microRNA Expression Research Articles

Relationship between Protein, MicroRNA Expression in Extracellular Vesicles and Rice Seed Vigor.

Plant extracellular vesicles are non-self-replicating particles released by living plant cells and delimited by a lipid bilayer. They contain a large amount of lipids, RNA, and proteins. Seed vigor plays an important role in agricultural production and preservation of germplasm resources. Extracellular vesicles with cross-species communication with bioactive molecules can resist pathogens, exhibit anti-aging properties, and perform other functions; however, its potential influence on seed vigor has not been reported. In this study, rice seeds with different germination percentages were used to extract extracellular vesicles, endogenous proteins, and RNA. Protein qualitative identification and miRNA differential analysis were performed to analyze the regulatory mechanism of extracellular vesicles on seed vigor. Results: The profiles of four miRNA families were found to be significantly different: osa-miR164, osa-miR168, osa-miR166, and osa-miR159. Protein correlation analysis predicted that extracellular vesicles might mediate the synthesis of the seed cell wall; glyoxic acid cycle and tricarboxylic acid cycle; non-specific lipid transfer; mitochondrial quality control; and other biological processes to regulate rice seed viability. In addition, cupin protein, phospholipase D, aldehyde dehydrogenase, seven heat shock proteins (especially BiP1 and BiP2), protein disulfide isomerase-like (PDI), thioredoxin, calnexin and calreticulin, glutathione transferase, and other proteins found in extracellular vesicles were closely related to seed vigor. This provides a novel direction for the study of the regulation mechanism of seed vigor.

Identification of hsa-miR-193a-5p-SURF4 axis related to the gut microbiota-metabolites- cytokines in lung cancer based on Mendelian randomization study and bioinformatics analysis

BackgroundLung cancer is a significant disease that affects people's physical and mental health. Currently, the treatment outcomes still do not meet clinical needs, and the causes of the disease are still unclear, therefore further exploration is needed.MethodsWe analyzed the exposure factors of lung cancer, including gut microbiota, serum metabolites, and cytokines, through Mendelian randomization studies and bioinformatics analysis. We identified common SNPs and performed gene annotation, leading to the discovery of the key gene SURF4, which may affect the onset of lung cancer. We validated the oncogenic function and mechanism of SURF4 through public data analysis using GO and KEGG, and constructed a ceRNA network, revealing the lung cancer oncogenic pathway involving lncRNA/pseudogene-microRNA-SURF4.ResultsWe first conducted a Mendelian randomization analysis on 418 gut microbiota, 1400 serum metabolites, and 41 cytokines in relation to lung cancer. We found that 16 gut microbiota, 29 serum metabolites, and 2 cytokines were closely associated with lung cancer. Further comparison of all differential SNPs revealed that rs550057 on chromosome 9 was a common SNP among these three exposure factors, indicating its crucial role in lung cancer formation. Through gene functional annotation using R language, we found that the expression of 15 genes, including SURF4, was influenced by rs550057. By querying these 15 genes from public databases for their differential expression and prognosis in lung cancer, we found significant differences in SURF4, MED22, and RPL7A. Furthermore, by querying the expression and correlation coefficients of upstream microRNAs of these three genes through the starBase website, we found that hsa-miR-193a-5p-SURF4 had the most significant effect on lung cancer. Through GO and KEGG analysis of SURF4-related genes, we identified the molecular pathways associated metabolic synthesis and microbial infection related to the promotion of lung cancer by SURF4. This validated the results of the previous Mendelian randomization study. Furthermore, we constructed a ceRNA network for SURF4 and identified two upstream differentially expressed pseudogenes and nine lncRNAs, confirming the functionality of the pseudogene/lncRNA-microRNA-SUFR4 pathway.ConclusionsIn summary, we have elucidated the regulatory role of the pseudogene/lncRNA-microRNA-SUFR4 pathway in the progression of lung cancer, combining the research hotspots of gut microbiota-serum metabolites-cytokines. We have also confirmed the pathway and mechanism through SURF4 and its related genes promoting lung cancer formation. This may provide effective therapeutic methods for lung cancer and serve as a potential prognostic marker.

