miR-146a Levels Research Articles

Crucial role of corticotropin-releasing hormone, corticotropin-releasing hormone -binding protein, mir-200c, and mir-181a in preterm delivery: A case-control study.

Preterm birth before 37 wk of gestation is called premature birth. Corticotropin-releasing hormone (CRH) and CRH-binding protein (BP) act on various maternal and fetal tissues during pregnancy, such as the myometrium, which regulates the transition from the dormant phase of the uterus to the active phase. Studies have shown that mir-200c and mir-181a interact with CRH and CRH-BP. The present study aimed to investigate the expression of mir-200c, mir-181a, CRH, and CRH-BP in women with a history of preterm birth. In this case-control study, the gene expression level of mir-200c, mir-181a, CRH, and CRH-BP in placental tissue samples obtained from 48 women with a history of preterm labor was assessed in the Mojibian hospital of Yazd, Iran, from January to March 2023. Differences between mir-200c, mir-181a CRH, and CRH-BP gene expressions among cases and controls were assessed. The outcomes indicated that the expression of CRH increased with going on to the regular parturition time (p 0.001). While outcomes indicated, CRH-BP decreased with going on to the regular parturition time (p 0.001). In addition, the results showed that the expression of mir-181a increased and mir-200c decreased with approaching the normal delivery time (p 0.001). In conclusion, the expressions of mir-200c, mir-181a, CRH, and CRH-BP were dissimilar in different weeks of gestation. It could be proposed to use mir-200c, mir-181a, CRH, and CRH-BP as biomarkers to weigh the exact delivery time, which could minimize the side effects of preterm labor for the mother and fetus.

Can atypical response in endothelial dysfunction-related genes and microRNAs arise from low hydrogen peroxide exposure?

Vascular endothelium is a tissue in which several vasoactive substances are produced and secreted. Reactive oxygen species can cause endothelial dysfunction (ED). miRNAs can be implicated in the oxidative stress-related ED during vascular disease pathogeneses. Our aim is to investigate effect of H2O2-induced oxidative stress on expression levels of genes and miRNAs that are key players in ED. H2O2 effect on cell viability of human umbilical-vein endothelial cells (HUVEC) at 24-hour was measured with MTT. Low sub-cytotoxic H2O2 concentrations (25, 50µM) were selected to analyze their oxidative stress-inducing capacities with MDA assay and their effects on EDN1, NOS3, VCAM1, SERPINE1, miR21, miR22, miR126, and miR146a levels with RT-qPCR. Each tested H2O2 concentration reduced HUVEC cell viability. Fifty µM H2O2 augmented cellular MDA levels. Intriguingly, EDN1, VCAM1, and SERPINE1 and all analyzed miRNAs' levels attenuated upon H2O2 treatment whereas there was no change in NOS3 levels compared to control. There was a positive correlation between miR-21 and VCAM1. Rather than individual alterations in analyzed parameters, consistent changes in our findings i.e., parallel decreases in EDN1, VCAM1, SERPINE1 mRNA levels as well as miRNAs, suggests that H2O2 concentration-dependent modulation of expression patterns can bring about various impacts on ED (Tab. 1, Fig. 5, Ref. 63).

A systems biology approach and in vitro experiment indicated Rapamycin targets key cancer and cell cycle-related genes and miRNAs in triple-negative breast cancer cells.

An anticancer drug known as Rapamycin acts by inhibiting the mammalian target of the Rapamycin pathway. This agent has recently been investigated for its potential therapeutic benefits in sensitizing drug-resistant breast cancer (BC) treatment. The molecular mechanism underlying these effects, however, is still a mystery. Using a systems biology method and in vitro experiment, this study sought to discover essential genes and microRNAs (miRNAs) targeted by Rapamycin in triple-negative BC (TNBC) cells to aid prospective new medications with less adverse effects in BC treatment. We developed the transcription factor-miRNA-gene and protein-protein interaction networks using the freely accessible microarray data sets. FANMOD and MCODE were utilized to identify critical regulatory motifs, clusters, and seeds. Then, functional enrichment analyses were conducted. Using topological analysis and motif detection, the most important genes and miRNAs were discovered. We used quantitative real-time polymerase chain reaction (qRT-PCR) to examine the effect of Rapamycin on the expression of the selected genes and miRNAs to verify our findings. We performed flow cytometry to investigate Rapamycin's impact on cell cycle and apoptosis. Furthermore, wound healing and migration assays were done. Three downregulated (PTGS2, EGFR, VEGFA) and three upregulated (c-MYC, MAPK1, PIK3R1) genes were chosen as candidates for additional experimental verification. There were also three upregulated miRNAs (miR-92a, miR-16, miR-20a) and three downregulated miRNAs (miR-146a, miR-145, miR-27a) among the six selected miRNAs. The qRT-PCR findings in MDA-MB-231 cells indicated that c-MYC, MAPK1, PIK3R1, miR-92a, miR-16, and miR-20a expression levels were considerably elevated following Rapamycin treatment, whereas PTGS2, EGFR, VEGFA, miR-146a, and miR-145 expression levels were dramatically lowered (p < 0.05). These genes are engaged in cancer pathways, transcriptional dysregulation in cancer, and cell cycle, according to the top pathway enrichment findings. Migration and wound healing abilities of the cells declined after Rapamycin treatment, and the number of apoptotic cells increased. We demonstrated that Rapamycin suppresses cell migration and metastasis in the TNBC cell line. In addition, our data indicated that Rapamycin induces apoptosis in this cell line. The discovered vital genes and miRNAs affected by Rapamycin are anticipated to have crucial roles in the pathogenesis of TNBC and its therapeutic resistance.

