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The Role of ETNPPL in Dopaminergic Neuron Stability: Insights from Neuromelanin-Associated Protein Expression in Parkinson's Disease. ETNPPL在多巴胺能神经元稳定性中的作用:从帕金森病中神经髓鞘蛋白相关蛋白的表达看问题
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313107
Francesca A Schillaci, Giuseppe Lanza, Maria Grazia Salluzzo, Francesca L'Episcopo, Raffaele Ferri, Michele Salemi
{"title":"The Role of ETNPPL in Dopaminergic Neuron Stability: Insights from Neuromelanin-Associated Protein Expression in Parkinson's Disease.","authors":"Francesca A Schillaci, Giuseppe Lanza, Maria Grazia Salluzzo, Francesca L'Episcopo, Raffaele Ferri, Michele Salemi","doi":"10.3390/ijms252313107","DOIUrl":"https://doi.org/10.3390/ijms252313107","url":null,"abstract":"<p><p>More than six million people worldwide are affected by Parkinson's disease (PD), a multifactorial disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several immunohistochemical studies suggest that neuromelanin (NM), found in these neurons, plays a key role in their degeneration. In this study, twelve formalin-fixed, paraffin-embedded (FFPE) brain sections were analyzed, comprising six samples from PD patients and six from healthy controls. Immunohistochemistry (IHC) was conducted to assess the expression of the ETNPPL protein in these samples. ETNPPL was detected in both PD and control samples. Additionally, we examined the expression of ETNPPL mRNA using Quantitative Real-Time PCR (qRT-PCR) in the same sample set. Notably, in control samples, ETNPPL protein was closely associated with the dark NM pigment in the cytoplasm of SNc dopaminergic neurons. In contrast, PD samples showed weak cytoplasmic expression of ETNPPL, with no association with the NM pigment. No nuclear ETNPPL signal was detected in dopaminergic neurons from either PD patients or controls. qRT-PCR results revealed lower ETNPPL mRNA expression in individual PD patients compared to controls. Importantly, we observed a higher concentration of ETNPPL protein at the NM level in the SNc neurons of controls, consistent with mRNA expression patterns. These findings suggest a potential role for ETNPPL in the normal function of dopaminergic neurons and underscore its altered expression in Parkinson's disease.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836409","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}
引用次数: 0
A 0.2 T-0.4 T Static Magnetic Field Improves the Bone Quality of Mice Subjected to Hindlimb Unloading and Reloading Through the Dual Regulation of BMSCs via Iron Metabolism.
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313136
Jianping Wang, Chenxiao Zhen, Gejing Zhang, Zhouqi Yang, Peng Shang
{"title":"A 0.2 T-0.4 T Static Magnetic Field Improves the Bone Quality of Mice Subjected to Hindlimb Unloading and Reloading Through the Dual Regulation of BMSCs via Iron Metabolism.","authors":"Jianping Wang, Chenxiao Zhen, Gejing Zhang, Zhouqi Yang, Peng Shang","doi":"10.3390/ijms252313136","DOIUrl":"https://doi.org/10.3390/ijms252313136","url":null,"abstract":"<p><p>Osteoporosis is the most prevalent metabolic bone disease, especially when aggravated by aging and long-term bed rest of various causes and also when coupled with astronauts' longer missions in space. Research on the use of static magnetic fields (SMFs) has been progressing as a noninvasive method for osteoporosis due to the complexity of the disease, the inconsistency of the effects of SMFs, and the ambiguity of the mechanism. This paper studied the effects of mice subjected to hindlimb unloading (UL, HLU) and reloading by the 0.2 T-0.4 T static magnetic field (MMF). Primary bone marrow mesenchymal stem cells (BMSCs) were extracted to explore the mechanism. Eight-week-old male C57BL/6 mice were used as an osteoporosis model by HLU for four weeks. The HLU recovery period (reloading, RL) was carried out on all FVEs and recovered in the geomagnetic field (45-64 μT, GMF) and MMF, respectively, for 12 h/d for another 4 weeks. The tibia and femur of mice were taken; also, the primary BMSCs were extracted. MMF promoted the recovery of mechanical properties after HLU, increased the number of osteoblasts, and decreased the number of adipocytes in the bone marrow. MMF decreased the total iron content and promoted the total calcium content in the tibia. In vitro experiments showed that MMF promoted the osteogenic differentiation of BMSCs and inhibited adipogenic differentiation, which is related to iron metabolism, the Wnt/β-catenin pathway, and the PPARγ pathway. MMF accelerated the improvement in bone metabolism and iron metabolism in RL mice to a certain extent, which improved the bone quality of mice. MMF mainly promoted osteogenic differentiation and reduced the adipogenic differentiation of BMSCs, which provides a reliable research direction and transformation basis for the osteoporosis of elderly, bedridden patients and astronauts.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835669","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}
引用次数: 0
Development of Primer Panels for Amplicon Sequencing of Human Parainfluenza Viruses Type 1 and 2.