Comprehensive analysis of the expression and prognosis for cyclin-dependent protein kinase family in osteosarcoma

Background and Objective Cyclin-dependent protein kinases (CDKs) have been suggested as prospective therapeutic targets because they control processes vital to the survival and growth of cancer cells. However, research on the varied CDK expression profiles and prognostic factors in osteosarcoma is still lacking. Methods The osteosarcoma microRNA (GSE65071) and gene expression profiles were retrieved from the Gene Expression Omnibus (GEO) database (GSE42352). A substantial variation in prognosis was discovered in CDKs using the TARGET database. Cytoscape was used to construct the miRNAs-CDKs network, and functional and pathway enrichment analyses were completed. It was looked at how immune checkpoint genes, m6A-related genes, and CDKs interact. Results In patients with osteosarcoma compared to normal samples, CDK1-5, CDK18, CDK16, and CDK17 gene expression levels were considerably greater, whereas CDK7-9, CDK11B, CDK16, and CDK20 gene expression levels were significantly lower. Patients with osteosarcoma who had low CDK3 and 18 gene levels or high CDK6, 9 gene levels were predicted to have a favorable prognosis and a long-life expectancy. Immune checkpoint genes, m6A-related gene expression, and CDKs expression all showed some connection. Finally, a network of crucial CDKs and miRNAs was constructed. Conclusion According to our research, CDK3, 6, 9, and 18 have been identified as possible therapeutic targets for osteosarcoma, and CDKs may have a role in controlling m6A mutations in tumor cells as well as immune checkpoint regulation.

Diabetes and Early Development: Epigenetics, Biological Stress, and Aging.

Pregestational diabetes, either type 1 or type 2 diabetes, induces structural birth defects including neural tube defects and congenital heart defects in human fetuses. Rodent models of type 1 and type 2 diabetic embryopathy have been established and faithfully mimic human conditions. Hyperglycemia of maternal diabetes triggers oxidative stress in the developing neuroepithelium and the embryonic heart leading to the activation of proapoptotic kinases and excessive cell death. Oxidative stress also activates the unfolded protein response and endoplasmic reticulum stress. Hyperglycemia alters epigenetic landscapes by suppressing histone deacetylation, perturbing microRNA (miRNA) expression, and increasing DNA methylation. At cellular levels, besides the induction of cell apoptosis, hyperglycemia suppresses cell proliferation and induces premature senescence. Stress signaling elicited by maternal diabetes disrupts cellular organelle homeostasis leading to mitochondrial dysfunction, mitochondrial dynamic alteration, and autophagy impairment. Blocking oxidative stress, kinase activation, and cellular senescence ameliorates diabetic embryopathy. Deleting the mir200c gene or restoring mir322 expression abolishes maternal diabetes hyperglycemia-induced senescence and cellular stress, respectively. Both the autophagy activator trehalose and the senomorphic rapamycin can alleviate diabetic embryopathy. Thus, targeting cellular stress, miRNAs, senescence, or restoring autophagy or mitochondrial fusion is a promising approach to prevent poorly controlled maternal diabetes-induced structural birth defects. In this review, we summarize the causal events in diabetic embryopathy and propose preventions for this pathological condition. KEY POINTS: · Maternal diabetes induces structural birth defects.. · Kinase signaling and cellular organelle stress are critically involved in neural tube defects.. · Maternal diabetes increases DNA methylation and suppresses developmental gene expression.. · Cellular apoptosis and senescence are induced by maternal diabetes in the neuroepithelium.. · microRNAs disrupt mitochondrial fusion leading to congenital heart diseases in diabetic pregnancy..

Identification of common MicroRNAs expression signatures in antiphospholipid syndrome and thromboembolic disease: A scoping review.

