Journal of Biomedical Science最新文献

{"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}

{"title":"Targeting the fundamentals for tremors: the frequency and amplitude coding in essential tremor.","authors":"Ming-Kai Pan","doi":"10.1186/s12929-024-01112-8","DOIUrl":"10.1186/s12929-024-01112-8","url":null,"abstract":"<p><p>Essential tremor (ET) is one of the most common movement disorders with heterogeneous pathogenesis involving both genetic and environmental factors, which often results in variable therapeutic outcomes. Despite the diverse etiology, ET is defined by a core symptom of action tremor, an involuntary rhythmic movement that can be mathematically characterized by two parameters: tremor frequency and tremor amplitude. Recent advances in neural dynamics and clinical electrophysiology have provided valuable insights to explain how tremor frequency and amplitude are generated within the central nervous system. This review summarizes both animal and clinical evidence, encompassing the kinematic features of tremors, circuitry dynamics, and the neuronal coding mechanisms for the two parameters. Neural population coding within the olivocerebellum is implicated in determining tremor frequency, while the cerebellar circuitry synchrony and cerebellar-thalamo-cortical interactions play key roles in regulating tremor amplitude. Novel therapeutic strategies aimed at tuning tremor frequency and amplitude are also discussed. These neural dynamic approaches target the conserved mechanisms across ET patients with varying etiologies, offering the potential to develop universally effective therapies for ET.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"18"},"PeriodicalIF":9.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382311","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":"Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma.","authors":"Dinh-Xuan Pham, Tien Hsu","doi":"10.1186/s12929-024-01111-9","DOIUrl":"10.1186/s12929-024-01111-9","url":null,"abstract":"<p><p>Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney malignancy. ccRCC is considered a major health concern worldwide because its numbers of incidences and deaths continue to rise and are predicted to continue rising in the foreseeable future. Therefore new strategy for early diagnosis and therapeutics for this disease is urgently needed. The discovery of cancer stem cells (CSCs) offers hope for early cancer detection and treatment. However, there has been no definitive identification of these cancer progenitors for ccRCC. A majority of ccRCC is characterized by the loss of the von Hippel-Lindau (VHL) tumor suppressor gene function. Recent advances in genome analyses of ccRCC indicate that in ccRCC, tumor-initiating cells (TICs) and metastasis-initiating cells (MICs) are two distinct groups of progenitors. MICs result from various genetic changes during subclonal evolution, while TICs reside in the stem of the ccRCC phylogenetic tree of clonal development. TICs likely originate from kidney tubule progenitor cells bearing VHL gene inactivation, including chromatin 3p loss. Recent studies also point to the importance of microenvironment reconstituted by the VHL-deficient kidney tubule cells in promoting ccRCC initiation and progression. These understandings should help define the progenitors of ccRCC and facilitate early detection and treatment of this disease.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"17"},"PeriodicalIF":9.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370814","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":"Unlocking precision medicine: clinical applications of integrating health records, genetics, and immunology through artificial intelligence.","authors":"Yi-Ming Chen, Tzu-Hung Hsiao, Ching-Heng Lin, Yang C Fann","doi":"10.1186/s12929-024-01110-w","DOIUrl":"10.1186/s12929-024-01110-w","url":null,"abstract":"<p><p>Artificial intelligence (AI) has emerged as a transformative force in precision medicine, revolutionizing the integration and analysis of health records, genetics, and immunology data. This comprehensive review explores the clinical applications of AI-driven analytics in unlocking personalized insights for patients with autoimmune rheumatic diseases. Through the synergistic approach of integrating AI across diverse data sets, clinicians gain a holistic view of patient health and potential risks. Machine learning models excel at identifying high-risk patients, predicting disease activity, and optimizing therapeutic strategies based on clinical, genomic, and immunological profiles. Deep learning techniques have significantly advanced variant calling, pathogenicity prediction, splicing analysis, and MHC-peptide binding predictions in genetics. AI-enabled immunology data analysis, including dimensionality reduction, cell population identification, and sample classification, provides unprecedented insights into complex immune responses. The review highlights real-world examples of AI-driven precision medicine platforms and clinical decision support tools in rheumatology. Evaluation of outcomes demonstrates the clinical benefits and impact of these approaches in revolutionizing patient care. However, challenges such as data quality, privacy, and clinician trust must be navigated for successful implementation. The future of precision medicine lies in the continued research, development, and clinical integration of AI-driven strategies to unlock personalized patient care and drive innovation in rheumatology.