-
Frontiers in Genetics 2024In recent years, burgeoning research has underscored the pivotal role of non-coding RNA in orchestrating the growth, development, and pathogenesis of various diseases...
In recent years, burgeoning research has underscored the pivotal role of non-coding RNA in orchestrating the growth, development, and pathogenesis of various diseases across organisms. However, despite these advances, our understanding of the specific contributions of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) to lens development remains notably limited. Clarifying the intricate gene regulatory networks is imperative for unraveling the molecular underpinnings of lens-related disorders. In this study, we aimed to address this gap by conducting a comprehensive analysis of the expression profiles of messenger RNAs (mRNAs), lncRNAs, and circRNAs at critical developmental time points of the mouse lens, encompassing both embryonic (E10.5, E12.5, and E16.5) and postnatal stages (P0.5, P10.5, and P60). Leveraging RNA-sequencing technology, we identified key transcripts pivotal to lens development. Our analysis revealed differentially expressed (DE) mRNAs, lncRNAs, and circRNAs across various developmental stages. Particularly noteworthy, there were 1831 co-differentially expressed (CO-DE) mRNAs, 150 CO-DE lncRNAs, and 13 CO-DE circRNAs identified during embryonic stages. Gene Ontology (GO) enrichment analysis unveiled associations primarily related to lens development, DNA conformational changes, and angiogenesis among DE mRNAs and lncRNAs. Furthermore, employing protein-protein interaction networks, mRNA-lncRNA co-expression networks, and circRNA-microRNA-mRNA networks, we predicted candidate key molecules implicated in lens development. Our findings underscore the pivotal roles of lncRNAs and circRNAs in this process, offering fresh insights into the pathogenesis of lens-related disorders and paving the way for future exploration in this field.
PubMed: 38933921
DOI: 10.3389/fgene.2024.1405715 -
Aging Cell Jun 2024Alterations in the rate and accuracy of messenger RNA (mRNA) translation are associated with aging and several neurodegenerative disorders, including Alzheimer's disease...
Alterations in the rate and accuracy of messenger RNA (mRNA) translation are associated with aging and several neurodegenerative disorders, including Alzheimer's disease and related tauopathies. We previously reported that error-containing RNA that are normally cleared via nonsense-mediated mRNA decay (NMD), a key RNA surveillance mechanism, are translated in the adult brain of a Drosophila model of tauopathy. In the current study, we find that newly-synthesized peptides and translation machinery accumulate within nuclear envelope invaginations that occur as a consequence of tau pathology, and that the rate of mRNA translation is globally elevated in early stages of disease in adult brains of Drosophila models of tauopathy. Polysome profiling from adult heads of tau transgenic Drosophila reveals the preferential translation of specific mRNA that have been previously linked to neurodegeneration. Unexpectedly, we find that panneuronal elevation of NMD further elevates the global translation rate in tau transgenic Drosophila, as does treatment with rapamycin. As NMD activation and rapamycin both suppress tau-induced neurodegeneration, their shared effect on translation suggests that elevated rates of mRNA translation are an early adaptive mechanism to limit neurodegeneration. Our work provides compelling evidence that tau-induced deficits in NMD reshape the tau translatome by increasing translation of RNA that are normally repressed in healthy cells.
PubMed: 38932463
DOI: 10.1111/acel.14245 -
Viruses May 2024We previously reported that deletion of a 44-nucleotide element in the 3' untranslated region (UTR) of the Chikungunya virus (CHIKV) genome enhances the virulence of...
We previously reported that deletion of a 44-nucleotide element in the 3' untranslated region (UTR) of the Chikungunya virus (CHIKV) genome enhances the virulence of CHIKV infection in mice. Here, we find that while this 44-nucleotide deletion enhances CHIKV fitness in murine embryonic fibroblasts in a manner independent of the type I interferon response, the same mutation decreases viral fitness in C6/36 mosquito cells. Further, the fitness advantage conferred by the UTR deletion in mammalian cells is maintained in vivo in a mouse model of CHIKV dissemination. Finally, SHAPE-MaP analysis of the CHIKV 3' UTR revealed this 44-nucleotide element forms a distinctive two-stem-loop structure that is ablated in the mutant 3' UTR without altering additional 3' UTR RNA secondary structures.
