bims-traipa 2025-04-27 papers

bims-traipa

Biomed News

on Traumatic brain injury pathophysiology

Issue of 2025–04–27
fourteen papers selected by
Paul Weightman Potter, University of Exeter

Modeling biomarker kinetics of Aβ levels in serum following blast.
Vimentin and p53 Immunoreactivity in Cases of Traumatic Brain Injury.
An Approach for Studying the Direct Effects of Shock Waves on Neuronal Cell Structure and Function.
Balancing Anti-Inflammation and Neurorepair: The Role of Mineralocorticoid Receptor in Regulating Microglial Phenotype Switching After Traumatic Brain Injury.
Decoding Complex Biological Milieus: SHINER's Approach to Profiling and Functioning of Extracellular Vesicle Subpopulations.
The cell biology of Extracellular Vesicles: A jigsaw puzzle with a myriad of pieces.
Extracellular vesicles as precision therapeutics for psychiatric conditions: targeting interactions among neuronal, glial, and immune networks.
Exomeres and supermeres: Current advances and perspectives.
Oxiracetam ameliorates neurological function after traumatic brain injury through competing endogenous RNA regulatory network.
Stability Dynamics of Plant-Based Extracellular Vesicles Drug Delivery.
Natural Products in the Treatment of Neuroinflammation at Microglia: Recent Trend and Features.
Neuroimmune crosstalk in chronic neuroinflammation: microglial interactions and immune modulation.
Influence of Preexisting Diabetes Mellitus on Executive Function Deficits in Adult Traumatic Brain Injury.
Role of Toll-like receptors in exosome biogenesis and angiogenesis capacity.

Front Neurol. 2025 ;16 1548589

Modeling biomarker kinetics of Aβ levels in serum following blast.

Carly Norris, Harsha T Garimella, Walter Carr, Angela M Boutté, Raj K Gupta, Andrzej J Przekwas.

  Elucidating the unique neuropathological response to blast exposure remains a barrier towards the development of diagnostic approaches for those with blast-induced traumatic brain injury (bTBI). Quantification of biomarker concentrations in the blood post-injury is typically used to inform brain injury severity. However, injury progression and associated changes in biomarker concentrations are sensitive to parameters such as the blast overpressure (BOP) magnitude and frequency of blast exposure. Through this work, a blast-dose biomarker kinetics (BxK) platform was developed and validated for Aβ42 as a promising predictor of injury post-blast. Blast-dose responses accounting for BOP magnitude and frequency were integrated into a mathematical model accounting for whole-body Aβ peptide kinetics. Validation of the developed model was performed through comparison with acute monomer levels in the blood serum of 15 service members exposed to repeated low-level blast while undergoing three-day weapons training. Amyloid precursor protein (APP) synthesis was assumed to be proportional to blast magnitude and additive effects within a window of recovery were applied to account for cumulative exposure. Aβ42 concentrations in the blood serum were predicted within 6.5 ± 5.2% on average, demonstrating model feasibility and biomarker sensitivity to blast. Outcomes discuss how modulation of patient-specific factors (age, weight, genetic factors, years of exposure, sleep) and pathophysiological factors (BBB permeability, amyloidogenic pathology, neuroinflammation) can reveal potential sources of variability in experimental data and be incorporated into the blast-dose BxK platform in future iterations. Advancements in model complexity accounting for sex-specific factors, weapon system, stress levels, risk of symptom onset, and pharmacological treatment strategies are anticipated to improve model calibration. Utilization of this blast-dose BxK model to identify drivers of pathophysiological mechanisms and predict chronic outcomes has the potential to transform bTBI diagnostic, prognostic, and therapeutic strategies.

Keywords:  Aβ42; biomarker; blast; brain; diagnostics; modeling; serum

DOI:  https://doi.org/10.3389/fneur.2025.1548589
J Pers Med. 2025 Mar 31. pii: 135. [Epub ahead of print]15(4):

Vimentin and p53 Immunoreactivity in Cases of Traumatic Brain Injury.

Alice Chiara Manetti, Alessandra De Matteis, Gabriele Napoletano, Raffaele La Russa, Aniello Maiese, Paola Frati.

