Biomolecules最新文献

{"title":"Endogenous Ribonucleases: Therapeutic Targeting of the Transcriptome Through Oligonucleotide-Triggered RNA Inactivation.","authors":"Daria A Chiglintseva, Olga A Patutina, Marina A Zenkova","doi":"10.3390/biom15070965","DOIUrl":"10.3390/biom15070965","url":null,"abstract":"<p><p>The selective regulation of gene expression at the RNA level represents a rapidly evolving field offering substantial clinical potential. This review examines the molecular mechanisms of intracellular enzymatic systems that utilize single-stranded nucleic acids to downregulate specific RNA targets. The analysis encompasses antisense oligonucleotides and synthetic mimics of small interfering RNA (siRNA), microRNA (miRNA), transfer RNA-derived small RNA (tsRNA), and PIWI-interacting RNA (piRNA), elucidating their intricate interactions with crucial cellular machinery, specifically RNase H1, RNase P, AGO, and PIWI proteins, mediating their biological effects. The functional and structural characteristics of these endonucleases are examined in relation to their mechanisms of action and resultant therapeutic outcomes. This comprehensive analysis illuminates the interactions between single-stranded nucleic acids and their endonuclease partners, covering antisense inhibition pathways as well as RNA interference processes. This field of research has important implications for advancing targeted RNA modulation strategies across various disease contexts.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727644","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":"Lipid Profile Characterization of Human Micro-Fragmented Adipose Tissue via Untargeted Lipidomics.","authors":"Camillo Morano, Michele Dei Cas, Giulio Alessandri, Valentina Coccè, Francesca Paino, Monica Bignotto, Luisa Doneda, Carlo Tremolada, Augusto Pessina, Rita Paroni","doi":"10.3390/biom15070964","DOIUrl":"10.3390/biom15070964","url":null,"abstract":"<p><p>Mesenchymal stem cells (MSCs) exhibit low immunogenicity, multipotency, and are abundantly present in adipose tissue, making this tissue an easily accessible resource for regenerative medicine. Different commercial procedures have been developed to micro-fragment the adipose tissue aspirate from patients before its reinjection. We explored a commercial device which mechanically micro-fragments human lipoaspirate (LA) resulting in a homogeneous micro-fragmentation of fat tissue (MFAT). This device has been successfully employed in several clinical applications involving autologous adipose tissue transplantation. Here, we compare the untargeted/targeted lipidomic profile of LA and MFAT looking for differences in terms of qualitative modifications occurring during the handling of the original LA material. In MFAT, different lipid subclasses such as diacylglycerols, triacylglycerols, phospholipids, and sphingolipids are more represented than in LA. In addition, via targeted fatty acids analysis, we found a lower abundance of monounsaturated fatty acids in MFAT. The biological implications of these findings must be better investigated to contribute to a better understanding of the clinical efficacy of MFAT and for its potential use as a scaffold for drug delivery applications.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727608","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":"Identification of a Novel Antibacterial Function of Mammalian Calreticulin.","authors":"Yichao Ma, Jiachen Liu, Xinming Qin, Xiaojing Cui, Qian Yang","doi":"10.3390/biom15070966","DOIUrl":"10.3390/biom15070966","url":null,"abstract":"<p><p>Calreticulin is a highly conserved and multifunctional molecular chaperone ubiquitously expressed in humans and animals. Beyond its well-established roles in calcium homeostasis, protein folding, and immune regulation, recent studies in aquatic species have suggested a previously unrecognized antimicrobial function of calreticulin. These findings raise the question of whether calreticulin also exerts antibacterial activity in terrestrial mammals, which has not been systematically investigated to date. To address this knowledge gap, we successfully constructed and expressed recombinant goat calreticulin using the <i>Pichia pastoris</i> expression system, yielding a protein of over 99% purity that predominantly exists in dimeric form. Functional assays demonstrated that both recombinant goat and human calreticulin exhibited preliminary inhibitory activity against <i>Escherichia coli</i>, <i>Salmonella typhimurium</i>, and <i>Pasteurella multocida</i>. Calreticulin was capable of binding to these three bacterial species as well as bacterial lipopolysaccharides (LPS). Notably, in the presence of Ca²⁺, calreticulin induced bacterial aggregation, indicating a potential mechanism for limiting bacterial dissemination and proliferation. Given the high anatomical, genetic, and physiological similarity between goats and humans-particularly in respiratory tract structure and mucosal immune function-neonatal goats were selected as a relevant model for evaluating the in vivo antimicrobial efficacy of calreticulin. Accordingly, we established an intranasal infection model using <i>Pasteurella multocida</i> to assess the protective role of calreticulin against respiratory bacterial challenge. Following infection, calreticulin expression was markedly upregulated in the nasal mucosa, trachea, and lung tissues. Moreover, intranasal administration of exogenous calreticulin significantly alleviated infection-induced pathological injury to the respiratory system and effectively decreased bacterial loads in infected tissues. Collectively, this study systematically elucidates the antimicrobial activity of calreticulin in a mammalian model and highlights its potential as a natural immune effector, providing novel insights for the development of host-targeted antimicrobial strategies.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727584","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":"Quiescence Multiverse.","authors":"Damien Laporte, Isabelle Sagot","doi":"10.3390/biom15070960","DOIUrl":"10.3390/biom15070960","url":null,"abstract":"<p><p>Cellular quiescence is operationally defined as a temporary and reversible cessation of proliferation. This state encompasses a wide range of physiological situations since most cells, from microbes to cells composing complex tissues, spend most of their lives non-dividing, waiting for signals to reproliferate. As such, individual quiescent cells must withstand the effects of time not only to survive but also to maintain their ability to divide. These capacities are shaped by a combination of deterministic factors relying on cell history and cumulative stochastic events linked to the environment but also to time. In addition, with time, quiescence deepens, the quiescence exit process being extended. Yet, this deepening is not necessarily sensed evenly by each individual quiescent cell, and some cells exit quiescence faster than others. Hence, time generates heterogeneity within quiescent cell populations, heterogeneity that, in turn, increases cell population resilience and robustness to time. In this review, we discuss some of the loops that link quiescence and time.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727686","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":"Heparin-Binding Hemagglutinin-Induced Trained Immunity in Macrophages: Implications for Antimycobacterial Defense.","authors":"Yongqiang Li, Xiuping Jia, Jinhua Tang, Huilian Qiao, Jiani Zhou, Yueyun Ma","doi":"10.3390/biom15070959","DOIUrl":"10.3390/biom15070959","url":null,"abstract":"<p><p>Tuberculosis (TB) is a major global health threat, with the current <i>Bacillus Calmette-Guérin</i> (BCG) vaccine having limited efficacy against adult pulmonary disease. Trained immunity (TI) is a form of innate immune memory that enhances antimicrobial defense. It is characterized by the epigenetic and metabolic reprogramming of innate immune cells and holds promise as a promising approach to prevent TB. In this study, we investigated the capacity of heparin-binding hemagglutinin (HBHA), a methylated antigen of <i>Mycobacterium tuberculosis</i>, to induce TI in murine RAW264.7 macrophages, human-derived THP-1 macrophages, and human peripheral blood mononuclear cells (hPBMCs). HBHA-trained macrophages exhibited the enhanced expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) following secondary lipopolysaccharide stimulation. The epigenetic profiling indicated elevated levels of H3K4me1 and H3K4me3 histone marks at cytokine gene loci. Further, metabolic analysis revealed heightened lactate production and the increased expression of glycolytic enzymes. Functionally, HBHA-trained macrophages exhibited improved control of intracellular mycobacteria, as evidenced by a significant reduction in colony-forming units following BCG infection. These findings elucidate that HBHA induces a functional TI phenotype via coordinated epigenetic and metabolic changes, and suggest HBHA may serve as a valuable tool for studying TI and its relevance to host defense against mycobacterial infections, pending further in vivo and clinical validation.