Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Docosahexaenoic acid prevents peroxisomal and mitochondrial protein loss in a murine hepatic organoid model of severe malnutrition","authors":"José M. Horcas-Nieto ,&nbsp;W. Alfredo Rios-Ocampo ,&nbsp;Miriam Langelaar-Makkinje ,&nbsp;Rinse de Boer ,&nbsp;Albert Gerding ,&nbsp;Serhii Chornyi ,&nbsp;Ingrid A. Martini ,&nbsp;Justina C. Wolters ,&nbsp;Ronald J.A. Wanders ,&nbsp;Hans R. Waterham ,&nbsp;Ida J. Van der Klei ,&nbsp;Robert H.J. Bandsma ,&nbsp;Johan W. Jonker ,&nbsp;Barbara M. Bakker","doi":"10.1016/j.bbadis.2025.167849","DOIUrl":"10.1016/j.bbadis.2025.167849","url":null,"abstract":"<div><h3>Introduction</h3><div>Acute and chronic exposure of cells to low amino acid conditions have been shown to lead to a reduction in hepatic peroxisomal and mitochondrial content. There is limited understanding of the underlying mechanisms behind this loss, but data suggests degradation through autophagy. Both organelles play a key role in fatty acid metabolism, which may explain why dysfunction in either one of them might lead to hepatic steatosis.</div></div><div><h3>Methods</h3><div>Using a previously established murine hepatic organoid model of severe malnutrition, we characterized the effects of prolonged amino-acid restriction on peroxisomal and mitochondrial protein levels and on autophagic flux. To do so, we developed concatemers of ¹³C-labelled peptide standards for quantification of over 50 different peroxisomal proteins. To assess the autophagic flux, we transduced hepatic organoids with a GFP-LC3-RFP-LC3ΔG probe. Finally, the effect of PPAR-α activation on peroxisomal loss was determined with various agonists.</div></div><div><h3>Results</h3><div>Prolonged (96 h) amino-acid restriction led to a more severe loss of peroxisomes than a 48 h restriction, and with a substantial induction of autophagic flux. This was accompanied by accumulation of intracellular triglycerides, loss of mitochondrial and peroxisomal proteins, and loss of peroxisomal functionality. While PPAR-α agonists WY-14643 and linoleic acid (LA) had no effect, docosahexaenoic acid (DHA) supplementation partly prevented peroxisomal and mitochondrial loss under amino-acid restricted conditions and partly inhibited autophagy.</div></div><div><h3>Discussion</h3><div>The potential of DHA to prevent loss of peroxisomes and mitochondrial functions in low protein diets and severe malnutrition warrants further causal and translational testing in preclinical models and clinical trials, including its use as nutritional supplement.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167849"},"PeriodicalIF":4.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cisplatin reduces immunosuppression caused by tumor-associated macrophages through downregulating CD47-SIRPα signaling in glioblastoma","authors":"Yanyan Li ,&nbsp;Yufei Cao ,&nbsp;Linyan He ,&nbsp;Jie Wu ,&nbsp;Lize Cai ,&nbsp;Youxin Zhou ,&nbsp;Haiying Li ,&nbsp;Wei Yang ,&nbsp;Ting Sun","doi":"10.1016/j.bbadis.2025.167876","DOIUrl":"10.1016/j.bbadis.2025.167876","url":null,"abstract":"<div><div>The poor prognosis of glioblastoma (GBM) is partly attributed to the immunosuppressive microenvironment. The combination of standard temozolomide and other chemotherapy drugs can significantly enhance the therapeutic effect by reshaping the immune microenvironment. Cisplatin treatment induces immunogenic cell death in tumor cells, stimulating an immune response. Here, we investigated the immune-activating effect of cisplatin on tumor-associated macrophages (TAMs). The therapeutic benefit of temozolomide plus cisplatin was showed in a murine model of GBM, accompanied by the inhibition of tumor growth and enhancement of pro-inflammatory activation of TAMs. Furthermore, cisplatin treatment downregulated the expression of CD47 in glioma stem cells, SIRPα, and IL-6 in TAMs, thus promoting M1-like polarization of TAMs to enhance an immune-activating tumor microenvironment. Mechanically, cisplatin decreases the production of lactic acid by downregulating LDHA expression. A low level of lactate reduces histone H3K18 lactylation on the CD47 and IL-6 promoters, thereby suppressing gene transcription. Our study reveals a new mechanism by which cisplatin remodels the immune tumor microenvironment, suggesting that combining temozolomide with cisplatin chemotherapy may be a new treatment option for GBM.