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Journal of Nanobiotechnology Jun 2024Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our...
Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.
Topics: Animals; Autophagy; Mice; Exosomes; MicroRNAs; Cold Temperature; Osteogenesis; Mice, Inbred C57BL; Mesenchymal Stem Cells; Osteoporosis; Cell Differentiation; Bone and Bones; Female; Bone Density; Sirolimus
PubMed: 38910236
DOI: 10.1186/s12951-024-02640-z -
Signal Transduction and Targeted Therapy Jun 2024Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it. The tumor microenvironment...
Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it. The tumor microenvironment (TME) in pancreatic cancer, distinguished by fibrosis and the existence of cancer-associated fibroblasts (CAFs), exerts a pivotal influence on both tumor advancement and resistance to therapy. Recent advancements in the field of engineered extracellular vesicles (EVs) offer novel avenues for targeted therapy in pancreatic cancer. This study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic cancer. EVs obtained from bone marrow mesenchymal stem cells (BMSCs) were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone (PFD) and subjected to surface modification with integrin α5-targeting peptides (named IEVs-PFD/138) to reprogram CAFs and suppress their pro-tumorigenic effects. Integrin α5-targeting peptide modification enhanced the CAF-targeting ability of EVs. miR-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex, inhibiting TGF-β signaling pathway activation. In addition, miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 complex. The combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of CAFs. Preclinical experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising results. In particular, IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME, which resulted in decreased tumor pressure, enhanced gemcitabine perfusion, tumor hypoxia amelioration, and greater sensitivity of cancer cells to chemotherapy. Thus, the strategy developed in this study can improve chemotherapy outcomes. Utilizing IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.
Topics: Pancreatic Neoplasms; Extracellular Vesicles; Humans; Cancer-Associated Fibroblasts; Mice; MicroRNAs; Animals; Tumor Microenvironment; Cellular Reprogramming; Cell Line, Tumor; Mesenchymal Stem Cells; Neoplasm Proteins; Gemcitabine
PubMed: 38910148
DOI: 10.1038/s41392-024-01872-7 -
Hellenic Journal of Cardiology : HJC =... Jun 2024Aortic dissection (AD) is a catastrophic life-threatening cardiovascular emergency with a 1-2% per hour mortality rate post-diagnosis, characterized physiologically by... (Review)
Review
Aortic dissection (AD) is a catastrophic life-threatening cardiovascular emergency with a 1-2% per hour mortality rate post-diagnosis, characterized physiologically by the separation of aortic wall layers. AD initially presents as intense pain that can then radiate to the back, arms, neck or jaw along with neurological deficits like difficulty in speaking, and unilateral weakness in some patients. This spectrum of clinical features associated with AD is often confused with acute myocardial infarction, hence leading to a delay in AD diagnosis. Cardiac and vascular biomarkers are structural proteins and microRNAs circulating in the bloodstream that correlate to tissue damage and their levels become detectable even before symptom onset. Timely diagnosis of AD using biomarkers, in combination with advanced imaging diagnostics, will significantly improve prognosis by allowing earlier vascular interventions. This comprehensive review aims to investigate emerging biomarkers in the diagnosis of AD, as well as provide future directives for creating advanced diagnostic tools and imaging techniques.
PubMed: 38909846
DOI: 10.1016/j.hjc.2024.06.006 -
Lipids in Health and Disease Jun 2024Lipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype,...
BACKGROUND
Lipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype, lipid-droplet-accumulating microglia (LDAM), is notable for increased inflammatory factor secretion and diminished phagocytic capability. Lipophagy, the autophagy-mediated selective degradation of LDs, plays a critical role in this context. This study investigated the involvement of microRNAs (miRNAs) in lipophagy during demyelinating diseases, assessed their capacity to modulate LDAM subtypes, and elucidated the potential underlying mechanisms involved.