  Background: Traumatic brain injury (TBI) is one of the main causes of death in trauma pathology, especially among the youngest victims. After having evaluated the causality relationship between damage to the brain tissue and death, pathologists should try to estimate the duration between the TBI and death. Immunohistochemistry could be used in this field as a personalized medico-legal approach. This study aims to evaluate the possible role of vimentin and p53 as TBI markers to assess vitality and date the TBI. Methods: Twelve cases of TBI deaths were selected (two women and ten men, with a mean age of 46.83 years). In seven cases, death occurred immediately after the trauma, while in the others, death occurred after some days. An immunohistological study of brain samples using anti-p53 and anti-vimentin antibodies was performed. A semi-quantitative scale was adopted to grade the immunohistochemical reaction. Results: Our results showed a strong relationship between the p53 immunoreaction grade and TBI (X-squared value 10.971, p-value < 0.01), suggesting that p53 expression is enhanced in TBI cases. Vimentin is more expressed when the PTI is longer. Vimentin-immunoreaction was weaker than p53-immunoreaction (+0.75 vs. +1.83 mean values, respectively) in a group predominantly including short post-traumatic interval cases. Conclusions: The present research is limited by the small sample size; however, the molecules tested, vimentin and p53, have shown great potential to be used, in addition to others, as biological markers for the diagnosis and timing of TBI.

Keywords:  forensic neuropathology; p53; traumatic brain injury; vimentin; vitality

DOI:  https://doi.org/10.3390/jpm15040135
Cells. 2025 Apr 09. pii: 563. [Epub ahead of print]14(8):

An Approach for Studying the Direct Effects of Shock Waves on Neuronal Cell Structure and Function.

Michael Hanna, Bryan J Pfister.

  Recent U.S. military conflicts have underscored the knowledge gap regarding the neurological changes associated with blast-induced traumatic brain injury (bTBI). In vitro models of TBIs have the advantage of following the neuronal response to biomechanical perturbations in real-time, which can be exceedingly difficult in animal models. Here, we sought to develop an in vitro approach with controlled blast biomechanics to study the direct effects of the primary shock wave at the neuronal level. A blast injury apparatus mimicking the human skull and cerebrospinal fluid was developed. Primary neuronal cells were cultured inside the apparatus and exposed to a 70 kPa peak blast overpressure using helium gas in a blast tube. Neuronal viability was measured 24 h after blast exposure. The transmission of the pressure wave through the skull is believed to be a factor in injury to the cells of the brain. Three thicknesses in the apparatus wall were studied to represent the range of thicknesses in a human skull. To study the transmission of the shock wave to the neurons, the incident pressure at the apparatus location, as well as internal apparatus pressure, were measured. Analysis of the internal pressure wave revealed that wave oscillation frequency, not amplitude, was a significant factor in cell viability after a bTBI. This finding is related to the viscoelastic properties of the brain and suggests that the transmission of the shock wave through the skull is an important variable in blast injury.

Keywords:  blast injury; in vitro model; intracranial pressure; traumatic brain injury

DOI:  https://doi.org/10.3390/cells14080563
CNS Neurosci Ther. 2025 Apr;31(4): e70404

Balancing Anti-Inflammation and Neurorepair: The Role of Mineralocorticoid Receptor in Regulating Microglial Phenotype Switching After Traumatic Brain Injury.

Bin Zhang, Miao Bai, Mengshi Yang, Yumei Wang, Xueling Zhang, Xiyu Chen, Min Gao, Baiyun Liu, Guangzhi Shi.

