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International Journal of Molecular... Jun 2024The current hypothesis on the pathophysiology of multiple sclerosis (MS) suggests the involvement of both inflammatory and neurodegenerative mechanisms. Disease...
The current hypothesis on the pathophysiology of multiple sclerosis (MS) suggests the involvement of both inflammatory and neurodegenerative mechanisms. Disease Modifying Therapies (DMTs) effectively decrease relapse rates, thus reducing relapse-associated disability in people with MS. In some patients, disability progression, however, is not solely linked to new lesions and clinical relapses but can manifest independently. Progression Independent of Relapse Activity (PIRA) significantly contributes to long-term disability, stressing the urge to unveil biomarkers to forecast disease progression. Twenty-five adult patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled in a cohort study, according to the latest McDonald criteria, and tested before and after high-efficacy Disease Modifying Therapies (DMTs) (6-24 months). Through Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells. Multivariate logistic and linear models with interactions were generated. Robustness was assessed by randomization tests in R. A subset of miRNAs, correlated with PIRA, and the Expanded Disability Status Scale (EDSS), was selected. To refine the patient stratification connected to the disease trajectory, we computed a robust logistic classification model derived from baseline miRNA expression to predict PIRA status (AUC = 0.971). We built an optimal multilinear model by selecting four other miRNA predictors to describe EDSS changes compared to baseline. Multivariate modeling offers a promising avenue to uncover potential biomarkers essential for accurate prediction of disability progression in early MS stages. These models can provide valuable insights into developing personalized and effective treatment strategies.
Topics: Humans; MicroRNAs; Male; Female; Adult; Disease Progression; Multiple Sclerosis, Relapsing-Remitting; Middle Aged; Biomarkers; Multiple Sclerosis; Leukocytes, Mononuclear; Cohort Studies; Recurrence; Gene Expression Profiling
PubMed: 38928049
DOI: 10.3390/ijms25126342 -
International Journal of Molecular... Jun 2024Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and... (Review)
Review
Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial to developing new, specific and efficient treatments. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress and neuroinflammation. Furthermore, non-coding RNAs (ncRNAs) are critical in pathophysiology and recovery after cerebral ischemia. ncRNAs, particularly microRNAs, and long non-coding RNAs (lncRNAs) are essential for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. This review summarizes the intricate molecular mechanisms underlying ischemic and hemorrhagic stroke and delves into the function of miRNAs in the development of brain damage. Furthermore, we will analyze new perspectives on treatment based on molecular mechanisms in addition to traditional stroke therapies.
Topics: Humans; Ischemic Stroke; MicroRNAs; Hemorrhagic Stroke; Animals; RNA, Long Noncoding; Oxidative Stress; Brain Ischemia
PubMed: 38928006
DOI: 10.3390/ijms25126297 -
Genes Jun 2024The identification of new biomarkers of ocular diseases is nowadays of outmost importance both for early diagnosis and treatment. Epigenetics is a rapidly growing...
Extensive Contact Lens Wear Modulates Expression of miRNA-320 and miRNA-423-5p in the Human Corneal Epithelium: Possible Biomarkers of Corneal Health and Environmental Impact.
The identification of new biomarkers of ocular diseases is nowadays of outmost importance both for early diagnosis and treatment. Epigenetics is a rapidly growing emerging area of research and its involvement in the pathophysiology of ocular disease and regulatory mechanisms is of undisputable importance for diagnostic purposes. Environmental changes may impact the ocular surface, and the knowledge of induced epigenetic changes might help to elucidate the mechanisms of ocular surface disorders. In this pilot study, we investigated the impact of extensive contact lens (CL) wearing on human corneal epithelium epigenetics. We performed ex vivo analysis of the expression of the miR-320 and miR-423-5p involved in the processes of cellular apoptosis and chronic inflammation. The human corneal epithelium was harvested from healthy patients before the photorefractive keratectomy (PRK). The patients were divided into two age- and sex-matched groups accordingly to CL wearing history with no CL wearers used as a control. The epithelium was stored frozen in dry ice at -80 °C and forwarded for miRNA extraction; afterwards, miRNA levels were detected using real-time PCR. Both miRNAs were highly expressed in CL wearers ( < 0.001), suggesting epigenetic modifications occurring in chronic ocular surface stress. These preliminary results show the relationships between selected miRNA expression and the chronic ocular surface stress associated with extensive CL use. MicroRNAs might be considered as biomarkers for the diagnosis of ocular surface conditions and the impact of environmental factors on ocular surface epigenetic. Furthermore, they might be considered as new therapeutic targets in ocular surface diseases.
