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Georgian Medical News Dec 2023Physical activity stimulates numerous structural, metabolic, and morphological adaptations. These adaptations are vital for maintaining human health throughout life.... (Review)
Review
Physical activity stimulates numerous structural, metabolic, and morphological adaptations. These adaptations are vital for maintaining human health throughout life. Developments in molecular biology, biochemistry, and bioinformatics, along with exercise physiology have identified many signaling pathways, and transcriptional and translational processes responsible for exercise-related adaptations. The molecular mechanisms underlying the beneficial effects of exercise are not fully understood. Recently, the focus has been on microRNAs (miRNAs). They are small noncoding RNA molecules that negatively modulate gene expression and are involved in fundamental biological processes. This review describes miRNAs whose activities change in the heart, skeletal muscle, and circulation due to exercise. In addition, miRNAs with altered activity may be parameters adaptation to exercise, preventing injuries, and monitoring health status.
Topics: Humans; MicroRNAs; Gene Expression Regulation; Adaptation, Physiological; Exercise; Muscle, Skeletal
PubMed: 38325314
DOI: No ID Found -
Nature Communications Aug 2023Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles...
Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.
Topics: Animals; Mice; Adipose Tissue, White; Cachexia; Hypoxia; Leptin; MicroRNAs; Neoplasms
PubMed: 37620316
DOI: 10.1038/s41467-023-40571-9 -
JAMA Oncology Sep 2023Personalized treatment approaches for patients with oligometastatic colorectal liver metastases are critically needed. We previously defined 3 biologically distinct... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Personalized treatment approaches for patients with oligometastatic colorectal liver metastases are critically needed. We previously defined 3 biologically distinct molecular subtypes of colorectal liver metastases: (1) canonical, (2) immune, and (3) stromal.
OBJECTIVE
To independently validate these molecular subtypes in the phase 3 New EPOC randomized clinical trial.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective secondary analysis of the phase 3 New EPOC randomized clinical trial included a bi-institutional discovery cohort and multi-institutional validation cohort. The discovery cohort comprised patients who underwent hepatic resection for limited colorectal liver metastases (98% received perioperative chemotherapy) from May 31, 1994, to August 14, 2012. The validation cohort comprised patients who underwent hepatic resection for liver metastases with perioperative chemotherapy (fluorouracil, oxaliplatin, and irinotecan based) with or without cetuximab from February 26, 2007, to November 1, 2012. Data were analyzed from January 18 to December 10, 2021.
INTERVENTIONS
Resected metastases underwent RNA sequencing and microRNA (miRNA) profiling in the discovery cohort and messenger RNA and miRNA profiling with microarray in the validation cohort.
MAIN OUTCOMES AND MEASURES
A 31-feature (24 messenger RNAs and 7 miRNAs) neural network classifier was trained to predict molecular subtypes in the discovery cohort and applied to the validation cohort. Integrated clinical-molecular risk groups were designated based on molecular subtypes and the clinical risk score. The unique biological phenotype of each molecular subtype was validated using gene set enrichment analyses and immune deconvolution. The primary clinical end points were progression-free survival (PFS) and overall survival (OS).
RESULTS
A total of 240 patients were included (mean [range] age, 63.0 [56.3-68.0] years; 151 [63%] male), with 93 in the discovery cohort and 147 in the validation cohort. In the validation cohort, 73 (50%), 28 (19%), and 46 (31%) patients were classified as having canonical, immune, and stromal metastases, respectively. The biological phenotype of each subtype was concordant with the discovery cohort. The immune subtype (best prognosis) demonstrated 5-year PFS of 43% (95% CI, 25%-60%; hazard ratio [HR], 0.37; 95% CI, 0.20-0.68) and OS of 63% (95% CI, 40%-79%; HR, 0.38; 95% CI, 0.17-0.86), which was statistically significantly higher than the canonical subtype (worst prognosis) at 14% (95% CI, 7%-23%) and 43% (95% CI, 32%-55%), respectively. Adding molecular subtypes to the clinical risk score improved prediction (the Gönen and Heller K for discrimination) from 0.55 (95% CI, 0.49-0.61) to 0.62 (95% CI, 0.57-0.67) for PFS and 0.59 (95% CI, 0.52-0.66) to 0.63 (95% CI, 0.56-0.70) for OS. The low-risk integrated group demonstrated 5-year PFS of 44% (95% CI, 20%-66%; HR, 0.38; 95% CI, 0.19-0.76) and OS of 78% (95% CI, 44%-93%; HR, 0.26; 95% CI, 0.08-0.84), superior to the high-risk group at 16% (95% CI, 10%-24%) and 43% (95% CI, 32%-52%), respectively.
