Journal of Biomedical Science最新文献

{"title":"miR-193b-3p suppresses lung cancer cell migration and invasion through PRNP targeting.","authors":"Hsiang-Ling Ho, Shin-Chih Lin, Chao-Wei Chiang, Ching Lin, Che-Wei Liu, Yi-Chen Yeh, Mei-Yu Chen, Teh-Ying Chou","doi":"10.1186/s12929-025-01121-1","DOIUrl":"10.1186/s12929-025-01121-1","url":null,"abstract":"<p><strong>Background: </strong>Tumor metastasis is responsible for approximately 90% of mortality in lung cancer. Understanding the molecular mechanisms of lung cancer metastasis is crucial for developing new treatment strategies. Cellular prion protein (PrPc), encoded by PRNP gene, was previously found to enhance lung cancer invasiveness. However, research on the post-transcriptional regulation of PRNP remains limited.</p><p><strong>Methods: </strong>Dual-luciferase reporter assays identified miRNAs targeting the PRNP 3'-UTR, and RNA immunoprecipitation (RIP) confirmed the interaction between miR-193b-3p and PRNP mRNA. Promoter deletions and chromatin immunoprecipitation (ChIP) assays established c-Jun as a transcriptional repressor of miR-193b-3p. Functional validation of the c-Jun-miR-193b-3p-PrPc axis was conducted using transwell assays, LNA-in situ hybridization, RT-PCR, Western blot, and immunohistochemistry. Subcutaneous mouse xenograft models assessed the anti-tumor effects of miR-193b-3p in vivo.</p><p><strong>Results: </strong>We demonstrated that miR-193b-3p downregulates PrPc expression by directly targeting the 3'-UTR of PRNP. Overexpression of miR-193b-3p significantly suppressed PRNP expression at both mRNA and protein levels, and reduced lung cancer cell migration, invasion and proliferation, which was reversed by PrPc overexpression. Conversely, miR-193b-3p silencing enhanced PRNP expression as well as those oncogenic properties, which were mitigated by PRNP knockdown. Spearman correlation analysis revealed a significant negative association between miR-193b-3p and PrPc expression in lung cancer tissues (p = 0.017), and Kaplan-Meier survival analysis demonstrated that high PrPc (p = 0.039) or low miR-193b-3p (p = 0.027) expression correlated with poorer overall survival. Intra-tumoral injection of the miR-193b-3p mimic in mouse xenograft models significantly reduced tumor volume. In addition, c-Jun was identified as a transcriptional repressor of miR-193b-3p. Functional studies revealed that c-Jun knockdown inhibited lung cancer cell migration, invasion, and proliferation, effects that were reversed by either PrPc overexpression or miR-193b-3p inhibitor treatment. A significant association between PrPc and c-Jun expression in lung cancer tissues (p = 0.004) was observed. High expression of PrPc and/or c-Jun was found to be associated with poor overall survival of patients (p < 0.05).</p><p><strong>Conclusions: </strong>This study is the first to uncover a novel regulatory pathway where c-Jun acts as a transcriptional repressor of miR-193b-3p, leading to PRNP upregulation, which promotes lung cancer migration and invasion. This previously unrecognized c-Jun-miR-193b-3p-PrPc axis also provides valuable insights for the potential development of new therapeutic strategies against lung cancer metastasis through RNA-targeting technology.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"28"},"PeriodicalIF":9.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The zinc finger protein ZFP36L2 inhibits flavivirus infection via the 5'-3' XRN1-mediated RNA decay pathway in the replication complexes.","authors":"Ren-Jye Lin, Li-Hsiung Lin, Zih-Ping Chen, Bing-Cheng Liu, Pin-Chen Ko, Ching-Len Liao","doi":"10.1186/s12929-025-01122-0","DOIUrl":"10.1186/s12929-025-01122-0","url":null,"abstract":"<p><strong>Background: </strong>The zinc finger protein 36-like (ZFP36L) family is a CCCH-type group consisting of RNA-binding proteins, i.e., ZFP36L1 and ZFP36L2, which regulate cellular mRNA through the RNA decay pathway. ZFP36L1 combats flavivirus infections through the 5'-3' XRN1 and 3'-5' RNA exosome decay pathways. The present study clarified the role of human ZFP36L2 in the defense response of the host against flavivirus infection.