bims-hisfre 2025-06-15 papers

bims-hisfre

Biomed News

on HSF1 and Creatine

Issue of 2025–06–15
eleven papers selected by
James Heilman, Oregon Health & Science University

Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.
Neuron-Derived Extracellular Vesicles: Emerging Biomarkers and Functional Mediators in Alzheimer's Disease, With Comparative Insights Into Neurodevelopment and Aging.
Comprehensive account of exosome isolation from rat substantia nigra for mass spectrometry-based proteomics study.
Extracellular vesicle-mediated mitochondria delivery: Premise and promise.
Protrusion-Derived Extracellular Vesicles (PD-EVs) and Their Diverse Origins: Key Players in Cellular Communication, Cancer Progression, and T Cell Modulation.
The Role of Extracellular Vesicles in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease and Other Liver Diseases.
Functional significance of extracellular vesicles as mediators of cardiometabolic and cardiorenal diseases upon aging.
The Use of Extracellular Vesicles as a Promising Therapeutic Approach for Pulmonary Diseases.
The role of small extracellular vesicles in post-traumatic stress disorder.
Extracellular HSP90-Facilitated Degradation of Extracellular and Membrane Proteins by Bifunctional Small Molecules.
Small Extracellular Vesicles Derived From Damaged Muscle Aggravate Kidney Injury Progression.

Cells. 2025 Jun 04. pii: 845. [Epub ahead of print]14(11):

Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.

Jessica Tittelmeier, Carmen Nussbaum-Krammer.

  Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann-Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases.

Keywords:  lipostasis; lysosomal lipid storage diseases; lysosome; neurodegenerative diseases; prion-like propagation; proteostasis; sphingolipidoses

DOI:  https://doi.org/10.3390/cells14110845
Dev Neurobiol. 2025 Jul;85(3): e22984

Neuron-Derived Extracellular Vesicles: Emerging Biomarkers and Functional Mediators in Alzheimer's Disease, With Comparative Insights Into Neurodevelopment and Aging.

Ceren Perihan Gonul, Bilge Karacicek, Sermin Genc.

  Alzheimer's disease (AD) is one of the most common neurodegenerative disorders characterized by the accumulation of amyloid-β (Aβ) peptide and phosphorylated tau protein in the brain. Despite intensive efforts, early diagnosis and monitoring of AD remain challenging due to the lack of reliable biomarkers that can detect the disease in its preclinical stages. As a result, there exists a requirement for novel approaches to the diagnosis and treatment of the disease. Extracellular vesicles provide the transfer of Aβ peptides and tau proteins between the cells and participates in the spreading/propagation of disease pathology. Neuron-derived extracellular vesicles (NDEVs) that are found in plasma have emerged as promising candidates, especially for biomarker studies on neurodegenerative diseases because they are reachable and comparable with cerebrospinal fluid (CSF) studies. In addition to known proteins, synaptic proteins, transcription factors, or microRNAs have been suggested as new biomarkers, aiming to help differential or early diagnosis. Beyond their involvement in AD pathology, NDEVs also play essential roles in neurodevelopment and aging by mediating cell-to-cell communication and regulating processes such as synaptic formation, neuronal differentiation, and neuroinflammation. Age-related alterations in EV composition and secretion may contribute to the decline in neuroplasticity, thereby increasing susceptibility to neurodegenerative diseases like AD. Several challenges such as heterogeneous isolation of NDEVs limit the widespread clinical application of them as biomarkers for AD. Furthermore, the lack of standardized protocols for vesicle isolation and molecular analysis poses a barrier to reproducibility and clinical validation. The aim of this review is to elucidate the role of NDEVs in AD pathogenesis in comparison with their functions in neurodevelopment and aging, evaluate their potential as biomarkers for early diagnosis, while addressing the challenges in their isolation, characterization, and clinical application.