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313119
Oula Mansour, Artem V Fadeev, Alexander A Perederiy, Daria M Danilenko, Dmitry A Lioznov, Andrey B Komissarov
{"title":"Development of Primer Panels for Amplicon Sequencing of Human Parainfluenza Viruses Type 1 and 2.","authors":"Oula Mansour, Artem V Fadeev, Alexander A Perederiy, Daria M Danilenko, Dmitry A Lioznov, Andrey B Komissarov","doi":"10.3390/ijms252313119","DOIUrl":"https://doi.org/10.3390/ijms252313119","url":null,"abstract":"<p><p>Human parainfluenza viruses (hPIVs) are major contributors to respiratory tract infections in young children worldwide. Despite their global significance, genomic surveillance of hPIV1 and hPIV2 had not previously been conducted in Russia. This study aimed to develop a robust amplicon-based sequencing protocol for these viruses. The designed primer sets were tested on clinical samples containing hPIV RNA to evaluate their performance and efficiency. Sequencing results demonstrated high-quality genome data and efficient amplification across various Ct values. As a result, 41 hPIV1 and 13 hPIV2 near-complete genome sequences were successfully obtained from clinical specimens collected in Saint Petersburg (Russia). Phylogenetic analysis of the HN gene sequences showed that Russian hPIV1 strains clustered into clades II and III, while hPIV2 strains were distributed between clusters G1a and G3. The whole-genome-based trees confirmed the same distribution of the strains. These findings highlight the potential of our primer panels and contribute to a better understanding of the molecular characteristics and phylogenetic diversity of circulating hPIV strains. Notably, this study presents the first evolutionary analysis of hPIVs in Russia.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835705","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}
引用次数: 0
Non-Helicobacter pylori Helicobacters, a Treatable Provocateur of Parkinson's Disease: Hypothesis, Evidence and Species Specificity. 非幽门螺旋杆菌--帕金森病的可治疗诱因:假说、证据和物种特异性。
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313123
Wenjing Wang, Melvyn Smith, Richard Ellis, Antonella Savio, Amanda Nevel, Chianna Umamahesan, Polychronis Pavlidis, Bu' Hussain Hayee, David Taylor, Allan H Young, André Charlett, Sylvia M Dobbs, R John Dobbs
{"title":"Non-<i>Helicobacter pylori Helicobacters</i>, a Treatable Provocateur of Parkinson's Disease: Hypothesis, Evidence and Species Specificity.","authors":"Wenjing Wang, Melvyn Smith, Richard Ellis, Antonella Savio, Amanda Nevel, Chianna Umamahesan, Polychronis Pavlidis, Bu' Hussain Hayee, David Taylor, Allan H Young, André Charlett, Sylvia M Dobbs, R John Dobbs","doi":"10.3390/ijms252313123","DOIUrl":"https://doi.org/10.3390/ijms252313123","url":null,"abstract":"<p><p>Epidemiological and eradication trial evidence indicates that <i>Helicobacter pylori</i>, a major causative factor in peptic ulcer and gastric cancer, is a driver of the hypokinesia of Parkinson's disease (PD). Psychological (cognitive impairment, depression and anxiety) and gastrointestinal (peptic ulceration and constipation) PD features can precede the symptomatic onset of motor features by decades. We hypothesise that the non-<i>H. pylori Helicobacters</i> (NHPH), which have farm, companion and wild animals as their main hosts, can have a role in PD aetiopathogenesis. In those occupationally at risk of NHPH infection, we address whether there is increased mortality with PD, or depression or suicide. Our systematic review gave evidence that occupational exposure to