• Aortic stenosis
• Fibrosis
• Inflammation
• Pressure overload
• miR-210

• Angiogenesis
• Cardiovascular disease
• Circular RNA
• Exosome
• Long non-coding RNA
• MicroRNA
• Non-coding RNAs

• Humans
• Cardiovascular Diseases/genetics
• Cardiovascular Diseases/metabolism
• Cardiovascular Diseases/pathology
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• RNA, Untranslated/genetics
• RNA, Untranslated/metabolism
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/metabolism
• Animals
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Circular/genetics
• RNA, Circular/metabolism
• Neovascularization, Physiologic/genetics
• Angiogenesis

• Cell survival
• Cell therapy
• Pre-treatment
• Preconditioning
• Stem cells
• Super stem cells

• COPD
• MiR-210
• apoptosis
• cigarette smoke extract

• Advanced glycation end products (AGEs)
• Diallyl trisulfide (DATS)
• Forkhead box O3a (FoxO3a)
• c-Jun N-terminal kinase (JNK)
• microRNA-210

• Humans
• Up-Regulation
• Diabetic Cardiomyopathies/prevention & control
• Glycation End Products, Advanced
• Maillard Reaction
• Sulfides/pharmacology
• Apoptosis
• Cell Line, Tumor
• Mitogen-Activated Protein Kinase Kinases
• MicroRNAs/genetics
• Allyl Compounds

• Cell culture
• Epigenetics
• Gamete
• Infection
• Marker
• Protocol
• Reproduction

• Humans
• Animals
• Female
• Male
• Ovary/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Zebrafish/genetics
• Oocytes/metabolism
• Meiosis

• National Key Research and Development Project
• National Natural Science Foundation of China
• Grant from Science and Technology Commission of Shanghai Municipality
• the “Dawn” Program of Shanghai Education Commission

• Cell survival
• Cell therapy
• Ferroptosis
• Hydrogen sulfide
• Preconditioning
• Stem cells
• Umbilical cord

• biomarkers
• cardiovascular diseases
• diagnosis
• extracellular vesicles
• intercellular communication
• prognosis

• Humans
• Cardiovascular Diseases/metabolism
• Extracellular Vesicles/metabolism
• Signal Transduction
• Cell Communication/physiology
• Heart Diseases/metabolism

• (PID2022-138163OB-C32) Ministry of Education and Science of the Spanish Government
• CTS-466 Junta de Andalucía Regional Council.

• cardiac regeneration
• exosomes
• mesenchymal stem cells
• microRNA
• myocardial infarction

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Myocardial Infarction/metabolism
• Mesenchymal Stem Cell Transplantation
• Heart
• Mesenchymal Stem Cells/metabolism

• R01 HL168282 NHLBI NIH HHS
• T35 HL110854 NHLBI NIH HHS
• R01 HL155957 NIH HHS
• R01 HL168282 NIH HHS
• R01 HL155957 NHLBI NIH HHS

• Angiogenesis
• Bone repair
• Dual delivery
• Gene therapy
• Nano-hydroxyapatite
• Non-viral vector
• Scaffold
• miR-16
• miR-210
• microRNA

• Humans
• Rats
• Animals
• Osteogenesis/genetics
• Tissue Scaffolds
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Bone and Bones/metabolism
• Tissue Engineering
• Collagen
• Bone Regeneration
• Cell Differentiation

• angiogenesis
• endothelial
• endothelial progenitor cells
• miRNA
• small extracellular vesicles
• stem cells

• And reoxygenation (H/R) injury
• Endothelial progenitor cells (EPCs)
• Exosomes
• Hypoxia
• Neurons
• Oxidative stress
• miR-210

• Humans
• Culture Media, Serum-Free/metabolism
• Endothelial Progenitor Cells/metabolism
• Exosomes/metabolism
• Hypoxia/metabolism
• Ischemic Stroke
• MicroRNAs/metabolism
• Neurons/metabolism
• Reactive Oxygen Species/metabolism