</p><p><strong>Methods: </strong>Cell lines with overexpression or knockdown of ZFP36L2 were established using lentiviral vectors carrying genes for overexpression and short-hairpin RNA targeting specific genes, respectively. A plaque assay was employed to determine the viral titer. Immunofluorescence and real-time quantitative polymerase chain reaction were used to measure the viral RNA levels. The in vitro-transcribed RNA transcript derived from a replication-dead Japanese encephalitis virus (JEV) replicon containing the renilla luciferase reporter gene (J-R2A-NS5mt) was used to assess the stability of the flavivirus RNA. An RNA immunoprecipitation assay was used to detect the protein-RNA binding ability. Confocal microscopic images were captured to analyze protein colocalization.</p><p><strong>Results: </strong>ZFP36L2 served as an innate host defender against JEV and dengue virus. ZFP36L2 inhibited flavivirus infection solely through the 5'-3' XRN1 RNA decay pathway, whereas ZFP36L1 inhibited JEV infection via the 5'-3' XRN1 and 3'-5' RNA exosome RNA decay pathways. The direct binding between viral RNA and ZFP36L2 via its CCCH-type zinc finger motifs facilitated the degradation of flavivirus RNA mediated by 5'-3' XRN1. Furthermore, ZFP36L2 was localized in processing bodies (PBs), which participate in the 5'-3' XRN1-mediated RNA decay pathway. Nonetheless, the disruption of PBs did not affect the antiviral activity of ZFP36L2, suggesting that its localization is not essential for the function of the protein. Interestingly, the colocalization of ZFP36L2 and XRN1 with viral RNA and NS3 revealed that the antiviral activity of ZFP36L2 occurred within the replication complexes (RCs).</p><p><strong>Conclusions: </strong>In summary, ZFP36L2 bound to and degraded viral RNA through the XRN1-mediated RNA decay pathway in the RCs, thereby inhibiting flavivirus replication. These findings provide valuable insights into the diverse antiviral mechanisms of the ZFP36-like family of proteins in the innate immune response against flavivirus infection.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"27"},"PeriodicalIF":9.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGF receptor in organ development, tissue homeostasis and regeneration.","authors":"Claudia Tito, Silvia Masciarelli, Gianni Colotti, Francesco Fazi","doi":"10.1186/s12929-025-01119-9","DOIUrl":"10.1186/s12929-025-01119-9","url":null,"abstract":"<p><p>The epidermal growth factor receptor (EGFR) is a protein embedded in the outer membrane of epithelial and mesenchymal cells, bone cells, blood and immune cells, heart cells, glia and stem neural cells. It belongs to the ErbB family, which includes three other related proteins: HER2/ErbB2/c-neu, HER3/ErbB3, and HER4/ErbB4. EGFR binds to seven known signaling molecules, including epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α). This binding triggers the formation of receptor pairs (dimers), self-phosphorylation of EGFR, and the activation of several signaling pathways within the cell. These pathways influence various cellular processes like proliferation, differentiation, migration, and survival. EGFR plays a critical role in both development and tissue homeostasis, including tissue repair and adult organ regeneration. Altered expression of EGFR is linked to disruption of tissue homeostasis and various diseases, among which cancer. This review focuses on how EGFR contributes to the development of different organs like the placenta, gut, liver, bone, skin, brain, T cell regulation, pancreas, kidneys, mammary glands and lungs along with their associated pathologies. The involvement of EGFR in organ-specific branching morphogenesis process is also discussed. The level of EGFR activity and its impact vary across different organs. Factors as the affinity of its ligands, recycling or degradation processes, and transactivation by other proteins or environmental factors (such as heat stress and smoking) play a role in regulating EGFR activity. Understanding EGFR's role and regulatory mechanisms holds promise for developing targeted therapeutic strategies.