animals/their products is associated with excess mortality with PD. Indeed, whilst livestock farming increased the risk, crop farming decreased it. Moreover, excess mortality from non-Hodgkin lymphoma in livestock farmers is compatible with NHPH being causal. Our scoping review showed that farmers, veterinarians and abattoir workers have an increased risk of depression and suicide; whether their depression is associated with being down the pathway to PD and/or the presence of <i>Helicobacter</i> infection needs investigation. Regarding <i>Helicobacter</i> species specificity, the link between the presence of NHPH in gastric biopsy and PD was described using a <i>ureA</i> polymerase chain reaction (PCR) assay, targeting the most-commonly named NHPH, <i>H. suis</i>. We describe its redesign and optimisation as a probe-based PCR, confirming the exclusion of <i>H. pylori</i> but not <i>H. suis</i> specificity (additionally identifying 6 species of a 22-NHPH-species panel). The exploration of the zoonotic hypothesis requires a non-invasive pan-<i>Helicobacter</i> PCR screen, allowing the detection and molecular grouping of <i>Helicobacter</i> species.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836123","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}
引用次数: 0
Hesperetin Increases Lifespan and Antioxidant Ability Correlating with IIS, HSP, mtUPR, and JNK Pathways of Chronic Oxidative Stress in Caenorhabditis elegans. 橙皮甙能延长草履虫的寿命并提高其抗氧化能力,这与草履虫慢性氧化应激的 IIS、HSP、mtUPR 和 JNK 途径有关。
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313148
Run-Jia Wang, Ya-Jing Ni, Yan-Qiang Liu
{"title":"Hesperetin Increases Lifespan and Antioxidant Ability Correlating with IIS, HSP, mtUPR, and JNK Pathways of Chronic Oxidative Stress in <i>Caenorhabditis elegans</i>.","authors":"Run-Jia Wang, Ya-Jing Ni, Yan-Qiang Liu","doi":"10.3390/ijms252313148","DOIUrl":"https://doi.org/10.3390/ijms252313148","url":null,"abstract":"<p><p>Hesperetin (Hst) is a common citrus fruit flavonoid with antioxidant, anti-inflammatory, and anti-neurodegenerative effects. To explore the antioxidant and anti-aging effects and mechanisms of Hst, we induced chronic oxidative stress in <i>Caenorhabditis elegans (C. elegans)</i> using low-concentration H<sub>2</sub>O<sub>2</sub> and examined its effects on lifespan, healthy life index, reactive oxygen species (ROS), antioxidant enzymes, and transcriptomic metrics. Hst significantly prolonged lifespan, increased body bending and pharyngeal pumping frequency, decreased ROS accumulation, and increased antioxidant enzyme activity in normal and stressed <i>C. elegans</i>. Hst significantly upregulated <i>daf-18</i>, <i>daf-16</i>, <i>gst-2</i>, <i>gst-3</i>, <i>gst-4</i>, <i>gst-39</i>, <i>hsp-16.11</i>, <i>sip-1</i>, <i>clpp-1</i>, and <i>dve-1</i> and downregulated <i>ist-1</i> and <i>kgb-1</i> mRNAs in stressed <i>C. elegans</i>. These genes are involved in the insulin/insulin-like growth factor-1 signaling (IIS), heat shock protein (HSP), mitochondrial unfolded protein response (mtUPR), and c-Jun N-terminal kinase (JNK) pathways. In summary, Hst increases lifespan and antioxidant ability, correlating with these pathways, during chronic oxidative stress in <i>C. elegans</i>.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835294","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}
引用次数: 0
Metagenomic Analysis of the Buccal Microbiome by Nanopore Sequencing Reveals Structural Differences in the Microbiome of a Patient with Molar Incisor Hypomineralization (MIH) Compared to a Healthy Child-Case Study.