• U54 GM104942 NIGMS NIH HHS

Tumour hypoxia is a known and extensively researched phenomenon that occurs in both solid and haematological malignancies. As cancer cells proliferate, demand for oxygen can outstrip supply reducing tumour oxygenation. In solid tumours this is contributed to by disorganized blood vessel development. Tumour hypoxia is associated with resistance to treatment, more aggressive disease behaviour and an increased likelihood of metastatic progression. It can be measured using both invasive and non-invasive methods to varying degrees of accuracy. The presence of hypoxia stimulates a complex cellular network of downstream factors including Hypoxia Inducible Factor 1 (HIF1), C-X-C motif chemokine 4 (CXCR4) and Hypoxia‐inducible glycolytic enzyme hexokinase‐2 (HK2) amongst many others. They work by affecting different mechanisms including influencing angiogenesis, treatment resistance, immune surveillance and the ability to metastasize all of which contribute to a more aggressive disease pattern. Tumour hypoxia has been correlated with poorer outcomes and worse prognosis in patients. The correlation between hypoxic microenvironments and poor prognosis has led to an interest in trying to therapeutically target this phenomenon. Various methods have been used to target hypoxic microenvironments. Hypoxia-activated prodrugs (HAPs) are drugs that are only activated within hypoxic environments and these agents have been subject to investigation in several clinical trials. Drugs that target downstream factors of hypoxic environments including HIF inhibitors, mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (anti-VEGF) therapies are also in development and being used in combination in clinical trials. Despite promising pre-clinical data, clinical trials of hypoxia targeting strategies have proven challenging. Further understanding of the effect of hypoxia and related molecular mechanisms in human rather than animal models is required to guide novel therapeutic strategies and future trial design. This review will discuss the currently available methods of hypoxia targeting and assessments that may be considered in planning future clinical trials. It will also outline key trials to date in both the solid and haemato-oncology treatment spheres and discuss the limitations that may have impacted on clinical success to date.

• Cancer
• Haematological
• Hypoxia
• Solid tumours

Apoptotic cell death is a deleterious consequence of hypoxia-induced cellular stress. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxia stress. We have recently demonstrated that miR-210 attenuates hypoxia-induced apoptotic cell death. In this paper, we unveil that the miR-210-induced inhibition of the serine/threonine kinase Glycogen Synthase Kinase 3 beta (GSK3β) in AC-16 cardiomyocytes subjected to hypoxia stress underlies the salutary protective response of miR-210 in mitigating the hypoxia-induced apoptotic cell death. Using transient overexpression vectors to augment miR-210 expression concomitant with the ectopic expression of the constitutive active GSK3β S9A mutant (ca-GSK3β S9A), we exhaustively performed biochemical and molecular assays to determine the status of the hypoxia-induced intrinsic apoptosis cascade. Caspase-3 activity analysis coupled with DNA fragmentation assays cogently demonstrate that the inhibition of GSK3β kinase activity underlies the miR-210-induced attenuation in the hypoxia-driven apoptotic cell death. Further elucidation and delineation of the upstream cellular events unveiled an indispensable role of the inhibition of GSK3β kinase activity in mediating the miR-210-induced mitigation of the hypoxia-driven BAX and BAK insertion into the outer mitochondria membrane (OMM) and the ensuing Cytochrome C release into the cytosol. Our study is the first to unveil that the inhibition of GSK3β kinase activity is indispensable in mediating the miR-210-orchestrated protective cellular response to hypoxia-induced apoptotic cell death.

• AC-16 cardiomyocytes
• BAK
• BAX
• Cytochrome C
• GSK3β
• apoptosis
• hypoxia
• miR-210
• mitochondria

• Apoptosis/genetics
• Glycogen Synthase Kinase 3 beta/genetics
• Glycogen Synthase Kinase 3 beta/metabolism
• Humans
• Hypoxia/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Signal Transduction

• Beating cardiomyocyte
• Embryoid bodies
• Serum response factor
• miR210
• miR30c

• Cardiovascular diseases
• Exosomes
• Mesenchymal stem cells

The growth of endometrial stromal cells (ESCs) at implantation sites may be a potential factor affecting the success rate of embryo implantation. Incremental proofs demonstrated that ncRNAs (e.g. miRNAs, lncRNAs and circRNAs) were involved in various biological procedures, including proliferation and apoptosis. In this study, the role of miR‐100‐5p on proliferation and apoptosis of goat ESCs in vitro and embryo implantation in vivo was determined. The mRNA expression of miR‐100‐5p was significantly inhibited in the receptive phase (RE) rather than in the pre‐receptive phase (PE). Overexpression of miR‐100‐5p suppressed ESCs proliferation and induced apoptosis. The molecular target of MiR‐100‐5p, HOXA1, was confirmed by 3′‐UTR assays. Meanwhile, the product of HOXA1 mRNA RT‐PCR increased in the RE more than that in the PE. The HOXA1‐siRNA exerted significant negative effects on growth arrest. Instead, incubation of ESCs with miR‐100‐5p inhibitor or overexpressed HOXA1 promoted the cell proliferation. In addition, Circ‐9110 which acted as a sponge for miR‐100‐5p reversed the relevant biological effects of miR‐100‐5p. The intrinsic apoptosis pathway was suppressed in ESCs, revealing a crosstalk between Circ‐9110/miR‐100‐5p/HOXA1 axis, PI3K/AKT/mTOR, and ERK1/2 pathways. To further evaluate the progress in study on embryo implantation regulating mechanism of miR‐100‐5p in vivo, the pinopodes of two phases were observed and analysed, suggesting that, as similar as in situ, miR‐100‐5p was involved in significantly regulating embryo implantation in vivo. Mechanistically, miR‐100‐5p performed its embryo implantation function through regulation of PI3K/AKT/mTOR and ERK1/2 pathways by targeting Circ‐9110/miR‐100‐5p/HOXA1 axis in vivo.