Keywords:  Alzheimer's disease; aging; biomarker; extracellular vesicle; neurodevelopment; neuron‐derived extracellular vesicles

DOI:  https://doi.org/10.1002/dneu.22984
Methods. 2025 Jun 06. pii: S1046-2023(25)00142-2. [Epub ahead of print]241 150-162

Comprehensive account of exosome isolation from rat substantia nigra for mass spectrometry-based proteomics study.

Satyajit Ghosh, Surojit Ghosh, Aniket Jana, Rajsekhar Roy, Surajit Ghosh.

Exosomes, small extracellular vesicles originating from endocytic processes, have garnered increasing attention due to their roles in both physiological functions and pathological conditions. Initially identified in the 1980 s, exosomes are formed within multivesicular bodies (MVBs) through the invagination of the endosomal membrane, leading to the creation of intraluminal vesicles (ILVs). These ILVs can either be degraded by lysosomes or released into the extracellular space as exosomes, facilitating intercellular communication. In the nervous system, exosomes are implicated in various functions, including neural development and the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. This study presents a novel protocol for the isolation and proteomic analysis of exosomes derived from the substantia nigra (SN) of rat brains. By employing a combination of differential centrifugation and immunocapture techniques, we achieved a purer exosome fraction and higher exosome yield compared to traditional ultracentrifugation methods. Our proteomics analysis identified 51, 48, and 70 proteins from three distinct exosome samples (SN-EV-1, SN-EV-2, and SN-EV-4), with Gene Ontology annotation revealing their involvement in diverse biological functions. This research not only establishes a reliable method for isolating brain-derived exosomes but also sets the stage for comparative studies between healthy and neurodegenerative conditions. Ultimately, our findings aim to enhance the understanding of exosomal roles in disease mechanisms and contribute to the identification of potential biomarkers and therapeutic targets for neurodegenerative disorders.

DOI: https://doi.org/10.1016/j.ymeth.2025.06.002
J Cereb Blood Flow Metab. 2025 Jun 11. 271678X251349304

Extracellular vesicle-mediated mitochondria delivery: Premise and promise.

Devika S Manickam, Paromita Paul Pinky, Purva Khare.

  Mitochondrial transfer is highly significant under physiological as well as pathological states given the emerging recognition of mitochondria as cellular "processors" akin to microchip processors that control the operation of a mobile device. Mitochondria play indispensable roles in healthy functioning of the brain, the organ with the highest energy demand in the human body and therefore, loss of mitochondrial function plays a causal role in multiple brain diseases. In this review, we will discuss various aspects of extracellular vesicle (EV)-mediated mitochondrial transfer and their effects in increasing recipient cell/tissue bioenergetics with a focus on these processes in brain cells. A subset of EVs with particle diameters >200 nm, referred to as medium-to-large EVs (m/lEVs), are known to entrap mitochondria during EV biogenesis. The entrapped mitochondria are likely a combination of either polarized, depolarized mitochondria or a mixture of both. We will also discuss engineering approaches to control the quality and quantity of mitochondria entrapped in the m/lEVs. Controlling mitochondrial quality can allow for optimizing/maximizing the therapeutic potential of m/lEV mitochondria-a novel drug with immense potential to treat a wide range of disorders associated with mitochondrial dysfunction.

Keywords:  Extracellular vesicles (EVs); medium-to-large EVs; microvesicles; mitochondria; small EVs

DOI:  https://doi.org/10.1177/0271678X251349304
Biol Cell. 2025 Jun;117(6): e70018

Protrusion-Derived Extracellular Vesicles (PD-EVs) and Their Diverse Origins: Key Players in Cellular Communication, Cancer Progression, and T Cell Modulation.

Mireia Gomez Duro, Lucas Alves Tavares, Izadora Peter Furtado, Julien Saint-Pol, Gisela D'Angelo.