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313143
Wojciech Tynior, Małgorzata Kłósek, Silvia Salatino, Piotr Cuber, Dorota Hudy, Dariusz Nałęcz, Yuen-Ting Chan, Carla Gustave, Joanna Katarzyna Strzelczyk
{"title":"Metagenomic Analysis of the Buccal Microbiome by Nanopore Sequencing Reveals Structural Differences in the Microbiome of a Patient with Molar Incisor Hypomineralization (MIH) Compared to a Healthy Child-Case Study.","authors":"Wojciech Tynior, Małgorzata Kłósek, Silvia Salatino, Piotr Cuber, Dorota Hudy, Dariusz Nałęcz, Yuen-Ting Chan, Carla Gustave, Joanna Katarzyna Strzelczyk","doi":"10.3390/ijms252313143","DOIUrl":"https://doi.org/10.3390/ijms252313143","url":null,"abstract":"<p><p>Molar incisor hypomineralization (MIH) is a qualitative developmental defect that affects the enamel tissue of permanent molars and can also occur in permanent incisors. Enamel affected by MIH has reduced hardness, increased porosity, and a higher organic content than unaffected enamel. These characteristics predispose the enamel to accumulation of bacteria and a higher prevalence of caries lesions. Through a groundbreaking metagenomic analysis of the buccal mucosal sample from a patient with MIH, we explored the intricacies of its microbiome compared to a healthy control using state-of-the-art nanopore long-read sequencing. Out of the 210 bacterial taxa identified in the MIH microbiome, we found <i>Streptococcus</i> and <i>Haemophilus</i> to be the most abundant genera. The bacteria with the highest read counts in the patient with MIH included <i>Streptococcus mitis</i>, <i>Haemophilus parainfluenzae</i>, <i>Streptococcus pneumoniae</i>, <i>Rothia dentocariosa</i>, and <i>Gemella haemolysans</i>. Our results revealed a striking contrast between healthy and MIH affected children, with a higher dominance and number of pathogenic species (<i>S. pneumoniae</i>, <i>H. influenzae</i>, and <i>N. meningitidis</i>) and reduced diversity in the MIH-affected patient. This distinct microbial profile not only sheds light on MIH-affected patients, but paves the way for future research, inspiring deeper understanding and larger scale studies.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836062","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}
引用次数: 0
Magnetic Isolation of the Linear Trinuclear Anion in [Cu(Him)6] {Cu(Him)4[Cu(μ-EDTA)(Him)]2}·6H2O (1) as the Novel Imidazolium(+) Salt (H2im)2[Cu(Him)4{(µ-EDTA)Cu(Him)}2]·2H2O (2)-A Comparative Look to Their Crystal Structures, Thermal, Spectral and Magnetic Properties and DFT Calculations. 磁性分离[Cu(Him)6]{Cu(Him)4[Cu(μ-EDTA)(Him)]2}-6H2O (1)中的线性三核阴离子以及新型咪唑(+)盐 (H2im)2[Cu(Him)4{(µ-EDTA)Cu(Him)}2]-2H2O (2)--它们的晶体结构、热学、光谱和磁学性质以及 DFT 计算的比较。
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313130
Jeannette Carolina Belmont-Sánchez, Duane Choquesillo-Lazarte, Antonio Frontera, Luis Lezama, Alfonso Castiñeiras, Juan Niclós-Gutiérrez
{"title":"Magnetic Isolation of the Linear Trinuclear Anion in [Cu(Him)<sub>6</sub>] {Cu(Him)<sub>4</sub>[Cu(μ-EDTA)(Him)]<sub>2</sub>}·6H<sub>2</sub>O (1) as the Novel Imidazolium(+) Salt (H<sub>2</sub>im)<sub>2</sub>[Cu(Him)<sub>4</sub>{(µ-EDTA)Cu(Him)}<sub>2</sub>]·2H<sub>2</sub>O (2)-A Comparative Look to Their Crystal Structures, Thermal, Spectral and Magnetic Properties and DFT Calculations.","authors":"Jeannette Carolina Belmont-Sánchez, Duane Choquesillo-Lazarte, Antonio Frontera, Luis Lezama, Alfonso Castiñeiras, Juan Niclós-Gutiérrez","doi":"10.3390/ijms252313130","DOIUrl":"https://doi.org/10.3390/ijms252313130","url":null,"abstract":"<p><p>Inspired by the reported crystal structure of compound <b>1</b>, we aimed to synthesize and determine the structure of compound <b>2</b>, where two imidazolium (H<sub>2</sub>im<sup>+</sup>) ions serve as diamagnetic countercations. Here, we