Martina Magistrati, Luisa Zupin, Eleonora Lamantea, Enrico Baruffini, Daniele Ghezzi, Andrea Legati, Fulvio Celsi, Flora Maria Murru, Valeria Capaci, Maurizio Pinamonti, Rossana Bussani, Marco Carrozzi, Cristina Dallabona, Massimo Zeviani, Maria Teresa Bonati
{"title":"De Novo <i>DNM1L</i> Pathogenic Variant Associated with Lethal Encephalocardiomyopathy-Case Report and Literature Review.","authors":"Martina Magistrati, Luisa Zupin, Eleonora Lamantea, Enrico Baruffini, Daniele Ghezzi, Andrea Legati, Fulvio Celsi, Flora Maria Murru, Valeria Capaci, Maurizio Pinamonti, Rossana Bussani, Marco Carrozzi, Cristina Dallabona, Massimo Zeviani, Maria Teresa Bonati","doi":"10.3390/ijms26020846","DOIUrl":"10.3390/ijms26020846","url":null,"abstract":"<p><p>Pathogenic variants in <i>DNM1L</i>, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo <i>DNM1L</i> variant identified by whole exome sequencing performed more than 10 years after the patient's death. Meanwhile, we reviewed the broadness and specificities of <i>DNM1L</i>-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the <i>DNM1L</i> variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of <i>petite</i>, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. <i>DNM1L</i>-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Irina S Sesorova, Eugeny V Bedyaev, Pavel S Vavilov, Sergei L Levin, Alexander A Mironov
{"title":"Regeneration of Vascular Endothelium in Different Large Vessels.","authors":"Irina S Sesorova, Eugeny V Bedyaev, Pavel S Vavilov, Sergei L Levin, Alexander A Mironov","doi":"10.3390/ijms26020837","DOIUrl":"10.3390/ijms26020837","url":null,"abstract":"<p><p>The regeneration of endothelial cells (ECs) lining arteries, veins, and large lymphatic vessels plays an important role in vascular pathology. To understand the mechanisms of atherogenesis, it is important to determine what happens during endothelial regeneration. A comparison of these processes in the above-mentioned vessels reveals both similarities and some significant differences. Regeneration is carried out by moving intact ECs from the edges of the viable endothelial layer towards the centre of the EC damage zone. A sharp decrease in contact inhibition leads to the spreading of the edges of the ECs situated on the damage border. This stimulates the second row of ECs to enter the S-phase, then the G2 phase of cell cycle, and finally mitosis. In all three types of vessels studied, mitotically dividing ECs were found using correlation light and electron microscopy. These ECs have a body protruding into the lumen of the vessel, covered with micro-villi and other outgrowths. The level of EC rounding and protruding is highest in the arteries and least pronounced in the lymphatic vessels. The intercellular contacts of mitotically dividing cells become wider. The EC division leads to an increase in the density of ECs. ECs moving over the damaged area and partially outside the damaged area acquire a fusiform shape. <i>In the process of regeneration of arterial endothelium, the damaged ECs are removed. Then health ECs move to a surface devoid of endothelium, and detach spreading out, flattened platelets from the luminal surface of the vessel.</i> In the veins, ECs grow on the surface of platelets and microthrombi. In lymphatic vessels, ECs detach from the basement membrane slower than in the veins and arteries. There, the migrating ECs grow under fibrin fibres. After some time (usually after 30 days), the EC mosaic returns to normal in all three types of vessels.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11766047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Norah A AlJunaydil, Rhodanne Nicole A Lambarte, Terrence S Sumague, Osama G Alghamdi, Abdurahman A Niazy
