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Infiltration of CD4 + T cells was found in brain tissue samples from PD patients, suggesting their involvement in developing central nervous system (CNS) disease. The idea of the gut-brain axis further corroborates intestinal T cells' activation as the central immune response initiation. However, the specific factors and molecular pathways regulating intestinal T-cell activation are unclear. We used the GSE156287 and GSE145814 datasets from the GEO database to analyze and obtain the miRNAs, which are aberrantly expressed in intestinal CD4 + T cells in PD patients and predict their regulatory target mRNAs. Further, combined with the GSE174473 dataset of CD4 + T cells sequencing in PD patients, we finally clarified the aberrant genes expressed in CD4 + T cells from the intestine of PD patients and constructed a miRNA-mRNA regulatory network. The highlight of our findings showed pathways, networks, biological functions, and key molecules potentially involved in the miRNA-mediated functional effects in CD4 + T cell from the intestine of PD patients. The hsa-miR-3180-3p mediated CBX8, etc. were determined as most effective in enhancing T cell survival. PEG10, etc. regulated by hsa-miR-20a-3p targets were possibly involved in T cell differentiation. The JPT2 regulated by hsa-miR-1281 were involved in influencing T cell infiltration. The discovery of this interaction between miRNA and mRNA in CD4 + T cell has important implications for understanding the intestinal initial of PD pathological molecular and anti-inflammation of T cell activation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Backgrounds: In inflammatory bowel disease microenvironment, transdifferentiation of myeloid-derived suppressor cells (MDSCs) and M2 macrophage accumulation are crucial for the transition of colitis-to-cancer. New insights into the cross-talk and the underling mechanism between MDSCs and M2 macrophage during colitis-to-cancer transition are opening new avenues for colitis-associated cancer (CAC) prevention and treatment., Methods: The role and underlying mechanism that granulocytic MDSCs (G-MDSCs) or exosomes (Exo) regulates the differentiation of monocytic MDSCs (M-MDSCs) into M2 macrophages were investigated using immunofluorescence, FACS, IB analysis, etc , and employing siRNA and antibodies. In vivo efficacy and mechanistic studies were conducted with dextran sulfate sodium-induced CAC mice, employed IL-6 Abs and STAT3 inhibitor., Results: G-MDSCs promote the differentiation of M-MDSC into M2 macrophages through exosomal miR-93-5 p which downregulating STAT3 activity in M-MDSC. IL-6 is responsible for miR-93-5 p enrichment in G-MDSC exosomes (GM-Exo). Mechanistically, chronic inflammation-driven IL-6 promote the synthesis of miR-93-5 p in G-MDSC via IL-6R/JAK/STAT3 pathway. Early use of IL-6 Abs enhances the effect of STAT3 inhibitor against CAC., Conclusions: IL-6-driven secretion of G-MDSC exosomal miR-93-5 p promotes the differentiation of M-MDSC into M2 macrophages and involves a STAT3 signaling mechanism that promote colitis-to-cancer transition. Combining STAT3 inhibitors with strategies that inhibit IL-6-mediated G-MDSC exosomal miR-93-5 p production is beneficial for the prevention and treatment of CAC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ischemic stroke is the leading cause of mortality and disability in aging populations. Dysregulation of microRNA is associated with the pathophysiology of ischemic brain injury. Previously, we found that miR-338-3p was prominently downregulated in OGD-treated neurons, which indicates that miR-338-3P potentially plays an important role in ischemic injury. Furthermore, we performed a bioinformatic analysis and found that conventional protein kinase cγ (cPKCγ), an important autophagy regulator, is a potential target of miR-338-3p, and it is upregulated in neurons after ischemic injury. Therefore, we speculated that miR-338-3P may play a role in neuronal autophagy associated with ischemic brain injury by regulating cPKCγ levels. In the present study, oxygen glucose deprivation was used to test this hypothesis. Our results show that miR-338-3p expression is prominently downregulated after OGD. Additionally, miR-338-3p knockdown attenuated ischemic injury and simultaneously reduced the microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, which contributes to neuronal survival after ischemia. Moreover, the cPKCγ protein level increased, and miR-338-3p recognized the 3'-untranslated region of the cPKCγ messenger RNA (mRNA) and negatively regulated the cPKCγ protein level by promoting the degradation of its mRNA. In addition, Lv-cPKCγ blocked the pri-miR-338-3p-induced decrease of the Akt and mammalian target of rapamycin (mTOR) phosphorylation levels, as well as the accompanying increase of the LC3-II/LC3-I ratio, thereby alleviating ischemic injury. This suggests that miR-338-3p downregulation following ischemic injury alleviates neuronal injury by targeting cPKCγ, thereby activating the Akt/mTOR signaling cascade and decreasing downstream autophagy. These results provide a potential therapeutic target for ischemic stroke., (Copyright © 2022. Published by Elsevier Ltd.)