METHODS
C57BL/6 mice were used for in vivo experiments. Two weeks post demyelination induction at cervical level 4 (C4), histological assessments and confocal imaging were performed to examine LD accumulation in microglia within the lesion site. Autophagic changes were observed using transmission electron microscopy. miRNA and mRNA multi-omics analyses identified differentially expressed miRNAs and mRNAs under demyelinating conditions and the related autophagy target genes. The role of miR-223 in lipophagy under these conditions was specifically explored. In vitro studies, including miR-223 upregulation in BV2 cells via lentiviral infection, validated the bioinformatics findings. Immunofluorescence staining was used to measure LD accumulation, autophagy levels, target gene expression, and inflammatory mediator levels to elucidate the mechanisms of action of miR-223 in LDAM.
RESULTS
Oil Red O staining and confocal imaging revealed substantial LD accumulation in the demyelinated spinal cord. Transmission electron microscopy revealed increased numbers of autophagic vacuoles at the injury site. Multi-omics analysis revealed miR-223 as a crucial regulatory gene in lipophagy during demyelination. It was identified that cathepsin B (CTSB) targets miR-223 in autophagy to integrate miRNA, mRNA, and autophagy gene databases. In vitro, miR-223 upregulation suppressed CTSB expression in BV2 cells, augmented autophagy, alleviated LD accumulation, and decreased the expression of the inflammatory mediator IL-1β.
CONCLUSION
These findings indicate that miR-223 plays a pivotal role in lipophagy under demyelinating conditions. By inhibiting CTSB, miR-223 promotes selective LD degradation, thereby reducing the lipid burden and inflammatory phenotype in LDAM. This study broadens the understanding of the molecular mechanisms of lipophagy and proposes lipophagy induction as a potential therapeutic approach to mitigate inflammatory responses in demyelinating diseases.
Topics: Animals; MicroRNAs; Microglia; Mice; Autophagy; Lipid Droplets; Mice, Inbred C57BL; Demyelinating Diseases; Cathepsin B; Lysophosphatidylcholines; Disease Models, Animal; Male; Gene Expression Regulation; Cell Line
PubMed: 38909243
DOI: 10.1186/s12944-024-02185-y -
Biomedicine & Pharmacotherapy =... Jun 2024The global public health crisis caused by the COVID-19 pandemic has intensified the global concern regarding viral respiratory tract infections. Despite their... (Review)
Review
The global public health crisis caused by the COVID-19 pandemic has intensified the global concern regarding viral respiratory tract infections. Despite their considerable impact on health, society and the economy, effective management of these conditions remains a significant challenge. Integrating high-throughput analyses is pivotal for early detection, prognostication of adverse outcomes, elucidating pathogenetic pathways and developing therapeutic approaches. In recent years, microRNAs (miRNAs), a subset of small noncoding RNAs (ncRNAs), have emerged as promising tools for molecular phenotyping. Current evidence suggests that miRNAs could serve as innovative biological markers, aiding in informed medical decision-making. The cost-effective quantification of miRNAs in standardized samples using techniques routinely employed in clinical laboratories has become feasible. In this context, samples obtained from the airways represent a valuable source of information due to their direct exposure to the infectious agent and host response within the respiratory tract. This review explores viral and host miRNA profiling in airway-derived biosamples as a source of molecular information to guide patient management, with a specific emphasis on SARS-CoV-2 infection.
PubMed: 38908203
DOI: 10.1016/j.biopha.2024.116984 -
Journal of Orthopaedic Surgery and... Jun 2024Long non-coding RNAs (LncRNAs) are recognized as a pivotal element in the processes of fracture healing and the osteogenic differentiation of stem cells. This study...
BACKGROUND
Long non-coding RNAs (LncRNAs) are recognized as a pivotal element in the processes of fracture healing and the osteogenic differentiation of stem cells. This study investigated the molecular mechanism and regulatory significance of lncRNA MAGI2-AS3 (MAGI2-AS3) in fracture healing.