• HOXA1
• Circ-9110
• dairy goat
• endometrial stromal cells
• miR-100-5p

• angiogenesis
• cardiovascular diseases
• diabetes
• miR-210

Stroke is one of the major causes of death and long-term disability, of which acute ischemic stroke (AIS) is the most common type. Although circular RNA (circRNA) expression profiles of AIS patients have been reported to be significantly altered in blood and peripheral blood mononuclear cells, the role of exosome-containing circRNAs after AIS is still unknown. Plasma exosomes from 10 AIS patients and 10 controls were isolated, and through microarray and bioinformatics analysis, the profile and putative function of circRNAs in the plasma exosomes were studied. A total of 198 circRNAs were differentially quantified (|log2 fold change| ≥ 1.00, p < 0.05) between AIS patients and controls. The levels of 12 candidate circRNAs were verified by qRT-PCR, and the quantities of 10 of these circRNAs were consistent with the data of microarray. The functions of host genes of differentially quantified circRNAs, including RNA and protein process, focal adhesion, and leukocyte transendothelial migration, were associated with the development of AIS. As a miRNA sponge, differentially quantified circRNAs had the potential to regulate pathways related to AIS, like PI3K-Akt, AMPK, and chemokine pathways. Of 198 differentially quantified circRNAs, 96 circRNAs possessing a strong translational ability could affect cellular structure and activity, like focal adhesion, tight junction, and endocytosis. Most differentially quantified circRNAs were predicted to bind to EIF4A3 and AGO2—two RNA-binding proteins (RBPs)—and to play a role in AIS. Moreover, four of ten circRNAs with verified levels by qRT-PCR (hsa_circ_0112036, hsa_circ_0066867, hsa_circ_0093708, and hsa_circ_0041685) were predicted to participate in processes of AIS, including PI3K-Akt, AMPK, and chemokine pathways as well as endocytosis, and to be potentially useful as diagnostic biomarkers for AIS. In conclusion, plasma exosome-derived circRNAs were significantly differentially quantified between AIS patients and controls and participated in the occurrence and progression of AIS by sponging miRNA/RBPs or translating into proteins, indicating that circRNAs from plasma exosomes could be crucial molecules in the pathogenesis of AIS and promising candidates as diagnostic biomarkers and therapeutic targets for the condition.

• National Natural Science Foundation of China
• Health Commission of Sichuan Province

Astrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands that regulate protein expression in a post-transcriptional manner. Understanding the miR expression profile of astrocytes in disease settings provides insight into the cellular stresses present in the microenvironment and may uncover pathways of therapeutic interest.

Laser-capture microdissection was used to isolate human astrocytes surrounding stroke lesions and those from neurological control tissue. Astrocytic miR expression profiles were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Primary human fetal astrocytes were cultured under in vitro stress conditions and transfection of a miR mimic was used to better understand how altered levels of miR-210 affect astrocyte function. The astrocytic response to stress was studied using qPCR, enzyme-linked immunosorbent assays (ELISAs), measurement of released lactate, and Seahorse.

Here, we measured miR expression levels in astrocytes around human ischemic stroke lesions and observed differential expression of miR-210 in chronic stroke astrocytes compared to astrocytes from neurological control tissue. We also identified increased expression of miR-210 in mouse white matter tissue around middle cerebral artery occlusion (MCAO) brain lesions. We aimed to understand the role of miR-210 in primary human fetal astrocytes by developing an in vitro assay of hypoxic, metabolic, and inflammatory stresses. A combination of hypoxic and inflammatory stresses was observed to upregulate miR-210 expression. Transfection with miR-210-mimic (210M) increased glycolysis, enhanced lactate export, and promoted an anti-inflammatory transcriptional and translational signature in astrocytes. Additionally, 210M transfection resulted in decreased expression of complement 3 (C3) and semaphorin 5b (Sema5b).