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by distinct pathophysiological mechanisms leading to heterogeneous manifestations, including venous and arterial thrombosis. Despite the lack of specific markers of thrombosis risk in APS, some of the mechanisms responsible for thrombosis in APS may overlap with those of other thromboembolic diseases. Understanding these similarities is important for improving the assessment of thrombosis risk in APS. MicroRNAs (MiRNAs) are RNA molecules that regulate gene expression and may influence the autoimmune response and coagulation. In this scoping review we aimed to investigate shared miRNAs profiles associated with APS and other thromboembolic diseases as a means of identifying markers indicative of a pro-thrombotic profile among patients with APS. Through a comprehensive search of scientific databases, 45 relevant studies were identified out of 1020 references. miRs-124-3p, 125b-5p, 125a-5p, and 17-5p, were associated with APS and arterial thrombosis, while miRs-106a-5p, 146b-5p, 15a-5p, 222-3p, and 451a were associated with APS and venous thrombosis. Additionally, miR-126a-3p was associated with APS and both arterial and venous thrombosis. We observed that APS shares a common miRNAs signature with non-APS related thrombosis, suggesting that miRNA expression profiles may serve as markers of thrombotic risk in APS. Further validation of a pro-thrombotic miRNA signature in APS is warranted to improve risk assessment, diagnosis, and management of APS.

Homocysteine metabolites impair the PHF8/H4K20me1/mTOR/autophagy pathway by upregulating the expression of histone demethylase PHF8-targeting microRNAs in human vascular endothelial cells and mice.

The inability to efficiently metabolize homocysteine (Hcy) due to nutritional and genetic deficiencies, leads to hyperhomocysteinemia (HHcy) and endothelial dysfunction, a hallmark of atherosclerosis which underpins cardiovascular disease (CVD). PHF8 is a histone demethylase that demethylates H4K20me1, which affects the mammalian target of rapamycin (mTOR) signaling and autophagy, processes that play important roles in CVD. PHF8 is regulated by microRNA (miR) such as miR-22-3p and miR-1229-3p. Biochemically, HHcy is characterized by elevated levels of Hcy, Hcy-thiolactone and N-Hcy-protein. Here, we examined the effects of these metabolites on miR-22-3p, miR-1229-3p, and their target PHF8, as well as on the downstream consequences of these effects on H4K20me1, mTOR-, and autophagy-related proteins and mRNAs expression in human umbilical vein endothelial cells (HUVEC). We found that treatments with N-Hcy-protein, Hcy-thiolactone, or Hcy upregulated miR-22-3p and miR-1229-3p, attenuated PHF8 expression, upregulated H4K20me1, mTOR, and phospho-mTOR. Autophagy-related proteins (BECN1, ATG5, ATG7, lipidated LC3-II, and LC3-II/LC3-I ratio) were significantly downregulated by at least one of these metabolites. We also found similar changes in the expression of miR-22-3p, Phf8, mTOR- and autophagy-related proteins/mRNAs invivo in hearts of Cbs-/- mice, which show severe HHcy and endothelial dysfunction. Treatments with inhibitors of miR-22-3p or miR-1229-3p abrogated the effects of Hcy-thiolactone, N-Hcy-protein, and Hcy on miR expression and on PHF8, H4K20me1, mTOR-, and autophagy-related proteins/mRNAs in HUVEC. Taken together, these findings show that Hcy metabolites upregulate miR-22-3p and miR-1229-3p expression, which then dysregulate the PHF8/H4K20me1/mTOR/autophagy pathway, important for vascular homeostasis.

Suppression of CNS APOE4 Expression by miRNAs Delivered by the S2 AAVrh.10 Capsid-modified AAV Vector.