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"16"},"PeriodicalIF":9.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364916","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":"Targeting the G-quadruplex as a novel strategy for developing antibiotics against hypervirulent drug-resistant Staphylococcus aureus.","authors":"Maria Sultan, Maria Razzaq, Joohyun Lee, Shreyasi Das, Shrute Kannappan, Vinod Kumar Subramani, Wanki Yoo, Truc Kim, Hye-Ra Lee, Akhilesh K Chaurasia, Kyeong Kyu Kim","doi":"10.1186/s12929-024-01109-3","DOIUrl":"10.1186/s12929-024-01109-3","url":null,"abstract":"<p><strong>Background: </strong>The rapid emergence of multiple drug-resistant (MDR) bacterial pathogens and the lack of a novel antibiotic pipeline pose a serious threat to global healthcare. The limited number of established targets further restricts the identification of novel antibiotics to treat life-threatening MDR infections caused by Staphylococcus aureus strains. Therefore, novel targets for developing antibiotics are urgently required. In this study, we hypothesized that the G-quadruplex (G4)-binding ligands can be used as novel antibiotics as their binding can possibly downregulate/block the expression of vital genes.</p><p><strong>Methods: </strong>To test this, first we screened the antibiotic properties of representative G4-binding ligands against hypervirulent and MDR S. aureus USA300 and determined the in vitro and in vivo antibacterial activity; and proposed the mechanism of action by applying various microbiological, infection, microscopic, and biophysicochemical techniques.</p><p><strong>Results: </strong>Herein, among screened G4-binding ligands, N-methyl mesoporphyrin IX (NMM) showed the highest antibacterial activity against S. aureus USA300. NMM exhibited a minimum inhibitory concentration (MIC) of 5 μM against S. aureus USA300, impacting cell division and the cell wall by repressing the expressions of genes in the division cell wall (dcw) gene cluster. Genome-wide bioinformatics analysis of G4 motifs and their mapping on S. aureus genome, identified the presence of G4-motif in the promoter of mraZ, a conserved master regulator of the dcw cluster regulating the coordinated cell division and cell wall synthesis. Physicochemical assessments using UV-visible, circular dichroism, and nuclear magnetic resonance spectroscopy confirmed that the G4-motif present in the mraZ promoter formed an intramolecular parallel G4 structure, interacting with NMM. In vivo reporter followed by coupled in vitro transcription/translation (IVT) assays confirmed the role of mraZ G4 as a target interacting NMM to impose extreme antibacterial activity against both the gram-positive and -negative bacteria. In-cell and in vivo validation of NMM using RAW264.7 cells and Galleria mellonella; respectively, demonstrated that NMM exhibited superior antibiotic activity compared to well-established antibiotics, with no observed cytotoxicity.</p><p><strong>Conclusions: </strong>In summary, the current study identified NMM as a broad-spectrum potent antibacterial agent and elucidated its plausible mechanism of action primarily by targeting G4-motif in the mraZ promoter of the dcw gene cluster.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"15"},"PeriodicalIF":9.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189270","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 Data Artifacts Glossary: a community-based repository for bias on health datasets.","authors":"Rodrigo R Gameiro, Naira Link Woite, Christopher M Sauer, Sicheng Hao, Chrystinne Oliveira Fernandes, Anna E Premo, Alice Rangel Teixeira, Isabelle Resli, An-Kwok Ian Wong, Leo Anthony Celi","doi":"10.1186/s12929-024-01106-6","DOIUrl":"10.1186/s12929-024-01106-6","url":null,"abstract":"<p><strong>Background: </strong>The deployment of Artificial Intelligence (AI) in healthcare has the potential to transform patient care through improved diagnostics, personalized treatment plans, and more efficient resource management. However, the effectiveness and fairness of AI are critically dependent on the data it learns from. Biased datasets can lead to AI outputs that perpetuate disparities, particularly affecting social minorities and marginalized groups.