Exosomes play a role as mediators of cell-to-cell communication, thus exhibiting pleiotropic activities to homeostasis regulation. Exosomal non-coding RNAs (ncRNAs), mainly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are closely related to a variety of biological and functional aspects of human health. When the exosomal ncRNAs undergo tissue-specific changes due to diverse internal or external disorders, they can cause tissue dysfunction, aging, and diseases. In this review, we comprehensively discuss the underlying regulatory mechanisms of exosomes in human diseases. In addition, we explore the current knowledge on the roles of exosomal miRNAs, lncRNAs, and circRNAs in human health and diseases, including cancers, metabolic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and infectious diseases, to determine their potential implication in biomarker identification and therapeutic exploration.

Roles and mechanisms of exosomal non-coding RNAs in human health and diseases.

miR-21 and miR-146a: The microRNAs of inflammaging and age-related diseases.

Sp1-mediated upregulation of Prdx6 expression prevents podocyte injury in diabetic nephropathy via mitigation of oxidative stress and ferroptosis

Exosomes are discoid vesicles with a diameter of 40-160 nm. They are mainly derived from the multivesicular body formed by the invagination of lysosomal particles in the cell, which are released into the extracellular matrix after the fusion of the outer membrane. Exosomes are widespread and distributed in various body fluids, they are rich in nucleic acids (microRNA, lncRNA, circRNA, mRNA, tRNA, etc.), proteins, lipids, etc. As an important mediator of cellular communication, exosomes carry and transmit important signaling molecules and are widely involved in intercellular material transport and information transfer, they regulate cellular physiological activities and are closely related to the occurrence and course of various diseases. In recent years, with the deepening of exosome-related research, we discovered that exosomal non-coding RNAs are associated with diabetic complications such as diabetic retinopathy, diabetic nephropathy, diabetic foot ulcer. This article reviews the new findings of exosomal non-coding RNAs (mainly microRNAs, lncRNAs, circRNAs) in diabetic complications, and analyzes the potential of exosomal ncRNA as new biomarkers and new cell-free therapies in the diagnosis and treatment of diabetic complications, hoping to provide new ideas for the prevention, diagnosis, and treatment of diabetic complications. 

Exosomal ncRNAs: Novel Therapeutic Target and Biomarker for Diabetic Complications.

Diabetic nephropathy (DN) leads to high morbidity and disability. Inflammation plays a critical role in the pathogenesis of DN, which involves renal cells and immune cells, the microenvironment, as well as extrinsic factors, such as hyperglycemia, chemokines, cytokines, and growth factors. Epigenetic modifications usually regulate gene expression via DNA methylation, histone modification, and non-coding RNAs without altering the DNA sequence. During the past years, numerous studies have been published to reveal the mechanisms of epigenetic modifications that regulate inflammation in DN. This review aimed to summarize the latest evidence on the interplay of epigenetics and inflammation in DN, and highlight the potential targets for treatment and diagnosis of DN.

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Epigenetics and Inflammation in Diabetic Nephropathy.

Podocyte pyroptosis, characterized by inflammasome activation, plays an important role in inflammation-mediated diabetic nephropathy (DN). Our study aimed to investigate whether miR-21-5p in macrophage-derived extracellular vesicles (EVs) could affect podocyte injury in DN. EVs were extracted after the treatment of RAW 264.7 (mouse macrophage line) with high glucose (HG). The podocyte pyroptosis was determined using the flow cytometry and the western blot. After the knockdown of miR-21-5p in HG-induced RAW264.7 cells, we injected the extracted EVs into DN model mice. The level of miR-21-5p was higher in HG-stimulated macrophage-derived EVs than in normal glucose-cultured macrophage-derived EVs. The co-culture of EVs and podocytes promoted reactive oxygen species (ROS) production and activation of inflammatory in MPC5 cells (mouse podocyte line). However, restraint of miR-21-5p in EVs reduced ROS production and inhibit inflammasome activation in MPC5 cells, thereby reducing podocytes injury. Meanwhile, we found that miR-21-5p inhibited the A20 expression through binding with its 3′-untranslated regions in MPC5 cells. Further studies showed that A20 was also involved in the regulation of miR-21-5p of RAW 264.7-derived EVs on MPC5 injury. At the same time, it was also proved in the DN model mice that miR-21-5p in macrophage-derived EVs could regulate podocyte injury. MiR-21-5p in macrophage-derived EVs can regulate pyroptosis-mediated podocyte injury by A20 in DN.