We conclude that miR-210 expression in human astrocytes is modulated in response to ischemic stroke disease and under in vitro stress conditions, supporting a role for miR-210 in the astrocytic response to disease conditions. Further, the anti-inflammatory and pro-glycolytic impact of miR-210 on astrocytes makes it a potential candidate for further research as a neuroprotective agent.

The online version contains supplementary material available at 10.1186/s12974-021-02373-y.

• Astrocyte
• Hypoxia
• Inflammation
• Ischemia
• MicroRNA-210
• Multiple sclerosis
• Stroke

• AC-16 cardiomyocytes
• apoptosis
• hypoxia
• hypoxia-reoxygenation
• miR-210

• 10940 The Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology (NTNU).

• Ewing sarcoma
• extracellular vesicles
• immunosuppression
• metastasis
• reprogramming
• tumor microenvironment

• cu nanoparticles
• transcriptomics
• microrna expression
• hepg2 cells
• signaling pathways
• microrna target filter analysis

• Carcinoma, Hepatocellular/genetics
• Copper/toxicity
• Hep G2 Cells
• Humans
• Liver Neoplasms/genetics
• Metal Nanoparticles/toxicity
• MicroRNAs
• Oxidative Stress
• Proto-Oncogene Mas
• RNA, Messenger

• EPA999999 Intramural EPA

• Autophagy
• Cellular senescence
• Hypoxic preconditioning
• Intracerebral hemorrhage
• Mesenchymal stem cells
• miRNAs

• HIF1A
• fusion
• hypoxia-inducible factor 1 alpha
• muscle regeneration
• satellite cells

• RNA metabolism
• RNA processing
• extracellular vesicles
• hypoxia
• tumor microenvironment

• Humans
• MicroRNAs/genetics
• Neoplasms/metabolism
• RNA, Circular/genetics
• Transcriptome
• Tumor Microenvironment/genetics

• Wellcome Trust

• Apoptosis
• Casp8ap2
• Hypoxia
• Myocardial injury
• miR-210

• Aging
• Bone marrow stromal cells
• Kynurenine

• Apoptosis
• CASP8AP2
• Cardiomyocyte
• DHA
• Hypoxia
• MicroRNA-210-3p
• Omega-3 fatty Acid

A thrombus in a coronary artery causes ischemia, which eventually leads to myocardial infarction (MI) if not removed. However, removal generates reactive oxygen species (ROS), which causes ischemia–reperfusion (I/R) injury that damages the tissue and exacerbates the resulting MI. The mechanism of I/R injury is currently extensively understood. However, supplementation of exogenous antioxidants is ineffective against oxidative stress (OS). Enhancing the ability of endogenous antioxidants may be a more effective way to treat OS, and exosomes may play a role as targeted carriers. Exosomes are nanosized vesicles wrapped in biofilms which contain various complex RNAs and proteins. They are important intermediate carriers of intercellular communication and material exchange. In recent years, diagnosis and treatment with exosomes in cardiovascular diseases have gained considerable attention. Herein, we review the new findings of exosomes in the regulation of OS in coronary heart disease, discuss the possibility of exosomes as carriers for the targeted regulation of endogenous ROS generation, and compare the advantages of exosome therapy with those of stem-cell therapy. Finally, we explore several miRNAs found in exosomes against OS.

• coronary heart disease
• exosome
• exosome therapy
• myocardial infarction
• oxidative stress
• reactive oxygen radicals

• Animals
• Clinical Trials as Topic
• Coronary Disease/complications
• Coronary Disease/genetics
• Coronary Disease/therapy
• Disease Models, Animal
• Drug Carriers/chemistry
• Exosomes/chemistry
• Exosomes/transplantation
• Gene Expression Regulation
• Humans
• MicroRNAs/administration & dosage
• Myocardial Reperfusion Injury/genetics
• Myocardial Reperfusion Injury/therapy
• Oxidative Stress/genetics
• Reactive Oxygen Species/metabolism
• Treatment Outcome