report the thermal stabilities, FT-IR, visible, and RSE spectra, as well as the magnetic properties of both compounds. In these structures, µ-EDTA acts as a pentadentate chelator for both terminal Cu centers within the centrosymmetric linear trinuclear anion. The Cu(µ-EDTA) chelates bind to the central Cu(Him)<sub>4</sub> unit in subtly different ways: in compound <b>1</b>, µ-EDTA has a free acetate arm and binds the central Cu(II) center through a syn,anti-carboxylate group. In contrast, in compound <b>2</b>, the non-chelating acetate arm serves as a monodentate O-donor to the central Cu(II) atom, increasing the Cu(terminal)···Cu(central) distance from 6.08 Å in <b>1</b> to 6.80 Å in <b>2</b>. Additionally, pairs of H<sub>2</sub>im<sup>+</sup> ions in compound <b>2</b> display antiparallel π-stacking interactions. We conclude that the H<sub>2</sub>im<sup>+</sup> counterions in compound <b>2</b> enable the magnetic isolation of the nearly identical trinuclear anion present in both compounds. DFT calculations further support the role of different interactions in stabilizing each crystal structure. In compound <b>2</b>, dominant contributions from N-H···O hydrogen bonds and π-stacking interactions are accompanied by other, less conventional interactions, such as multiple C-H···O contacts and an O···CO(π-hole) interaction within the trinuclear anion.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836189","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}
引用次数: 0
Overcoming Challenges in Small-Molecule Drug Bioavailability: A Review of Key Factors and Approaches.
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313121
Ke Wu, Soon Hwan Kwon, Xuhan Zhou, Claire Fuller, Xianyi Wang, Jaydutt Vadgama, Yong Wu
{"title":"Overcoming Challenges in Small-Molecule Drug Bioavailability: A Review of Key Factors and Approaches.","authors":"Ke Wu, Soon Hwan Kwon, Xuhan Zhou, Claire Fuller, Xianyi Wang, Jaydutt Vadgama, Yong Wu","doi":"10.3390/ijms252313121","DOIUrl":"https://doi.org/10.3390/ijms252313121","url":null,"abstract":"<p><p>The bioavailability of small-molecule drugs remains a critical challenge in pharmaceutical development, significantly impacting therapeutic efficacy and commercial viability. This review synthesizes recent advances in understanding and overcoming bioavailability limitations, focusing on key physicochemical and biological factors influencing drug absorption and distribution. We examine cutting-edge strategies for enhancing bioavailability, including innovative formulation approaches, rational structural modifications, and the application of artificial intelligence in drug design. The integration of nanotechnology, 3D printing, and stimuli-responsive delivery systems are highlighted as promising avenues for improving drug delivery. We discuss the importance of a holistic, multidisciplinary approach to bioavailability optimization, emphasizing early-stage consideration of ADME properties and the need for patient-centric design. This review also explores emerging technologies such as CRISPR-Cas9-mediated personalization and microbiome modulation for tailored bioavailability enhancement. Finally, we outline future research directions, including advanced predictive modeling, overcoming biological barriers, and addressing the challenges of emerging therapeutic modalities. By elucidating the complex interplay of factors affecting bioavailability, this review aims to guide future efforts in developing more effective and accessible small-molecule therapeutics.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836247","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}
引用次数: 0
Ezetimibe Enhances Lipid Droplet and Mitochondria Contact Formation, Improving Fatty Acid Transfer and Reducing Lipotoxicity in Alport Syndrome Podocytes.