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"24"},"PeriodicalIF":9.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intratumoral microbiome: implications for immune modulation and innovative therapeutic strategies in cancer.","authors":"Na Wang, Si Wu, Lanxiang Huang, Yue Hu, Xin He, Jourong He, Ben Hu, Yaqi Xu, Yuan Rong, Chunhui Yuan, Xiantao Zeng, Fubing Wang","doi":"10.1186/s12929-025-01117-x","DOIUrl":"10.1186/s12929-025-01117-x","url":null,"abstract":"<p><p>Recent advancements have revealed the presence of a microbiome within tumor tissues, underscoring the crucial role of the tumor microbiome in the tumor ecosystem. This review delves into the characteristics of the intratumoral microbiome, underscoring its dual role in modulating immune responses and its potential to both suppress and promote tumor growth. We examine state-of-the-art techniques for detecting and analyzing intratumoral bacteria, with a particular focus on their interactions with the immune system and the resulting implications for cancer prognosis and treatment. By elucidating the intricate crosstalk between the intratumoral microbiome and the host immune system, we aim to uncover novel therapeutic strategies that enhance the efficacy of cancer treatments. Additionally, this review addresses the existing challenges and future prospects within this burgeoning field, advocating for the integration of microbiome research into comprehensive cancer therapy frameworks.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"23"},"PeriodicalIF":9.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"K27-linked RORγt ubiquitination by Nedd4 potentiates Th17-mediated autoimmunity.","authors":"Qiuming Zeng, Hui Guo, Na Tang, Pranav S Renavikar, Nitin J Karandikar, Amy E Lovett-Racke, Michael K Racke, Chengkai Yan, Rong Tang, Sushmita Sinha, Krishnendu Ghosh, Jeremy P Ryal, Song Ouyang, Min Chen, Foued Amari, Coppola Vincenzo, R Marshall Pope, Yalan Li, Huan Yang, Wallace Y Langdon, Jian Zhang","doi":"10.1186/s12929-025-01120-2","DOIUrl":"10.1186/s12929-025-01120-2","url":null,"abstract":"<p><strong>Background: </strong>The HECT E3 ubiquitin ligase Nedd4 has been shown to positively regulate T cell responses, but its role in T helper (Th) cell differentiation and autoimmunity is unknown. Th17 cells are believed to play a pivotal role in the development and pathogenesis of autoimmune diseases. Nevertheless, the regulation of RORγt activation during Th17 cell differentiation by TCR signaling is yet to be elucidated. These uncharted aspects inspire us to explore the potential role of Nedd4 in Th17-mediated autoimmunity.</p><p><strong>Methods: </strong>We evaluated the impact of Nedd4 deficiency on mouse T cell development and differentiation using flow cytometry and siRNA transfection, and subsequently validated these findings in T cells from patients with multiple sclerosis (MS). Furthermore, we investigated the influence of Nedd4 deficiency on Th17-mediated autoimmunity through experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Subsequently, we elucidated the molecular mechanism underlying the interaction between Nedd4 and RORgt through immunoprecipitation, mass spectrometry analysis, and lentiviral transduction. Additionally, we identified Nedd4 as an E3 ubiquitin ligase for RORγt. Moreover, we characterized the tyrosine residue sites and polyubiquitination patterns involved in RORγt ubiquitination.</p><p><strong>Results: </strong>In this study, we report that loss of Nedd4 in T cells specifically impairs pathogenic and non-pathogenic Th17 responses, and Th17-mediated EAE development. At the molecular level, Nedd4 binds to the PPLY motif within the ligand binding domain of RORγt, and targets RORγt at K112 for K27-linked polyubiquitination, thus augmenting its activity.