Lipids are indispensable architectural and functional components of central nervous system (CNS) myelin, with cholesterol, sphingolipids, and phospholipids collectively constituting 70%-80% of myelin membrane composition. Oligodendrocytes (OLs), the sole myelin-producing cells in the CNS, exhibit exquisite metabolic specialization to sustain lifelong myelination and remyelination. Mounting evidence implicates lipid metabolic dysregulation-spanning cholesterol efflux defects, sphingolipid imbalance, and peroxisomal dysfunction-as a convergent mechanism underlying OL differentiation failure and progressive demyelination in neurodegenerative diseases. This review explores the role of lipid metabolic rewiring in governing OPCs fate determination, highlighting three crucial axes: the interplay between mitochondria and peroxisomes in lipid biosynthesis, the potential toxicity of accumulated myelin debris in the microenvironment, and the regulation of OPC differentiation through lactylation modification on lipid metabolism and the interaction between glycolipid metabolisms. We further synthesize emerging therapeutic strategies targeting these pathways, including immunometabolism modulators, precision lipid interventions; diet-microbiome synergies: ketogenic diets combined with butyrate-producing probiotics to amplify endogenous remyelination. By integrating lipidomics datasets and recent clinical trial evidence, we propose a shift from broad metabolic suppression to spatially resolved modulation of lipid flux. This synthesis not only clarifies the dual roles of lipids in OL development and degeneration but also highlights druggable targets for personalized treatment of neurodegenerative diseases.

Malignant tumors remain a major global health challenge. Despite substantial improvements in survival rates for patients with cancer, a translational bottleneck persists, which hinders the clinical application of abundant experimental and preclinical findings. This issue reflects the inherent complexity and heterogeneity of tumors and highlights the urgent need for more clinically predictive tumor models. Over the past decade, growing evidence has highlighted the pivotal roles of extracellular vesicles (EVs) and organoids in cancer research. EVs function as stable carriers of intercellular communication, transporting key signaling molecules that regulate tumor growth, migration and angiogenesis. Organoids are three-dimensional (3D) cell culture models grown in an extracellular matrix that can be co-cultured with different cell types to mimic complex cellular interactions within a 3D environment. Increasingly, organoid and other 3D culture models are being used to study the physiological and pathological functions of EVs. In the present review, the classification, characteristics and functions of EVs in oncology are systematically outlined and the application of organoid models in cancer therapeutics are highlighted. Furthermore, the integration of organoids with EVs-based approaches is explored as an emerging research direction in oncology. Finally, the challenges and future opportunities for combined organoid-EVs models are discussed. The review aims to provide insights into organoids and EVs that may help to drive innovation in the development of cancer treatment strategies.

Oral drug delivery is the most patient-friendly and safest approach for disease treatment; however, the bioavailability of macromolecular drugs and poorly soluble small molecules is severely limited by gastrointestinal degradation and the blood-brain barrier (BBB). Here, we developed a cost-effective, chitosan-based isolation method to efficiently isolate milk-derived extracellular vesicles (mEVs), which exhibit good stability in the gastrointestinal tract and intrinsic BBB-penetrating capability. Biodistribution studies showed that mEVs were absorbed in both healthy and experimental autoimmune encephalomyelitis (EAE) mice, with increased CNS accumulation under neuroinflammation, especially in oligodendrocytes and neurons. To address the poor stability and bioavailability of ellagic acid (EA) and to explore the therapeutic potential of mEVs in neuroinflammation treatment, we encapsulated EA and interferon-β (IFN-β) into mEVs and evaluated their therapeutic effects in experimental autoimmune encephalomyelitis (EAE) and lipopolysaccharide-induced neuroinflammation models. The results showed that mEV@IFN-β and mEV@EA significantly relieved disease progression and improved neuroinflammation compared to free drugs, with enhanced stability and bioavailability. Overall, our study findings establish mEVs as an efficient oral delivery platform capable of overcoming biological barriers for treating neuroinflammatory diseases, with the chitosan-based isolation method offering a scalable production approach.