Circular RNAs play essential roles in the development of various human diseases. However, how circRNAs are involved in diabetic nephropathy (DN) are not fully understood. Our study aimed to investigate the effects of circRNA circEIF4G2 on DN. Experiments were performed in the db/db mouse model of type 2 diabetes and NRK-52E cells. We found that circEIF4G2 was significantly up-regulated in the kidneys of db/db mice and NRK-52E cells stimulated by high glucose. circEIF4G2 knockdown inhibited the expressions of TGF-β1, Collagen I and Fibronectin in high glucose-stimulated NRK-52E cells, which could be rescued by miR-218 inhibitor. Knockdown of SERBP1 reduced the expression of TGF-β1, Collagen I and Fibronectin in HG-stimulated NRK-52E cells. In summary, our findings suggested that circEIF4G2 promotes renal tubular epithelial cell fibrosis via the miR-218/SERBP1 pathway, presenting a novel insight for DN treatment., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

As one of the most aggressive malignancies, non-small cell lung carcinoma (NSCLC) has high risks of death. It has been demonstrated that circRNAs accelerate NSCLC progression, but the underlying molecular mechanisms of circRNAs in NSCLC were still obscure. In the first place, the circRNA microarray of NSCLC was investigated in this study, and hsa_circ_0008003 (circ-0008003) was chosen as the research object. Then, it was unveiled that the expression of circ-0008003 examined via qRT-PCR was elevated in tumour tissues relative to the non-tumour tissues, which was associated with TNM stage and lymphatic metastasis in NSCLC. Additionally, the prognosis of NSCLC patients with high circ-0008003 level was poor. Besides, circ-0008003 silencing dampened the invasion and proliferation of NSCLC cells. Next, according to the mechanistic studies, circ-0008003 functioned as a ceRNA of ZNF281 in NSCLC by acting as the endogenous sponge for miR-488, which was proved to be a tumour suppressor in NSCLC. Additionally, ZNF281 overexpression and miR-488 suppression recovered the influences of repressed circ-0008003 on NSCLC cellular processes. It was validated in this research that circ-0008003 triggered tumour formation in NSCLC, which was adjusted via miR-488/ZNF281 axis, casting a novel light on the resultful target for treating NSCLC and predicting the prognosis., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Diabetic retinopathy (DR) is a type of diabetes complication, which can result in loss of vision in adults worldwide. Increasing evidence has revealed that microRNAs (miRs) can regulate DR progression. Thus, the present study was aimed at assessing the possible mechanism of miR-139-5p in high glucose- (HG-) incubated retinal pigment epithelial (ARPE-19) cells. The present results demonstrated that miR-139-5p expression was notably reduced in the serum samples of patients with DR, as well as in ARPE-19 cells treated with HG in a time-dependent manner. Moreover, miR-139-5p was markedly overexpressed by transfection of miR-139-5p mimics into ARPE-19 cells. Overexpression of miR-139-5p markedly induced cell viability and repressed HG-triggered apoptosis. Furthermore, overexpression of miR-139-5p relived HG-enhanced oxidative stress injury. It was found that HG induced malondialdehyde levels but decreased superoxide dismutase and glutathione peroxidase activities in ARPE-19 cells. In addition, overexpression of miR-139-5p could markedly decrease intracellular stress. The results demonstrated that overexpression of miR-139-5p effectively repressed HG-activated inflammation, as indicated by the upregulation of inflammation cytokines, including TNF- α , IL-6, and Cox-2, in ARPE-19 cells. Subsequently, it was identified that LIM-only factor 4 (LMO4) could act as a downstream target for miR-139-5p. LMO4 expression was significantly increased in patients with DR and HG-treated ARPE-19 cells. Mechanistically, knockdown of LMO4 reversed the biological role of miR-139-5p in proliferation, apoptosis, oxidative stress, and release of inflammation factors in vitro . Collectively, these results suggested that miR-139-5p significantly decreased ARPE-19 cell injury caused by HG by inducing proliferation and suppressing cell apoptosis, oxidant stress, and inflammation by modulating LMO4., Competing Interests: The authors declare no financial or commercial conflict of interest., (Copyright © 2021 Kan Shao et al.)