Differential Expression of Peripheral Circulating MicroRNA-146a Between Patients with Atherosclerotic Vulnerable Plaque and Stable Plaque.

Atherosclerotic plaque rupture and subsequent cardiovascular complications threaten the population's health worldwide. The polymorphism of miR-146a rs2910164 was significantly associated with the risk of vulnerable plaques. However, it remains unclear whether the circulating miR-146a is differentially expressed in stable and vulnerable plaques and thus, serves as a potential biomarker.This study aims to analyze the differential expression of circulating miR-146a between patients with stable and vulnerable plaques to explore the potential molecular mechanisms.Public databases were searched from their inception up to November 2022. A study reporting the specific circulating miR-146a levels between patients with stable and vulnerable plaques was included. The study quality was assessed using the modified genetic 8-stars Newcastle-Ottawa scale. The differential expression levels of miR-146a were evaluated using the standardized mean difference (SMD).Eight studies with 978 patients were included and analyzed. The results showed that miR-146a expression levels were significantly higher in the vulnerable plaque population than in the stable plaque population (SMD: 1.91; 95% confidence interval: 1.35, 2.47; P < 0.01). A similar statistical significance was found in subgroup analyses regarding sample source, disease type, and vulnerable plaque characteristics. Sensitivity analysis suggested the robustness of the results. Analysis of downstream genes suggested that miR-146a-targeted regulation of ACTN4, SARM1, and ULK2 may affect intraplaque hemorrhage.Patients with vulnerable plaque have higher circulating miR-146a levels than those with stable plaque. However, based on the limitations of this study, high-quality studies are still needed to confirm the results.

MiR-126 and miR-146a as Melatonin-Responsive Biomarkers for Neonatal Brain Ischemia

Despite advances in obstetric and neonatal care, challenges remain in early identification of neonates with encephalopathy due to hypoxia-ischemia who are undergoing therapeutic hypothermia. Therefore, there is a deep search for biomarkers that can identify brain injury. The aims of this study were to investigate the serum and brain expressions of two potential biomarkers, miR-126/miR-146a, in a preclinical model of hypoxia-ischemia (HI)–induced brain injury, and to explore their modulation during melatonin treatment. Seven-day-old rats were subjected to permanent ligation of the right carotid artery followed by 2.5 h hypoxia (HI). Melatonin (15 mg/kg) was administered 5 min after HI. Serum and brain samples were collected 1, 6 and 24 h after HI. Results show that HI caused a significant increase in the circulating levels of both miR-126 and miR-146a during the early phase of ischemic brain damage development (i.e. 1 h), with a parallel and opposite pattern in the ischemic cerebral cortex. These effects are not observed 24 h later. Treatment with melatonin restored the HI-induced effects on miR-126/miR-146a expressions, both in the cerebral cortex and in serum. We conclude that miR-126/miR-146a are promising biomarkers of HI injury and demonstrate an associated change in concentration following melatonin treatment.

Selected miRNA and Psoriasis-Cardiovascular Disease (CVD)-Overweight/Obesity Network-A Pilot Study.