BACKGROUND AND PURPOSE:Microglia undergo rapid activation following ischaemic stroke, and this activation is correlated with patient prognosis. Cordycepin (3'-deoxyadenosine), a natural compound, possesses anti-inflammatory and neuroprotective properties. The specific impact of cordycepin on ischaemic stroke and its underlying mechanisms remain largely under investigated. Here, we explored the potential protective effects of cordycepin against ischaemic stroke through the modulation of microglial activation to elucidate the underlying mechanisms involved. EXPERIMENTAL APPROACH:In vivo, ischaemic stroke was induced in male mice using middle cerebral artery occlusion (MCAO). Sensorimotor and cognitive functions, neuroinflammation and microglia activation were examined. In vitro, a cell model of ischaemic brain injury was established by oxygen-glucose deprivation in primary cultured microglia. Cordycepin intervention was performed on the cell model to elucidate its effects and underlying mechanism. KEY RESULTS:MCAO mice receiving cordycepin therapy exhibited reduced brain oedema, improved morphological abnormalities, mitigated neurological deficit scores, and ameliorated sensorimotor and cognitive functions. We found that cordycepin suppressed microglial hyperactivation and reduced the expression of proinflammatory factors, thereby inhibiting neuroinflammation after ischaemic stroke. Mechanistically, cordycepin accelerated the lysosomal degradation of the Notch1 intracellular domain (NICD) and subsequently blocked the activation of the Notch1 signalling pathway in microglia. CONCLUSION AND IMPLICATIONS:Cordycepin prevents neuroinflammation in primary cultured microglia and reduces ischaemic brain injury in male mice. These findings elucidate a potential molecular mechanism underlying the action of cordycepin, indicating its potential as a therapeutic candidate for the treatment of ischaemic stroke and other neurological disorders characterised by excessive neuroinflammation.

Myelin injury, a hallmark of several neurological diseases, is highly sensitive to glucose metabolism disruptions. Here, we reveal that oligodendrocytes (OLs) within demyelinating lesions exhibit reduced glycolytic efficiency and lactate production compared with mature OLs. Administration of lactate, the product of glycolysis, or specific overexpression of lactate dehydrogenase A (LDHA), the enzyme in lactate production, in Olig1+ OLs significantly enhances remyelination. In contrast, conditional knockout of LDHA in the Olig1+ lineage or CNPase+ premyelinating OLs leads to severe neuropathy with dysmyelination in a development-dependent and cell-specific manner. Mechanistic insights show that OLs within demyelinating lesions undergo lactylation silencing, a lactate-induced epigenetic modification that impedes myelin restoration. Furthermore, lactylation of LDHA and carbonic anhydrase II (CAII) couples glycolysis with OL maturation. Our findings elucidate the metabolic interplay among glycolysis, lactylation, and OL maturation and provide novel enzymatic therapeutic perspectives for demyelinating disorders, for which effective therapies are currently lacking.

Androgenetic alopecia (AGA) is a common type of hair loss, primarily caused by the miniaturization of hair follicles induced by dihydrotestosterone (DHT). Current therapies are limited by systemic side effects and poor patient compliance. In this study, we engineered TGF-β-enriched exosomes (MSCT-Exos) through lentiviral transduction of mesenchymal stem cells (MSCs) and delivered them via dissolving hyaluronate microneedles (MNs) for sustained transdermal release. In vitro characterization confirmed that MSCT-Exos retained typical exosomal properties, while MNs exhibited robust mechanical strength and rapid dissolution. In vivo studies using a DHT-induced AGA mouse model demonstrated that MNs-mediated delivery of MSCT-Exos significantly increased the proportion of anagen hair follicles. Immunohistochemistry revealed upregulation of hair follicle stem cell marker CD34 and proliferation biomarker Ki67. The transcriptomic analysis indicates that the therapeutic effect is achieved through the Notch pathway. This minimally invasive strategy provides a targeted, compliant approach to AGA treatment with translational potential for tissue regeneration.