</p><p><strong>Conclusion: </strong>Nedd4 is a crucial E3 ubiquitin ligase for RORγt in the regulating Th17 cell development and offers potential therapeutic benefits for treating Th17-mediated autoimmune diseases.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"26"},"PeriodicalIF":9.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.","authors":"Fasih A Rahman, Mackenzie Q Graham, Amanda M Adam, Emma S Juracic, A Russell Tupling, Joe Quadrilatero","doi":"10.1186/s12929-025-01118-w","DOIUrl":"10.1186/s12929-025-01118-w","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly understood.</p><p><strong>Methods: </strong>We used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC; 150 mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4 mg/kg/day) to inhibit autophagy.</p><p><strong>Results: </strong>Our study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 activation.</p><p><strong>Conclusion: </strong>These findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilization. Targeting mitophagy may offer new strategies to preserve muscle function during prolonged periods of immobilization.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"29"},"PeriodicalIF":9.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergence of population heterogeneity in Klebsiella pneumoniae with a bla_OXA-232-harboring plasmid: carbapenem resistance, virulence, and fitness.","authors":"Yun Young Cho, Sun Ju Kim, Kwan Soo Ko","doi":"10.1186/s12929-024-01108-4","DOIUrl":"10.1186/s12929-024-01108-4","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to investigate the population heterogeneity on carbapenem susceptibility in Klebsiella pneumoniae strains that acquired a bla_OXA-232-bearing ColE-type plasmid.</p><p><strong>Methods: </strong>A bla_OXA-232-bearing plasmid was electroporated into two carbapenem-susceptible K. pneumoniae strains. High- and low-carbapenem-resistant subpopulations were identified and isolated using patch plating. The strains were subsequently subcultured in antibiotic-free media, yielding two distinct populations: a stable, high-level carbapenem-resistant strains and a heterogeneous strains. Antibiotic susceptibility tests, time-killing assays, and population profiles were conducted, along with a competition assay was performed and the growth curve analysis. To assess virulence, we performed human serum resistance and Galleria mellonella infection assays, and measured the expression of virulence genes using qRT-PCR. Additionally, whole genome sequencing was carried out for further anaysis.</p><p><strong>Results: </strong>Introduction of pOXA-232 into carbapenem-susceptible K. pneumoniae strains resulted in two isogenic transformants with distinct resistance profiles: an unstable, high-level carbapenem-resistant (HCR), and highly virulent subpopulation; and a stable, low-level carbapenem-resistant (LCR), and low-virulence subpopulation. Whole genome and expression analyses revealed dysfunctionality of ompK36 in HCR subpopulations. Subculturing of HCR led to the re-emergence of heterogeneous populations with variations in carbapenem resistance and an additional compensatory mutation of 9,000 bp deletion in the genome. Thus, stable HCR strains featuring both mutations in ompK36 and compensatory mutations developed.</p><p><strong>Conclusion: </strong>This study demonstrated that underlying heterogeneity can promote the emergence of stable, high-level antibiotic resistance, even with the introduction of a plasmid carrying a low-level antibiotic resistance gene, such as bla_OXA-232. This highlights the critical need to closely monitor bacterial population dynamics.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"22"},"PeriodicalIF":9.