   BACKGROUND: As potent anti-inflammatory agents, glucocorticoids (GCs) have been widely used in the treatment of traumatic brain injury (TBI). However, their use remains controversial. Our previous study indicated that although dexamethasone (DEX) exerted anti-inflammatory effects and protected the blood-brain barrier (BBB) by activating the glucocorticoid receptor (GR) after TBI, it also impeded tissue repair processes due to excessive anti-inflammation. Conversely, fludrocortisone, acting as a specific mineralocorticoid receptor (MR) agonist, has shown potential in controlling neuroinflammation and promoting neurorepair, but the underlying mechanisms need further exploration.
OBJECTIVE: This study aimed to explore the impact of the MR agonist fludrocortisone on microglia polarization, angiogenesis, functional rehabilitation, and associated mechanisms after TBI.
METHODS: We established a mice controlled cortical impact model, and then immunofluorescence staining, western blot, rt-PCR, and MRI were performed to investigate microglia polarization, angiogenesis, and brain edema in the ipsilateral hemisphere after TBI and fludrocortisone treatment. Subsequently, functional tests including morris water maze, sucrose preference test, and forced swimming test were conducted to evaluate the effects of fludrocortisone treatment on neurofunction after TBI.
RESULTS: Our results revealed that fludrocortisone suppressed neuroinflammation, enhanced angiogenesis and neuronal survival, and promoted functional rehabilitation by inducing a shift in microglia phenotype from M1 to M2 via the JAK/STAT6/PPARγ pathway. Additionally, the PI3K/Akt/HIF-1α pathway was involved in VEGF expression and in the process of angiogenesis.
CONCLUSION: Fludrocortisone, the specific MR agonist, exerted anti-neuroinflammatory and neuroprotective effects by regulating phenotypic switching of microglia from M1 to M2 rather than suppressing all types of microglia. Our study provided a theoretical basis for the therapeutic strategy of GCs targeting neuroinflammation after TBI.

Keywords:  fludrocortisone; mineralocorticoid receptor microglia polarization; neuroinflammation; traumatic brain injury

DOI:  https://doi.org/10.1111/cns.70404
Small. 2025 Apr 21. e2503638

Decoding Complex Biological Milieus: SHINER's Approach to Profiling and Functioning of Extracellular Vesicle Subpopulations.

Chen-Wei Hsu, Yao-Ching Fang, Jhih-Fong Li, Chi-An Cheng.

  Extracellular vesicles (EVs) are celebrated for their pivotal roles in cellular communication and their potential in disease diagnosis and therapeutic applications. However, their inherent heterogeneity acts as a double-edged sword, complicating the isolation of specific EV subpopulations. Conventional EV isolation methods often fall short, relying on biophysical properties, while affinity-based techniques may compromise EV integrity and utility with harsh recovery conditions. To address these limitations, the SHINER (subpopulation homogeneous isolation and nondestructive EV release) workflow is introduced, which redefines how EVs are isolated and recoverd, featuring the innovative SWITCHER (switchable extracellular vesicle releaser) tool. The SHINER workflow facilitates the precise purification and gentle recovery of target EV subpopulations from complex biological mixtures, preserving their structural integrity and biological functionality. Importantly, SHINER demonstrates exceptional adaptability to multiple markers and clinical applications. It not only enhances the ability to trace EV origins for accurate disease diagnosis but also advances fundamental EV research and provides standardized EV materials for therapeutic innovations. By improving the understanding of EVs and enabling the development of personalized diagnostics and treatments, SHINER propels EV-based science into new frontiers of advanced medicine, offering transformative potential for healthcare.

Keywords:  EV isolation; EV marker; EV recovery; EV therapeutics; extracellular vesicle (EV)

DOI:  https://doi.org/10.1002/smll.202503638
Curr Opin Cell Biol. 2025 Apr 22. pii: S0955-0674(25)00057-2. [Epub ahead of print]94 102519

The cell biology of Extracellular Vesicles: A jigsaw puzzle with a myriad of pieces.

G D'Angelo, P D Stahl, G Raposo.

Extracellular vesicle (EV) research has expanded beyond traditional boundaries, evolving into an inter-kingdom endeavor. First described over 50 years ago, EVs are now recognized as playing diverse roles in basic cellular functions, such as intercellular communication, transport, and cell migration. Their biogenesis and secretion involve complex molecular processes, with cargos that include proteins, lipids, and genetic material. Despite advances, isolation and purification methods are still developing. EVs are present in all body fluids, with different subtypes fulfilling distinct roles. Nonetheless, in biological ecosystems, vesicle diversity can be seen as a strength where each one complements the other in the dialogue between cells and tissues. The involvement of EVs in homeostasis and disease and their well-recognized potential for diagnosis and therapeutics will continue to boost investigations to reveal their fundamental biology.

DOI: https://doi.org/10.1016/j.ceb.2025.102519
Front Immunol. 2025 ;16 1454306

Extracellular vesicles as precision therapeutics for psychiatric conditions: targeting interactions among neuronal, glial, and immune networks.

Ivana Kawiková, Václav Špička, James C K Lai, Philip W Askenase, Li Wen, Zdeněk Kejík, Milan Jakubek, Karel Valeš, Filip Španiel.