The maternal gut microbiome plays a crucial role in regulating offspring neurodevelopment through microbial metabolite signalling, yet its influence on CNS myelinogenesis, a pivotal process for neural circuit maturation, remains poorly understood. Here, using antibiotic-induced maternal dysbiosis models, we identify propionate (PA), a short-chain fatty acid (SCFA) derived from the maternal microbiome, as a key epigenetic modulator of oligodendrocyte precursor cell (OPC) differentiation. Maternal antibiotic-induced gut dysbiosis led to significant hypomyelination in offspring, an effect that could be rescued by postnatal PA supplementation. PA not only enhanced developmental myelination but also promoted remyelination following lysolecithin-induced demyelination by inducing OPC differentiation. Mechanistically, PA induced histone H4 lysine 12 lactylation (H4K12la), thereby activating transcription of cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signalling components (e.g. Gna12) and upregulating Sox family transcription factors essential for oligodendrocyte differentiation. Taken together, our findings delineate a PA-H4K12la-cGMP-PKG pathway that links maternal microbial metabolism to offspring myelination, offering a promising SCFA-mediated epigenetic strategy for the treatment of CNS demyelinating disorders.

Inflammation underlies a wide variety of physiological and pathological processes, the Lipopolysaccharide (LPS)-induced inflammation model is widely recognized as a classical inflammatory paradigm, while Transforming growth factor-β (TGF-β) serves as a potent immunosuppressant capable of inhibiting immune responses and mitigating inflammation. However, its in vivo instability and the high cost associated with purification have imposed limitations on its clinical application. Therefore, we propose a therapeutic strategy for genetically modifying extracellular vesicles (HEVs) derived from HEK-293 T cells to incorporate TGF-β which holds potential for mitigating LPS-induced inflammation. In this study, we engineered a TGF-β lentivirus that specific incorporates TGF-β into HEVs and efficiently produces highly expressed TGF-β HEVs (HEVTs) through infection of HEK293 cells. Our data demonstrated that, compared to the LPS group, HEVTs internalized by immune cells significantly regulated pro-inflammatory cytokine expression in RAW 264.7 cells, such as IL-1β (p < 01), TNF-α (p < 001). Moreover, HEVTs were found to effectively reach the lesion area, compared to the LPS group, resulting in a remarkable inhibition in the activation of macrophages (p < 0.0001), dendritic cells (p < 0.0001), and neutrophils (p < 0.0001) in the peripheral immune system as well as microglia in the central nervous system of LPS-induced inflammation model mice. The utilization of this endogenous loading technique may present a promising strategy for the protein-based pharmacotherapy of inflammatory disorders.

Imatinib mesylate has been identified as a tyrosine kinase inhibitor that selectively inhibits Abl tyrosine kinases, including Bcr-Abl. It exhibits many polymorphic forms, with the most stable and commercialized polymorphs known as the α and β forms. In the present study, the compatibility between the polymorphs of Imatinib mesylate and selected excipients (MCC, HPMC, PVPP, SiO2, MS, and CaHPO4) was investigated by differential scanning calorimetry (DSC), Raman spectra, X-ray diffraction (XRD) technique, and isothermal stress testing (IST). The results revealed that polymorph α of Imatinib mesylate has poor compatibility with selected excipients at high temperatures. As a contrary, polymorph β of Imatinib mesylate shows high compatibility with the selected excipients except MS under high temperatures.

Cervical cancer (CC) is a prevalent gynecological malignancy. Increasing evidence suggests that circular RNAs (circRNAs) play a pivotal role in the pathogenesis of CC. However, the regulatory function of circ_ASH1L in CC remains elusive. In this study, we aim to elucidate the precise role and underlying mechanism of circ_ASH1L in the malignant progression of CC. The human CC dataset GSE102686 was extracted from the Gene Expression Omnibus (GEO) database for the analysis of differentially expressed circRNAs. Target gene prediction softwares were utilized to predict the binding of miRNAs to circ_ASH1L sponge. The expression level of circ_ASH1L in CC tissues and cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The characteristics of circ_ASH1L were determined by RNase R digestion, actinomycin D, and nucleo-plasmic separation assays. The effects of circ_ASH1L, miR-1254, and CD36 gain-and-loss on the malignant progression of CC were investigated using Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, wound scratch, transwell, and Western blot assay. The effect of circ_ASH1L on tumorigenicity of CC cells in vivo was evaluated in nude mice through tumor xenograft assay. The targeted regulatory relationship between circ_ASH1L/miR-1254 as well as miR-1254/CD36 was validated by dual-luciferase reporter assay. We screened the differentially expressed circ_ASH1L from the GEO dataset GSE102686 and confirmed its circular structure. Furthermore, we observed a significant upregulation of circ_ASH1L in both CC tissues and cells. Overexpression of circ_ASH1L promotes proliferation, invasion, and migration of CC cells while inhibiting cell apoptosis. However, silencing circ_ASH1L showed opposite results and inhibited tumorigenicity of CC cells in nude mice. Furthermore, we have identified circ_ASH1L as a miR-1254 sponge in CC cells. Notably, our in vitro experiments demonstrated that exogenously modulating the expression of miR-1254 effectively counteracted the impact of circ_ASH1L on the malignant phenotypic characteristics of CC cells. Similarly, modulation of CD36 expression efficiently counteracted the effect of miR-1254 on the malignant biological behavior of CC cells. In conclusion, circ_ASH1L promoted the malignant progression of CC via upregulating CD36 expression through sponging miR-1254.