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167876"},"PeriodicalIF":4.2,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrinsic amyloid deposition following proteostasis impairment in osteoarthritic chondrocytes: Insights and therapeutic approaches","authors":"Veronica Panichi ,&nbsp;Paolo Dolzani ,&nbsp;Luca Cattini ,&nbsp;Francesco Alabiso ,&nbsp;Irene Bissoli ,&nbsp;Silvia Cetrullo ,&nbsp;Marta Columbaro ,&nbsp;Flavio Flamigni ,&nbsp;Carla Renata Arciola ,&nbsp;Giuseppe Filardo ,&nbsp;Alessandro Di Martino ,&nbsp;Stefania D'Adamo ,&nbsp;Rosa Maria Borzì","doi":"10.1016/j.bbadis.2025.167865","DOIUrl":"10.1016/j.bbadis.2025.167865","url":null,"abstract":"<div><div>Osteoarthritis (OA) is the most common age-related and degenerative joint disease. Proteostasis and protein quality control (autophagy, unfolded protein response, and the ubiquitin-proteasome system) are pivotal for cellular homeostasis and their impairment leads to protein misfolding and amyloid deposition in aged tissues. We here investigated amyloid deposition in OA. Amyloid fibrils were observed in chondrocytes in <em>ex vivo</em> cartilage samples. The underlying mechanisms were assessed <em>in vitro</em>: chondrocytes and cartilage organ cultures were treated with chloroquine and/or lipopolysaccharide for assessment (Western Blotting, immunohistochemistry, histochemistry cytofluorimetry) of amyloid deposition after induction of ER stress with/without blockage of autophagy. Overall, our data show for the first time that proteostasis impairment leads to intrinsic amyloid deposition in OA chondrocytes. These effects were mitigated by selected polyphenols. In conclusion, amyloidosis could contribute to OA progression, and the failure of proteostasis, a hallmark of aging, represents a promising therapeutic target.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167865"},"PeriodicalIF":4.2,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2BP1 exacerbates neuroinflammation and cerebral ischemia/reperfusion injury by regulating neuronal ferroptosis and microglial polarization","authors":"Youjun Li ,&nbsp;Junwen Jiang ,&nbsp;Yi Zhuo ,&nbsp;Jiameng Li ,&nbsp;You Li ,&nbsp;Ying Xia ,&nbsp;Zhengtao Yu","doi":"10.1016/j.bbadis.2025.167877","DOIUrl":"10.1016/j.bbadis.2025.167877","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral ischemia/reperfusion (I/R) injury induces neuronal ferroptosis and microglial phenotypic shifts, driving post-ischemic neurological deficits. This study examines the regulatory role of the N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in coordinating these pathological processes through Keap1/Nrf2 signaling.</div></div><div><h3>Methods</h3><div>Cerebral I/R injury was modeled in C57BL/6 mice via middle cerebral artery occlusion (MCAO) and in hippocampal neurons and microglia through oxygen-glucose deprivation/reperfusion (OGD/R). Pro-inflammatory microglial polarization was induced by LPS/IFN-γ stimulation. IGF2BP1's functional impacts were assessed through knockdown and overexpression approaches, with mechanistic evaluations focusing on ferroptosis biomarkers, microglial polarization states, and Keap1/Nrf2 pathway activity. A microglia-neuron co-culture system elucidated cellular crosstalk mechanisms.</div></div><div><h3>Results</h3><div>MCAO-operated mice demonstrated upregulated IGF2BP1 expression accompanied by neuronal apoptosis and microglial M1 polarization. IGF2BP1 silencing significantly attenuated OGD/R-induced neuronal ferroptosis, evidenced by reduced iron overload (Fe²⁺), lipid peroxidation (MDA), and reactive oxygen species (ROS) alongside restored glutathione (GSH) levels, while concurrently enhancing GPX4 activity through Keap1/Nrf2 pathway regulation. This intervention further shifted microglial polarization toward the M2 phenotype, effectively mitigating neuroinflammatory responses. Importantly, the neuroprotective effects of IGF2BP1 knockdown were abolished upon Keap1 overexpression. Co-culture experiments revealed that IGF2BP1-depleted microglia suppressed neuronal ferroptosis via phenotypic reprogramming. In vivo validation confirmed that IGF2BP1 knockdown ameliorated neurological deficits and reduced ferroptosis markers in MCAO-challenged mice.