</p><p><strong>Objective: </strong>This paper introduces the \"Data Artifacts Glossary\", a dynamic, open-source framework designed to systematically document and update potential biases in healthcare datasets. The aim is to provide a comprehensive tool that enhances the transparency and accuracy of AI applications in healthcare and contributes to understanding and addressing health inequities.</p><p><strong>Methods: </strong>Utilizing a methodology inspired by the Delphi method, a diverse team of experts conducted iterative rounds of discussions and literature reviews. The team synthesized insights to develop a comprehensive list of bias categories and designed the glossary's structure. The Data Artifacts Glossary was piloted using the MIMIC-IV dataset to validate its utility and structure.</p><p><strong>Results: </strong>The Data Artifacts Glossary adopts a collaborative approach modeled on successful open-source projects like Linux and Python. Hosted on GitHub, it utilizes robust version control and collaborative features, allowing stakeholders from diverse backgrounds to contribute. Through a rigorous peer review process managed by community members, the glossary ensures the continual refinement and accuracy of its contents. The implementation of the Data Artifacts Glossary with the MIMIC-IV dataset illustrates its utility. It categorizes biases, and facilitates their identification and understanding.</p><p><strong>Conclusion: </strong>The Data Artifacts Glossary serves as a vital resource for enhancing the integrity of AI applications in healthcare by providing a mechanism to recognize and mitigate dataset biases before they impact AI outputs. It not only aids in avoiding bias in model development but also contributes to understanding and addressing the root causes of health disparities.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"14"},"PeriodicalIF":9.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122853","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":"Utilisation of an in vivo malaria model to provide functional proof for RhopH1/CLAG essentiality and conserved orthology with P. falciparum.","authors":"Mitchell L Trickey, Mrittika Chowdury, Georgina Bramwell, Natalie A Counihan, Tania F de Koning-Ward","doi":"10.1186/s12929-024-01105-7","DOIUrl":"10.1186/s12929-024-01105-7","url":null,"abstract":"<p><strong>Background: </strong>Malaria parasites establish new permeation pathways (NPPs) at the red blood cell membrane to facilitate the transport of essential nutrients from the blood plasma into the infected host cell. The NPPs are critical to parasite survival and, therefore, in the pursuit of novel therapeutics are an attractive drug target. The NPPs of the human parasite, P. falciparum, have been linked to the RhopH complex, with the monoallelic paralogues clag3.1 and clag3.2 encoding the protein RhopH1/CLAG3 that likely forms the NPP channel-forming component. Yet curiously, the combined knockout of both clag3 genes does not completely eliminate NPP function. The essentiality of the clag3 genes is, however, complicated by three additional clag paralogs (clag2, clag8 and clag9) in P. falciparum that could also be contributing to NPP formation.</p><p><strong>Methods: </strong>Here, the rodent malaria species, P. berghei, was utilised to investigate clag essentiality since it contains only two clag genes, clagX and clag9. Allelic replacement of the regions encompassing the functional components of P. berghei clagX with either P. berghei clag9 or P. falciparum clag3.1 examined the relationship between the two P. berghei clag genes as well as functional orthology across the two species. An inducible P. berghei clagX knockout was created to examine the essentiality of the clag3 ortholog to both survival and NPP functionality.</p><p><strong>Results: </strong>It was revealed P. berghei CLAGX and CLAG9, which belong to two distinct phylogenetic clades, have separate non-complementary functions, and that clagX is the functional orthologue of P. falciparum clag3. The inducible clagX knockout in conjunction with a guanidinium chloride induced-haemolysis assay to assess NPP function provided the first evidence of CLAG essentiality to Plasmodium survival and NPP function in an in vivo model of infection.</p><p><strong>Conclusions: </strong>This work provides valuable insight regarding the essentiality of the RhopH1 clag genes to the NPPs functionality and validates the continued investigation of the RhopH complex as a therapeutic target to treat malaria infections.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"13"},"PeriodicalIF":9.