LncRNAs are reported to participate in the progression of various diseases including diabetic nephropathy. Currently, we reported that SNHG16 was obviously upregulated in db/db mice and high glucose-treated mice mesangial cells. Then, functional experiments showed that SNHG16 silencing significantly inhibited proliferation of mice mesangial cells, which induced the apoptosis and triggered cell cycle arrest. Meanwhile, proliferation-related biomarkers PCNA and Cyclin D1 (CCND1) were greatly repressed. Furthermore, western blot analysis was conducted to test fibrogenesis-associated genes Fibronectin and α-SMA. Meanwhile, the increased protein expression levels of Fibronectin and α-SMA under high glucose conditions were reversed by loss of SNHG16. miR-141-3p has been reported to be involved in various diseases. Then, RNA immunoprecipitation assay revealed the relation between SNHG16 and miR-141-3p. Downregulation of SNHG16 was able to induce expression of miR-141-3p, which was obviously reduced in db/db diabetic nephropathy mice. In addition, CCND1 is a crucial cell cycle master in human diseases. CCND1 was speculated as the target of miR-141-3p and miR-141-3p inhibited CCND1 expression significantly. Meanwhile, we observed that loss of CCND1 greatly repressed mice mesangial cell proliferation and induced cell apoptosis. Taken these together, we revealed for the first time that SNHG16 induced proliferation and fibrogenesis via modulating miR-141-3p and CCND1 in diabetic nephropathy. SNHG16/miR-141-3p/CCND1 axis can suggest a pathological mechanism of progression of diabetic nephropathy.

Acne vulgaris (AV) is a chronic inflammatory disease of the pilosebaceous unit, and Propionibacterium acnes (P. acnes) has been implicated in acne inflammation. Numerous studies have shown that non-coding RNAs play important roles in regulating the pathophysiological processes of acne. In addition, the first imprinted long non-coding RNA (lncRNA) identified, H19, plays a critical role in inflammatory disease. However, the expression and role of H19 in AV remain unclear. In this study, we investigated the effects of H19 in keratinocytes and explored the regulatory mechanisms underlying these effects. H19 was upregulated in keratinocytes treated with P. acnes in a concentration-dependent manner. The phosphorylated forms of the nuclear factor (NF)-κB-related proteins IκBα (p-IκBα) and p65 (p-P65) were significantly upregulated after P. acnes treatment. Additionally, secretion of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 was upregulated in a concentration-dependent manner. Knockdown of H19 inhibited the expression of p-IκBα and p-P65 as well as the secretion of TNF-α, IL-6, and IL-8 in keratinocytes treated with P. acnes. Moreover, H19 was found to exert its proinflammatory effects by activating NF-κB. H19, which was localized mainly in the cytoplasm of keratinocytes, facilitated Toll-like receptor 2 (TLR2) expression by acting as a miR-196a sponge. H19 thus promoted the activation of NF-κB and the secretion of inflammatory cytokines through the miR-196a/TLR2 axis. These findings provide novel insight into the pathogenesis of AV.