Demyelination is a prominent feature of multiple sclerosis (MS), where the ability of damaged areas to regenerate myelin is limited. Oligodendrocyte precursor cells (OPCs) accumulate in these areas but struggle to mature into oligodendrocytes (OLGs). Microglia also gather at the lesion site, but their impact on OPCs differentiation is not well understood. Here, we found that miR-155-5p was significantly elevated in the expression profile of exosomes extracted from activated microglia. This miRNA binds to the 3' UTR of the transcription factor Nrf2 in OPCs, inhibiting their differentiation. In a mouse model of demyelination induced by cuprizone, inhibiting miR-155-5p in microglia led to improved motor function recovery, increased the number of mature oligodendrocytes and promoted remyelination. In this study, we highlight a potential new target for treating demyelinating diseases.

Immunosuppressants currently approved for the treatment of autoimmune diseases and organ transplant rejection present diverse adverse effects that impair the life quality of patients. Therefore, the development of novel immunomodulators with high efficiency and low toxicity is essential. Ellagic acid (EA), a natural polyphenol compound widely distributed in berries, is metabolically transformed by gut microbiome to exert systemic health benefits. Here, we identified that intraperitoneal administration of EA with no cytotoxicity, beyond its well-known oral metabolic fate, effectively decreased clinical severity and central nervous system (CNS) inflammation/demyelination in experimental autoimmune encephalomyelitis, a mouse model of an autoimmune disease multiple sclerosis. Interestingly, intraperitoneal EA administration at incredibly low doses (0.1 mg/(kgday)) is dose-sparing with fingolimod (FTY720), the first FDA-approved oral drug for MS. In addition, intraperitoneal EA also ameliorated the brain damage in a neuromyelitis optica (NMO) model, and significantly prevented the immune rejection of allograft skin graft. Evidence from pharmacological studies combined with RNA-seq indicate that prototype EA functions by a mechanism that involves direct inhibition of casein kinase II (CKII) to suppress the expression of IL-17 and promote the expression of Cpt1a to regulate T helper cell 17 differentiation. In conclusion, our study demonstrates that the prototype EA entering the blood circulation acts as a novel therapeutic immunomodulator for the treatment of autoimmune diseases and transplant rejection through the CKII-mediated Janus kinase/signal transducer and activator of transcription 3 Cpt1a signaling pathway.