  The critical role of the immune system in brain function and dysfunction is well recognized, yet development of immune therapies for psychiatric diseases has been slow due to concerns about iatrogenic immune deficiencies. These concerns are emphasized by the lack of objective diagnostic tools in psychiatry. A promise to resolve this conundrum lies in the exploitation of extracellular vesicles (EVs) that are physiologically produced or can be synthetized. EVs regulate recipient cell functions and offer potential for EVs-based therapies. Intranasal EVs administration enables the targeting of specific brain regions and functions, thereby facilitating the design of precise treatments for psychiatric diseases. The development of such therapies requires navigating four dynamically interacting networks: neuronal, glial, immune, and EVs. These networks are profoundly influenced by brain fluid distribution. They are crucial for homeostasis, cellular functions, and intercellular communication. Fluid abnormalities, like edema or altered cerebrospinal fluid (CSF) dynamics, disrupt these networks, thereby negatively impacting brain health. A deeper understanding of the above-mentioned four dynamically interacting networks is vital for creating diagnostic biomarker panels to identify distinct patient subsets with similar neuro-behavioral symptoms. Testing the functional pathways of these biomarkers could lead to new therapeutic tools. Regulatory approval will depend on robust preclinical data reflecting progress in these interdisciplinary areas, which could pave the way for the design of innovative and precise treatments. Highly collaborative interdisciplinary teams will be needed to achieve these ambitious goals.

Keywords:  extracellular vesicle-based therapies; extracellular vesicles; immune system; neurological and psychiatric disorders; pharmacodynamics; pharmacokinetics; regulatory agencies

DOI:  https://doi.org/10.3389/fimmu.2025.1454306
Bioact Mater. 2025 Aug;50 322-343

Exomeres and supermeres: Current advances and perspectives.

Li Yu, Hui Shi, Tingxin Gao, Wenrong Xu, Hui Qian, Jiajia Jiang, Xiao Yang, Xingdong Zhang.

  Recent studies have revealed a great diversity and complexity in extracellular vesicles and particles (EVPs). The developments in techniques and the growing awareness of the particle heterogeneity have spurred active research on new particle subsets. Latest discoveries highlighted unique features and roles of non-vesicular extracellular nanoparticles (NVEPs) as promising biomarkers and targets for diseases. These nanoparticles are distinct from extracellular vesicles (EVs) in terms of their smaller particle sizes and lack of a bilayer membrane structure and they are enriched with diverse bioactive molecules particularly proteins and RNAs, which are widely reported to be delivered and packaged in exosomes. This review is focused on the two recently identified membraneless NVEPs, exomeres and supermeres, to provide an overview of their biogenesis and contents, particularly those bioactive substances linked to their bio-properties. This review also explains the concepts and characteristics of these nanoparticles, to compare them with other EVPs, especially EVs, as well as to discuss their isolation and identification methods, research interests, potential clinical applications and open questions.

Keywords:  Disease diagnosis and treatment; Exomeres; Nanoparticles; Separation and extraction; Supermeres

DOI:  https://doi.org/10.1016/j.bioactmat.2025.04.012
Psychopharmacology (Berl). 2025 Apr 24.

Oxiracetam ameliorates neurological function after traumatic brain injury through competing endogenous RNA regulatory network.

Liyi Wang, Han Guo, Weidong Zhao, Jiahao Wang, Xuhua Cao.

   RATIONALE: Oxiracetam (ORC) has been demonstrated to improve neurological function resulting from traumatic brain injury (TBI).
OBJECTIVES: This study aims to explore the precise molecular mechanism of ORC in the treatment of TBI.
METHODS: TBI rat model was established and treated with ORC. Modified Garcia score, rotarod test and HE staining were employed to evaluate the neuroprotective effects of ORC. Subsequently, RNA-seq was conducted on the hippocampus of sham, TBI and ORC rats to identify differential expression (DE) lncRNAs and mRNAs. Functional analysis of DE lncRNAs and mRNAs was performed. The real-time quantitative polymerase chain reaction (qRT-PCR) was used to determine the expression of DE lncRNAs and DE mRNAs. Western blot was performed to explore important pathway in ceRNA networks.
RESULTS: ORC has been demonstrated to effectively improve neurological function in TBI rats. A total of 10 ORC-treated DE lncRNAs and 61 DE mRNAs were obtained. A co-expression network comprising 79 lncRNA-mRNA pairs associated with the treatment of ORC was constructed. Furthermore, an lncRNA-miRNA-mRNA regulated ceRNA network was constructed, comprising 15 mRNAs, 41 miRNAs and 10 lncRNAs. Functional enrichment, qRT-PCR, and Western blot analysis showed that ORC improve neurological function of TBI rats by regulating multiple signaling pathways, including the JAK-STAT/PI3K-Akt pathway, as well as affecting the expression of key genes Prlr, Cdkn1a, and Cldn1.
CONCLUSION: Our study reveals the mechanism of ORC therapy in TBI rats, which mainly relies on the regulation of the JAK-STAT/PI3K-Akt pathway and the influence on the expression of key genes Prlr, Cdkn1a, and Cldn1.