The homozygous APOE4 genotype is the major risk factor for the development of early Alzheimer's disease. Genome engineering studies in mouse models of human APOE4-dependent pathology have established that reduction of APOE4 expression can rescue the phenotype. We hypothesized that APOE4 could be suppressed in the CNS of APOE4 homozygotes using adeno-associated virus (AAV) expression of microRNAs (miRNA) designed to hybridize to APOE mRNA. We screened 9 different miRNAs targeting APOE following transfection in HEK293T and Huh7 cells. Optimal APOE suppression was obtained with mir2A (targeting coding region nt330-351) and mirN4 (3' untranslated region nt1142-1162). miRNA expression cassettes were designed with two copies of each of these two miRNAs co-expressed with a mCherry transgene. To optimize delivery of these miRNAs, an engineered AAVrh.10 variant was identified from a screen of multiple peptide insertions into capsid loop IV and substitutions in loop VIII. This led to identifying the AAV.S2 capsid with enhanced transduction of both neurons and glia and enhanced distribution in the brain. The engineered capsid was used to deliver the APOE miRNA suppression cassette to the hippocampus of TRE4 mice (human APOE4 knock-in replacement of the murine apoE locus). Two weeks after intra-hippocampus administration, regional expression of miRNA at the injection site was quantified at the mRNA level relative to an endogenous reference. The AAV.S2 capsid provided 2.31 ± 0.37-fold higher expression of miRNA over that provided by AAVrh.10 (p<0.05). In the targeted region, a single intra-hippocampus AAV.S2 administration suppressed hippocampal APOE4 mRNA levels by 76.5 ± 3.9% compared to 41.3 ± 3.3% with the same cassette delivered by the wildtype AAVrh.10 capsid (p<0.0001). We conclude that an expression cassette with two different miRNAs targeting APOE4 delivered by the AAV.S2 capsid will generate highly significant suppression of APOE4 in the CNS.

Autism spectrum disorder: difficulties in diagnosis and microRNA biomarkers.

We performed a PubMed search for microRNAs in autism spectrum disorder that could serve as diagnostic biomarkers in patients and selected 17 articles published from January 2008 to December 2023, of which 4 studies were performed with whole blood, 4 with blood plasma, 5 with blood serum, 1 with serum neural cell adhesion molecule L1-captured extracellular vesicles, 1 with blood cells, and 2 with peripheral blood mononuclear cells. Most of the studies involved children and the study cohorts were largely males. Many of the studies had performed microRNA sequencing or quantitative polymerase chain reaction assays to measure microRNA expression. Only five studies had used real-time polymerase chain reaction assay to validate microRNA expression in autism spectrum disorder subjects compared to controls. The microRNAs that were validated in these studies may be considered as potential candidate biomarkers for autism spectrum disorder and include miR-500a-5p, -197-5p, -424-5p, -664a-3p, -365a-3p, -619-5p, -664a- 3p, -3135a, -328-3p, and -500a-5p in blood plasma and miR-151a-3p, -181b-5p, -320a, -328, -433, -489, -572, -663a, -101-3p, -106b-5p, -19b-3p, -195-5p, and -130a-3p in blood serum of children, and miR-15b-5p and -6126 in whole blood of adults. Several important limitations were identified in the studies reviewed, and need to be taken into account in future studies. Further studies are warranted with children and adults having different levels of autism spectrum disorder severity and consideration should be given to using animal models of autism spectrum disorder to investigate the effects of suppressing or overexpressing specific microRNAs as a novel therapy.

Multifaceted role of microRNA-301a in human cancer: from biomarker potential to therapeutic targeting.

With the growing data on microRNA (miRNA) expression in tissues and circulation, there is increasing evidence for the potential of microRNAs to serve as biomarkers in cancer diagnosis and prognosis, as well as novel therapeutic targets. The expression level of miRNA-301a (miR-301a) is altered in a wide range of human tumor types, and numerous studies have revealed the roles of miR-301a in tumorigenesis and tumor progression. Herein, we comprehensively summarize, compare, and contrast the research advancements on the role of miR-301a in different cancers. Differential expression patterns of miR-301a in tissues and biofluids are implicated in cancer diagnosis, treatment response, and prognosis. MiR-301a modulates the expression of multiple genes, other noncoding RNAs, and signaling cascade via direct or indirect regulation in human cancer proliferation, migration, invasion, angiogenesis, and radio- or chemotherapy resistance. Cancer cell-associated miR-301a affects the tumor microenvironment through the alteration of immune function and cancer metabolism. These findings highlight the functional roles, clinical implications, and therapeutic relevance of miR-301a in various human cancers.

