bims-lypmec 2025-10-12 papers

Sci Bull (Beijing). 2025 Sep 10. pii: S2095-9273(25)00925-9. [Epub ahead of print]

Structural insight into GPR155-mediated cholesterol sensing and signal transduction.

Delin Li, Xiaokang Zhang, Jie Feng, Yufeng Xie, Pu Han, Ming He, Lin Hao, Tianling Guo, Xiaoyi Bai, Kai Yuan, Junqing Sun, Xuefei Pang, Yan Wu, Yingxia Liu, George Fu Gao, Niu Huang, Haixia Xiao, Feng Gao.

Cholesterol (CHL) serves as a building block for membrane biogenesis and a precursor to oxysterols, steroid hormones, bile acids, and vitamin D. The lysosome serves as a major sorting station for low-density lipoproteins (LDLs), which carry dietary CHL, and it is also the cellular site where the master growth regulator, the protein kinase mechanistic Target of Rapamycin Complex 1 (mTORC1), is activated. Recently, the lysosomal transmembrane protein GPR155 was reported to signals CHL sufficiency to mTORC1 through sequestration of the GTPase-activating protein towards the Rags 1 (GATOR1). Although the recently reported structures of GPR155 have revealed the CHL binding site, how the signal is transduced from the CHL binding site to the soluble parts of GPR155 and GATOR1 remains unknown. Here, with our three cryo-EM structures of GPR155 captured in different conformations in complex with CHL, complemented by long-time scale molecular dynamics simulations, the dynamic rearrangement of different domains was observed. CHL binding induces a widening of the crevice between the transporter and GPCR domains. The extending helix preceding transmembrane helix (TM) 16, which was unresolved in other structures, acts as a linkage lever that transmits the rotation of the GPCR domain to the soluble parts of GPR155 in response to CHL binding. This work not only answers the question of how CHL is sensed by GPR155, but also addresses a more profound question: how the signal perceived by the TMs regions is transduced to the LED and DEP domains.

Keywords: Cholesterol; GATOR1; GPCR; LYCHOS; Transporter; mTORC1

DOI: https://doi.org/10.1016/j.scib.2025.09.012

Anal Chem. 2025 Oct 09.

Visual Whole-Process Monitoring Dynamic Phase Separation of Autophagic Lysosomes in Alzheimer's Disease by a Lysosome-Targeted pH-Activated Fluorescence Probe.

Fei Gao, Wanquan Lin, Tingting Zhao, Jinlong Zhang, Dong Pei, Duolong Di, Zhongxiong Fan, Lichao Yang, Jun Hai.

Although liquid-liquid phase separation (LLPS) of amyloid-β (Aβ) aggregates is a critical driver of Alzheimer's disease (AD) progression, the role of lysosomal acidification defects remains poorly understood during this process. Herein, we successfully develop a synthetic strategy involving the construction of pH-activated probe backbones by the atom transfer radical polymerization technique with methacrylates with different substituents as monomers. Subsequently, a fluorescence probe is prepared by integrating hydrophobic aggregation-induced luminescence (AIE) fluorescence dyes and aggregation-induced bursting (ACQ) dyes into ACQ/AIE ratio imaging nanoparticles through covalent bonding and self-assembly techniques. Such AIE probe can monitor lysosomal acidification defects in AD and elucidate their role in Aβ phase separation. Interestingly, our new findings reveal that Aβ accumulation synergizes with lysosomal dysfunction (the pH value itself has not changed) to induce pathological LLPS, thereby providing a novel approach for phase modulation and attenuating AD progression. Taken together, our design concept provides a novel strategy to regulate phase separation, potentially reducing or delaying Aβ aggregation and AD progression.

DOI: https://doi.org/10.1021/acs.analchem.5c02994

FASEB J. 2025 Oct 15. 39(19): e71104

Exploring the Role of Exercise and the Lysosomal Cathepsin Family in the Regulation of Vascular-Musculoskeletal Degenerative Diseases.

Kangcheng Fan, Xin Li, Zhuo Wang.