{"title":"Lovastatin and Resveratrol Synergistically Improve Wound Healing and Inhibit Bacterial Growth.","authors":"Norah A AlJunaydil, Rhodanne Nicole A Lambarte, Terrence S Sumague, Osama G Alghamdi, Abdurahman A Niazy","doi":"10.3390/ijms26020851","DOIUrl":"10.3390/ijms26020851","url":null,"abstract":"<p><p>Wound healing is a complex physiological process, with scarring and infection caused by <i>Staphylococcus aureus</i> and <i>Pseudomonas aeruginosa</i> being the most common complications. The reutilization of known medications has received increased attention for their role in cell function as small molecules. Examples of these include lovastatin, a cholesterol-lowering agent, and resveratrol, which have multiple biological properties. Both molecules have been reported to improve wound healing and possess antibacterial properties, with conflicting results. The wound-healing capabilities of human mesenchymal stem cells were evaluated after exposure to lovastatin, resveratrol, and their combination through scratch test, migrations assay, and qPCR. Protein docking was performed to assess the lovastatin/resveratrol combination as potential wound-healing targets. AlamarBlue assay was used to determine cell viability. Additionally, the impact of lovastatin and resveratrol combination to inhibit the growth of <i>S. aureus</i> and <i>P. aeruginosa</i> was tested using broth microdilution test and checkerboard assay to determine synergism. The combination of lovastatin 0.1 μM and resveratrol 0.1 μM synergistically improved wound healing and demonstrated an additive effect against <i>S. aureus</i> and <i>P. aeruginosa</i>, presenting potential antibacterial applications.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11766293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandra D Remnitz, Roey Hadad, Robert W Keane, W Dalton Dietrich, Juan Pablo de Rivero Vaccari
{"title":"Comparison of Methods of Detecting IL-1β in the Blood of Alzheimer's Disease Subjects.","authors":"Alexandra D Remnitz, Roey Hadad, Robert W Keane, W Dalton Dietrich, Juan Pablo de Rivero Vaccari","doi":"10.3390/ijms26020831","DOIUrl":"10.3390/ijms26020831","url":null,"abstract":"<p><p>Interleukin (IL)-1β is a pro-inflammatory cytokine whose levels are increased in the brains of Alzheimer's disease (AD) patients. Despite the role of IL-1β in the pathology of AD, the fact that it is expressed at very low levels makes it a challenging cytokine to measure, hence limiting its potential use as a reliable biomarker. Moreover, being able to accurately and reliably measure the levels of IL-1 β in blood makes it possible to evaluate this cytokine as a potential biomarker of the inflammatory response in AD. In this study, we compared three quantification methodologies, Meso-Scale Discovery (MSD), both V-Plex and S-Plex versions, and Quanterix's SIMOA (Single-Molecule Array), to measure IL-1β in the serum of AD patients and age-matched controls. These assays are routinely used to measure IL-1β serum levels with high specificity and sensitivity in human AD patients, yet to the best of our knowledge, no study has compared all three techniques for their accuracy to measure IL-1β as biomarkers. Our findings indicate the two MSD assays can be used to measure IL-1β levels in AD and control serum, but the SIMOA assay showed the highest receiver operating characteristics (ROCs), with an area under the curve (AUC) of 0.9532, which can be compared to the AUC values for the V-Plex assay, 0.5660, and the S-Plex assay, 0.6632. Taken together, these data show that although all technologies are useful in the measurement of IL-1β in the blood, the SIMOA IL-1β 3.0 assay is more reliable and sensitive in measuring biomarkers of AD.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juan Bautista De Sanctis, Germán Balda Noria, Alexis Hipólito García