The miR-338-3p expression level in pemphigus diagnosis

BACKGROUND: Pemphigus is a group of potentially fatal chronic cutaneous diseases in which blisters appear on the skin and mucous membranes as a result of IgG autoantibodies binding to desmosomes in the epidermis, leading to keratinocytes acantholysis. Currently, methods to monitor disease activity and therapy efficiency using various biomarkers are being investigated. MicroRNA expression, in particular miR-338-3p, has been one of these biomarkers, as changes in miR-338-3p expression may trigger the Th1/Th2 cell imbalance and possibly be involved in the pathogenesis of the disease. AIM: This study aimed to design a protocol to evaluate the level of miR-338-3p expression in peripheral blood mononuclear cells and verify the diagnostic value of miR-338-3p expression in pemphigus. MATERIALS AND METHODS: Experimental prospective comparative study was conducted from February 2023 to February 2024 at the Dermatology Department of Sechenov University. The study included 10 patients with pemphigus in the active stage of the disease, 3 patients in remission, and 9 participants of the control group. The expression of miRNA-338-3p was analyzed by real-time polymerase chain reaction, cDNA was obtained using StemLoop method. The evaluation of miRNA-338-3p expression level was based on its comparison with the expression of U6 gene using 2-ΔΔСt method. RESULTS: The expression level of miR-338-3p was analyzed in 10 patients in the active stage of the disease (5 men, 50%; 5 women, 50%; mean age 46±10.7 years), 3 patients in remission (2 women, 66.7%; 1 man, 33.3%; mean age 57±8 years), 9 control group (8 women, 88.9%; 1 man, 11.1%; mean age 36±16.8 years). The mean expression level of miR-338-3p was 8.64 (SD±5.72) in patients with active disease, 3.38 (SD±1.44) in patients in remission, and 1.48 (SD±1.12) in controls. A statistically significant increase in the expression level of miR-338-3p was found in patients in the active disease stage compared to the control group (p=0.002). A statistically significant correlation was found between the level of miR-338-3p expression and the PDAI index score (p 0.001). CONCLUSION: Based on the data obtained in this study, it can be assumed that microRNAs are important in pemphigus, and miR-338-3p expression in particular may serve as a key element in pemphigus pathogenesis. More detailed study of microRNAs and analysis of expression variability according to clinical data may provide the basis for developing new diagnostic methods and severity scoring, allowing more accurate and less invasive diagnostic methods, as well as monitoring and predicting disease progression.

Fabry nephropathy. Urinary expression of podocyte proteins mRNA and microRNAs in non-albuminuric patients

Fabry nephropathy. Urinary expression of podocyte proteins mRNA and microRNAs in non-albuminuric patients

An in vitro assessment of ionizing radiation impact on the efficacy of radiotherapy for breast cancer

Abstract Objectives Ionizing radiation is still one of the most effective treatment options for various cancers. It is possible to reduce the side effects of this effective treatment method and increase the chance of success by elucidating the responses it creates at the molecular level in the cell. This study aims to investigate of the molecular effects of therapeutic ionizing radiation on breast cancer, which is the most prevalent cancer type. Methods MDA-MB-231 and MCF7 cell lines were irradiated with 4 and 8 Gy ionizing radiation and monitored for up to 7 days. RNA was collected at 48 and 96 h, when cellular molecular mechanisms became most evident, and quantitative expression levels of microRNAs (miR-208a, miR-124, miR-145), for which cancer-radiation associations have been determined from existing literature and databases, were evaluated. Results Exposure to ionizing radiation resulted in a dose-dependent reduction in cell viability in both MCF7 and MDA-MB-231 breast cancer cell lines. Furthermore, microRNA expression analysis revealed notable changes at all levels. The research demonstrates that miR-208a, miR-145, and miR-124 are crucial in the biological response to ionizing radiation. Conclusions Therapeutic ionizing radiation profoundly affects cell viability and microRNA expression in breast cancer cell lines, showing dose and time-dependent effects. The observed microRNA expression patterns suggest potential biomarkers for radiation response and therapeutic targets to improve radiotherapy efficacy. Further in vivo validation and exploration of these microRNAs’ roles in modulating cellular response to ionizing radiation are needed.