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313134
Jin-Ju Kim, Eun-Jeong Yang, Judith Molina David, Sunjoo Cho, Maria Ficarella, Nils Pape, Josephin Elizabeth Schiffer, Rachel Njeim, Stephanie S Kim, Claudia Lo Re, Antonio Fontanella, Maria Kaber, Alexis Sloan, Sandra Merscher, Alessia Fornoni
{"title":"Ezetimibe Enhances Lipid Droplet and Mitochondria Contact Formation, Improving Fatty Acid Transfer and Reducing Lipotoxicity in Alport Syndrome Podocytes.","authors":"Jin-Ju Kim, Eun-Jeong Yang, Judith Molina David, Sunjoo Cho, Maria Ficarella, Nils Pape, Josephin Elizabeth Schiffer, Rachel Njeim, Stephanie S Kim, Claudia Lo Re, Antonio Fontanella, Maria Kaber, Alexis Sloan, Sandra Merscher, Alessia Fornoni","doi":"10.3390/ijms252313134","DOIUrl":"https://doi.org/10.3390/ijms252313134","url":null,"abstract":"<p><p>Mitochondrial dysfunction is a critical factor in the pathogenesis of Alport syndrome (AS), contributing to podocyte injury and disease progression. Ezetimibe, a lipid-lowering drug, is known to inhibit cholesterol and fatty acid uptake and to reduce triglyceride content in the kidney cortex of mice with AS. However, its effects on lipid droplet (LD) utilization by mitochondria have not been explored. Transmission electron microscopy (TEM) and mitochondrial functional assays (ATP production, mitochondrial membrane potential, and citrate synthase activity) were used to investigate the impact of ezetimibe on LD-mitochondria contact formation and mitochondrial function in <i>Col4a3</i>KO (AS) and wildtype (WT) podocytes. TEM analysis revealed significant mitochondrial abnormalities in AS podocytes, including swollen mitochondria and reduced cristae density, while mitochondrial function assays showed decreased ATP production and lowered mitochondrial membrane potential. AS podocytes also demonstrated a higher content of LD but with reduced LD-mitochondria contact sites. Ezetimibe treatment significantly increased the number of LD-mitochondria contact sites, enhanced fatty acid transfer efficiency, and reduced intracellular lipid accumulation. These changes were associated with a marked reduction in the markers of lipotoxicity, such as apoptosis and oxidative stress. Mitochondrial function was significantly improved, evidenced by increased basal respiration, ATP production, maximal respiration capacity, and the restoration of mitochondrial membrane potential. Additionally, mitochondrial swelling was significantly reduced in ezetimibe-treated AS podocytes. Our findings reveal a novel role for ezetimibe in enhancing LD-mitochondria contact formation, leading to more efficient fatty acid transfer, reduced lipotoxicity, and improved mitochondrial function in AS podocytes. These results suggest that ezetimibe could be a promising therapeutic agent for treating mitochondrial dysfunction and lipid metabolism abnormalities in AS.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836015","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}
引用次数: 0
Growth, Quality, and Nitrogen Metabolism of Medicago sativa Under Continuous Light from Red-Blue-Green LEDs Responded Better to High Nitrogen Concentrations than Under Red-Blue LEDs.
IF 5.6 2区 生物学
International Journal of Molecular Sciences Pub Date : 2024-12-06 DOI: 10.3390/ijms252313116
Ren Chen, Yanqi Chen, Kunming Lin, Yiming Ding, Wenke Liu, Shurong Wang
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