Topics: Humans; MicroRNAs; Epithelium, Corneal; Female; Male; Adult; Biomarkers; Contact Lenses; Pilot Projects; Epigenesis, Genetic; Gene Expression Regulation
PubMed: 38927751
DOI: 10.3390/genes15060816 -
Genes Jun 2024Infant consumption of human milk (HM) is associated with a reduced risk of overweight and obesity, but the reasons for this relationship are not completely understood....
Infant consumption of human milk (HM) is associated with a reduced risk of overweight and obesity, but the reasons for this relationship are not completely understood. There is emerging evidence that micro RNAs (miRNAs) regulate infant development and metabolism, but the associations between HM miRNAs and infant growth remain poorly understood. We examined the relationship between HM miRNA consumption and infant obesity in 163 mother-infant dyads to determine (1) if miRNA profiles differentiate infants with obesity, and (2) if individual miRNAs accurately predicted infant obesity status at one year of age. Infant obesity was categorized as weight-for-length (WFL) Z scores or conditional weight gain (CWG) in the 95th percentile. HM miRNA profile was associated with infant age (r = 6.4%, = 0.001), but not maternal obesity status (r = 1.5%, = 0.87) or infant weight status (WFL Z-score) at birth (r = 0.6%, = 0.4), 1 month (r = 0.5%, = 0.6), or 4 months (r = 0.8%, = 0.2). Nine HM miRNAs were associated with either 12-month CWG or 12-month WFL Z scores. Among these 9 miRNAs, miR-224-5p remained significant in a logistic regression model that accounted for additional demographic factors (estimate = -27.57, = 0.004). These findings suggest involvement of HM miRNAs and particularly miR-224-5p in infant growth, warranting further investigation. To our knowledge, this is the largest study of HM miRNAs and early-life obesity and contributes to the understanding of the relationship between HM miRNAs and infant growth.
Topics: Humans; Milk, Human; Female; MicroRNAs; Infant; Male; Adult; Infant, Newborn; Obesity; Pediatric Obesity; Breast Feeding
PubMed: 38927748
DOI: 10.3390/genes15060813 -
Genes Jun 2024Eggshell color plays important biological roles and attracts the attention of both egg retailers and researchers. However, whether non-coding RNAs are involved in...
Eggshell color plays important biological roles and attracts the attention of both egg retailers and researchers. However, whether non-coding RNAs are involved in pigment deposition among different eggshell colors remains unknown. In this study, RNA sequencing was used to analyse the uterine gland transcriptome (CircRNA and miRNA) of Changshun chicken blue-shell hens producing four different eggshell color eggs including dark blue PK(DB) and light blue (LB), dark brown and greenish (between blue and pink, DP) and pink (p). We found that , targeting , was expressed in DB, DP, and LB groups compared with the PK group, which indicates that may play a role in the blue eggshell color. KEGG and GO analyses showed that the "metabolic pathways" with targeted genes such and were detected in dark and light blue color eggshell chickens, which confirms the different ratios of biliverdin and involved in the deposition of blue color. As annotated by connectivity analysis, and , belonging to the family, are involved in the signaling pathway, which plays an important role in cell growth, differentiation, metastasis and apoptosis. Our findings enrich the database of circRNA, miRNAs and genes for chicken uterine tissue, which will be useful in accelerating molecular selection for blue eggshell color layers.
