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Project description:Aging is a major risk factors for osteoarthritis (OA), and cartilage of the elder are more sensitive to mechanical loading stress. Recently, cartilage progenitor cells (CPCs) arose much interests due to its important role in maintaining cartilage homeostasis. However, the potential mechanism of increased sensitivity to mechanical stress in CPCs has not been elucidated. The aim of this study was to investigate the potential links between aging and age-related OA through establish CPCs replicative senescence model and fluid flow shear stress (FFSS) stimulated degeneration model. Small RNA and mRNA sequence were conducted to investigate miRNA-related mechanisms in this process. By gain-and-lost strategy we investigated the age-related miRNAs and their impacts on exacerbating the progression of biomechanical stimulated TMJ-OA. miR-708-5p was identified as age-related miRNA in CPCs, and TLR4 was identified as its direct target through luciferase report assay. Age-related miR-708-5p deficiency increased sensitivity of CPCs for exposure to FFSS by liberating TLR4 expression. Intra-articular delivery agomiR-708-5p alleviated TMJ osteoarthritic cartilage lesions in mice. In conclusion, age-related miR-708-5p deficiency increases the sensitivity to mechanical loading stress and promotes CPCs senescence like degeneration via TLR4.
2023-07-11 | GSE236978 | GEO
Project description:Aging is a major risk factors for osteoarthritis (OA), and cartilage of the elder are more sensitive to mechanical loading stress. Recently, cartilage progenitor cells (CPCs) arose much interests due to its important role in maintaining cartilage homeostasis. However, the potential mechanism of increased sensitivity to mechanical stress in CPCs has not been elucidated. The aim of this study was to investigate the potential links between aging and age-related OA through establish CPCs replicative senescence model and fluid flow shear stress (FFSS) stimulated degeneration model. Small RNA and mRNA sequence were conducted to investigate miRNA-related mechanisms in this process. By gain-and-lost strategy we investigated the age-related miRNAs and their impacts on exacerbating the progression of biomechanical stimulated TMJ-OA. miR-708-5p was identified as age-related miRNA in CPCs, and TLR4 was identified as its direct target through luciferase report assay. Age-related miR-708-5p deficiency increased sensitivity of CPCs for exposure to FFSS by liberating TLR4 expression. Intra-articular delivery agomiR-708-5p alleviated TMJ osteoarthritic cartilage lesions in mice. In conclusion, age-related miR-708-5p deficiency increases the sensitivity to mechanical loading stress and promotes CPCs senescence like degeneration via TLR4.
2023-07-11 | GSE236977 | GEO
Project description:BACKGROUND:Duchenne (DMD) and Becker (BMD) muscular dystrophies are caused by mutations in the DMD gene coding for dystrophin, a protein being part of a large sarcolemmal protein scaffold that includes the neuronal nitric oxide synthase (nNOS). The nNOS was shown to play critical roles in a variety of muscle functions and alterations of its expression and location in dystrophic muscle fiber leads to an increase of the muscle fatigability. We previously revealed a decrease of nNOS expression in BMD patients all presenting a deletion of exons 45 to 55 in the DMD gene (BMDd45-55), impacting the nNOS binding site of dystrophin. Since several studies showed deregulation of microRNAs (miRNAs) in dystrophinopathies, we focused on miRNAs that could target nNOS in dystrophic context. METHODS:By a screening of 617 miRNAs in BMDd45-55 muscular biopsies using TLDA and an in silico study to determine which one could target nNOS, we selected four miRNAs. In order to select those that targeted a sequence of 3'UTR of NOS1, we performed luciferase gene reporter assay in HEK393T cells. Finally, expression of candidate miRNAs was modulated in control and DMD human myoblasts (DMDd45-52) to study their ability to target nNOS. RESULTS:TLDA assay and the in silico study allowed us to select four miRNAs overexpressed in muscle biopsies of BMDd45-55 compared to controls. Among them, only the overexpression of miR-31, miR-708, and miR-34c led to a decrease of luciferase activity in an NOS1-3'UTR-luciferase assay, confirming their interaction with the NOS1-3'UTR. The effect of these three miRNAs was investigated on control and DMDd45-52 myoblasts. First, we showed a decrease of nNOS expression when miR-708 or miR-34c were overexpressed in control myoblasts. We then confirmed that DMDd45-52 cells displayed an endogenous increased of miR-31, miR-708, and miR-34c and a decreased of nNOS expression, the same characteristics observed in BMDd45-55 biopsies. In DMDd45-52 cells, we demonstrated that the inhibition of miR-708 and miR-34c increased nNOS expression, confirming that both miRNAs can modulate nNOS expression in human myoblasts. CONCLUSION:These results strongly suggest that miR-708 and miR-34c, overexpressed in dystrophic context, are new actors involved in the regulation of nNOS expression in dystrophic muscle.