Myelin injury occurs in brain ageing and in several neurological diseases. Failure of spontaneous remyelination is attributable to insufficient differentiation of oligodendrocyte precursor cells (OPCs) into mature myelin-forming oligodendrocytes in CNS demyelinated lesions. Emerging evidence suggests that peroxisome proliferator-activated receptor γ (PPARγ) is the master gatekeeper of CNS injury and repair and plays an important regulatory role in various neurodegenerative diseases. Although studies demonstrate positive effects of PPARγ in oligodendrocyte ontogeny in vitro, the cell-intrinsic role of PPARγ and the molecular mechanisms involved in the processes of OPC development and CNS remyelination in vivo are poorly understood. Here, we identify PPARγ as an enriched transcription factor in the dysfunctional OPCs accumulated in CNS demyelinated lesions. Its expression increases during OPC differentiation and myelination and is closely related to the process of CNS demyelination/remyelination. Administration of pharmacological agonists of PPARγ not only promotes OPC differentiation and CNS myelination, but also causes a significant increase in remyelination in both cuprizone- and lysophosphatidylcholine-induced demyelination models. In contrast, the attenuation of PPARγ function, either through the specific knockout of PPARγ in oligodendrocytes in vivo or through its inhibition in vitro, leads to decreased OPC maturation, hindered myelin generation and reduced therapeutic efficacy of PPARγ agonists. At a mechanistic level, PPARγ induces myelin repair by directly targeting glycoprotein non-metastatic melanoma protein B (GPNMB), a novel regulator that drives OPCs to differentiate into oligodendrocytes, promotes myelinogenesis in the developing CNS of postnatal mice and enhances remyelination in mice with lysophosphatidylcholine-induced demyelination. In conclusion, our evidence reveals that PPARγ is a positive regulator of endogenous OPC differentiation and CNS myelination/remyelination and suggests that PPARγ and/or its downstream sensor (GPNMB) might be a candidate pharmacological target for regenerative therapy in the CNS.

Acute myocardial infarction (AMI) is the main cause of death worldwide. We aim to compare the differences in plasma lipid metabolites between AMI patients and normal controls to search for biomarker molecules for AMI with different infarct sites. We enrolled 12 patients in Group A (left coronary artery occlusion), 15 in Group B (right coronary artery occlusion), and 14 in Group C (normal controls) from June 2020 to June 2021. Non-targeted lipidomic analysis was performed and a total of 93 differential lipid molecules were identified. Diagnostic efficiency was evaluated by receiver operating curve. Compared with Group C, there were nine lipid molecules with AUC>0.8 in Groups A and B. Compared with Group B, Group A had six lipid molecules with AUC>0.8. These lipid molecules belonged to the LPC, PC, TG, and DG classes. We focused on LPC (20:4) as a biomarker in AMI.

Increasing evidence demonstrates that helminth and its components can ameliorate ulcerative colitis. Clonorchis sinensis (C. sinensis) is a kind of helminth that dwells in the bile ducts for many years, but the roles and underlying mechanisms of C. sinensis-induced protection from colitis are not elucidated. In the present study, the mice were infected with 50 C. sinensis metacercariae and further administrated with 4% Dextran Sodium Sulfate (DSS) in drinking water for 7 days on days 49 post-infection. The disease severity and the integrity of gut barriers were evaluated. Gut microbiota was measured using 16sRNA sequencing, and bile acids in the colon were detected by Liquid Chromatography Mass Spectrometry (LC/MS). The Co-housing approach or microbiota deletion with additional supplies of secondary bile acids (SBAs) was employed to investigate the roles of gut microbiota in the protection from colitis. C. sinensis infection moderated the dysbiosis of the intestinal microbiota and increased the levels of SBAs and bile acid receptor Takeda G protein-coupled receptor 5 (TGR5), which finally benefited anti-inflammation and ameliorated the severity of DSS-induced colitis. Co-housing with C. sinensis-infected mice, and non-infected mice with colitis also showed an increase of TGR5, decreased pro-inflammatory cytokines, and a reduction in the severity of colitis, compared to those mice suffering from colitis without co-housing. Furthermore, C. sinensis-induced protective effects on colitis were attenuated by microbiota deletion, while SBAs (lithocholic acid, LCA) supplementation reversed the colitis. The present study demonstrates that C. sinensis infection ameliorates DSS-induced ulcerative colitis in mice, which is dependent on gut microbiota-associated SBAs.

This review delves into the crosstalk network between oligodendrocytes and other glial cells in the context of demyelinating diseases.Oligodendrocytes,the myelin-forming cells in the central nervous system(CNS),are crucial for maintaining the function and integrity of axons and myelin sheaths.In demyelination pathologies,various factors hinder the normal differentiation of oligodendrocyte precursor cells,obstructing the myelin re-generation process,which is a primary barrier to therapeutic myelin repair.Emerging evidence highlights the critical role of glial cell interactions in CNS homeostasis and myelin regeneration,increasing interest in the treat-ment of demyelinating diseases.This article reviews the role of interactions between oligodendrocytes and other CNS glial cells in demyelinating and neurological diseases.Previous findings suggest that other CNS glial cells influence the survival and metabolic activity of oligodendrocytes through cell interactions,significantly affecting myelin formation and impacting demyelinating diseases characterized by myelin regeneration disorders.Targeted modulation of oligodendrocytes and their interactions with other cells at specific temporal stages may indicate a novel therapeutic direction for demyelinating diseases and offer fresh perspectives on the study of mechanisms and therapeutic approaches for related neurological conditions.