</div></div><div><h3>Conclusion</h3><div>IGF2BP1 serves as a critical regulator of cerebral I/R injury by exacerbating neuronal ferroptosis and sustaining detrimental microglial activation. These findings nominate IGF2BP1 inhibition as a promising strategy for ischemic stroke intervention.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167877"},"PeriodicalIF":4.2,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143903732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PGC-1α role in rescuing ferroptosis in cerebral ischemia/reperfusion injury through promoting mitochondrial biogenesis and UCP2 expression","authors":"Jiahui Yang,&nbsp;Xiaohua Shi,&nbsp;Ming Ma,&nbsp;Zheng Li,&nbsp;Hongyu Liu,&nbsp;Yang Cui,&nbsp;Zhongxin Xu,&nbsp;Jiaoqi Wang","doi":"10.1016/j.bbadis.2025.167874","DOIUrl":"10.1016/j.bbadis.2025.167874","url":null,"abstract":"<div><div>Cerebral ischemia/reperfusion injury (CIRI) is a critical factor leading to adverse outcomes in acute ischemic stroke with reperfusion therapy. The occurrence of CIRI involves several cell death pathways, such as ferroptosis. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) a vital role in mitochondrial biogenesis and induces several crucial reactive oxygen species (ROS) detoxifying enzymes. Nonetheless, the role of activated PGC-1α in CIRI is still unclear. In this research, we utilized a PGC-1α agonist (ZLN005) in both in vitro and in vivo models of CIRI and found that ZLN005 ameliorates neurologic deficits, reduces infarct volume, and inhibits neuronal ferroptosis in CIRI. Furthermore, CIRI led to a decrease in neuronal mitochondrial quantity and downregulation of uncoupling protein 2 (UCP2) expression. Treatment with ZLN005 activated PGC-1α, promoted neuronal mitochondrial biogenesis, and upregulated UCP2 expression, thereby reducing mitochondrial oxidative stress. The application of the mitochondria-targeted antioxidant Mito-TEMPO inhibited ferroptosis, while UCP2 silencing induced mitochondrial oxidative stress and weakened ZLN005 inhibitory effect of ferroptosis, confirming the dependency of ferroptosis on mitochondrial oxidative stress in CIRI. According to these findings, targeting PGC-1α may offer an effective therapeutic strategy for CIRI by regulating mitochondrial homeostasis and protecting neurons from ferroptotic damage.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167874"},"PeriodicalIF":4.2,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The therapeutic potential of a polyunsaturated fatty acid-enriched high-fat diet in Leigh syndrome: Insights from a preclinical model","authors":"Luciano Willemse,&nbsp;Karin Terburgh,&nbsp;Roan Louw","doi":"10.1016/j.bbadis.2025.167873","DOIUrl":"10.1016/j.bbadis.2025.167873","url":null,"abstract":"<div><h3>Introduction</h3><div>Leigh syndrome is often caused by <em>Ndufs4</em> mutations. The <em>Ndufs4</em> knockout (KO) mouse model recapitulates key disease features, including systemic inflammation, neurodegeneration, and motor deficits. While dietary interventions such as the ketogenic diet show promise in mitigating mitochondrial dysfunction, conflicting results highlight uncertainties regarding its efficacy. Here, we evaluate the therapeutic potential of a polyunsaturated fatty acid (PUFA)-enriched high-fat diet (HFD) in <em>Ndufs4</em> KO mice.</div></div><div><h3>Methods</h3><div>Dietary intervention began at postnatal day 23, with mice receiving either a normal diet (ND) or a HFD enriched with PUFAs. Phenotypic evaluation, including locomotor function, clasping behaviour, and survival, continued until natural death. In a second group of animals, biochemical analyses were conducted after three weeks on the diets, using Western blot to evaluate neurometabolic and inflammatory regulators, flow cytometry to quantify serum inflammation markers, and metabolic profiling to identify alterations in neurometabolism and the neurolipidome.</div></div><div><h3>Results</h3><div>The HFD significantly extended lifespan and improved clasping behaviour in <em>Ndufs4</em> KO mice but had no effect on locomotor activity or grip strength decline. While whole-brain mTOR (p70S6K1, 4E-BP1) and SIRT1 (PGC1-α, TNF-α) signalling pathways remained unaffected, the diet significantly reduced serum pro-inflammatory markers TNF and IL-6. Furthermore, the PUFA-enriched HFD partially restored disruptions in TCA cycle, ketone body, branched-chain amino acid, and lipid metabolism, indicating potential metabolic reprogramming.