The occurrence of and development in the early pathological stage of pancreatic cancer has proved to be associated with microRNAs. However, it remains a great challenge to directly monitor low-expression, and downregulation of, microRNA among living cells, tissues, and serum samples. In this work, Staudinger reduction is first applied in intracellular microRNA detection, establishing a set of smart hybridization-mediated Staudinger reduction probes ( HMSR-probe ) which contain designed oligonucleotide sequences. Meanwhile, 40 serum samples (healthy people (6), patients with pancreatitis (22), and pancreatic cancer patients (12)) are tested for exploring the potential clinical application. Of note, the molecules bound to nucleic acid confine the reactive site to close proximity in a compact space, and nonconnected product from Staudinger reaction facilitates turnover amplification to an ameliorative detection limit (1.3 × 10 -15 M). Moreover, compared with qRT-PCR, a low false positive signal and an excellent specificity makes the probe more suitable and convenient for pancreatic cancer diagnosis in blood samples. For practical applications, HMSR-probe enable accurate differentiation in cell and tissue samples under both 488 and 785 nm and have good coherence to known research. As a proof of concept, the reliable results in distinguishing pancreatic cancer patients from different morbid stages might supply a feasible method for endogenous microRNA detection in fundamental research and clinical diagnostics.

Objective: To elucidate the regulatory effect of hypoxic preconditioning bone marrow mesenchymal stem cells (BMSCs)-exosomes on cardiomyocyte apoptosis in acute myocardial infarction (AMI) rats., Materials and Methods: BMSCs-derived exosomes were extracted by Exoquick method. Expressions of exosome surface markers were determined by Western blot. The AMI model in rats was established by LAD ligation. Rats were randomly assigned into sham group, AMI group, AMI+H-exo group and AMI+N-exo group. MicroRNA-24 expression in rat myocardium was detected at different time points. Subsequently, hypoxic preconditioning or normoxic preconditioning BMSCs-exosomes were intramyocardially injected into rats. Infarct size was calculated through TTC (triphenyltetrazolium chloride) staining. Cardiomyocyte apoptosis was accessed with Terminal Deoxynucleotidyl Transferase dUTP Nick-end Labeling (TUNEL). Heart function of AMI rats was evaluated by echocardiography. Protein expressions of apoptotic genes in rat myocardium were detected by Western blot., Results: The mRNA level of microRNA-24 was higher in H-exo group than N-exo group. Injection of hypoxic preconditioning BMSCs-exosomes markedly upregulated microRNA-24 level, reduced infarct size and improved cardiac function in AMI rats. Protein expressions of Bax, caspase-3 and cleaved-caspase-3 were downregulated by BMSCs-exosomes treatment. H9c2 cells showed upregulated microRNA-24 level and decreased apoptotic rate after incubation with hypoxic preconditioning BMSCs-exosomes. The above cellular performances were partially reversed by transfection of microRNA-24 inhibitor., Conclusions: Hypoxic preconditioning BMSCs-exosomes inhibit cardiomyocyte apoptosis in AMI rats by upregulating microRNA-24.

Objective: To investigate the roles of microRNA-21 (miR-21) in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) with high-fat diet-induced insulin resistance (IR) and diabetes mellitus (DM) mice model., Methods: Eight-week-old C57BL/6 mice were allocated into control group, IR group, and DM group. Body mass was recorded. Intraperitoneal glucose tolerance test was performed to determine any abnormal glucose metabolism. The liver pathological changes were detected by biopsy. Changes in free blood glucose, free serum insulin, blood fat and tumor necrosis factor Α level were measured. Differences in miR-21 expression and peroxidase proliferator-activated receptor subtypes (PPAR-Γ and PPAR-Α) and adipocyte fatty acid binding protein (aP2) in the liver were detected both at the mRNA and protein levels., Results: After one 8-week high-fat diet, the body mass, free serum insulin, and homeostasis model IR index significantly increased in the IR group (P<0.01, P<0.05, compared with control group), while the free blood glucose increased and the free serum insulin decreased in DM group (P<0.05). Free serum insulin level were significantly increased in IR group (P<0.05). Serum tumor necrosis factor-Α levels exhibited an upward trend in control group, IR group, and DM group (P<0.05, P<0.01). With exacerbation in NAFLD, liver miR-21 expression level went further down in both IR and DM groups (P<0.05). The downregulated miR-21 expression level showed negative correlation with upregulated PPAR-Α, ΑP2, and PPAR-Γ genetic expression (r=-0.696, r=-0.664, and r=-0.766, respectively; P<0.05) in IR group and with upregulated PPAR-Α and PPAR-Γ genetic expression in DM group (r=-0.676 and r=-0.550, respectively; P<0.05). In terms of the changes in protein expression level,only on the protein expressions of aP2 and PPAR-Γ in IR group showed significant change (P<0.05, P<0.01, compared with control group)., Conclusions: The miR-21 expression is downregulated in both IR and DM-induced NAFLD mice. It may be involved in the pathogenesis of NAFLD by regulating the expressions of PPAR subtypes.