{"title":"Exploring How Adipose Tissue, Obesity, and Gender Influence the Immune Response to Vaccines: A Comprehensive Narrative Review.","authors":"Juan Bautista De Sanctis, Germán Balda Noria, Alexis Hipólito García","doi":"10.3390/ijms26020862","DOIUrl":"10.3390/ijms26020862","url":null,"abstract":"<p><p>Vaccines represent an essential tool for the prevention of infectious diseases. Upon administration, a complex interaction occurs between the vaccine formulation and the recipient's immune system, ultimately resulting in protection against disease. Significant variability exists in individual and population responses to vaccination, and these differences remain the focus of the ongoing research. Notably, well-documented factors, such as age, gender, and genetic predisposition, influence immune responses. In contrast, the effects of overweight and obesity have not been as thoroughly investigated. The evidence indicates that a high body mass index (BMI) constitutes a significant risk factor for infections in general, with adipose tissue playing a crucial role in modulating the immune response. Furthermore, suboptimal levels of vaccine seroconversion have been observed among individuals with obesity. This review provides a plausible examination of the immunity and protection conferred by various vaccines in individuals with an overweight status, offering a comprehensive analysis of the mechanisms to enhance vaccination efficiency.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Establishment of iPSC-Derived MSCs Expressing hsa-miR-4662a-5p for Enhanced Immune Modulation in Graft-Versus-Host Disease (GVHD).","authors":"Susie Lee, Eung-Won Kim, Hae-Ri Lee, Sun-Ung Lim, Chan Kwon Jung, Young-Ju Kang, Gyung-Ah Jung, Il-Hoan Oh","doi":"10.3390/ijms26020847","DOIUrl":"10.3390/ijms26020847","url":null,"abstract":"<p><p>The immune-modulatory effects of mesenchymal stromal cells (MSCs) are widely used to treat inflammatory disorders, with indoleamine 2,4-dioxygenase-1 (IDO-1) playing a pivotal role in suppressing stimulated T-cell proliferation. Taking that three-dimensional (3D) cultures enhance MSCs' anti-inflammatory properties compared with two-dimensional (2D) cultures, the differentially expressed miRNAs were examined. Thus, we identified hsa-miR-4662a-5p (miR-4662a) as a key inducer of IDO-1 via its suppression of bridging integrator-1 (BIN-1), a negative regulator of the IDO-1 gene. The IDO-1-inducing potential of miR-4662a was conserved across primary MSCs from various donors and sources but exhibited variability. Notably, iPSC-derived MSCs (iMSCs) demonstrated superior IDO-1 induction and immune-modulatory efficacy compared with their donor-matched primary MSCs. Accordingly, iMSCs expressing miR-4662a (4662a/iMSC) exhibited stronger suppressive effects on T-cell proliferation and more potent suppressive effects on graft-versus-host disease (GVHD), improving survival rates and reducing tissue damage in the liver and gut. Our results point to the therapeutic potential of standardized, off-the-shelf 4662a/iMSC as a robust immune-modulating cell therapy for GVHD.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11766046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pierre Leonel K Tafokeu Taguimjeu, Yannick Stéphane Fotsing Fongang, Manon Genva, Lahngong Methodius Shinyuy, Jana Held, Michel Frederich, Silvère Augustin Ngouela, Marie-Laure Fauconnier
{"title":"Antiplasmodial Activity of a New Chemotype of <i>Croton sylvaticus</i> Hochst. Ex C. Krauss Essential Oil.","authors":"Pierre Leonel K Tafokeu Taguimjeu, Yannick Stéphane Fotsing Fongang, Manon Genva, Lahngong Methodius Shinyuy, Jana Held, Michel Frederich, Silvère Augustin Ngouela, Marie-Laure Fauconnier","doi":"10.3390/ijms26020858","DOIUrl":"10.3390/ijms26020858","url":null,"abstract":"<p><p><i>Croton sylvaticus</i>, a tropical African plant, is traditionally used to treat several diseases, including fever, inflammation, and malaria. Essential oils (EOs) from the plant's leaves, roots, and trunk bark were obtained by hydrodistillation, and their chemical composition was analyzed by gas chromatography-mass spectrometry (GC-MS). The major constituents identified were virdiflorene (18.13 ± 0.46%) in root EO, (E)-β-caryophyllene (18.40 ± 0.60%) in trunk bark EO, and farnesyl acetone (15.26 ± 0.25%) in leaf EO. Notably, Cameroonian <i>C. sylvaticus</i> leaf EO exhibited a distinct and newly described chemotype with high levels of farnesyl acetone, β-copaene-4-α-ol, β-cadinene, α-humulene, and <i>trans</i>-longipinocarveol. In vitro testing revealed