| S-EPMC5924477 | biostudies-literature
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression post-transcriptionally. They are crucial for normal development and maintaining homeostasis. Researchers have discovered that dysregulated miRNA expression contributes to many pathological conditions, including cancer. miRNAs can augment or suppress tumorigenesis based on their expression and transcribed targetome in various cell types. In recent years, researchers have begun to identify miRNAs commonly dysregulated in cancer. One recently identified miRNA, miR-708-5p, has been shown to have profound roles in promoting or suppressing oncogenesis in a myriad of solid and hematological tumors. This review highlights the diverse, sometimes controversial findings reported for miR-708-5p in cancer, and the importance of further exploring this exciting miRNA.
| S-EPMC5642637 | biostudies-literature
Project description:Cartilage protein distribution and the changes that occur in cartilage ageing and disease are essential in understanding the process of cartilage ageing and age related diseases such as osteoarthritis. The aim of this study was to investigate the peptide profiles in ageing and osteoarthritic (OA) cartilage sections using matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI).The distribution of proteins in young, old and OA equine cartilage was compared following tryptic digestion of cartilage slices and MALDI-MSI undertaken with a MALDI SYNAPT™ HDMS system. Protein identification was undertaken using database searches following multivariate analysis. Peptide intensity differences between young, ageing and OA cartilage were imaged with Biomap software. Analysis of aggrecanase specific cleavage patterns of a crude cartilage proteoglycan extract were used to validate some of the differences in peptide intensity identified. Immunohistochemistry studies validated the differences in protein abundance.Young, old and OA equine cartilage was discriminated based on their peptide signature using discriminant analysis. Proteins including aggrecan core protein, fibromodulin, and cartilage oligomeric matrix protein were identified and localised. Fibronectin peptides displayed a stronger intensity in OA cartilage. Age-specific protein markers for collectin-43 and cartilage oligomeric matrix protein were identified. In addition potential fibromodulin and biglycan peptides targeted for degradation in OA were detected.MALDI-MSI provided a novel platform to study cartilage ageing and disease enabling age and disease specific peptides in cartilage to be elucidated and spatially resolved.
| S-EPMC4095688 | biostudies-literature
Project description:MicroRNAs (miRNAs) are small non-coding RNA species that have been shown to have roles in multiple processes that occur in higher eukaryotes. They act by binding to specific sequences in the 3' untranslated region of their target genes and causing the transcripts to be degraded by the RNA-induced silencing complex (RISC). MicroRNAs have previously been reported to demonstrate altered expression in several aging phenotypes such as cellular senescence and age itself. Here, we have measured the expression levels of 521 small regulatory microRNAs (miRNAs) in spleen tissue from young and old animals of 6 mouse strains with different median strain lifespans by quantitative real-time PCR. Expression levels of 3 microRNAs were robustly associated with strain lifespan, after correction for multiple statistical testing (miR-203-3p [β-coefficient = -0.6447, p = 4.8 × 10-11], miR-664-3p [β-coefficient = 0.5552, p = 5.1 × 10-8] and miR-708-5p [β-coefficient = 0.4986, p = 1.6 × 10-6]). Pathway analysis of binding sites for these three microRNAs revealed enrichment of target genes involved in key aging and longevity pathways including mTOR, FOXO and MAPK, most of which also demonstrated associations with longevity. Our results suggests that miR-203-3p, miR-664-3p and miR-708-5p may be implicated in pathways determining lifespan in mammals.
| S-EPMC5356331 | biostudies-literature
Project description:Lung cancer is a collection of aggressive tumors generally not diagnosed until late-stage, resulting in high mortality rates. The vast majority of non-small cell lung cancer (NSCLC) patients undergo combinatory chemotherapeutic treatment, which initially reduces tumor growth, but frequently becomes ineffective due to toxicity and resistance. Researchers have identified multiple signaling pathways involved in lung cancer chemoresistance, including cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1) derived prostaglandin E2 (PGE2). While COX-2 inhibitors have shown promise in the clinic, their use is limited due to severe side effects. One novel approach to effectively suppress COX-2 signaling is through microRNA (miRNA). MiRNAs are small-noncoding RNAs commonly misexpressed in cancer. One tumor suppressive miRNA, miR-708-5p, has been shown to repress pro-resistant signaling pathways, including COX-2 and mPGES-1. Here, we demonstrate that chemotherapies reduce COX-2 expression, possibly through induction of miR-708-5p. Moreover, combination treatment of erlotinib (ERL) or paclitaxel (PAC) with miR-708-5p enhances COX-2 and mPGES-1 protein suppression. We also show that combination chemotherapeutic and miR-708-5p treatment intensifies the anti-proliferative and pro-apoptotic effects of ERL and PAC. We also created ERL and PAC resistant lung cancer cell lines, which have increased COX-2 expression and diminished miR-708-5p levels compared to naïve lung cancer cells. While ERL and PAC treatments do not alter resistant cell phenotype alone, combination treatment with miR-708-5p partially restores the chemotherapies' anti-proliferative effects and fully restores their pro-apoptotic qualities. These data suggest miR-708-5p may have potential combinatory therapeutic value to more efficaciously treat lung tumors while overcoming chemoresistance.