In this study, we analyzed the microRNA (miRNA) expression profile of 119 paired ESCC samples by microarray and identified a four-miRNA signature that predicted patient survival. The signature derived from the training set (n=60) had a good prognostic value in the test set (n=59) and the independent cohort (n=58), indicating the replicability of its prognostic value. Furthermore, the stratified analysis showed that the signature could predict the survival of TNM stage II and stage III patients, indicating that the four-miRNA signature could help to more accurately predict ESCC patient survival., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Recently, microRNA-99 family members, such as miR-99a/b and miR-100, have been reported to exhibit abnormal expression in various malignant tumors, but their functions in carcinomas are controversial. In this study, we focused on miR-99a and miR-100, which were determined to be universally downregulated in esophageal squamous cell carcinoma, and investigated their functions and potential mechanisms of action. The downregulation of miR-99a/100 was validated by qRT-PCR in 101 ESCC surgical tissue samples and in 3 ESCC cell lines. The overexpression of miR-99a and miR-100 via the transient transfection of the corresponding precursor molecules inhibited cell proliferation by inducing apoptosis in the ESCC cell lines. To investigate the molecular mechanism of miR-99a/100-induced apoptosis, luciferase reporter assays and Western blots were performed to demonstrate that the overexpression of miR-99a/100 suppressed the expression of mTOR by directly targeting its 3'UTR in a post-transcriptional manner. Clinically, the decreased expression of miR-99a/100 was associated with worse overall survival in ESCC patients. In conclusion, these results indicated that miR-99a and miR-100 inhibited cell proliferation by suppressing mTOR in ESCC cell lines, and therefore, the miR-99a/100-mTOR signaling pathway is a potential therapeutic target for inducing apoptosis to combat ESCC.

MicroRNAs (miRNAs) as a species of small non coding single stranded RNA of about 21-25 nucleotides have important roles in the development of different cancers. In present study, we found that the expression of miR-25 was up-regulated in 60 esophageal squamous cell carcinoma (ESCC) tissues compared with matched adjacent non-cancer tissues. Moreover, we demonstrated that the up-regulation of miR-25 was significantly correlated with the status of lymph node metastasis and TNM (Tumor, Node and Metastasis) stage. Furthermore, over-expression of miR-25 markedly promoted migration and invasion of ESCC cells. On the contrary, down-regulation of miR-25 inhibited the migration and invasion of cells. E-cadherin(CDH1) is a very important tumor metastasis suppressor. We further identified that miR-25 directly targeted CDH1 3'-untranslated region (3'UTR) and repressed the expression of CDH1. These results, for the first time, demonstrate that miR-25 promotes ESCC cell migration and invasion by suppressing CDH1 expression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In HCT116 colorectal cancer cells, HeLa cervical cancer cells and HuH-7 hepatoma cells, miR-223 is expressed at a low level. Through infection with lentivirus containing miR-223 precursor, miR-223 [corrected] was overexpressed in all these cells. Interestingly, the expression levels of FOXO1 mRNA and protein, and phosphorylation levels became significantly lower than those of their control. FOXO1 was down-regulated mainly in the cytoplasm, while the nuclear FOXO1 level became relatively high compared to the cytoplasm. As the unphosphorylated active form of FOXO1 increased in the cells, cyclin D1/p21/p27 were up-regulated at either mRNA or protein level. Proliferation of the cells was also greatly inhibited when miR-223 was over-expressed. Therein, our data suggest that miR-223 regulates FOXO1 expression and cell proliferation., (Copyright © 2012 Federation of European Biochemical Societies. All rights reserved.)