Keywords:  Bioinformatics analysis; Competing endogenous RNA; Oxiracetam; Traumatic brain injury; lncRNA-mRNA co-expression network

DOI:  https://doi.org/10.1007/s00213-025-06797-9
J Xenobiot. 2025 Apr 13. pii: 55. [Epub ahead of print]15(2):

Stability Dynamics of Plant-Based Extracellular Vesicles Drug Delivery.

Satyavati Rawat, Sanchit Arora, Madhukiran R Dhondale, Mansi Khadilkar, Sanjeev Kumar, Ashish Kumar Agrawal.

  Plant-based extracellular vesicles (PBEVs) have been recognized for their wide range of applications in drug delivery however, the extent of their medicinal applicability depends on how well they are preserved and stored. Assessing their physicochemical properties, such as size, particle concentration, shape, and the activity of their cargo, forms the foundation for determining their stability during storage. Moreover, the evaluation of PBEVs is essential to ensure both safety and efficacy, which are critical for advancing their clinical development. Maintaining the biological activity of EVs during storage is a challenging task, similar to the preservation of cells and other cell-derived products like proteins. However, despite limited studies, it is expected that storing drug-loaded EVs may present fewer challenges compared to cell-based therapies, although some limitations are inevitable. This article provides a comprehensive overview of current knowledge on PBEVs preservation and storage methods, particularly focusing on their role as drug carriers. PBEVs hold promise as potential candidates for oral drug administration due to their effective intestinal absorption and ability to withstand both basic and acidic environments. However, maintaining their preservation and stability during storage is critical. Moreover, this review centers on the isolation, characterization, and storage of PBEVs, exploring the potential advantages they offer. Furthermore, it highlights key areas that require further research to overcome existing challenges and enhance the development of effective preservation and storage methods for therapeutic EVs.

Keywords:  exosomes; plant-based extracellular vesicles; stability; storage; therapeutic

DOI:  https://doi.org/10.3390/jox15020055
Cells. 2025 Apr 10. pii: 571. [Epub ahead of print]14(8):

Natural Products in the Treatment of Neuroinflammation at Microglia: Recent Trend and Features.

Chi-Su Yoon.

  Natural products (NPs) are considered to be the oldest medicine in human history and numerous NPs have been investigated to search for therapeutic agents in various diseases. Neurodegenerative diseases such as dementia, Parkinson's, Alzheimer's, and Huntington's disease have been increasing following the extension of human lifespans. Neuroinflammation is a key factor in the genesis of several neurodegenerative diseases; therefore, many studies have been focused on finding therapeutics for the reduction in neuroinflammation. Microglia cells are found in the central nervous system (CNS) and these play a crucial role in the regulation of neuroinflammation; thus, the importance of microglia research has been recognized. This review focuses on recent research trends in finding neuroinflammatory regulators in microglia by using NPs.

Keywords:  microglia; natural products; neurodegenerative disease; neuroinflammation

DOI:  https://doi.org/10.3390/cells14080571
Front Cell Neurosci. 2025 ;19 1575022

Neuroimmune crosstalk in chronic neuroinflammation: microglial interactions and immune modulation.

Ludmila Müller, Svetlana Di Benedetto.