CONCLUSIONS AND RELEVANCE
In this prognostic study, biologically derived colorectal liver metastasis molecular subtypes and integrated clinical-molecular risk groups were highly prognostic. This novel molecular classification warrants further study as a possible predictive biomarker for personalized systemic treatment for colorectal liver metastases.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN22944367.
Topics: Humans; Male; Middle Aged; Female; Colorectal Neoplasms; Retrospective Studies; Oxaliplatin; Fluorouracil; Liver Neoplasms; MicroRNAs; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37471075
DOI: 10.1001/jamaoncol.2023.2535 -
Circulation Research Sep 2023Experiments in mammalian models of cardiac injury suggest that the cardiomyocyte-specific overexpression of CCND2 (cyclin D2, in humans) improves recovery from...
BACKGROUND
Experiments in mammalian models of cardiac injury suggest that the cardiomyocyte-specific overexpression of CCND2 (cyclin D2, in humans) improves recovery from myocardial infarction (MI). The primary objective of this investigation was to demonstrate that our specific modified mRNA translation system (SMRTs) can induce CCND2 expression in cardiomyocytes and replicate the benefits observed in other studies of cardiomyocyte-specific CCND2 overexpression for myocardial repair.
METHODS
The CCND2-cardiomyocyte-specific modified mRNA translation system (cardiomyocyte SMRTs) consists of 2 modRNA constructs: one codes for CCND2 and contains a binding site for L7Ae, and the other codes for L7Ae and contains recognition elements for the cardiomyocyte-specific microRNAs miR-1 and miR-208. Thus, L7Ae suppresses CCND2 translation in noncardiomyocytes but is itself suppressed by endogenous miR-1 and -208 in cardiomyocytes, thereby facilitating cardiomyocyte-specific CCND2 expression. Experiments were conducted in both mouse and pig models of MI, and control assessments were performed in animals treated with an SMRTs coding for the cardiomyocyte-specific expression of luciferase or green fluorescent protein (GFP), in animals treated with L7Ae modRNA alone or with the delivery vehicle, and in Sham-operated animals.
RESULTS
CCND2 was abundantly expressed in cultured, postmitotic cardiomyocytes 2 days after transfection with the CCND2-cardiomyocyte SMRTs, and the increase was accompanied by the upregulation of markers for cell-cycle activation and proliferation (eg, Ki67 and Aurora B kinase). When the GFP-cardiomyocyte SMRTs were intramyocardially injected into infarcted mouse hearts, the GFP signal was observed in cardiomyocytes but no other cell type. In both MI models, cardiomyocyte proliferation (on day 7 and day 3 after treatment administration in mice and pigs, respectively) was significantly greater, left-ventricular ejection fractions (days 7 and 28 in mice, days 10 and 28 in pigs) were significantly higher, and infarcts (day 28 in both species) were significantly smaller in animals treated with the CCND2-cardiomyocyte SMRTs than in any other group that underwent MI induction.
CONCLUSIONS
Intramyocardial injections of the CCND2-cardiomyocyte SMRTs promoted cardiomyocyte proliferation, reduced infarct size, and improved cardiac performance in small and large mammalian hearts with MI.