Musculoskeletal degenerative diseases significantly compromise patient quality of life through muscle loss, bone fragility, and cartilage degeneration. Given the established link between vascular aging and musculoskeletal disorders, the vascular-skeletomuscular axis represents a complex network wherein conditions interact via mechanisms including impaired blood flow, inflammation, oxidative stress, and hormonal imbalances. As pharmacological interventions targeting lysosomal cathepsins face developmental and application challenges, exploring non-pharmacological alternatives becomes imperative. This review investigates the regulatory roles of the lysosomal cathepsin family, especially cathepsins B, K, and L, in musculoskeletal degenerative diseases and evaluates how exercise interventions modulate their activities. It proposes exercise as a viable non-pharmacological strategy to selectively influence lysosomal cathepsin functions, thereby offering therapeutic potential in managing vascular-musculoskeletal degenerative diseases. The review elucidates several key concepts: the intricate interaction between vascular aging and musculoskeletal degenerative pathologies; the pivotal roles of lysosomal cathepsins in disease progression through metabolic regulation, inflammatory modulation, macrophage polarization, and autophagy dysfunction; and the multifaceted mechanisms by which exercise influences cathepsin activity, including calcium homeostasis, cellular energy metabolism enhancement, inflammatory response reduction, autophagy stimulation, myokine secretion, and vascular function improvement. This comprehensive analysis provides novel insights into exercise as a selective modulator of lysosomal cathepsin activity, highlighting its significant potential for advancing diagnostic and clinical therapeutic approaches.

Keywords: exercise; lysosomal cathepsin family; musculoskeletal degenerative diseases; vascular aging

DOI: https://doi.org/10.1096/fj.202501901R

J Pharm Pharm Sci. 2025 ;28 15503

The need to redefine diabetic cardiomyopathy as a unique clinical entity that requires pharmacotherapy.

Alexa N King, John R Ussher.

Keywords: diabetic cardiomyopathy; diastolic dysfunction; energy metabolism; heart failure; type 2 diabetes

DOI: https://doi.org/10.3389/jpps.2025.15503

Arch Physiol Biochem. 2025 Oct 09. 1-14

Hyperglycaemia to heart failure: molecular pathophysiology, clinical manifestations, and novel therapeutic targets for diabetic cardiomyopathy.

Bhagyalakshmi Balakrishnan, Raghu Chandrashekar Hariharapura, Veena Nayak, Divyashree M Somashekara.

CONTEXT: Diabetic cardiomyopathy (DCM) is a chronic cardiac disorder that develops independently of coronary artery disease or hypertension in individuals with diabetes. Despite being identified over fifty years ago, it remains poorly recognized, and its management lacks standardization. The rising global prevalence of diabetes has amplified the incidence of DCM, underscoring the urgent need to clarify its molecular underpinnings and clinical progression.
OBJECTIVE: To provide a comprehensive review of the molecular and physiological mechanisms underlying diabetic cardiomyopathy, elucidating how metabolic dysregulation contributes to cardiac structural and functional alterations. This study also aims to highlight the potential therapeutic targets involved in the key signaling pathways of DCM pathogenesis.
METHODS: A systematic literature review was conducted using major scientific databases, including PubMed, Scopus, and Web of Science, covering studies published between 2000 and 2025. Keywords used included "diabetic cardiomyopathy," "hyperglycemia," "insulin resistance," "oxidative stress," "inflammation," "mitochondrial dysfunction," and "therapeutic targets."
DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: Peer-reviewed articles, original research papers, and review articles focusing on molecular mechanisms, signaling pathways, and therapeutic interventions related to DCM were included. Studies involving both experimental models and human subjects were considered. Data were extracted regarding metabolic alterations, key signaling cascades (NF-κB, PARP1, GLUT4, AT1R), and their association with cardiac remodeling, fibrosis, and functional impairment. The information was synthesized to illustrate the progression from metabolic imbalance to clinical manifestations and to identify promising molecular targets for therapy.

Keywords: AT1R; Diabetic cardiomyopathy; GLUT4; NFKB; PARP; heart failure; ventricular dysfunction

DOI: https://doi.org/10.1080/13813455.2025.2567336