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-200c inhibition and catalase accelerate diabetic wound healing.","authors":"Marco D'Agostino, Sara Sileno, Daniela Lulli, Naomi De Luca, Claudia Scarponi, Massimo Teson, Alessio Torcinaro, Francesca De Santa, Corrado Cirielli, Sergio Furgiuele, Chris H Morrell, Elena Dellambra, Teresa Odorisio, Edward G Lakatta, Daniele Avitabile, M C Capogrossi, Alessandra Magenta","doi":"10.1186/s12929-024-01113-7","DOIUrl":"10.1186/s12929-024-01113-7","url":null,"abstract":"<p><strong>Background: </strong>Reactive oxygen species (ROS) are increased in diabetic conditions and play a causal role in diabetic foot ulcers (DFU). We previously showed that ROS up-regulate miR-200c expression, that in turns causes apoptosis, senescence, ROS upregulation and nitric oxide decrease, leading to endothelial disfunction.</p><p><strong>Methods: </strong>The aim of this study is to dissect miR-200c role in DFU and to explore the potential role of anti-miR-200c and antioxidant catalase (CAT) in promoting wound healing (WH). miR-200c inhibition and CAT treatment were performed either in immortalized keratinocytes (HaCaT) or in primary fibroblasts (FBs) and keratinocytes (KCs) deriving from diabetic patients (pts) undergoing amputations. Primary cells deriving from pts undergoing saphenectomies were used as controls. The miR-200c blockade was performed either via lentiviral particles bearing an anti-miR-200c sequence or locked nucleic acid (LNA) anti-miR-200c oligos. Equine CAT was administered on cell medium. The WH assay was performed in vivo on diabetic (db/db) mice by a topical treatment with CAT and LNA anti-miR-200c on wounds dissolved in a Pluronic gel mixture, administered every three days.</p><p><strong>Results: </strong>We found that miR-200c levels were increased by different stimuli known to induce ROS, such as ultraviolet radiation (UV), hydrogen peroxide (H₂O₂), and high glucose in HaCaT. miR-200c was also upregulated in skin biopsies, in FBs and KCs isolated from pts with DFU vs controls. Forced miR-200c expression induced ROS in both FBs and KCs, and CAT reduced it. miR-200c inhibition improved WH in HaCaT, both under basal conditions and after UV and H₂O₂ treatment, and the simultaneous treatment with CAT accelerated it. miR-200c inhibition accelerated WH in KCs of DFU pts, increasing its protein targets: sirtuin 1 (SIRT1), the transcription factors FOXO1 and ZEB1 and decreasing p66Shc phosphorylation at Ser-36, that is induced by ROS, and the co-treatment with CAT showed synergistic effects in reducing ROS and cytotoxicity. Interestingly, CAT treatment decreased miR-200c expression in FBs and KCs of DFU pts. Topical administration of anti-miR-200c and CAT in a WH model of diabetic mice accelerated closure.</p><p><strong>Conclusions: </strong>Anti-miR-200c and CAT could be considered a novel treatment for DFU and, possibly, for other types of non-diabetic skin ulcers.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"21"},"PeriodicalIF":9.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy.","authors":"Yu Mei Yang, Hang Bin Ma, Yue Xiong, Qian Wu, Xiu Kui Gao","doi":"10.1186/s12929-024-01115-5","DOIUrl":"10.1186/s12929-024-01115-5","url":null,"abstract":"<p><strong>Background: </strong>Diabetic neuropathy (DN) is a prevalent and painful complication of diabetes; however, the mechanisms underlying its pathogenesis remain unclear, and effective clinical treatments are lacking. This study aims to explore the role of peroxisomes in Schwann cells in DN.</p><p><strong>Methods: </strong>The abundance of peroxisomes in the sciatic nerves of mice or Schwann cells was analyzed using laser confocal super-resolution imaging and western blotting. The RFP-GFP-SKL (Ser-Lys-Leu) probe was utilized to assess pexophagy (peroxisomes autophagy) levels. To evaluate the palmitoylation of PEX11B, the acyl-resin assisted capture (acyl-RAC) assay and the Acyl-Biotin Exchange (ABE) assay were employed. Additionally, MR (Mendelian randomization) analysis was conducted to investigate the potential causal relationship between DN and MS (Multiple sclerosis).