METHODS
Serum levels of MAGI2-AS3 in patients with normal and delayed fracture healing were verified by RT-qPCR assays. The predictive efficacy of MAGI2-AS3 for delayed fracture healing was analyzed by ROC curve. Osteogenic markers were quantified by RT-qPCR assays. MC3T3-E1 cell viability was detected using CCK-8 assay, and flow cytometry was utilized to measure cell apoptosis. The dual-luciferase reporter gene assay was used to determine the targeted binding between MAGI2-AS3 and miR-223-3p.
RESULTS
Serum MAGI2-AS3 expression was decreased in patients with delayed fracture healing compared with patients with normal healing. Elevated MAGI2-AS3 resulted in an upregulation of the proliferative capacity of MC3T3-E1 cells and a decrease in mortality, along with increased levels of both osteogenic markers. However, after transfection silencing MAGI2-AS3, the trend was reversed. Additionally, miR-223-3p was the downstream target of MAGI2-AS3 and was controlled by MAGI2-AS3. miR-223-3p mimic reversed the promoting effects of MAGI2-AS3 overexpression on osteogenic marker levels and cell growth, and induced cell apoptosis.
CONCLUSION
The upregulation of MAGI2-AS3 may expedite the healing of fracture patients by targeting miR-223-3p, offering a novel biomarker for diagnosing patients with delayed healing.
Topics: MicroRNAs; RNA, Long Noncoding; Fracture Healing; Humans; Down-Regulation; Mice; Animals; Osteogenesis; Male; Female; Apoptosis; Adaptor Proteins, Signal Transducing; Adult; Cell Proliferation; Cell Differentiation
PubMed: 38907263
DOI: 10.1186/s13018-024-04850-5 -
Communications Biology Jun 2024Mammalian reproduction relies on precise maternal-fetal communication, wherein immune modifications foster tolerance toward the semi-allogeneic embryo. Extracellular... (Review)
Review
Mammalian reproduction relies on precise maternal-fetal communication, wherein immune modifications foster tolerance toward the semi-allogeneic embryo. Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as crucial mediators, transporting molecules like microRNAs securely. EVs influence various reproductive stages, from gamete maturation to implantation, and impact pathologies like pregnancy loss. In the embryo-maternal dialogue, EVs notably affect oviductal interactions, gene expression, and the embryo-endometrial interface, crucial for successful implantation. Key queries persist about EV uptake, cargo delivery, and the specific biomolecules driving communication. Their potential in diagnostics, therapeutics, and understanding environmental impacts on fertility signals an exciting future, reliant on collaborative efforts for transformative strides in reproductive health.
Topics: Extracellular Vesicles; Humans; Female; Pregnancy; Animals; Maternal-Fetal Exchange; Embryo, Mammalian; Cell Communication; Embryo Implantation; MicroRNAs
PubMed: 38906986
DOI: 10.1038/s42003-024-06442-9 -
Scientific Reports Jun 2024Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction....
Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction. Dysregulation of miRNAs plays a crucial role in DPN development. However, the role of miR-503-5p in DPN remains unknown. Herein, T2DM mice (db/db) were used as a DPN model in vivo, and astrocytes isolated from db/db mice were induced with high glucose levels as a DPN model in vitro. MiR-503-5p expression was analyzed using qRT-PCR. GFAP, MCP-1, and SEPT9 protein levels were analyzed using western blotting and immunofluorescence. Luciferase assays were performed to investigate the interaction between miR-503-5p and SEPT9. We found that miR-503-5p expression decreased in the spinal cord of DPN model mice and astrocytes treated with high glucose (HG). The db/db mice displayed higher body weight and blood glucose, lower mechanical withdrawal threshold and thermal withdrawal latency, and higher GFAP and MCP-1 protein levels than db/m mice. However, tail vein injection of agomiR-503-5p remarkably reversed these parameters, whereas antigomiR-503-5p enhanced them. HG markedly facilitated GFAP and MCP-1 protein expression in astrocytes, whereas miR-503-5p mimic or inhibitor transfection markedly blocked or elevated GFAP and MCP-1 protein expression, respectively, in astrocytes with HG. SEPT9 was a target of miR-503-5p. In addition, SEPT9 protein levels were found to be elevated in db/db mice and astrocytes treated with HG. Treatment with agomiR-503-5p and miR-503-5p mimic was able to reduce SEPT9 protein levels, whereas treatment with antigomiR-503-5p and miR-503-5p inhibitor led to inhibition of the protein. Furthermore, SEPT9 overexpression suppressed the depressing effect of miR-503-5p overexpression in astrocytes subjected to HG doses. In conclusion, miR-503-5p was found to alleviate peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 expression.