Topics: Animals; Chickens; MicroRNAs; Egg Shell; RNA, Circular; Female; Pigmentation; Transcriptome; Sequence Analysis, RNA; Gene Regulatory Networks
PubMed: 38927747
DOI: 10.3390/genes15060812 -
Genes Jun 2024Green eggs are mainly caused by inserting an avian endogenous retrovirus (EVA-HP) fragment into the gene. Although the genotypes for this insertion allele are...
Green eggs are mainly caused by inserting an avian endogenous retrovirus (EVA-HP) fragment into the gene. Although the genotypes for this insertion allele are consistent, eggshell color (ESC) may vary after a peak laying period; light-colored eggs are undesired by consumers and farmers and result in financial loss, so it is necessary to resolve this problem. miRNAs are small non-coding RNAs that exert essential functions in animal development and diseases. However, the regulatory miRNAs and detailed molecular mechanisms regulating eggshell greenness remain unclear. In the present study, we determined the genotype of green-eggshell hens through the detection of a homozygous allele insertion in the gene. The shell gland epithelium was obtained from green-eggshell hens that produced white and green shell eggs to perform transcriptome sequencing and investigate the important regulatory mechanisms that influence the ESC. Approximately 921 miRNAs were expressed in these two groups, which included 587 known miRNAs and 334 novel miRNAs, among which 44 were differentially expressed. There were 22 miRNAs that were significantly upregulated in the green and white groups, respectively, which targeted hundreds of genes, including , , and several solute carrier family genes. A Gene Ontology enrichment analysis of the target genes showed that the differentially expressed miRNA-targeted genes mainly belonged to the functional categories of homophilic cell adhesion, gland development, the Wnt signaling pathway, and epithelial tube morphogenesis. A KEGG enrichment analysis showed that the Hedgehog signaling pathway was significantly transformed in this study. The current study provides an overview of the miRNA expression profiles and the interaction between the miRNAs and their target genes. It provides valuable insights into the molecular mechanisms underlying green eggshell pigmentation, screening more effective hens to produce stable green eggs and obtaining higher economic benefits.
Topics: Animals; Chickens; MicroRNAs; Egg Shell; Pigmentation; Transcriptome; Female
PubMed: 38927746
DOI: 10.3390/genes15060811 -
Genes May 2024PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs (sncRNAs) with 24-32 nucleotides (nt), were initially identified in the reproductive system. Unlike... (Review)
Review
PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs (sncRNAs) with 24-32 nucleotides (nt), were initially identified in the reproductive system. Unlike microRNAs (miRNAs) or small interfering RNAs (siRNAs), piRNAs normally guide P-element-induced wimpy testis protein (PIWI) families to slice extensively complementary transposon transcripts without the seed pairing. Numerous studies have shown that piRNAs are abundantly expressed in the brain, and many of them are aberrantly regulated in central neural system (CNS) disorders. However, the role of piRNAs in the related developmental and pathological processes is unclear. The elucidation of piRNAs/PIWI would greatly improve the understanding of CNS development and ultimately lead to novel strategies to treat neural diseases. In this review, we summarized the relevant structure, properties, and databases of piRNAs and their functional roles in neural development and degenerative disorders. We hope that future studies of these piRNAs will facilitate the development of RNA-based therapeutics for CNS disorders.
Topics: Humans; RNA, Small Interfering; Animals; Argonaute Proteins; Nervous System Diseases; Neurogenesis
PubMed: 38927589
DOI: 10.3390/genes15060653 -
Biomedicines Jun 2024Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis,... (Review)
Review
Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These mutations can also trigger a cellular surveillance mechanism known as nonsense-mediated mRNA decay (NMD) that degrades the PTC-containing mRNA. The activation of NMD can attenuate the consequences of truncated, defective, and potentially toxic proteins in the cell. Since approximately 20% of all single-point mutations are disease-causing nonsense mutations, it is not surprising that this field has received significant attention, resulting in a remarkable advancement in recent years. In fact, since our last review on this topic, new examples of nonsense suppression approaches have been reported, namely new ways of promoting the translational readthrough of PTCs or inhibiting the NMD pathway. With this review, we update the state-of-the-art technologies in nonsense suppression, focusing on novel modalities with therapeutic potential, such as small molecules (readthrough agents, NMD inhibitors, and molecular glue degraders); antisense oligonucleotides; tRNA suppressors; ADAR-mediated RNA editing; targeted pseudouridylation; and gene/base editing. While these various modalities have significantly advanced in their development stage since our last review, each has advantages (e.g., ease of delivery and specificity) and disadvantages (manufacturing complexity and off-target effect potential), which we discuss here.
