bims-hisfre Biomed News
on HSF1 and Creatine
Issue of 2025–06–29
six papers selected by
James Heilman, Oregon Health & Science University
  1. Vesicular trafficking and cell-cell communication in neurodevelopment and neurodegeneration.
  2. Denaturation of firefly luciferase at heat shock temperatures captured in silico.
  3. Oxidative Stress in Neurodegenerative Disorders: A Key Driver in Impairing Skeletal Muscle Health.
  4. External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.
  5. Stress Management: How the Endoplasmic Reticulum Mitigates Protein Misfolding and Oxidative Stress by the Dual Role of Glutathione Peroxidase 8.
  6. Neuroprotective Proteins in Hypoxia-stressed Astrocyte-Derived Extracellular Vesicles.
  1. Front Cell Dev Biol. 2025 ;13 1600034
    Vesicular trafficking and cell-cell communication in neurodevelopment and neurodegeneration.
    Salma Amin, Elena Taverna.
      Regulation of vesicle biology and trafficking plays a critical role in cell viability. Vesicular trafficking is a process that entails vesicle biogenesis, transport, and sorting of materials such as proteins, enzymes, hormones, and neurotransmitters to different cellular compartments. This phenomenon is especially important in cells of the central nervous system, including neural progenitors, neurons, and glial cell populations, because of their highly polarized architecture. In line with that, disruption in vesicular trafficking during cortical development affects progenitor proliferation and differentiation and leads to brain malformations. On the other hand, neuronal cells require long-range vesicular trafficking to reach distant locations, such as the distal part of the axons, and synaptic vesicles are essential for cell-cell communication. Neurons have high energy demands. Therefore, any malfunction in vesicular trafficking is a trigger to spiraling into neurodegeneration. Here, we give a comprehensive review of the role of intracellular and extracellular vesicles in cortical development and neurodegeneration, and we discuss how trafficking between organelles in specific cell types contributes to brain pathologies. Finally, we highlight the emerging evidence linking disruption in vesicular trafficking to neurological disorders such as Alzheimer's disease, Parkinson's disease, and autism.
    Keywords:  brain development; golgi apparatus; lysosomes; neural stem cells; neurons; retrograde and anterograde transport
    DOI:  https://doi.org/10.3389/fcell.2025.1600034
  2. Biophys J. 2025 Jun 19. pii: S0006-3495(25)00381-9. [Epub ahead of print]
    Denaturation of firefly luciferase at heat shock temperatures captured in silico.
    Vishal D Lashkari, Piotr E Marszalek.
      Firefly luciferase (Fluc) is a bioluminescent protein that is widely used in cell and molecular biology research. Specifically, it is a gold standard substrate in chaperone protein studies because its bioluminescence decrease and recovery are related to Fluc misfolding and chaperone-assisted refolding, respectively. Fluc is moderately stable at room temperature but quickly loses bioluminescent activity at elevated temperatures as a stable, misfolded conformation is induced which persists upon cooling Fluc to room temperature. The heat shock protein 70 chaperone system can revert such structural changes, restoring bioluminescent activity. While thermal denaturation of Fluc is often used in chaperone-assisted refolding reactions, little is known about the specific structural alterations that occur in Fluc at heat shock temperatures. In this study, we use comprehensive all-atom molecular dynamics simulations to investigate the structural dynamics of Fluc at room (∼25 °C) and heat shock temperatures (∼42 °C). We conduct simulations totaling over 100 μs across replicates which allows a misfolded equilibrium to be approached. We find that at heat shock temperatures, Fluc undergoes subtle but long-lasting and reproducible conformational changes, namely the complete and irreversible denaturation of the α-helix at residues 405-411. We show the potential for this discrete change to inhibit Fluc bioluminescent activity. This consistent α-helix denaturation, along with other small secondary structure changes outlined in this work, are potential targets for chaperone systems known to restore Fluc activity after thermal denaturation. Therefore, our results inform a refined mechanism for chaperone-assisted refolding in which chaperone proteins may restore protein function by fixing localized structural perturbations as opposed to refolding an entirely denatured polypeptide chain.
    Keywords:  bioluminescence; chaperone proteins; luciferase; molecular dynamics; protein folding; thermal denaturation
    DOI:  https://doi.org/10.1016/j.bpj.2025.06.021
  3. Int J Mol Sci. 2025 Jun 16. pii: 5782. [Epub ahead of print]26(12):
    Oxidative Stress in Neurodegenerative Disorders: A Key Driver in Impairing Skeletal Muscle Health.
    Serena Castelli, Emily Carinci, Sara Baldelli.