MiR-21-5p in macrophage-derived extracellular vesicles affects podocyte pyroptosis in diabetic nephropathy by regulating A20.

Urinary exosomal miRNAs can reflect the physiological and possibly pathophysiological state of cells lining the kidney and participate in the regulation of transcription and translation of proteins, which are playing an important role in the pathogenesis of diabetic kidney disease. In the present study, urine was collected from DM and DKD patients with a duration more than 10 years and urinary exosomal miRNA profiling was conducted in urinary exosomes obtained from three patients with type 2 diabetes (DM) and three patients with type 2 diabetic kidney disease (DKD) using Exiqon's microRNA arrays. In total, the expression of 14 miRNAs (miR-4491, miR-2117, miR-4507, miR-5088-5P, miR-1587, miR-219a-3p, miR-5091, miR-498, miR-4687-3p, miR-516b-5p, miR-4534, miR-1275, miR-5007-3p, and miR-4516) was up-regulated (>2-fold) in DKD patients compared to healthy controls and DM patients. We used qRT-PCR based analysis of these 14 miRNAs in urinary exosomes from 14 DKD to 14 DM patients in confirmation cohort, among which seven miRNAs were consistent with the microarray results. The expressions of miR-4534 and miR-516b-5p correlated with trace proteinuria levels in the confirmation cohort. In conclusion, it has been confirmed that the expression of urinary exosomal miRNA in patients with type 2 diabetes DKD has changed. Mir-4534 might affect the FoxO signaling pathway by targeting BNIP3, and is expected to become a new biomarker for the progression of type 2 DKD disease, which will provide further research on the pathogenesis of DKD.

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Urinary Exosomal MiRNA-4534 as a Novel Diagnostic Biomarker for Diabetic Kidney Disease.

Recent evidence has indicated that overexpression of the epigenetic reader bromodomain‐containing protein 4 (BRD4) contributes to a poor prognosis of lung cancers, and the suppression of its expression promotes cell apoptosis and leads to tumor shrinkage. Proteolysis targeting chimera (PROTAC) has recently emerged as a promising therapeutic strategy with the capability to precisely degrade targeted proteins. Herein, a novel style of versatile nano‐PROTAC (CREATE (CRV‐LLC membrane/DS‐PLGA/dBET6)) is developed, which is constructed by using a pH/GSH (glutathione)‐responsive polymer (disulfide bond‐linked poly(lactic‐co‐glycolic acid), DS‐PLGA) to load BRD4‐targeted PROTAC (dBET6), followed by the camouflage with engineered lung cancer cell membranes with dual targeting capability. Notably, CREATE remarkably confers simultaneous targeting ability to lung cancer cells and tumor‐associated macrophages (TAMs). The pH/GSH‐responsive design improves the release of dBET6 payload from nanoparticles to induce pronounced apoptosis of both cells, which synergistically inhibits tumor growth in both subcutaneous and orthotopic tumor‐bearing mouse model. Furthermore, the efficient tumor inhibition is due to the direct elimination of lung cancer cells and TAMs, which remodels the tumor microenvironment. Taken together, the results elucidate the construction of a versatile nano‐PROTAC enables to eliminate both lung cancer cells and TAMs, which opens a new avenue for efficient lung cancer therapy via PROTAC.

Ao Shen

Papers

MiR-21-5p in macrophage-derived extracellular vesicles affects podocyte pyroptosis in diabetic nephropathy by regulating A20.

Urinary Exosomal MiRNA-4534 as a Novel Diagnostic Biomarker for Diabetic Kidney Disease.

Versatile Nano‐PROTAC‐Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy

Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9

PDE4D binds and interacts with YAP to cooperatively promote HCC progression.