PubMed: 38927491
DOI: 10.3390/biomedicines12061284 -
Biomolecules Jun 2024MicroRNAs (miRNAs) are highly conserved endogenous single-stranded non-coding RNA molecules that play a crucial role in regulating gene expression to maintain normal...
Downregulation of miR-1388 Regulates the Expression of Antiviral Genes via Tumor Necrosis Factor Receptor ()-Associated Factor 3 Targeting Following poly(I:C) Stimulation in Silver Carp ().
MicroRNAs (miRNAs) are highly conserved endogenous single-stranded non-coding RNA molecules that play a crucial role in regulating gene expression to maintain normal physiological functions in fish. Nevertheless, the specific physiological role of miRNAs in lower vertebrates, particularly in comparison to mammals, remains elusive. Additionally, the mechanisms underlying the control of antiviral responses triggered by viral stimulation in fish are still not fully understood. In this study, we investigated the regulatory impact of miR-1388 on the signaling pathway mediated by IFN regulatory factor 3 (). Our findings revealed that following stimulation with the viral analog poly(I:C), the expression of miR-1388 was significantly upregulated in primary immune tissues and macrophages. Through a dual luciferase reporter assay, we corroborated a direct targeting relationship between miR-1388 and tumor necrosis factor receptor ()-associated factor 3 (). Furthermore, our study demonstrated a distinct negative post-transcriptional correlation between miR-1388 and . We observed a significant negative post-transcriptional regulatory association between miR-1388 and the levels of antiviral genes following poly(I:C) stimulation. Utilizing reporter plasmids, we elucidated the role of miR-1388 in the antiviral signaling pathway activated by . By intervening with siRNA-, we validated that miR-1388 regulates the expression of antiviral genes and the production of type I interferons () through its interaction with . Collectively, our experiments highlight the regulatory influence of miR-1388 on the -mediated signaling pathway by targeting post poly(I:C) stimulation. These findings provide compelling evidence for enhancing our understanding of the mechanisms through which fish miRNAs participate in immune responses.
Topics: Animals; MicroRNAs; Poly I-C; Carps; TNF Receptor-Associated Factor 3; Down-Regulation; Interferon Regulatory Factor-3; Gene Expression Regulation; Fish Proteins; Signal Transduction
PubMed: 38927097
DOI: 10.3390/biom14060694 -
Biomolecules May 2024Chronic myeloid leukemia (CML) is an oncological myeloproliferative disorder that accounts for 15 to 20% of all adult leukemia cases. The molecular basis of this disease... (Review)
Review
Chronic myeloid leukemia (CML) is an oncological myeloproliferative disorder that accounts for 15 to 20% of all adult leukemia cases. The molecular basis of this disease lies in the formation of a chimeric oncogene BCR-ABL1. The protein product of this gene, p210 BCR-ABL1, exhibits abnormally high constitutive tyrosine kinase activity. Over recent decades, several targeted tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1 have been developed and introduced into clinical practice. These inhibitors suppress BCR-ABL1 activity through various mechanisms. Furthermore, the advent of RNA interference technology has enabled the highly specific inhibition of BCR-ABL1 transcript expression using small interfering RNA (siRNA). This experimental evidence opens avenues for the development of a novel therapeutic strategy for CML, termed siRNA therapy. The review delves into molecular genetic mechanisms underlying the pathogenesis of CML, challenges in CML therapy, potential molecular targets for drug development, and the latest results from the application of siRNAs in in vitro and in vivo CML models.
Topics: Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Humans; RNA, Small Interfering; Fusion Proteins, bcr-abl; Molecular Targeted Therapy; Animals; Protein Kinase Inhibitors; RNA Interference
PubMed: 38927048
DOI: 10.3390/biom14060644