significant antiplasmodial activity against <i>Plasmodium falciparum</i> asexual (<i>Pf</i>3D7) and sexual (NF-54 strain) stages, with trunk bark EO showing the highest potency (IC<sub>50</sub>: 9.06 ± 2.15 µg/mL for <i>Pf</i>3D7 and 0.56 µg/mL for gametocytes). These findings support the traditional antimalarial use of <i>C. sylvaticus</i> and represent the first chemical profile and antiplasmodial efficacy report for its root and trunk bark EOs against both parasite stages. To the best of our knowledge, we also report for the first time the antiplasmodial activity of an EO that exerts significant activity against both the asexual and sexual forms of <i>P. falciparum</i>.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vladimir Khristov, Sarah R Weber, Mireille Caton-Darby, Gregory Campbell, Jeffrey M Sundstrom
{"title":"Diagnostic and Therapeutic Utility of Extracellular Vesicles in Ocular Disease.","authors":"Vladimir Khristov, Sarah R Weber, Mireille Caton-Darby, Gregory Campbell, Jeffrey M Sundstrom","doi":"10.3390/ijms26020836","DOIUrl":"10.3390/ijms26020836","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are lipid bilayer particles released by virtually all cells, with prominent roles in both physiological and pathological processes. The size, number, and molecular composition of released EVs correlate to the cells of origin, modulated by the cell's environment and pathologic state. The proteins, DNA, RNA, and protein cargo carried by EVs are protected by degradation, with a prominent role in targeted intercellular signaling. These properties make EVs salient targets as both carriers of biomarkers and potential therapeutic delivery vehicles. The majority of EV research has focused on blood, urine, saliva, and cerebrospinal fluid due to easy accessibility. EVs have also been identified and studied in all ocular biofluids, including the vitreous humor, the aqueous humor, and the tear film, and the study of EVs in ocular disease is a new, promising, and underexplored direction with unique challenges and considerations. This review covers recent advances in the diagnostic and therapeutic use of ocular EVs, with a focus on human applications and key preceding in vitro and in vivo animal studies. We also discuss future directions based on the study of EVs in other organ systems and disease sates.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pyoseung Kim, Sunggeun Joe, Heeyoung Kim, Hyejeong Jeong, Sunghwan Park, Jihwan Song, Wondong Kim, Yong Gu Lee
{"title":"Hidden Partner of Immunity: Microbiome as an Innovative Companion in Immunotherapy.","authors":"Pyoseung Kim, Sunggeun Joe, Heeyoung Kim, Hyejeong Jeong, Sunghwan Park, Jihwan Song, Wondong Kim, Yong Gu Lee","doi":"10.3390/ijms26020856","DOIUrl":"10.3390/ijms26020856","url":null,"abstract":"<p><p>Recent studies have highlighted that the microbiome is the essential factor that can modulate the clinical activity of immunotherapy. However, the role of the microbiome varies significantly across different immunotherapies, suggesting that it is critical to understand the precise function of the microbiome in each type of immunotherapy. While many previous studies primarily focus on summarizing the role of the microbiome in immune checkpoint inhibitors, we seek to explore a novel aspect of the microbiome in other immunotherapies such as mesenchymal stem cell therapy, chimeric antigen receptor T cell therapy, and antibodies-based therapy (e.g., adalimumab, infliximab, bevacizumab, denosumab, etc.) which are rarely summarized in previous reviews. Moreover, we highlight innovative strategies for utilizing microbiome and microbial metabolites to enhance the clinical response of immunotherapy. Collectively, we believe that our manuscript will provide novel insights and innovative approaches to the researchers, which could drive the development of the next generation of personalized therapeutic interventions using microbiomes.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 2","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}