</p><p><strong>Results: </strong>There was a decrease in peroxisomal abundance in the sciatic nerves of diabetic mice, and palmitic acid (PA) induced a reduction in peroxisomal abundance by inhibiting peroxisomal biogenesis in Schwann cells. Mechanistically, PA induced the palmitoylation of PEX11B at C25 site, disrupting its self-interaction and impeding peroxisome elongation. Fenofibrate, a PPARα agonist, effectively rescued peroxisomal dysfunction caused by PA and restored the peroxisomal abundance in diabetic mice. Lastly, MR analysis indicates a notable causal influence of DN on MS, with its onset and progression intricately linked to peroxisomal dysfunction.</p><p><strong>Conclusions: </strong>Targeting the peroxisomal biogenesis pathway may be an effective strategy for preventing and treating DN, underscoring the importance of addressing MS risk at the onset of DN.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"20"},"PeriodicalIF":9.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11818136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional hyaluronic acid-based biomimetic/pH-responsive hybrid nanostructured lipid carriers for treating bacterial sepsis.","authors":"Eman Elhassan, Calvin A Omolo, Mohammed A Gafar, Eman A Ismail, Usri H Ibrahim, Rene Khan, Mathieu Lesouhaitier, Paul Kubes, Thirumala Govender","doi":"10.1186/s12929-024-01114-6","DOIUrl":"10.1186/s12929-024-01114-6","url":null,"abstract":"<p><strong>Introduction: </strong>The application of biomimetic and stimuli-responsive nanocarriers displays considerable promise in improving the management of bacterial sepsis and overcoming antimicrobial resistance. Therefore, the study aimed to synthesize a novel hyaluronic acid-lysine conjugate (HA-Lys) and to utilize the attributes of the synthesized HA-Lys with Tocopherol succinate (TS) and Oleylamine (OLA) in the formulation of multifunctional biomimetic pH-responsive HNLCs loaded with vancomycin (VCM-HNLCs), to combat bacterial sepsis.</p><p><strong>Methods: </strong>A novel hyaluronic acid-lysine conjugate (HA-Lys) was synthesized and characterized using FTIR and ¹H NMR spectroscopy. Vancomycin-loaded hybrid nanosystems (VCM-HNLCs) were prepared through hot homogenization ultrasonication and evaluated for particle size, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE%). In vitro biocompatibility was assessed via MTT assay and red blood cell hemolysis test. The binding affinity to TLR2 and TLR4 was measured using microscale thermophoresis (MST). Drug release was evaluated using the dialysis bag method. Antimicrobial activity against MRSA and efflux pump inhibition were also determined. Efficacy was demonstrated in an MRSA-induced sepsis mice model.</p><p><strong>Results: </strong>The VCM-HNLCs, produced via hot homogenization ultrasonication, exhibited particle size (PS), polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE%) of 110.77 ± 1.692 nm, 0.113 ± 0.022, - 2.92 ± 0.210 mV, and 76.27 ± 1.200%, respectively. In vitro, biocompatibility was proven by hemolysis and cytotoxicity studies. The VCM-HNLCs demonstrated targetability to human Toll-like receptors (TLR 2 and 4) as validated by microscale thermophoresis (MST). VCM-HNLCs showed a twofold reduction in MIC values at physiological pH compared to the bare VCM against S. aureus and MRSA for 48 h. While at pH 6.0, MIC values were reduced by fourfold in the first 24 h and by eightfold in the subsequent 48 and 72 h against tested strains. Furthermore, VCM-HNLCs showed inhibitory effects against MRSA efflux pumps, reactive oxygen species (ROS), and lipopolysaccharide (LPS)-induced hyperinflammation. In an MRSA-induced sepsis mice model, VCM-HNLCs demonstrated superior efficacy compared to free VCM, significantly eliminated bacteria and improved survival rates.</p><p><strong>Conclusions: </strong>Overall, these results highlight the potential of VCM-HNLCs as novel multifunctional nanocarriers to combat antimicrobial resistance (AMR) and enhance sepsis outcomes.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"19"},"PeriodicalIF":9.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11812216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}