TET proteins regulate Drosha expression and impact microRNAs in iNKT cells.

DNA demethylases TET2 and TET3 play a fundamental role in thymic invariant natural killer T (iNKT) cell differentiation by mediating DNA demethylation of genes encoding for lineage specifying factors. Paradoxically, differential gene expression analysis revealed that significant number of genes were upregulated upon TET2 and TET3 loss in iNKT cells. This unexpected finding could be potentially explained if loss of TET proteins was reducing the expression of proteins that suppress gene expression. In this study, we discover that TET2 and TET3 synergistically regulate Drosha expression, by generating 5hmC across the gene body and by impacting chromatin accessibility. As DROSHA is involved in microRNA biogenesis, we proceed to investigate the impact of TET2/3 loss on microRNAs in iNKT cells. We report that among the downregulated microRNAs are members of the Let-7 family that downregulate in vivo the expression of the iNKT cell lineage specifying factor PLZF. Our data link TET proteins with microRNA expression and reveal an additional layer of TET mediated regulation of gene expression.

Circulating microRNAs in Carotid Atherosclerosis: Complex Interplay and Possible Associations with Atherothrombotic Stroke.

Atherosclerosis is a chronic inflammatory disorder which remains the main cause of cardiovascular morbidity and mortality, with carotid atherosclerosis (CA) being a major cause of ischemic stroke. Epigenetic regulation plays a significant role in CA progression and stroke, yet the impact of circulating microRNA expression, associated with atherogenesis, has not been clearly defined. We included 81 patients with moderate-severe CA (mean age 67 ± 7 years, 53% male), 42% of whom had prior ipsilateral ischemic stroke (i.e., were symptomatic). A total of 24 miRs were identified and their plasma expression levels were measured. We observed that several microRNAs were up-regulated in stroke survivors, namely miR-200c-3p (30.6 vs. 29.7, p = 0.047), miR-106b-3p (31.01 vs. 30.25, p = 0.004), and miR-494-5p (39 vs. 33, p < 0.001), while others (miR183-3p [25.5 vs. 28.6, p < 0.001], miR-126-5p [35.6 vs. 37.1, p = 0.03], and miR-216-3p [12.34 vs. 16.2, p < 0.001]) had lower plasma levels in symptomatic patients. In a multivariable logistic regression model for symptomatic CA, the only miRs showing statistical significance were miR-106b-5p, miR-183-3p, miR-216-3p, and miR-494-5p. Cluster analysis demonstrated differential miR expression in CA patients depending on their stroke status. Epigenetic modulation, represented as complex interplay between circulating miRs of different atherogenic potential, may play a significant role in CA development and progression. In our study, we show possible candidates for future research regarding CA and stroke.

Genotype Characterization and MiRNA Expression Profiling in Usher Syndrome Cell Lines.