  Protrusion-derived extracellular vesicles (PD-EVs) are a specialized subset of extracellular vesicles (EVs) generated from dynamic cellular extensions. These structures play a crucial role in cellular communication and have emerged as pivotal mediators in various biological processes, including cancer progression and immune modulation. In cancer, PD-EVs facilitate tumor growth, invasion, and metastasis by delivering oncogenic cargo that remodels the tumor microenvironment, promotes angiogenesis, and supports immune evasion. They are also implicated in establishing pre-metastatic niches and enabling cancer cells to colonize distant organs. PD-EVs are characterized by a distinct molecular signature linked to their origin from specialized plasma membrane domains. Their unique composition makes them promising biomarkers for early cancer detection, disease monitoring, metastatic potential assessment, and therapeutic response evaluation. Targeting PD-EV biogenesis, release, or uptake represents a novel therapeutic strategy to disrupt tumor progression and overcome resistance to current treatments. However, distinguishing PD-EVs from other EV subtypes remains challenging due to overlapping characteristics. This review consolidates the latest evidence on PD-EVs, focusing on their biogenesis, limitations in their study, functional roles in cancer, and potential applications in diagnostics and therapeutics, especially concerning immune modulation and T-cell activation.

Keywords:  PD‐EV biogenesis; T‐cell activation; cancer progression; cellular protrusions; cell‐cell communication; immune response; protrusion‐derived extracellular vesicles (PD‐EVs)

DOI:  https://doi.org/10.1111/boc.70018
Int J Mol Sci. 2025 May 23. pii: 5033. [Epub ahead of print]26(11):

The Role of Extracellular Vesicles in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease and Other Liver Diseases.

Elena Grossini, Mohammad Mostafa Ola Pour, Sakthipriyan Venkatesan.

  The increasing prevalence of liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD), presents considerable medical challenges, particularly given the absence of approved pharmacological treatments, which underscores the necessity to comprehend its underlying mechanisms. Extracellular vesicles (EVs), which are tiny particles released by cells, play a crucial role in facilitating communication and can transport harmful molecules that promote inflammation and tissue damage. These EVs are involved in the progression of various types of liver disorders since they aggravate inflammation and oxidative stress. Because of their critical role, it is believed that EVs are widely involved in the initiation and progression of MASLD, as well as in viral hepatitis, alcoholic liver disease, drug-induced liver injury, and hepatocellular carcinoma. This review emphasizes recent findings regarding the functions of EVs in the above liver pathologies and underscores their potential as new therapeutic targets, paving the way for innovative approaches to address those detrimental liver conditions.

Keywords:  alcoholic liver disease; exosomes; microvesicles; mitochondrial dysfunction; pathogenesis; viral hepatitis

DOI:  https://doi.org/10.3390/ijms26115033
Mech Ageing Dev. 2025 Jun 05. pii: S0047-6374(25)00054-5. [Epub ahead of print]226 112078

Functional significance of extracellular vesicles as mediators of cardiometabolic and cardiorenal diseases upon aging.

Wing Yan Chung, Sabrina Lam, Brooke Pernari, Yoojung Kim, Ssang-Goo Cho, Dylan Burger, Gary Sweeney.

  Aging increases the risk of cardiometabolic and cardiorenal disease and this is associated with cellular dysregulation including oxidative stress, chronic inflammation, insulin resistance and senescence. Extracellular vesicles (EV) facilitate inter-organ communication and are now well established as important pathophysiological mediators in many aging-associated diseases. Our knowledge of EV biosynthesis, cargo composition, cellular targeting and functional effects has expanded significantly over the past decade. Here we provide a comprehensive review on the characteristics and functional significance of EV in cardiometabolic and cardiorenal diseases in the context of aging. Specifically, we focus on heart failure, type 2 diabetes, metabolic dysfunction-associated steatohepatitis (MASH), hypertension, and chronic kidney disease and discuss aging-associated changes in bioactive molecules transferred via EV and how these are associated with healthspan. Furthermore, we summarize current potential therapeutic applications of EV. Overall, this review summarizes current knowledge indicating an important role for EV in aging-related cardiometabolic and cardiorenal diseases, and how insights from basic research can potentially be translated to the clinic in order to combat aging-associated metabolic decline and improve longevity and healthspan.