Psoriasis is nowadays recognized as a multifactorial systemic disease with complex and not fully understood pathogenesis. In psoriatic patients, the increased cardiovascular disease (CVD) risk and frequent comorbidities like obesity are observed. The aim of this study was to investigate differences in miRNA (miR-22-3p, miR-133a-3p, miR-146a-5p, miR-369-3p, and Let-7b-5p) involved in CVD risk among psoriatic patients with overweight/obesity and with normal weight. The study comprised 28 male psoriatic patients and 16 male healthy controls. miRNA isolated from peripheral blood mononuclear cells was reverse-transcribed and RT-qPCR was performed. We have found decreased levels of miR-22, miR-133a, miR-146a, and miR-369 among the psoriatic patients. There was a statistically significant difference in miR-22 and miR-146a levels between psoriatic patients with overweight/obesity and with normal weight. There were positive correlations between miR-22 and miR-146a levels and psoriatic arthritis (PsA) in psoriatic patients with normal weight and between the miR-133a level and PsA in the overweight/obese patients. The decreased levels of selected miRNA are consistent with the levels observed in CVD indicating their impact on the CVD risk in psoriatic patients. miR-22 and miR-146 may be recognized as one of the contributing factors in the obesity-CVD-psoriasis network.

Assessment of tissue levels of miR-146a and proinflammatory cytokines in experimental cerebral toxoplasmosis following atovaquone and clindamycin treatment: An in vivo study

BackgroundDespite recent advances for treating cerebral toxoplasmosis (CT), monitoring the parasite burden and treatment response is still challenging. miRNAs are small non-coding RNAs with regulatory functions that can be used in diagnosis and treatment monitoring. We investigated the changes in miR-146a, BAG-1 gene, IL-6, and IL-10 tissue levels in the brain of BALB/c mice with chronic CT caused by the PRU strain of T. gondii following anti-parasitic and antibiotic treatment. MethodFifty-three 6-to 8-week-old BALB/c mice were infected using intraperitoneal inoculation of cerebral cysts of T. gondii PRU strain and then divided into five groups as follows: group 1 included mice treated with 100 mg/kg/d Atovaquone (AT), group 2 included mice treated with 400 mg/kg/d clindamycin (CL), group 3 included mice treated with combination therapy (AT + CL), group 4 included infected untreated mice as a positive control (PC), and; group 5 included uninfected untreated mice as negative control (NC). After the completion of the treatment course, tissue level of mir-146a, miR-155, BAG-1 gene, IL-6, and IL-10 was investigated with real-time polymerase chain reaction. The IL-6/IL-10 ratio was calculated as an indicator of immune response. Moreover, brain cyst numbers were counted on autopsy samples. ResultsmiR-146a, IL-6, IL-10, and BAG-1 genes were expressed in PC, but not in the NC group; miR-146a, IL-6, IL-10, and BAG-1 gene expression were significantly lower in AT, CL, and AT + CL compared with PC. MiR-146a and BAG-1 levels in AT and CL were not different statistically, however, they both had lower levels compared to AT + CL (P < 0.01). There was no difference in the expression of IL-6 and IL-10 between treatment groups. BAG-1 expression was significantly lower in AT, than in CL and AT + CL (P < 0.0089 and < 0.002, respectively). The PC group showed a higher ratio of IL-6/IL-10, although this increase was not statistically significant. It is noteworthy that the treatment with AT reduced this ratio; in the inter-group comparison, this ratio showed a decrease in the AT and AT + CL compared to the PC. The number of brain tissue cysts was significantly lower in AT, CL, and AT + CL, than in PC (p < 0.0001). AT had significantly lower brain cysts than CL and AT + CL (P < 0.0001). ConclusionIt seems that the factors studied in the current research (microRNA and cytokines) are a suitable index for evaluating the response to antiparasitic and antibiotic treatment. However, more studies should be conducted in the future to confirm our findings.

MiR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling

IntroductionMir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)1–42. MethodsTo create a model of AD, SH-SY5Y cells were treated with Aβ1–42 and mice received intracerebroventricular injections of Aβ1–42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations. ResultsAβ1–42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ1–42, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway. ConclusionsOur research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.

Conjugated linoleic acid and L-carnitine combination effects on obesity-related miRNAs in diet-induced obese rats