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727578","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":"The Role of Myeloid Differentiation Factor 2 in Stroke: Mechanisms and Therapeutic Potential.","authors":"Deyuan Zhu, Jihu Zhao, Qian Chen, Qiong Liu, Yibin Fang","doi":"10.3390/biom15070961","DOIUrl":"10.3390/biom15070961","url":null,"abstract":"<p><p>Stroke represents a significant public health burden, ranking as a leading cause of death and disability globally. The prevalence of stroke increases with age, with ischemic stroke accounting for nearly 87% of cases globally. The pathophysiology of stroke is characterized by neuronal injury, neuroinflammation, and oxidative stress, which exacerbate brain damage and hinder recovery. Myeloid Differentiation Factor 2 (MD2), an accessory protein of Toll-like receptor 4 (TLR4), has emerged as a key player in mediating inflammatory responses in stroke. This short review discusses the molecular mechanisms by which MD2 contributes to neuroinflammation and neuronal death following stroke and highlights MD2 as a promising therapeutic target for stroke treatment. Subsequently, we investigate the potential of MD2 inhibitors, their underlying mechanisms, and the therapeutic prospects of such inhibitors in reducing stroke-induced brain damage.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727727","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":"The Proteomic Landscape of Parkin-Deficient and Parkin-Overexpressing Rat Nucleus Accumbens: An Insight into the Role of Parkin in Methamphetamine Use Disorder.","authors":"Akhil Sharma, Tarek Atasi, Florine Collin, Weiwei Wang, TuKiet T Lam, Rolando Garcia-Milian, Tasnim Arroum, Lucynda Pham, Maik Hüttemann, Anna Moszczynska","doi":"10.3390/biom15070958","DOIUrl":"10.3390/biom15070958","url":null,"abstract":"<p><p>In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). We previously determined that ubiquitin-protein ligase parkin is involved in the regulation of METH addictive behaviors in rat models of MUD. Parkin is not yet a \"druggable\" drug target; therefore, this study aimed to determine which biological processes, pathways, and proteins downstream of parkin are likely drug targets against MUD. Employing young adult Long Evans male rats with parkin deficit or excess in the nucleus accumbens (NAc), label-free proteomics, and molecular biology, we determined that the pathways downstream of parkin that are candidates for regulating METH addictive behaviors in young adult male rats are mitochondrial respiration, oxidative stress, AMPA receptor trafficking, GABAergic neurotransmission, and actin cytoskeleton dynamics.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727721","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":"Hepatic Lipoprotein Metabolism: Current and Future In Vitro Cell-Based Systems.","authors":"Izabella Kiss, Nicole Neuwert, Raimund Oberle, Markus Hengstschläger, Selma Osmanagic-Myers, Herbert Stangl","doi":"10.3390/biom15070956","DOIUrl":"10.3390/biom15070956","url":null,"abstract":"<p><p>Changes in hepatic lipoprotein metabolism are responsible for the majority of metabolic dysfunction-associated disorders, including familial hypercholesterolemia (FH), metabolic syndrome (MetS), metabolic dysfunction-associated fatty liver disease (MAFLD), and age-related diseases such as atherosclerosis, a major health burden in modern society. This review aims to advance the understanding of state-of-the-art mechanistic concepts in lipoprotein metabolism, with a particular focus on lipoprotein uptake and secretion and their dysregulation in disease, and to provide a comprehensive overview of experimental models used to study these processes. Human lipoprotein research faces several challenges. First, significant differences in lipoprotein metabolism between humans and other species hinder the reliability of non-human model systems. Additionally, ethical constraints often limit studies on human lipoprotein metabolism using tracers. Lastly, while 2D hepatocyte cell culture systems are widely used, they are commonly of cancerous origins, limiting their physiological relevance and necessitating the use of more physiologically representative models. In this review, we will elaborate on key findings in lipoprotein metabolism, as well as limitations and challenges of currently available study tools, highlighting mechanistic insights throughout discussion of these models. These include human tracer studies, animal studies, 2D tissue culture-based systems derived from cancerous tissue as well as from induced pluripotent stem cells (iPSCs)/embryonic stem cells (ESCs). Finally, we will discuss precision-cut liver slices, liver-on-a-chip models, and, particularly, improved 3D models: (i) spheroids generated from either hepatoma cancer cell lines or primary human hepatocytes and (ii) organoids generated from liver tissues or iPSCs/ESCs. In the last section, we will explore future perspectives on liver-in-a-dish models in studying mechanisms of liver diseases, treatment options, and their applicability in precision medicine approaches. By comparing traditional and advanced models, this review will highlight the future directions of lipoprotein metabolism research, with a focus on the growing potential of 3D liver organoid models.