      The fine regulation of antioxidant systems and intracellular production of reactive oxygen species (ROS) is responsible for cellular redox balance. The main organelles responsible for ROS production are mitochondria, and they complete this process through the electron transport chain. These potentially harmful molecules are buffered by enzymatic and non-enzymatic antioxidant systems. Oxidative stress is determined by an imbalance between the production and clearance of ROS in favor of the accumulation of these detrimental species, which generate cellular damage by interacting with macromolecules. In neurodegenerative diseases, oxidative stress has been demonstrated to be a crucial component, both causal and consequential to the disease itself. On the other hand, neurodegeneration disrupts neuromuscular junctions, leading to reduced muscle use and subsequent atrophy. Additionally, systemic inflammation and metabolic dysfunction associated with neurodegenerative diseases exacerbate muscle degeneration. Thus, sarcopenia and atrophy are common consequences of neurodegeneration and play a significant role in these disorders. Regarding this, ROS have been defined as promoting sarcopenia, stimulating the expression of genes typical of this condition. Overall, this review aims to contribute to filling the gap in the literature regarding the consequences at the muscular level of the relationship between oxidative stress and neurodegenerative diseases.
    Keywords:  atrophy; neurodegenerative disease; oxidative stress; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms26125782
  4. Sci Adv. 2025 Jun 27. 11(26): eads6132
    External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.
    Ziming Chen, Peilin Chen, Jiayue Li, Euphemie Landao-Bassonga, John Papadimitriou, Junjie Gao, Delin Liu, Andrew Tai, Jinjin Ma, David Lloyd, Brendan F Kennedy, Ming Hao Zheng.
      Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.
    DOI:  https://doi.org/10.1126/sciadv.ads6132
  5. Biomolecules. 2025 Jun 10. pii: 847. [Epub ahead of print]15(6):
    Stress Management: How the Endoplasmic Reticulum Mitigates Protein Misfolding and Oxidative Stress by the Dual Role of Glutathione Peroxidase 8.
    Yong Yang, Hao Peng, Danni Meng, Zizhu Fa, Chen Yao, Xinyu Lin, Joel Schick, Xiang Jin.
      The endoplasmic reticulum mediates essential processes such as protein folding, transport, and post-translational modifications. Disruptions in endoplasmic reticulum function can lead to the accumulation of unfolded or misfolded proteins, initiating endoplasmic reticulum stress. This stress activates the unfolded protein response, a multifaceted signaling pathway aimed at restoring proteostasis, which is crucial for cellular survival and fate determination. This review summarizes the current knowledge of three major branches of the unfolded protein response: the IRE1, PERK, and ATF6 signaling pathways. A key novel component in endoplasmic reticulum stress adaptation is the redox-sensitive enzyme glutathione peroxidase 8 (GPX8), which plays a dual role in detoxifying hydrogen peroxide and supporting proper protein folding. By connecting unfolded protein response branches, GPX8 reduces oxidative damage while maintaining redox homeostasis, emphasizing its importance in endoplasmic reticulum stability. Furthermore, plant glutathione peroxidases exhibit parallel functions in endoplasmic reticulum redox homeostasis and unfolded protein response activation, highlighting the evolutionary conservation of this protective mechanism across kingdoms. Understanding the intricate relationship between GPX8, endoplasmic reticulum stress, and unfolded protein response signaling provides novel insights into therapeutic strategies for diseases characterized by protein folding defects and oxidative stress.
    Keywords:  GPX8; endoplasmic reticulum; oxidative stress; reactive oxygen species; unfolded protein response
    DOI:  https://doi.org/10.3390/biom15060847
  6. Curr Neuropharmacol. 2025 Jun 19.
    Neuroprotective Proteins in Hypoxia-stressed Astrocyte-Derived Extracellular Vesicles.
    Berenice N Bernal Vicente, Isaac Ponce, Manuel Santos Gutiérrez, Emmanuel Ríos Castro, Luis B Tovar-Y-Romo.
       BACKGROUND: Mass spectrometry-based proteomic analysis advancements have generated extensive protein data from cells involved in neurodegenerative diseases. The field of neuroproteomics is expanding to include the study of extracellular vesicles (EVs) to identify potential biomarkers for disease prevention and endogenous factors involved in neuroprotection.
    METHODS: In this study, the cortical astrocytes in normoxia were cultured and subjected to hypoxic conditions and obtained astrocyte-derived EVs released in supernatant separately then performed label- free mass spectrometry-based proteomics of these EVs to determine which is the effect of the hypoxic event on the cargo proteins. A meta-analysis of the results compared with previously published databases was conducted. Data was deposited in the ProteomeXchange Consortium with the identified PXD050160.
    RESULTS: This study revealed a differential expression of 83 upregulated proteins under hypoxic conditions and 61 downregulated proteins under normoxic conditions, highlighting the protective protein signatures elicited by astrocytes.
    CONCLUSION: The present study makes a novel contribution by employing proteomic techniques to characterize the protein cargo of EVs isolated from primary rat astrocytes. This approach allows for a more refined analysis of astrocyte-specific intercellular signaling under hypoxic conditions. It offers valuable insights into the roles of astrocytes in maintaining brain homeostasis and contributing to pathological processes.
    Keywords:  Astrocyte; EV cargo; extracellular vesicles; hypoxia; meta-analysis; neuroprotection; proteomics; stroke.
    DOI:  https://doi.org/10.2174/011570159X359837250611052037
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