• Acute lymphoblastic leukemia
• CASP8AP2
• CTBP2
• relapse

Intercellular communication between tumor cells within the hypoxic microenvironment promote aggressiveness and poor patient prognoses for reasons that remain unclear. Here we show that hypoxic Ewing’s sarcoma (EWS) cells release exosomes that promote sphere formation, a stem-like phenotype, in EWS cells by enhancing survival. Analysis of the hypoxic exosomal miRNA cargo identified a HIF-1α regulated miRNA, miR-210, as a potential mediator of sphere formation in cells exposed to hypoxic exosomes. Knockdown of HIF-1α in hypoxic EWS cells led to decreased exosomal miR-210 levels and reduced the capacity of hypoxic exosomes to form spheres. Inhibition of miR-210 in hypoxic spheres attenuated sphere formation and overexpression of miR-210 in normoxic spheres significantly enhanced the number of EWS spheres. Our results indicate that hypoxic exosomal miR-210 targets the proapoptotic protein CASP8AP2 in recipient cells. Moreover, the suppression of CASP8AP2 led to a reduction in apoptotic cells and increased sphere formation. Together, the findings in this study suggest that hypoxic exosomes promote stemness in EWS cells by delivering enriched miR-210 that is capable of down-regulating apoptotic pathways, resulting in the survival of cells with increased sphere formation. Future studies will further investigate the effects of EWS derived exosomal miRNAs on target genes and the role these interactions play in driving aggressiveness in hypoxic EWS tumors.

• Ewing’s sarcoma
• exosomes
• hypoxia
• miR-210
• stemness

Impaired kidney function and increased inflammatory process occurring in the course of Chronic Kidney Disease (CKD) contribute to the development of complex amino-acid alterations. The essential amino-acid tryptophan (TRP) undergoes extensive metabolism along several pathways, resulting in the production of many biologically active compounds. The results of many studies have shown that its metabolism via the kynurenine pathway is potently increased in the course of CKD. Metabolites of this pathway exhibit differential, sometimes opposite, roles in several biological processes. Their accumulation in the course of CKD may induce oxidative cell damage which stimulates inflammatory processes. They can also modulate the activity of numerous cellular signaling pathways through activation of the aryl hydrocarbon receptor, leading to the disruption of homeostasis of various organs. As a result, they can contribute to the development of the systemic disorders accompanying the course of chronic renal failure. This review gathers and systematizes reports concerning the knowledge connecting the kynurenine pathway metabolites to systemic disorders accompanying the development of CKD.

• Cardioprotection
• acute myocardial infarction
• drug delivery
• exosomes
• extracellular vesicles
• heart failure

• K99 HL130416 NHLBI NIH HHS
• R00 HL130416 NHLBI NIH HHS
• R01 HL148756 NHLBI NIH HHS

Since the first publication regarding the existence of stem cells in cancer [cancer stem cells (CSCs)] in 1994, many studies have been published providing in-depth information about their biology and function. This research has paved the way in terms of appreciating the role of CSCs in tumour aggressiveness, progression, recurrence and resistance to cancer therapy. Targeting CSCs for cancer therapy has still not progressed to a sufficient degree, particularly in terms of exploring the mechanism of dynamic interconversion between CSCs and non-CSCs. Besides the CSC scenario, the problem of cancer dissemination has been analyzed in-depth with the identification and isolation of microRNAs (miRs), which are now considered to be compelling molecular markers in the diagnosis and prognosis of tumours in general and specifically in patients with non-small cell lung cancer. Paracrine release of miRs via “exosomes” (small membrane vesicles (30-100 nm), the derivation of which lies in the luminal membranes of multi-vesicular bodies) released by fusion with the cell membrane is gaining popularity. Whether exosomes play a significant role in maintaining a dynamic equilibrium state between CSCs and non-CSCs and their mechanism of activity is as yet unknown. Future studies on CSC-related exosomes will provide new perspectives for precision-targeted treatment strategies.

• Cancer
• Cancer stem cells
• Exosomes
• Lungs
• miRNA
• Microvesicles
• Non-small cell lung cancer

• Gastric cancer
• biomarker
• curative
• microRNAs
• postoperative delirium
• univariate

• Atherosclerosis
• Blood vessels
• Cardiovascular diseases
• Hypoxia-Inducible factor 1
• Macrophages
• Myocardial infarction

• hypoxia-inducible factor prolyl hydroxylase 2
• hypoxic preconditioning
• intercellular signaling peptides and proteins
• regeneration
• tissue engineering
• vascular endothelial growth factor A

• 3T3-L1 Cells
• Adipose Tissue/drug effects
• Adipose Tissue/metabolism
• Animals
• Diabetes Mellitus, Type 2/metabolism
• Electron Transport Complex IV/metabolism
• Exosomes/drug effects
• Exosomes/metabolism
• Glucose/pharmacology
• Macrophages/drug effects
• Macrophages/metabolism
• Mice
• MicroRNAs/metabolism
• Obesity/metabolism
• RAW 264.7 Cells

• apoptosis
• kidney development
• microRNA-210

• Human bone marrow stromal cells
• Kynurenine
• Oxidative stress
• microRNAs