Given the high energy demand of the nervous system, mitochondrial dysfunction is a key factor in the pathogenesis of neurodegenerative diseases. Thus, a comprehensive understanding of its mechanisms and potential therapeutic targets is essential. This review discusses the roles of mitochondrial oxidative stress, mitochondrial dynamics alterations, and mtDNA damage in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and multiple sclerosis (MS). In addition, it summarizes the contributions of novel technological approaches in detecting mitochondrial dysfunction, which assist in disease diagnosis. We also emphasize emerging therapeutic strategies and drugs aimed at enhancing mitochondrial quality control and reducing oxidative stress, thereby laying the groundwork for innovative therapeutic approaches in neurodegenerative disease treatment.

BACKGROUND AND OBJECTIVES:Demyelinating diseases are neurologic disorders characterized by the loss of the myelin sheath and impaired regeneration. Retinoid X receptor γ (RXRγ) is a member of the nuclear receptor superfamily and plays a crucial role in oligodendrocyte biology and myelin formation. However, the clinical application of drugs targeting RXRγ for demyelinating diseases is limited. Selecting small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) that have high binding activity to RXRγ may be an effective strategy for treating demyelinating disorders. METHODS:We used an online molecular docking tool to predict that spironolactone (SPIR), an FDA-approved drug, displays strong binding activity to RXRγ. Subsequently, we verified the impact of SPIR on oligodendrocyte precursor cell (OPC) differentiation and myelin sheath formation through in vitro OPC culture and pharmacologic experiments in mice. Furthermore, using genetic models with CRISPR-LSL-Cas9, we confirmed that the effect of SPIR on OPCs relies on RXRγ. RESULTS:In this study, we identified that SPIR, an FDA-approved drug, functions as an RXRγ agonist in OPCs. RXRγ was identified as a crucial factor of myelin production. Its activation promotes the differentiation of OPCs and enhances myelin generation. We confirmed the specificity of SPIR's target, demonstrating that SPIR facilitates OPC differentiation and myelin generation in a RXRγ-dependent manner. Our findings not only identify the RXRγ agonist to promote OPC differentiation but also provide new experimental evidence for expanding the clinical indications of SPIR. DISCUSSION:The promotion of OPC differentiation by SPIR in animal models suggests its potential for treating demyelinating diseases.

BACKGROUND:Extracellular vesicles (EVs) are emerging as potential drug carriers in the fight against COVID-19. This study investigates the ability of EVs as drug carriers to target SARS-CoV-2-infected cells. METHODS:EVs were modified using Xstamp technology to carry the virus's RBD, enhancing targeting ability to hACE2+ cells and improving drug delivery efficiency. Characterization confirmed EVs' suitability as drug carriers. For in vitro tests, A549, Caco-2, and 4T1 cells were used to assess the targeting specificity of EVRs (EVs with membrane-surface enriched RBD). Moreover, we utilized an ex vivo lung tissue model overexpressing hACE2 as an ex vivo model to confirm the targeting capability of EVRs toward lung tissue. The study also evaluated drug loading efficiency and assessed the potential of the anti-inflammatory activity on A549 lung cancer cells exposed to lipopolysaccharide. RESULTS:The results demonstrate the successful construction of RBD-fused EVRs on the membrane- surface. In both in vitro and ex vivo models, EVRs significantly enhance their targeting ability towards hACE2+ cells, rendering them a safe and efficient drug carrier. Furthermore, ultrasound loading efficiently incorporates IL-10 into EVRs, establishing an effective drug delivery system that ameliorates the pro-inflammatory response induced by LPS-stimulated A549 cells. CONCLUSION:These findings indicate promising opportunities for engineered EVs as a novel nanomedicine carrier, offering valuable insights for therapeutic strategies against COVID-19 and other diseases.