Topics: Animals; MicroRNAs; Astrocytes; Mice; Septins; Diabetic Neuropathies; Diabetes Mellitus, Type 2; Male; Neuralgia; Disease Models, Animal
PubMed: 38906977
DOI: 10.1038/s41598-024-65096-z -
Biomedicine & Pharmacotherapy =... Jun 2024Malignant tumors and central nervous system (CNS) disorders are intricately linked to a process known as "aberrant cell cycle re-entry," which plays a critical role in... (Review)
Review
Malignant tumors and central nervous system (CNS) disorders are intricately linked to a process known as "aberrant cell cycle re-entry," which plays a critical role in the progression of these diseases. Addressing the dysregulation in cell cycles offers a promising therapeutic approach for cancers and CNS disorders. MicroRNAs (miRNAs) play a crucial role as regulators of gene expression in cell cycle transitions, presenting a promising therapeutic avenue for treating these disorders and their comorbidities. This review consolidates the progress made in the last three years regarding miRNA-based treatments for diseases associated with aberrant cell cycle re-entry. It encompasses exploring fundamental mechanisms and signaling pathways influenced by miRNAs in cancers and CNS disorders, particularly focusing on the therapeutic effects of exosome-derived miRNAs. The review also identifies specific miRNAs implicated in comorbidity of cancers and CNS disorders, discusses the future potential of miRNA reagents in managing cell cycle-related diseases.
PubMed: 38906026
DOI: 10.1016/j.biopha.2024.116979 -
Poultry Science May 2024Within the poultry industry, hens' reproductive performance is of great economic significance. The development and growth of follicles is a key aspect of hen egg...
Within the poultry industry, hens' reproductive performance is of great economic significance. The development and growth of follicles is a key aspect of hen egg production, and ovarian follicle growth and development are closely associated with granulosa cells (GCs) proliferation and the synthesis of steroid hormones. It has been confirmed by numerous studies that microRNAs (miRNAs) play important roles in the steroid hormone synthesis and proliferation of GCs. In this study, we examined the main miRNAs influencing hens' ability to reproduce, identified the miR-223 that is mainly expressed in atretic follicles based on sequencing, and investigated its role in GCs. Then, we used miR-223 mimic and inhibitor to knockdown or overexpress miR-223 expression. The result showed that miR-223 significantly inhibits both the steroid hormone synthesis and the proliferation of GCs. Subsequently, the results of the dual luciferase reporter experiment and bioinformatics prediction demonstrated that cysteine rich transmembrane BMP regulator 1 (CRIM1) was a downstream target gene of miR-223, and overexpression of miR-223 prevented CRIM1 expression. The function of CRIM1 was further investigated, and we observed a significant reduction in the synthesis of steroid hormones and the proliferation of GCs after transfection with CRIM1 siRNA. The opposite function of miR-223 was observed for CRIM1 in our study. Additionally, we demonstrated the involvement of the miR-223/CRIM1 axis in GCs through modulation of the AKT signaling pathway. Our data demonstrate the pivotal role of the miR-223 in the proliferation and steroid hormone synthesis of chicken GCs, which helps to explain how non-coding RNA (ncRNA) affects chicken reproductive function.
PubMed: 38905756
DOI: 10.1016/j.psj.2024.103910