Topics: Chikungunya virus; Animals; Mice; 3' Untranslated Regions; Chikungunya Fever; Virus Replication; RNA, Viral; Virulence; Cell Line; Fibroblasts; Genetic Fitness; Humans; Sequence Deletion; Nucleic Acid Conformation; Disease Models, Animal
PubMed: 38932154
DOI: 10.3390/v16060861 -
Viruses May 2024The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as one of the most significant...
The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as one of the most significant global health crises in recent history. The clinical characteristics of COVID-19 patients have revealed the possibility of immune activity changes contributing to disease severity. Nevertheless, limited information is available regarding the immune response in human lung tissue, which is the primary site of infection. In this study, we conducted an extensive analysis of lung tissue to screen for differentially expressed miRNAs and mRNAs in five individuals who died due to COVID-19 and underwent a rapid autopsy, as well as seven control individuals who died of other causes unrelated to COVID-19. To analyze the host response gene expression, miRNA microarray and Nanostring's nCounter XT gene expression assay were performed. Our study identified 37 downregulated and 77 upregulated miRNAs in COVID-19 lung biopsy samples compared to the controls. A total of 653 mRNA transcripts were differentially expressed between the two sample types, with most transcripts (472) being downregulated in COVID-19-positive specimens. Hierarchical and PCA K-means clustering analysis showed distinct clustering between COVID-19 and control samples. Enrichment and network analyses revealed differentially expressed genes important for innate immunity and inflammatory response in COVID-19 lung biopsies. The interferon-signaling pathway was highly upregulated in COVID-19 specimens while genes involved in interleukin-17 signaling were downregulated. These findings shed light on the mechanisms of host cellular responses to COVID-19 infection in lung tissues and could help identify new targets for the prevention and treatment of COVID-19 infection.
Topics: Humans; COVID-19; Lung; Gene Regulatory Networks; MicroRNAs; Autopsy; SARS-CoV-2; Male; Female; Middle Aged; Aged; Gene Expression Profiling; RNA, Messenger; Adult
PubMed: 38932146
DOI: 10.3390/v16060853 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Alzheimer's disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive... (Review)
Review
Alzheimer's disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system's role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research. Advances in targeting antibodies against amyloid-β (Aβ) and using messenger RNA for genetic translation have revolutionized the production of antibodies and drug development, opening new possibilities for treatment. Despite these advancements, conventional therapies for AD, such as Cognex, Exelon, Razadyne, and Aricept, often have limited long-term effectiveness, underscoring the need for innovative solutions. This necessity has led to the incorporation advanced technologies like artificial intelligence and machine learning into the drug discovery process for neurodegenerative diseases. These technologies help identify therapeutic targets and optimize lead compounds, offering a more effective approach to addressing the challenges of AD and similar conditions.
PubMed: 38931409
DOI: 10.3390/ph17060741 -
Life (Basel, Switzerland) Jun 2024Amino acids are one of the most important building blocks of life. During the biochemical process of translation, cells sequentially connect amino acids via amide bonds...
From Zero to Hero: The Cyanide-Free Formation of Amino Acids and Amides from Acetylene, Ammonia and Carbon Monoxide in Aqueous Environments in a Simulated Hadean Scenario.
Amino acids are one of the most important building blocks of life. During the biochemical process of translation, cells sequentially connect amino acids via amide bonds to synthesize proteins, using the genetic information in messenger RNA (mRNA) as a template. From a prebiotic perspective (i.e., without enzymatic catalysis), joining amino acids to peptides via amide bonds is difficult due to the highly endergonic nature of the condensation reaction. We show here that amides can be formed in reactions catalyzed by the transition metal sulfides from acetylene, carbon monoxide and ammonia under aqueous conditions. Some α- and β-amino acids were also formed under the same conditions, demonstrating an alternative cyanide-free path for the formation of amino acids in prebiotic environments. Experiments performed with stable isotope labeled precursors, like NHCl and C-acetylene, enabled the accurate mass spectroscopic identification of the products formed from the starting materials and their composition. Reactions catalyzed using the transition metal sulfides seem to offer a promising alternative pathway for the formation of amides and amino acids in prebiotic environments, bypassing the challenges posed by the highly endergonic condensation reaction. These findings shed light on the potential mechanisms by which the building blocks of life could have originated on early Earth.