</div></div><div><h3>Conclusion</h3><div>Dietary interventions, such as a PUFA-enriched HFD, may alleviate systemic inflammation, partially correct metabolic imbalances, and mitigate specific disease phenotypes in Leigh syndrome, warranting further investigation into the underlying mechanisms and broader therapeutic applications.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167873"},"PeriodicalIF":4.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTLA4 modulates B cell receptor signals to inhibit HBsAb secretion in chronic hepatitis B patients","authors":"Shengxia Yin ,&nbsp;Minxin Mao ,&nbsp;Linyan Gong ,&nbsp;Yijia Zhu ,&nbsp;Yawen Wan ,&nbsp;Xin Tong ,&nbsp;Jian Wang ,&nbsp;Guiyang Wang ,&nbsp;Yong Liu ,&nbsp;Chao Wu ,&nbsp;Rui Huang ,&nbsp;Yuxin Chen","doi":"10.1016/j.bbadis.2025.167848","DOIUrl":"10.1016/j.bbadis.2025.167848","url":null,"abstract":"<div><div>Restoring B cell defects is crucial to achieve the functional cure of chronic hepatitis B virus (CHB) infection, yet the specific targets remain largely unexplored. Our study identified that CTLA4 was highly upregulated in both peripheral and hepatic HBsAg-specific B cells from CHB patients, while effective peginterferon-α treatment could reduce the frequency of CTLA4⁺HBsAg⁺ B cells. Single-cell RNA-seq analysis revealed that the diminished IL-6 JAK/STAT3 and IL-2/STAT5 signaling pathways in memory B cells from CHB patients,which might contribute to the incapability of HBsAb antibody secretion. CTLA4⁺ B cells, especially from CHB patients, consistently showed defective responses in B cell receptor signaling and inflammatory responses compared to CTLA4⁻ B cells. Notably, CTLA4 depletion partially restored the secretion of HBsAb in vitro from peripheral B cells from CHB patients, but also could restore anti-HBs humoral responses and potentiate viral clearance in HBV mouse model. Mechanistic analysis revealed that CTLA4 is directly bound to SHP-1, resulting in the impaired Jak-STAT and B cell receptor signaling pathway. Collectively, our data highlights an unappreciated role of CTLA4 on B cell responses. Targeting CTLA4 on B cells holds promise to achieve the functional cure of CHB patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167848"},"PeriodicalIF":4.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial progenitor cells improve intestinal homeostasis after hematopoietic stem cell transplantation in mice","authors":"Shengyun Zhu ,&nbsp;Chaoran Lv ,&nbsp;Pengjie Wu ,&nbsp;Huiqi Li ,&nbsp;Lu Liu ,&nbsp;Kai Zhao ,&nbsp;Lingyu Zeng ,&nbsp;Kailin Xu","doi":"10.1016/j.bbadis.2025.167871","DOIUrl":"10.1016/j.bbadis.2025.167871","url":null,"abstract":"<div><div>Transplant conditioning regimens disrupt the intestinal barriers, leading to delayed vascularity and impeded the regenerative process. However, our understanding of the specific mechanisms underlying the use of cellular therapy to accelerate revascularization for intestinal repair is currently limited. To address this knowledge gap, we conducted a longitudinal study to investigate the effects and potential benefits of endothelial progenitor cells (EPCs) infusion on the restoration of intestinal homeostasis in a murine model of bone marrow transplantation (BMT). Our results revealed that the EPCs infusion improved the structure status of the intestine, as demonstrated by a well-preserved crypt structure, longer villi, reduced infiltration of inflammatory cells, and increased expression of ZO-1 and MECA-32. Additionally, EPCs infusion resulted in significantly lower proportions of Tc1 and Th1 cells on day 10, as well as a delayed peak in Tc17 cells on day 20, with no differences compared with BMT group thereafter. Moreover, EPCs infusion enhanced the expression of immune regulatory molecules <em>IL-10, IL-17, IL-18,</em> and <em>NLRP6</em> on day 15. Mechanistically, EPCs infusion up-regulated phos-ERK1/2 and down-regulated phos-p38 MAPK on day 5 (early transplantation). The richness of intestinal microbiota changed significantly, and <em>Erysipelotrichaceae</em> was identified as the main index to differentiate the BMT and EPC treatments, exhibiting a significant negative correlation with <em>IL-10</em> and <em>IL-18</em> in the EPC group. Taken together, this study highlights the protective role of EPCs in post-transplantation intestinal damage, and identifies critical immune cells, signaling pathways, and selectively enriched intestinal microbes contributing to the beneficial effects of EPCs during intestinal repair.