ObjectivesObesity is a major global health issue, resulting in significant costs and increased mortality rates. Finding effective treatments for obesity is therefore essential. This study investigated the combined effects of L-Carnitine (LC) and Conjugated Linoleic Acid (CLA) on weight loss and adipose tissue microRNA levels. Subjects /methodsForty male Wistar rats weighing 150–200 g and about 8 weeks old were fed either a normal fat diet (NFD) or a high-fat diet (HFD) for 8 weeks. Afterwards, the HFD group was randomly divided into four subgroups: control, LC (200 mg kg−1), CLA (500 mg kg−1), and both (n = 8 in each group). The study lasted for an additional 4 weeks. The animals' weights were recorded regularly, and after 12 weeks, miRNAs were extracted from epididymal adipose tissue and analysed using real-time PCR. The miRNA expression levels of miR-27a and miR-143 were compared between groups using Kolmogorov-Smirnov and one-way ANOVA tests in SPSS software. ResultsAt the end of the first 8 weeks, the HFD group weighed significantly more than the NFD group. LC significantly decreased weight gain (4.2%) compared to the control group, whereas CLA alone (3.5%) or in combination with LC (3.1%) did not significantly slow weight gain. Real-time PCR results showed that the HFD group had higher miR-143 levels and lower miR-27a levels compared to the NFD group. LC and CLA increased miR-27a expression after 4 weeks, but their combination decreased miR-27a expression. CLA alone reduced miR-143 expression, whereas LC had almost no effect. Their combination also reduced miR-143 expression. ConclusionCLA and LC, which are considered weight loss supplements, can potentially regulate metabolism and cellular pathways. However, their combination did not show a synergistic effect on weight loss, possibly due to the reduction in miR-27a expression. Further studies are needed to evaluate the effects of combined fat burners on obesity treatment.

Circulating miR-146a predicts glucocorticoid response in thyroid eye disease.

Thyroid eye disease (TED) is an immune-mediated disorder of the eye. Intravenous glucocorticoid (GC) is the first-line treatment for patients with active moderate-to-severe TED. However, the response rate is between 50% and 80%. There are still no simple and reliable markers of responsiveness to GC therapy. We aimed to explore the possible role of miR-146a and miR-21 as predictors of responsiveness to GC treatment in TED. We carried out a prospective longitudinal study on 30 consecutive adult patients with active moderate-to-severe TED and eligible for GC therapy. All patients received the standard GC treatment with methylprednisolone i.v. In cases of progressive worsening of Gorman Score for diplopia or with duction restriction <30° in at least two consecutive controls, patients also underwent orbital radiotherapy. Response to GC treatment was defined as a decrease of two or more points in the clinical activity score (CAS) or CAS <4/10 at 24 weeks. Circulating miRNAs were extracted from patients' serum and quantified by real-time PCR. Twenty-three (77%) patients responded to GC. Thyroid surgery, higher CAS, greater proptosis and higher pre-treatment circulating levels of miR-146a emerged as predictive factors of responsiveness to GC. A ROC analysis revealed that miR-146a could predict responsiveness to GC with a positive predictive value of 100%. This is the first study investigating the role of pre-treatment circulating miR-21 and miR-146a to predict responsiveness to GC in TED. miR-146a emerged as a simple, objective, new marker of GC sensitivity that could be used to avoid ineffective administration of GC therapy to TED patients.

Differential Expression of miR-146 and miR-155 in Active and Latent Tuberculosis Infection.

Tuberculosis (TB) is one of the leading causes of death worldwide. Besides, one-third of the world population is infected with Mycobacterium tuberculosis (MTB) while staying clinically asymptomatic; the situation is called latent TB infection (LTBI). MiR-21, miR-31, miR-146a, and miR-155 play an important role in many immune and inflammatory pathways. In the present study the expression levels of MiR-21, miR-31, miR-146a, and miR-155 in peripheral blood mononuclear cells (PBMCs) from patients with active TB, latently infected individuals (LTBI), and healthy controls (HC) were investigated. Participants were recruited at the Bouali Hospital, Zahedan University of Medical Sciences, Zahedan, Iran from 2010 to 2011. PBMCs were stimulated with PPD before RNA extraction. TaqMan RT-qPCR assay was used to analyze the expression levels of miRNAs. The results indicated no significant differences in the expression of miR-21 and miR-31 between different groups; however, in patients with active TB, the expression of miR-21 (P=0.03) and miR-31 (P=0.04) were significantly increased after stimulation with PPD compared to the unstimulated condition. The expression of miR-146 in response to PPD in both LTBI (P=0.02) and TB (P=0.03) groups compared to the HC group was increased. No significant differences were found in the expression level of miR-155 in response to PPD between LTBI and HC groups. However, the fold change was significantly higher in the TB group in comparison with the HC (P=0.03) and LTBI (P=0.05) groups. The results confirm the main role of miR-146 and miR-155 in TB infection and suggest a role for miR-146 and miR-155 as infection and activation markers in tuberculosis infection, respectively.

Macrophage-Targeted Lipid Nanoparticle Delivery of microRNA-146a to Mitigate Hemorrhagic Shock-Induced Acute Respiratory Distress Syndrome.