Usher syndrome (USH) is an inherited disorder characterized by sensorineural hearing loss (SNHL), retinitis pigmentosa (RP)-related vision loss, and vestibular dysfunction. USH presents itself as three distinct clinical types, 1, 2, and 3, with no biomarker for early detection. This study aimed to explore whether microRNA (miRNA) expression in USH cell lines is dysregulated compared to the miRNA expression pattern in a cell line derived from a healthy human subject. Lymphocytes from USH patients and healthy individuals were isolated and transformed into stable cell lines using Epstein-Barr virus (EBV). DNA from these cell lines was sequenced using a targeted panel to identify gene variants associated with USH types 1, 2, and 3. Microarray analysis was performed on RNA from both USH and control cell lines using NanoString miRNA microarray technology. Dysregulated miRNAs identified by the microarray were validated using droplet digital PCR technology. DNA sequencing revealed that two USH patients had USH type 1 with gene variants in USH1B (MYO7A) and USH1D (CDH23), while the other two patients were classified as USH type 2 (USH2A) and USH type 3 (CLRN-1), respectively. The NanoString miRNA microarray detected 92 differentially expressed miRNAs in USH cell lines compared to controls. Significantly altered miRNAs exhibited at least a twofold increase or decrease with a p value below 0.05. Among these miRNAs, 20 were specific to USH1, 14 to USH2, and 5 to USH3. Three miRNAs that are known as miRNA-183 family which are crucial for inner ear and retina development, have been significantly downregulated as compared to control cells. Subsequently, droplet digital PCR assays confirmed the dysregulation of the 12 most prominent miRNAs in USH cell lines. This study identifies several miRNA signatures in USH cell lines which may have potential utility in Usher syndrome identification.

Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H2S.

The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans increases, cell senescence in renal aging is a growing challenge. Identifying age-related kidney disorders and their cause is one of the contemporary public health challenges. While the structural abnormalities to the extracellular matrix (ECM) occur, in part, due to changes in MMPs, EMMPRIN, and Meprin-A, a variety of epigenetic modifiers, such as DNA methylation, histone alterations, changes in small non-coding RNA, and microRNA (miRNA) expressions are proven to play pivotal roles in renal pathology. An aged kidney is vulnerable to acute injury due to ischemia-reperfusion, toxic medications, altered matrix proteins, systemic hemodynamics, etc., non-coding RNA and miRNAs play an important role in renal homeostasis, and alterations of their expressions can be considered as a good marker for AKI. Other epigenetic changes, such as histone modifications and DNA methylation, are also evident in AKI pathophysiology. The endogenous production of gaseous molecule hydrogen sulfide (H2S) was documented in the early 1980s, but its ameliorative effects, especially on kidney injury, still need further research to understand its molecular mode of action in detail. H2S donors heal fibrotic kidney tissues, attenuate oxidative stress, apoptosis, inflammation, and GFR, and also modulate the renin-angiotensin-aldosterone system (RAAS). In this review, we discuss the complex pathophysiological interplay in AKI and its available treatments along with future perspectives. The basic role of H2S in the kidney has been summarized, and recent references and knowledge gaps are also addressed. Finally, the healing effects of H2S in AKI are described with special emphasis on epigenetic regulation and matrix remodeling.

Association of MicroRNA Expression and Serum Neurofilament Light Chain Levels with Clinical and Radiological Findings in Multiple Sclerosis.

microRNAs (miRNAs) are promising biomarkers for many diseases, including multiple sclerosis (MS). The neurofilament light chain (NfL) is a biomarker that can detect axonal damage in different neurological diseases. The objective of this study was to evaluate the association of the expression profile of pre-selected miRNAs and NfL levels with clinical and radiological variables in MS patients. We conducted a 1-year longitudinal prospective study in MS patients with different clinical forms. We measured clinical disability using the expanded disability status scale (EDSS), the magnetic resonance imaging (MRI) volumetry baseline, and cognitive functioning using the processing speed test (PST) at baseline and 1 year later. Selected serum miRNAs and serum NfL (sNfL) levels were quantified. Seventy-three patients were recruited. MiR-126.3p correlated with EDSS and cognitive status at baseline and miR-126.3p and miR-9p correlated with cognitive deterioration at 1 year. Correlations with regional brain volumes were observed between miR-126.3p and the cortical gray matter, cerebellum, putamen, and pallidum; miR-146a.5p with the cerebellum and pallidum; miR-29b.3p with white matter and the pallidum; miR-138.5p with the pallidum; and miR-9.5p with the thalamus. sNfL was correlated with miR-9.5p. miR-146a.5p was also associated with the MS phenotype. These data justify future studies to further explore the utility of miRNAs (mirR-126.3p, miR-146.5p, and miR.9-5p) and sNfL levels as biomarkers of MS.