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167871"},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLK knockdown in hBMSCs enhance repair of critical-size bone defects by modulating neurogenic and osteogenic differentiation","authors":"Ke LI,&nbsp;Mengdi LI,&nbsp;Zhongning LIU,&nbsp;Jingwen YANG,&nbsp;Jian LI,&nbsp;Ting JIANG","doi":"10.1016/j.bbadis.2025.167870","DOIUrl":"10.1016/j.bbadis.2025.167870","url":null,"abstract":"<div><div>Nemo-like kinase (NLK), an evolutionarily conserved MAP kinase-related kinase, is highly expressed in neural tissues and critically regulates cell proliferation, migration, and apoptosis by regulating numerous transcriptional molecules. Despite the widespread application of mesenchymal stem cells (MSCs) in regenerative medicine, the functional role and molecular mechanisms of NLK in MSC-mediated tissue repair remained poorly understood. Here, the dual regulatory effects of NLK on both neurogenic and osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) were investigated. The results showed that NLK acted as a potent inhibitor of hBMSC neurogenesis in vitro and suppressed osteogenesis both in vitro and in vivo. Mechanistically, NLK downregulated the transcriptional coactivators LEF1 and TCF4, thereby impairing their pro-differentiation functions during neural and bone formation. These findings suggested that NLK-mediated suppression of LEF1/TCF4 signaling might hinder endogenous bone repair by dual inhibition of hBMSC neurogenic and osteogenic capacities. Targeting this pathway could offer novel therapeutic strategies for enhancing bone defect regeneration and inform the design of advanced biomaterials for bone tissue engineering.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167870"},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TSPO participates in the pathogenesis of diabetic periodontitis related to mitophagy","authors":"Weiqiu Jin ,&nbsp;Daiyu Lu ,&nbsp;Wei Wei ,&nbsp;Min Wang,&nbsp;Rixin Chen,&nbsp;Fuhua Yan,&nbsp;Yanfen Li","doi":"10.1016/j.bbadis.2025.167866","DOIUrl":"10.1016/j.bbadis.2025.167866","url":null,"abstract":"<div><h3>Objectives</h3><div>Diabetic periodontitis (DP) appears to be the sixth most common complication of diabetes; however, its underlying pathological mechanisms require further explored. Our study investigated the potential function of the translocator protein (TSPO) in the progression of DP, aiming to provide a theoretical foundation for novel treatment strategies.</div></div><div><h3>Methods</h3><div>The ultrastructure and TSPO expression of gingival tissue, collected from healthy individuals, people with periodontitis, and those with DP, were examined. <em>In vivo</em>, a DP model in rats was established using streptozotocin (STZ) and silk ligation. TSPO ligand antagonist PK 11195 was administered as a treatment. Microcomputed tomography (Micro-CT), quantitative real-time polymerase chain reaction (qPCR), histology and immunohistochemistry were employed to assess the destruction, inflammatory and mitophagy in rat periodontal tissues. In <em>in vitro</em> experiments, the inflammatory responses, mitochondrial function, mitophagy and the potential role of TSPO in macrophages were also examined under high-glucose inflammatory conditions, using flow cytometry, fluorescence probes, qPCR, Western blotting and transcription inhibition.</div></div><div><h3>Results</h3><div>Mitochondrial damage, mitophagy inhibition and increased TSPO expression were observed in gingivae from patients with DP. PK 11195 facilitated the restoration of mitophagy and alleviated the inflammatory destruction of DP rats. Additionally, the high-glucose inflammatory environment intensified the macrophage inflammatory response, ROS production, and mitochondrial damage. These pathological changes were reduced by TSPO inhibition, which could also upregulate the mitophagy.</div></div><div><h3>Conclusions</h3><div>The inflammation and destruction of periodontal tissue in DP are closely linked to mitophagy associated with TSPO. Immunotherapy targeting TSPO in macrophages could significantly influence the treatment of DP by modulating mitophagy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167866"},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}