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080184","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":"Temporal and spatial pattern of DNA damage in neurons following spinal cord Injury in mice.","authors":"Elle Em Scheijen, Naomi Veeningen, Sam Duwé, Anna Ivanova, Jana Van Broeckhoven, Sven Hendrix, David M Wilson","doi":"10.1186/s12929-024-01104-8","DOIUrl":"10.1186/s12929-024-01104-8","url":null,"abstract":"<p><strong>Background: </strong>Deficient DNA repair and excessive DNA damage contribute to neurodegenerative disease. However, the role of DNA damage and repair in spinal cord injury (SCI) is unclear. SCI, a debilitating disruption of the structural and biological network of the spinal cord, is characterized by oxidative stress. Nevertheless, the pathophysiological mechanisms leading to neuronal loss following SCI remain incompletely defined.</p><p><strong>Methods: </strong>Using a contusion model, a severe SCI was induced at the L1 spinal level in C57Bl/6J mice. The temporal and spatial presence of DNA damage was then determined via immunolabeling for the DNA damage marker, γH2AX, from 1 h post-injury (hpi) to 28 days post-injury (dpi).</p><p><strong>Results: </strong>Our analysis revealed that increased DNA damage foci were present from 1 hpi to 3 dpi in SCI mice relative to controls (sham surgery and naive), with the damage signal spreading over time longitudinally from the affected area to more rostral and caudal regions. Co-labeling of γH2AX with NeuN revealed neuronal specificity of DNA damage, with increased early cell death (pan-nuclear γH2AX) peaking at 1 dpi and apoptosis (cleaved Caspase-3) arising later at 3 dpi.</p><p><strong>Conclusion: </strong>Our study indicates a possible role of DNA damage in neuronal loss following SCI and highlights the need for early interventions targeting DNA repair to preserve neuronal tissue.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"12"},"PeriodicalIF":9.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023562","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 endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients.","authors":"Alina-Veronica Ghionescu, Mihaela Uta, Andrei Sorop, Catalin Lazar, Petruta R Flintoaca-Alexandru, Gabriela Chiritoiu, Livia Sima, Stefana-Maria Petrescu, Simona Olimpia Dima, Norica Branza-Nichita","doi":"10.1186/s12929-024-01103-9","DOIUrl":"https://doi.org/10.1186/s12929-024-01103-9","url":null,"abstract":"<p><strong>Background: </strong>Chronic hepatitis B virus (HBV) infection is a major risk for development of hepatocellular carcinoma (HCC), a frequent malignancy with a poor survival rate. HBV infection results in significant endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) signaling, a contributing factor to carcinogenesis. As part of the UPR, the ER-associated degradation (ERAD) pathway is responsible for removing the burden of misfolded secretory proteins, to re-establish cellular homeostasis. Emerging evidence indicates consistent upregulation of ERAD factors, including members of the ER degradation-enhancing alpha-mannosidase-like protein (EDEM) family in infection and various tumor types. However, the significance of this gene expression pattern in HBV-driven pathology is just beginning to be deciphered.</p><p><strong>Methods: </strong>In this study we quantified the expression of the ERAD factor EDEM3, in a cohort of HCC patients with and without HBV infection, and validated our results by analysis of publically available transcriptomic and microarray data sets. We performed mechanistic studies in HepaRG cells with modulated EDEM3 expression to address UPR, ERAD, autophagy and apoptosis signaling, and their consequences on HBV infection.</p><p><strong>Results: </strong>Our work revealed significantly elevated EDEM3 expression in HCC tissues irrespective of HBV infection, while the highest levels were observed in tissues from HBV-infected patients. Investigation of published transcriptomic data sets confirmed EDEM3 upregulation in independent HCC patient cohorts, associated with tumor progression, poor survival prognosis and resistance to therapy. EDEM3-overexpressing hepatic cells exhibited attenuated UPR and activated secretory autophagy, which promoted HBV production. Conversely, cell depletion of EDEM3 resulted in significant ER stress inducing pro-apoptotic mechanisms and cell death.</p><p><strong>Conclusions: </strong>We provide evidence of major implications of the ERAD pathway in HBV infection and HCC development and progression. Our results suggest that ERAD activation in HBV-infected cells is a protective mechanism against prolonged ER stress, potentially contributing to establishment of chronic HBV infection and promoting tumorigenesis. Developing specific inhibitors for ERAD factors may be an attractive approach to improve efficiency of current antiviral and anticancer therapies.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"11"},"PeriodicalIF":9.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059302","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}