Purpose: Recent studies have suggested that microRNA biomarkers could be useful for stratifying lung cancer subtypes, but microRNA signatures varied between different populations. Squamous cell carcinoma (SCC) is one major subtype of lung cancer that urgently needs biomarkers to aid patient management. Here, we undertook the first comprehensive investigation on microRNA in Chinese SCC patients., Experimental Design: MicroRNA expression was measured in cancerous and noncancerous tissue pairs strictly collected from Chinese SCC patients (stages I-III), who had not been treated with chemotherapy or radiotherapy prior to surgery. The molecular targets of proposed microRNA were further examined., Results: We identified a 5-microRNA classifier (hsa-miR-210, hsa-miR-182, hsa-miR-486-5p, hsa-miR-30a, and hsa-miR-140-3p) that could distinguish SCC from normal lung tissues. The classifier had an accuracy of 94.1% in a training cohort (34 patients) and 96.2% in a test cohort (26 patients). We also showed that high expression of hsa-miR-31 was associated with poor survival in these 60 SCC patients by Kaplan-Meier analysis (P = 0.007), by univariate Cox analysis (P = 0.011), and by multivariate Cox analysis (P = 0.011). This association was independently validated in a separate cohort of 88 SCC patients (P = 0.008, 0.011, and 0.003 in Kaplan-Meier analysis, univariate Cox analysis, and multivariate Cox analysis, respectively). We then determined that the tumor suppressor DICER1 is a target of hsa-miR-31. Expression of hsa-miR-31 in a human lung cancer cell line repressed DICER1 activity but not PPP2R2A or LATS2., Conclusions: Our results identified a new diagnostic microRNA classifier for SCC among Chinese patients and a new prognostic biomarker, hsa-miR-31., (©2011 AACR)

Cyclin E is reported to be an important cell cycle regulator, and its dysregulation is implicated in tumorigenesis including esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level and play important roles in tumor initiation and progression. However, the regulation of cyclin E by miRNAs is still unclear in ESCC. In the present study, we found that overexpression of miR-29c inhibited cyclin E expression by targeting 3' untranslated region of cyclin E messenger RNA in ESCC cells. Moreover, overexpression of miR-29c induced cell cycle G(1)/G(0) arrest through suppression of cyclin E expression, without affecting other G(1) phase-related proteins level, such as cyclin D1, cyclin D2, cyclin dependent kinase (CDK) 2 and CDK6. Furthermore, we demonstrated that overexpression of miR-29c inhibited proliferation of ESCC cells in vitro and in vivo. In addition, we detected miR-29c expression in 26 pairs of esophageal tumor-in-site-tissues and 60 pairs of ESCC tissues. The result showed that miR-29c level significantly decreased in ESCC tumor tissues and cell lines compared with normal esophageal epithelia. Taken together, our findings indicated that miR-29c was frequently downregulated in ESCC tissues and cells and suppressed tumor growth by inducing cell cycle G(1)/G(0) arrest mainly through modulating cyclin E expression.

Esophageal cancer is the sixth leading cause of death from cancer and one of the least studied cancers worldwide. The global microRNA expression profile of esophageal cancer has not been reported previously. Here, for the first time, we have investigated expressed microRNAs in cryopreserved esophageal cancer tissues using advanced microRNA microarray techniques. Our microarray analyses identified seven microRNAs that could distinguish malignant esophageal cancer lesions from adjacent normal tissues. Some microRNAs could be correlated with the different clinicopathologic classifications. High expression of hsa-miR-103/107 correlated with poor survival by univariate analysis as well as by multivariate analysis. These results indicate that microRNA expression profiles are important diagnostic and prognostic markers of esophageal cancer, which might be analyzed simply using economical approaches such as reverse transcription-PCR.