Keywords:  Cardiometabolic diseases; Cardiorenal diseases; Chronic kidney disease; Extracellular vesicles; Heart failure; Hypertension; Metabolic dysfunction-associated steatohepatitis; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.mad.2025.112078
Health Sci Rep. 2025 Jun;8(6): e70853

The Use of Extracellular Vesicles as a Promising Therapeutic Approach for Pulmonary Diseases.

Sirous Sadeghian Chaleshtori, Zanyar Pirkani, Massoumeh Jabbari Fakhr, Mona Mokhber.

   Background and Aims: Pulmonary disorders significantly impact worldwide healthcare, highlighting the necessity for enhanced diagnostic and treatment approaches. This narrative review seeks to investigate the potential of extracellular vesicles (EVs) as an innovative therapeutic strategy for diverse pulmonary disorders.
Methods: This review synthesizes existing data about the function of extracellular vesicles (EVs) in pulmonary health and pathology, emphasizing their modes of action, including the transfer of proteins, nucleic acids, and lipids for intercellular communication. It also examines the implications of EVs in targeted medication delivery, immunomodulation, and tissue regeneration.
Results: EVs, including microvesicles and exosomes, have demonstrated promise in treating respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, and acute respiratory distress syndrome (ARDS). Additionally, EVs may serve as valuable biomarkers for early disease detection, prognosis, and monitoring. However, challenges remain regarding the standardization of EV isolation methods and characterization protocols to ensure safety and clinical applicability.
Conclusion: In summary, extracellular vesicles hold potential for transforming the management of pulmonary diseases by providing insights into pathophysiology, enabling early diagnosis, and facilitating personalized treatment approaches. Further exploration of EV-based therapies is necessary to fully realize their potential in improving outcomes for lung disorders.

Keywords:  diagnostic; extracellular vesicles; pulmonary diseases; therapeutic

DOI:  https://doi.org/10.1002/hsr2.70853
Glob Med Genet. 2025 Sep;12(3): 100063

The role of small extracellular vesicles in post-traumatic stress disorder.

Haixin Zhang, Qile Zhang, Shicheng Li, Fanzhen Kong.

  Post-Traumatic Stress Disorder (PTSD) represents a significant mental health challenge closely associated with the consequences of traumatic experiences. Recently, small extracellular vesicles (sEVs) have been recognized as vital elements in the facilitation of intercellular communication. This review delves into the potential roles and mechanisms of sEVs in PTSD, concentrating on their involvement in neural signaling, immune system reactions, and the modulation of molecular biomarkers related to psychological disorders. By integrating recent research outcomes, this article aims to provide fresh insights into the pathophysiological aspects of PTSD and investigate prospective therapeutic approaches, underlining the significance of sEVs within the broader context of stress-related conditions.

Keywords:  Molecular biomarkers; Post-traumatic stress disorder; Small extracellular vesicles

DOI:  https://doi.org/10.1016/j.gmg.2025.100063
J Med Chem. 2025 Jun 11.

Extracellular HSP90-Facilitated Degradation of Extracellular and Membrane Proteins by Bifunctional Small Molecules.

Dongli Zhang, Jie Li, Yaqi Liang, Tao Li, Ming Ji, Xinmin Liu, Wenxin Li, Pengxiao Chen, Jiamin Zhang, Zhengduo Yang, Lulu Wang, He Chen.