PubMed: 38929702
DOI: 10.3390/life14060719 -
International Journal of Molecular... Jun 2024Aneurysms pose life-threatening risks due to the dilatation of the arteries and carry a high risk of rupture. Despite continuous research efforts, there are still no...
Aneurysms pose life-threatening risks due to the dilatation of the arteries and carry a high risk of rupture. Despite continuous research efforts, there are still no satisfactory or clinically effective pharmaceutical treatments for this condition. Accelerated inflammatory processes during aneurysm development lead to increased levels of matrix metalloproteinases (MMPs) and destabilization of the vessel wall through the degradation of the structural components of the extracellular matrix (ECM), mainly collagen and elastin. Tissue inhibitors of metalloproteinases (TIMPs) directly regulate MMP activity and consequently inhibit ECM proteolysis. In this work, the synthesis of TIMP-1 protein was increased by the exogenous delivery of synthetic TIMP-1 encoding mRNA into aortic vessel tissue in an attempt to inhibit MMP-9. In vitro, TIMP-1 mRNA transfection resulted in significantly increased TIMP-1 protein expression in various cells. The functionality of the expressed protein was evaluated in an appropriate ex vivo aortic vessel model. Decreased MMP-9 activity was detected using in situ zymography 24 h and 48 h post microinjection of 5 µg TIMP-1 mRNA into the aortic vessel wall. These results suggest that TIMP-1 mRNA administration is a promising approach for the treatment of aneurysms.
Topics: Tissue Inhibitor of Metalloproteinase-1; Matrix Metalloproteinase 9; RNA, Messenger; Animals; Humans; Rats; Aneurysm; Aorta; Male; Arteries; Matrix Metalloproteinase Inhibitors
PubMed: 38928311
DOI: 10.3390/ijms25126599 -
International Journal of Molecular... Jun 2024This study aimed to assess the expression profile of messenger RNA (mRNA) and microRNA (miRNA) related to the dopaminergic system in five types of breast cancer in...
This study aimed to assess the expression profile of messenger RNA (mRNA) and microRNA (miRNA) related to the dopaminergic system in five types of breast cancer in Polish women. Patients with five breast cancer subtypes were included in the study: luminal A ( = 130), luminal B ( = 196, including HER2-, = 100; HER2+, = 96), HER2+ ( = 36), and TNBC ( = 43); they underwent surgery, during which tumor tissue was removed along with a margin of healthy tissue (control material). The molecular analysis included a microarray profile of mRNAs and miRNAs associated with the dopaminergic system, a real-time polymerase chain reaction preceded by reverse transcription for selected genes, and determinations of their concentration using enzyme-linked immunosorbent assay (ELISA). The conducted statistical analysis showed that five mRNAs statistically significantly differentiated breast cancer sections regardless of subtype compared to control samples; these were dopamine receptor 2 (), dopamine receptor 3 (), dopamine receptor 25 (), transforming growth factor beta 2 (), and caveolin 2 (). The predicted analysis showed that hsa-miR-141-3p can regulate the expression of and , whereas hsa-miR-4441 is potentially engaged in the expression regulation of and . In addition, the expression pattern of mRNA can also be regulated by has-miR-16-5p. The overexpression of DRD2 and DRD3, with concomitant silencing of DRD5 expression, confirms the presence of dopaminergic abnormalities in breast cancer patients. Moreover, these abnormalities may be the result of miR-141-3P, miR-16-5p, and miR-4441 activity, regulating proliferation or metastasis.