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727579","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":"Transcript PHF19-207 May Be a Long Non-Coding RNA with Tumor-Promoting Role in Colon Cancer.","authors":"Dunja Pavlovic, Tamara Babic, Sofija Ignjatovic, Katarina Pavlovic, Sandra Dragicevic, Aleksandra Nikolic","doi":"10.3390/biom15070957","DOIUrl":"10.3390/biom15070957","url":null,"abstract":"<p><p>Recent pan-cancer transcriptome analysis has revealed differential activity of two alternative <i>PHF19</i> gene promoters in malignant versus non-malignant gut mucosa. One of these promoters upregulated in colon cancer leads to the expression of the PHF19-207 transcript, suggesting its potential role in tumor promotion. The objective of this study was to investigate the function of PHF19-207 using in silico tools and publicly available data, as well as to assess its expression in colon cancer. Expression analyses were conducted via qPCR and RNA sequencing on RNA extracted from the immortalized colonic epithelial cell line HCEC-1CT, as well as a series of colon cancer cell lines cultured in both 2D and 3D environments. The expression of PHF19-207 was found to be elevated in all malignant cell lines compared to the non-malignant HCEC-1CT cell line in both culture conditions, with the most prominent increase observed in cell lines derived from advanced stages of the disease and in the HCEC-1CT cell line overexpressing KRAS. Furthermore, the PHF19-207 transcript was detected in exosomes derived from malignant cells. These findings suggest that PHF19-207 holds potential as a diagnostic biomarker. In addition, in silico analyses indicate that this transcript may function as a long non-coding RNA involved in the regulation of gene expression. Further functional investigations are required to elucidate its precise role in colon carcinogenesis.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727733","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":"Presenilin-1 Familial Alzheimer Mutations Impair γ-Secretase Cleavage of APP Through Stabilized Enzyme-Substrate Complex Formation.","authors":"Sujan Devkota, Masato Maesako, Michael S Wolfe","doi":"10.3390/biom15070955","DOIUrl":"10.3390/biom15070955","url":null,"abstract":"<p><p>Familial Alzheimer's disease (FAD) is caused by dominant missense mutations in amyloid precursor protein (APP) and presenilin-1 (PSEN1), the catalytic component of γ-secretase that generates amyloid β-peptides (Aβ) from the APP C-terminal fragment C99. While most FAD mutations increase the ratio of aggregation-prone Aβ42 relative to Aβ40, consistent with the amyloid hypothesis of Alzheimer pathogenesis, some mutations do not increase this ratio. The γ-secretase complex produces amyloid β-peptide (Aβ) through processive cleavage along two pathways: C99 → Aβ49 → Aβ46 → Aβ43 → Aβ40 and C99 → Aβ48 → Aβ45 → Aβ42 → Aβ38. Understanding how FAD mutations affect the multistep γ-secretase cleavage process is critical for elucidating disease pathogenesis. In a recent study, we discovered that FAD mutations lead to stalled γ-secretase/substrate complexes that trigger synaptic loss independently of Aβ production. Here, we further investigate this \"stalled complex\" hypothesis, focusing on five additional PSEN1 FAD mutations (M84V, C92S, Y115H, T116I, and M139V). A comprehensive biochemical analysis revealed that all five mutations led to substantially reduced initial proteolysis of C99 to Aβ49 or Aβ48 as well as deficiencies in one or more subsequent trimming steps. Results from fluorescence lifetime imaging microscopy support increased stabilization of enzyme-substrate complexes by all five FAD mutations. These findings provide further support for the stalled complex hypothesis, highlighting that FAD mutations impair γ-secretase function by promoting the accumulation of stalled enzyme-substrate complexes.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 7","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12292344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727673","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}