| S-EPMC7771713 | biostudies-literature
Project description:Although the antitumor role of metformin has been widely reported, the molecular mechanism of this biguanide agent in the inhibition of tumor progression remains unclear. Here, we identified miR-708-5p as a novel target of metformin in prostate cancer cells. Metformin promotes increased expression of miR-708-5p, leading to suppression of endoplasmic reticulum (ER) membrane protein neuronatin (NNAT) expression and subsequently induces apoptosis of prostate cancer cells through the ER stress pathway. Further, miR-708-5p-induced knockdown of NNAT is associated with downregulated intracellular calcium levels and induced malformation of ER-ribosome structure revealed by electronic microscopy. Meanwhile, the unfolded protein response regulator CHOP, p-eIF2?, calreticulin, GRP78 and ATP2A1, all of which are also considered as ER stress markers, are upregulated by metformin and miR-708-5p. Taken together, our findings clearly demonstrate that metformin stimulates increased expression of miR-708-5p to target the NNAT-mediated response to ER stress and apoptosis. This novel regulatory mechanism of metformin in prostate cancer cells not only advances our knowledge on the molecular mechanism of metformin but also provides a promising therapeutic strategy by targeting miR-708-5p and NNAT for prostate cancer treatment.
| S-EPMC4491613 | biostudies-literature
Project description:Recent studies have shown that superoxide dismutase 1 (SOD1), SOD2, and SOD3 are significantly decreased in human osteoarthritic cartilage. SOD activity is a marker that can be used to comprehensively evaluate the enzymatic capacities of SOD1, SOD2, and SOD3; however, the trend of SOD activity in end-stage osteoarthritic tissues remains unknown. In the present study, we found that SOD activity in end-stage osteoarthritic synovium of the knee was significantly lower than that in control synovium without the influence of age. The SOD activity was significantly lower in the end-stage knee osteoarthritic cartilage than in the control, but a weak negative correlation was observed between aging and SOD activity. However, SOD activity in end-stage hip osteoarthritic cartilage was significantly lower than that in control cartilage without the influence of aging. The relationship between osteoarthritis and SOD activity was stronger than the relationship between aging and SOD activity. These results indicate that direct regulation of SOD activity in joint tissues may lead to suppression of osteoarthritis progression.
| S-EPMC6141073 | biostudies-literature
Project description:Many cancers maintain an inflammatory microenvironment to promote their growth. Lung cancer is of particular importance, as it is the deadliest cancer worldwide. One inflammatory pathway commonly dysregulated in cancer is the metabolism of arachidonic acid (AA) by Cyclooxygenase-2 (COX-2) and microsomal Prostaglandin E Synthase 1 (mPGES-1) into Prostaglandin E2 (PGE2). While researchers have identified PGE2's pro-tumorigenic functions, the mechanisms governing overexpression of COX-2 and mPGES-1 are incompletely understood. MicroRNAs (miRNAs) are important post-transcriptional regulators commonly dysregulated in cancer. Interestingly, miR-708-5p (miR-708) is predicted to target both COX-2 and mPGES-1. In this study, we show that high miR-708 expression is associated with survival rates in lung squamous cell carcinoma patients. miR-708 also represses PGE2 production by suppressing both COX-2 and mPGES-1 expression in lung cancer cells. miR-708 regulation of COX-2 and mPGES-1 is mediated through targeting of their 3' untranslated regions (UTRs). Moreover, miR-708 decreases proliferation, survival, and migration of lung cancer cells, which can be partially attributed to miR-708's inhibition of PGE2 signaling. Lastly, we identify novel miR-708 predicted targets and possible regulators of miR-708 expression in lung cancer. Collectively, these data demonstrate that dysregulated miR-708 expression contributes to exacerbated PGE2 production, leading to an enhanced pro-tumorigenic phenotype in lung cancer cells.
| S-EPMC7335672 | biostudies-literature