Topics: Humans; Female; MicroRNAs; Breast Neoplasms; Gene Expression Regulation, Neoplastic; Middle Aged; Dopamine; Adult; Gene Expression Profiling; Aged; RNA, Messenger; Receptors, Dopamine D3; Receptors, Dopamine D2; Transforming Growth Factor beta2
PubMed: 38928253
DOI: 10.3390/ijms25126546 -
International Journal of Molecular... Jun 2024Sepsis, a life-threatening condition caused by the body's dysregulated response to infection, presents a significant challenge in clinical management. Timely and... (Review)
Review
Sepsis, a life-threatening condition caused by the body's dysregulated response to infection, presents a significant challenge in clinical management. Timely and accurate diagnosis is paramount for initiating appropriate interventions and improving patient outcomes. In recent years, there has been growing interest in identifying biomarkers that can aid in the early detection and prognostication of sepsis. MicroRNAs (miRNAs) have emerged as potential biomarkers for sepsis due to their involvement in the regulation of gene expression and their stability in various biological fluids, including blood. MiRNAs are small non-coding RNA molecules that play crucial roles in post-transcriptional gene regulation by binding to target messenger RNAs (mRNAs), leading to mRNA degradation or translational repression. The diagnostic and prognostic potential of miRNAs in sepsis stems from their ability to serve as sensitive and specific biomarkers reflective of the underlying pathophysiological processes. Compared to traditional biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT), miRNAs offer several advantages, including their early and sustained elevation during sepsis, as well as their stability in stored samples, making them attractive candidates for clinical use. However, despite their promise, the clinical translation of miRNAs as sepsis biomarkers faces several challenges. These include the need for standardized sample collection and processing methods, the identification of optimal miRNA panels or signatures for differentiating sepsis from other inflammatory conditions, and the validation of findings across diverse patient populations and clinical settings. In conclusion, miRNAs hold great promise as diagnostic and prognostic biomarkers for sepsis, offering insights into the underlying molecular mechanisms and potential therapeutic targets. However, further research is needed to overcome existing challenges and realize the full clinical utility of miRNAs in improving sepsis outcomes.
Topics: Humans; Sepsis; Biomarkers; MicroRNAs; Prognosis; Animals; Gene Expression Regulation
PubMed: 38928179
DOI: 10.3390/ijms25126476 -
International Journal of Molecular... Jun 2024Obesity is a risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Adipose tissue (AT) extracellular vesicles (EVs) could play a role in...
Extracellular Vesicles Secreted by Adipose Tissue during Obesity and Type 2 Diabetes Mellitus Influence Reverse Cholesterol Transport-Related Gene Expression in Human Macrophages.
Obesity is a risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Adipose tissue (AT) extracellular vesicles (EVs) could play a role in obesity and T2DM associated CVD progression via the influence of their specific cargo on gene expression in recipient cells. The aim of this work was to evaluate the effects of AT EVs of patients with obesity with/without T2DM on reverse cholesterol transport (RCT)-related gene expression in human monocyte-derived macrophages (MDMs) from healthy donors. AT EVs were obtained after ex vivo cultivation of visceral and subcutaneous AT (VAT and SAT, respectively). , , , , and mRNA levels in MDMs as well as in origine AT were determined by a real-time PCR. T2DM VAT and SAT EVs induced gene expression whereas and mRNA levels were simultaneously downregulated. mRNA levels also decreased in the presence of VAT EVs of obese patients without T2DM. In contrast and mRNA levels tended to increase with the addition of obese AT EVs. Thus, AT EVs can influence RCT gene expression in MDMs during obesity, and the effects are dependent on T2DM status.
Topics: Humans; Diabetes Mellitus, Type 2; Extracellular Vesicles; Obesity; Liver X Receptors; Macrophages; Cholesterol; ATP Binding Cassette Transporter, Subfamily G, Member 1; Adipose Tissue; PPAR gamma; Female; ATP Binding Cassette Transporter 1; Male; Middle Aged; Biological Transport; Gene Expression Regulation; Adult; RNA, Messenger
PubMed: 38928163
DOI: 10.3390/ijms25126457