Topics: Animals; Mice; Cell Cycle; Cyclin D2; Disease Models, Animal; MicroRNAs; Myocardial Infarction; Myocytes, Cardiac; RNA, Messenger; Swine
PubMed: 37565345
DOI: 10.1161/CIRCRESAHA.123.322929 -
Annual Review of Physiology Feb 2024Exosomes are small extracellular vesicles that carry lipids, proteins, and microRNAs (miRNAs). They are released by all cell types and can be found not only in... (Review)
Review
Exosomes are small extracellular vesicles that carry lipids, proteins, and microRNAs (miRNAs). They are released by all cell types and can be found not only in circulation but in many biological fluids. Exosomes are essential for interorgan communication because they can transfer their contents from donor to recipient cells, modulating cellular functions. The miRNA content of exosomes is responsible for most of their biological effects, and changes in exosomal miRNA levels can contribute to the progression or regression of metabolic diseases. As exosomal miRNAs are selectively sorted and packaged into exosomes, they can be useful as biomarkers for diagnosing diseases. The field of exosomes and metabolism is expanding rapidly, and researchers are consistently making new discoveries in this area. As a result, exosomes have great potential for a next-generation drug delivery platform for metabolic diseases.
Topics: Humans; Exosomes; MicroRNAs; Biomarkers; Metabolic Diseases
PubMed: 38345906
DOI: 10.1146/annurev-physiol-042222-024535 -
Biochimica Et Biophysica Acta. Reviews... Jul 2023As ubiquitously expressed transcripts in eukaryotes, circular RNAs (circRNAs) are covalently closed and lack a 5'-cap and 3'-polyadenylation (poly (A)) tail. Initially,... (Review)
Review
As ubiquitously expressed transcripts in eukaryotes, circular RNAs (circRNAs) are covalently closed and lack a 5'-cap and 3'-polyadenylation (poly (A)) tail. Initially, circRNAs were considered non-coding RNA (ncRNA), and their roles as sponging molecules to adsorb microRNAs have been extensively reported. However, in recent years, accumulating evidence has demonstrated that circRNAs could encode functional polypeptides through the initiation of translation mediated by internal ribosomal entry sites (IRESs) or N-methyladenosine (mA). In this review, we collectively discuss the biogenesis, cognate mRNA products, regulatory mechanisms, aberrant expression and biological phenotypes or clinical relevance of all currently reported, cancer-relevant protein-coding circRNAs. Overall, we provide a comprehensive overview of circRNA-encoded proteins and their physiological and pathological functions.
Topics: Humans; RNA, Circular; MicroRNAs; RNA, Messenger; Carcinogenesis; Cell Transformation, Neoplastic
PubMed: 37172651
DOI: 10.1016/j.bbcan.2023.188909 -
Plant Physiology and Biochemistry : PPB Aug 2023Climate change significantly impacts crop production by inducing several abiotic and biotic stresses. The increasing world population, and their food and industrial... (Review)
Review
Climate change significantly impacts crop production by inducing several abiotic and biotic stresses. The increasing world population, and their food and industrial demands require focused efforts to improve crop plants to ensure sustainable food production. Among various modern biotechnological tools, microRNAs (miRNAs) are one of the fascinating tools available for crop improvement. miRNAs belong to a class of small non-coding RNAs playing crucial roles in numerous biological processes. miRNAs regulate gene expression by post-transcriptional target mRNA degradation or by translation repression. Plant miRNAs have essential roles in plant development and various biotic and abiotic stress tolerance. In this review, we provide propelling evidence from previous studies conducted around miRNAs and provide a one-stop review of progress made for breeding stress-smart future crop plants. Specifically, we provide a summary of reported miRNAs and their target genes for improvement of plant growth and development, and abiotic and biotic stress tolerance. We also highlight miRNA-mediated engineering for crop improvement and sequence-based technologies available for the identification of miRNAs associated with stress tolerance and plant developmental events.