Lysosome-targeting chimeras represent a promising strategy for degrading extracellular and membrane proteins via the lysosomal pathway, but the available receptor options remain limited. Herein, we report a novel strategy utilizing extracellular heat shock protein 90 (eHSP90) to facilitate lysosomal degradation of target proteins through bifunctional small molecules, termed extracellular heat shock protein 90-targeting chimeras (eHSPTACs). By connecting an HSP90 ligand to a target protein ligand, eHSPTACs effectively induced the internalization and subsequent lysosomal degradation of extracellular Alexa Fluor 488-labeled α-DNP antibody and membrane programmed cell death-ligand 1 (PD-L1). Notably, dPDL1-4 selectively degraded membrane PD-L1 in tumor cells over normal cells, leveraging the elevated expression of eHSP90 in cancer cells. Moreover, dPDL1-4 demonstrated robust in vivo degradation of membrane PD-L1 and significant tumor growth suppression in the B16F10 syngeneic mouse model. Overall, eHSPTACs offer a general platform for tumor-selective degradation of extracellular and membrane proteins, providing a new therapeutic avenue.

DOI: https://doi.org/10.1021/acs.jmedchem.5c00379
J Cachexia Sarcopenia Muscle. 2025 Jun;16(3): e13861

Small Extracellular Vesicles Derived From Damaged Muscle Aggravate Kidney Injury Progression.

Songling Jiang, Seunghee Kang, Oran Kwon, Wonhyo Seo, Eun-Jung Jin, Hunjoo Ha, Joo Young Huh.

   BACKGROUND: Muscle atrophy is commonly associated with kidney dysfunction in patients with renal disease. However, the effects of skeletal muscle loss per se on kidney function have not been fully elucidated. Here, we examined muscle-kidney crosstalk by evaluating the role of muscle-derived small extracellular vesicles (EVs) on the progression of kidney injury.
METHODS: A denervation-induced muscle loss model was established, and kidney inflammation and fibrosis were evaluated in unilateral ureteral obstruction (UUO)-induced kidney injury and adenine diet-induced chronic kidney disease models. Changes in small EV markers (CD9, CD63, CD81 and Alix) were measured. GW4869, an inhibitor of EV biogenesis and release, was used to confirm the role of denervated muscle-derived small EVs on the progression of kidney fibrosis. To obtain direct evidence on the crosstalk, EVs were isolated from plasma of denervated mice and conditioned media from differentiated myotubes and treated in vivo and in vitro. To determine the effect of exercise-induced EVs on kidney fibrosis, EVs isolated from exercised mice and trained humans were treated to TGFβ1-stimulated mProx24 renal tubular epithelial cells.
RESULTS: Denervation aggravated kidney injury, as shown by a 10% increase in albuminuria and upregulation of inflammatory and fibrotic markers in the kidney. Significant interactions between denervation and UUO were observed for renal αSMA (F = 47.19, p < 0.0001) and FN (F = 19.06, p = 0.0001) expression. EV production and secretion were markedly increased in damaged muscle, both in vivo and in vitro. Pharmacological depletion of EVs using GW4869 via intraperitoneal and intramuscular injection reduced kidney injury by over 20%. Furthermore, injection of EVs from denervated muscle into UUO mice, as well as treatment of mProx24 cells with EVs from either denervated mice or damaged C2C12 myotubes, significantly amplified renal injury. Among the EV cargo, miR-21a-3p-identified as a regulator of Ppargc1a-was elevated over 10-fold in EVs from denervated muscle compared with sham controls. Importantly, EV-induced injury in mProx24 cells was reversed by pretreatment with a miR-21a inhibitor. In contrast, exercise downregulated miR-21a-3p expression in muscle, and EVs derived from exercised mice and humans attenuated kidney fibrosis.
CONCLUSIONS: Our findings provide novel evidence that skeletal muscle loss can serve as an upstream contributor to kidney disease. Muscle-derived EVs from damaged tissue exacerbate, while those from exercised muscle ameliorate, kidney injury, partly through miR-21a-3p regulation. These results highlight the critical role of miRNAs within muscle-derived EVs in maintaining kidney homeostasis and suggest their potential as therapeutic targets.

Keywords:  extracellular vesicles; kidney injury; microRNA; muscle atrophy; muscle–kidney crosstalk

DOI:  https://doi.org/10.1002/jcsm.13861