  Neuroinflammation is a fundamental feature of many chronic neurodegenerative diseases, where it contributes to disease onset, progression, and severity. This persistent inflammatory state arises from the activation of innate and adaptive immune responses within the central nervous system (CNS), orchestrated by a complex interplay of resident immune cells, infiltrating peripheral immune cells, and an array of molecular mediators such as cytokines, chemokines, and extracellular vesicles. Among CNS-resident cells, microglia play a central role, exhibiting a dynamic spectrum of phenotypes ranging from neuroprotective to neurotoxic. In chronic neurodegenerative diseases, sustained microglial activation often leads to the amplification of inflammatory cascades, reinforcing a pathogenic cycle of immune-mediated damage. Intercellular communication within the inflamed CNS is central to the persistence and progression of neuroinflammation. Microglia engage in extensive crosstalk with astrocytes, neurons, oligodendrocytes, and infiltrating immune cells, shaping both local and systemic inflammatory responses. These interactions influence key processes such as synaptic pruning, phagocytosis, blood-brain barrier integrity, and cytokine-mediated signaling. Understanding the mechanisms of cell-cell signaling in this context is critical for identifying therapeutic strategies to modulate the immune response and restore homeostasis. This review explores the key players in CNS neuroinflammation, with a focus on the role of microglia, the molecular pathways underlying intercellular communication, and potential therapeutic approaches to mitigate neuroinflammatory damage in chronic neurodegenerative diseases.

Keywords:  astrocytes; cytokines; immune cells; microglia; neurodegenerative diseases; neuroimmune crosstalk; neuroinflammation; neurons

DOI:  https://doi.org/10.3389/fncel.2025.1575022
World Neurosurg. 2025 Apr 21. pii: S1878-8750(25)00355-9. [Epub ahead of print] 123999

Influence of Preexisting Diabetes Mellitus on Executive Function Deficits in Adult Traumatic Brain Injury.

Bei-Yi Su, Tee-Tau Eric Nyam, Che-Chuan Wang, Hsin-Fan Wang, Jinn-Rung Kuo.

   BACKGROUND: The study aims to examine the compounded effects of preexisting diabetes mellitus (DM) on executive functions (EFs) in young and middle-aged adults with traumatic brain injury (TBI).
METHODS: We conducted a cross-sectional analysis involving 97 individuals divided into three groups: adults with TBI, adults with both TBI and DM, and a healthy control group. We assessed the participants using various neuropsychological tests and functional status questionnaires.
RESULTS: The study found that participants with both TBI and DM exhibited significantly worse outcomes on measures of EF than those with TBI alone. Additionally, patients with TBI and a history of DM perceived a greater need for assistance with cognitive and emotional issues.
CONCLUSION: These findings underscore the need for integrated care strategies that specifically cater to the heightened neuropsychological impairments in young and middle-aged adults with TBI and DM. Future research should continue to explore these relationships longitudinally to understand and address the long-term impacts of combined TBI and DM on EFs within this age group.

Keywords:  Adult; Brain injury; Diabetes mellitus; Executive functions; Need; Neuropsychological test

DOI:  https://doi.org/10.1016/j.wneu.2025.123999
Bioimpacts. 2025 ;15 30333

Role of Toll-like receptors in exosome biogenesis and angiogenesis capacity.

Parisa Hassanpour, Fatemeh Sadeghsoltani, Mir-Meghdad Safari, Sanya Haiaty, Reza Rahbarghazi, Ali Mota, Mohamad Rahmati.

  Adaptive inflammation consists of multiple cellular changes and molecular reactions to protect host cells against several pathological conditions. Along with the activation of varied immune cells, the production and secretion of cytokines arrays can regulate the progression of inflammatory response in a paracrine manner. Among different molecular cascades, Toll-like receptors (TLRs) are activated in response to several pathological conditions and damage signals. It has been indicated that extracellular vesicles, especially exosomes (Exos) are key bioshuttles with specific cargoes and are involved in cell-to-cell communication. The role of Exos in the initiation, progression, and cession of inflammation has been previously addressed in terms of cytokine transmission. Whether and how the activation of TLRs can alter the Exo biogenesis and angiogenesis potential in immune cells and endothelial cells (ECs) remains to be elucidated. Here, the cross-talk between the TLRs, Exo biogenesis, and angiogenesis has been highlighted.

Keywords:  Angiogenesis; Endothelial cells; Exocytosis; Exosomes; Immune cells; Toll-like receptors

DOI:  https://doi.org/10.34172/bi.30333