Topics: MicroRNAs; Plant Breeding; Plants; Biotechnology; Stress, Physiological; Gene Expression Regulation, Plant
PubMed: 37437345
DOI: 10.1016/j.plaphy.2023.107857 -
Biomaterials Nov 2023Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer. Current pharmacological interventions marginally increase the 12-month overall survival...
Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer. Current pharmacological interventions marginally increase the 12-month overall survival of patients with GBM. Among the novel therapeutic strategies being pursued, micro-RNAs, a class of non-coding RNAs, are receiving considerable attention for their regulation of several pathways implicated in tumorigenesis and survival. Notably, microRNA-181a-5p (miR-181a) has consistently been reported to be downregulated in GBM clinical samples, and its overexpression negatively affects tumor growth both in vitro and in vivo. To improve the delivery of miR-181a to GBM cells, we sought to develop a modified lipid-based nanocarrier capable of encapsulating and delivering miR-181a to GBM cells in vitro and in vivo. Optimized ionizable-lipid containing lipid nanoparticles (LNP) were constructed by covering the miR-181a-loaded LNP with alternating layers of miR-181a, poly-l-arginine and hyaluronic acid through the layer-by-layer technique. The resulting hyaluronan-decorated lipid nanoparticles (HA-LNP) targeted GBM cells more efficiently than non-modified LNP and mediated siRNA and miRNA transfection in vitro. Finally, delivery of miR-181a by HA-LNP induced significant cellular death of U87 GBM cells in vitro and delayed tumor growth in an in vivo subcutaneous tumor model.
Topics: Humans; Glioblastoma; Hyaluronic Acid; Cell Line, Tumor; MicroRNAs; Lipids; Cell Proliferation
PubMed: 37778056
DOI: 10.1016/j.biomaterials.2023.122341 -
International Journal of Biological... Dec 2023Neuropathic pain (NP) is a kind of chronic pain caused by direct injury to the peripheral or central nervous system (CNS). microRNAs (miRNAs) are small noncoding RNAs... (Review)
Review
Neuropathic pain (NP) is a kind of chronic pain caused by direct injury to the peripheral or central nervous system (CNS). microRNAs (miRNAs) are small noncoding RNAs that mostly interact with the 3 untranslated region of messenger RNAs (mRNAs) to regulate the expression of multiple genes. NP is characterized by changes in the expression of receptors and mediators, and there is evidence that miRNAs may contribute to some of these alterations. In this review, we aimed to fully comprehend the connection between NP and miRNA; and also, to establish a link between neurology, biology, and dentistry. Studies have shown that targeting miRNAs may be an effective therapeutic strategy for the treatment of chronic pain and potential target for the prevention of NP.
Topics: Humans; MicroRNAs; Chronic Pain; Neuralgia
PubMed: 37730007
DOI: 10.1016/j.ijbiomac.2023.126893 -
DNA and Cell Biology Mar 2024Around 50% of all occurrences of infertility are attributable to the male factor, which is a significant global public health concern. There are numerous circumstances... (Review)
Review
Around 50% of all occurrences of infertility are attributable to the male factor, which is a significant global public health concern. There are numerous circumstances that might interfere with spermatogenesis and cause the body to produce abnormal sperm. While evaluating sperm, the count, the speed at which they migrate, and their appearance are the three primary characteristics that are analyzed. MicroRNAs, also known as miRNAs, are present in all physiological fluids and tissues. They participate in both physiological and pathological processes. Researches have demonstrated that the expression of microRNA genes differs in infertile men. These genes regulate spermatogenesis at various stages and in several male reproductive cells. Hence, microRNAs have the potential to act as useful indicators in the diagnosis and treatment of male infertility and other diseases affecting male reproduction. Despite this, additional research is necessary to determine the precise miRNA regulation mechanisms.
Topics: Humans; Male; MicroRNAs; Semen; Infertility, Male; Spermatozoa; Spermatogenesis; Fertility
PubMed: 38394131
DOI: 10.1089/dna.2023.0314