select items that can best predict body constitution (BC) classifications or BC scores. By utilizing subsets of items selected based on TPOT and corresponding machine learning algorithms, the accuracies of BC classifications prediction ranged from 0.819 to 0.936, with the root mean square errors of BC scores prediction stabilizing between 6.241 and 9.877. Overall, the results suggested that the automated machine learning algorithms performed better than the varclus algorithm for item selection. Additionally, based on an automated machine learning item selection procedure, we provided the top three ranked item combinations with each possible subscale length, along with their corresponding algorithms for predicting BC classification and severity. This approach could accommodate the needs of different practitioners in traditional Chinese medicine for rapid constitution determination.
    Keywords:  Automated machine learning (AutoML); Constitution in Chinese Medicine Questionnaire (CCMQ); Tree-based Pipeline Optimization Tool (TPOT); Unsupervised machine learning; Variable clustering (varclus)
    DOI:  https://doi.org/10.1186/s13020-024-00992-0
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