Genetic regulation of microRNAs in the older adult brain and their contribution to neuropsychiatric conditions.

MicroRNAs are essential post-transcriptional regulators of gene expression and involved in many biological processes; however, our understanding of their genetic regulation and role in brain illnesses is limited. Here, we mapped brain microRNA expression quantitative trait loci (miR-QTLs) using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex (dlPFC) samples of 604 older adult donors of European ancestry. miR-QTLs were identified for 224 miRNAs (48% of 470 tested miRNAs) at false discovery rate < 1%. We found that miR-QTLs were enriched in brain promoters and enhancers, and that intragenic miRNAs often did not share QTLs with their host gene. Additionally, we integrated the brain miR-QTLs with results from 16 GWAS of psychiatric and neurodegenerative diseases using multiple independent integration approaches and identified four miRNAs that contribute to the pathogenesis of bipolar disorder, major depression, post-traumatic stress disorder, schizophrenia, and Parkinson's disease. This study provides novel insights into the contribution of miRNAs to the complex biological networks that link genetic variation to disease.

A DNA machine-based magnetic resonance imaging nanoprobe for in vivo microRNA detection

In situ monitoring microRNA (miRNA) expression in vivo holds immense potential for directly visualizing the occurrence and progression of tumors. However, the significant barrier to developing a probe that can overcome the low abundance of miRNAs while providing an output signal with unlimited tissue penetration depth remains formidable. In this study, we developed a DNA machine-based magnetic resonance imaging nanoprobe (MRINP) for amplified detection of miR-21 in vivo. The MRINP was constructed with superparamagnetic Fe3O4 nanoparticles (NPs), paramagnetic Gd-DOTA complexes, and miR-21-activated DNA machines; the DNA machine was composed of hairpin DNAzyme (HD) strands serving as the DNAzyme walker and hairpin substrate (HS) strands serving as the track. Once uptake into tumor cells, the intracellular miR-21 specifically recognized and hybridized with the HD strand, restoring the activity of DNAzyme. Subsequently, the DNAzyme walker autonomously traveled on the surface of MRINP, and each step movement of the DNAzyme walker resulted in the cleavage of its substrate strands and the ensued release of the Gd-DOTA complex-labeled oligonucleotides, turning on the T1 signal of Gd-DOTA complexes for in situ imaging of miR-21 in tumor-bearing mice. This strategy would offer a promising approach for mapping tumor-specific biomarkers in vivo with unlimited penetration depth.

Comprehensive microRNA analyses using vitreous humor of ocular sarcoidosis.

MicroRNAs (miRNAs) are non-coding RNAs which have attracted attention as biomarkers in a variety of diseases. However, extensive unbiased analysis of miRNA in vitreous humor of sarcoidosis patients has not been reported. In the present study, we comprehensively analyzed the dysregulated miRNAs in ocular sarcoidosis to search for potential biomarkers. This study included seven patients diagnosed with ocular sarcoidosis (five definite and two presumed). Five patients with unclassified uveitis and 24 with non-inflammatory diseases served as controls. MicroRNA expression levels in vitreous humor samples were measured by microarray, and differentially expressed miRNAs between sarcoidosis and other diseases were explored. Next, pathway enrichment analysis was performed to evaluate the functions of the dysregulated miRNAs, and machine learning was used to search for candidate biomarkers. A total of 614 upregulated miRNAs and 8 downregulated miRNAs were detected in vitreous humor of patients with ocular sarcoidosis compared with patients with unclassified uveitis and non-inflammatory diseases. Some dysregulated miRNAs were involved in the TGF-β signaling pathway. Furthermore, we identified miR-764 as the best predictor for ocular sarcoidosis using Boruta selection. In this study, comprehensive miRNA analysis of vitreous humor samples identified dysregulated miRNAs in ocular sarcoidosis. This study suggests new insights into molecular pathogenetic mechanisms of sarcoidosis and may provide useful information toward developing novel diagnostic biomarkers and therapeutic targets for sarcoidosis.