The pro-inflammatory response of alveolar macrophages to injurious physical forces during mechanical ventilation is regulated by the anti-inflammatory microRNA, miR-146a. Increasing miR-146a expression to supraphysiologic levels using untargeted lipid nanoparticles reduces ventilator-induced lung injury but requires a high initial dose of miR-146a making it less clinically applicable. In this study, we developed mannosylated lipid nanoparticles that can effectively mitigate lung injury at the initiation of mechanical ventilation with lower doses of miR-146a. We used a physiologically relevant humanized in vitro coculture system to evaluate the cell-specific targeting efficiency of the mannosylated lipid nanoparticle. We discovered that mannosylated lipid nanoparticles preferentially deliver miR-146a to alveolar macrophages and reduce force-induced inflammation in vitro. Our in vivo study using a clinically relevant mouse model of hemorrhagic shock-induced acute respiratory distress syndrome demonstrated that delivery of a low dose of miR-146a (0.1 nmol) using mannosylated lipid nanoparticles dramatically increases miR-146a levels in mouse alveolar macrophages and decreases lung inflammation. These data suggest that mannosylated lipid nanoparticles may have the therapeutic potential to mitigate lung injury during mechanical ventilation.

Correlation between Circulating miR-16, miR-29a, miR-144 and miR-150, and the Radiotherapy Response and Survival of Non-Small-Cell Lung Cancer Patients.

Despite the success of current therapy concepts, patients with advanced non-small-cell lung cancer (NSCLC) still have a very poor prognosis. Therefore, biological markers are urgently needed, which allow the assessment of prognosis, or prediction of the success of therapy or resistance in this disease. Circulating microRNAs (miRs) have potential as biomarkers for the prognosis and prediction of response to therapy in cancer patients. Based on recent evidence that circulating miR-16, miR-29a, miR-144 and miR-150 can be regulated by ionizing radiation, the concentration of these four miRs was assessed in the plasma of NSCLC patients at different time points of radiotherapy by digital droplet PCR (ddPCR). Furthermore, their impact on patients' prognosis was evaluated. The mean plasma levels of miR-16, miR-29a, miR-144 and miR-150 significantly differed intra- and inter-individually, and during therapy in NSCLC patients, but showed a strong positive correlation. The individual plasma levels of miR-16, miR-29a and miR-144 had prognostic value in NSCLC patients during or at the end of radiotherapy in Cox's regression models. NSCLC patients with low levels of these three miRs at the end of radiotherapy had the worst prognosis. However, miR-150 plasma levels and treatment-dependent changes were not predictive. In conclusion, circulating miR-16, miR-29a and miR-144, but not miR-150, have a prognostic value in NSCLC patients undergoing radiotherapy.

Autophagy in combination therapy of temozolomide and IFN-γ in C6-induced glioblastoma: role of non-coding RNAs.

Aim: We predicted the modulation of autophagy and apoptosis in response to temozolomide (TMZ) and IFN-γbased on changes in the expression of non-coding RNAs in C6-induced glioblastoma (GBM). Materials & methods: Each rat received an intraperitoneal injection of TMZ (7.5mg/kg)and/or IFN-γ (50,000IU). Results: The reduced expression of H19 and colorectal neoplasia differentially expressed (CRNDE) was associated with a reduction in autophagy in response to TMZ, IFN-γand TMZ+IFN-γ therapy, whereas the decreased level of miR-29a (proapoptotic miRNA) was associated with an increase in apoptosis. Conclusion: It appears that H19 promotes switching from autophagy to apoptosis in response to combination therapy of TMZ and IFN-γ through the miR-29a/autophagy-related protein 9A (ATG9A) pathway in C6-induced GBM.

Long-Term LDL-Apheresis Treatment and Dynamics of Circulating miRNAs in Patients with Severe Familial Hypercholesterolemia.

Lipoprotein apheresis (LA) is a therapeutic option for patients with severe hypercholesterolemia who have persistently elevated LDL-C levels despite attempts at drug therapy. MicroRNAs (miRNAs), important posttranscriptional gene regulators, are involved in the pathogenesis of atherosclerosis. Our study aimed to monitor the dynamics of twenty preselected circulating miRNAs in patients under long-term apheresis treatment. Plasma samples from 12 FH patients (men = 50%, age = 55.3 ± 12.2 years; mean LA overall treatment time = 13.1 ± 7.8 years) were collected before each apheresis therapy every sixth month over the course of four years of treatment. Eight complete follow-up (FU) samples were measured in each patient. Dynamic changes in the relative quantity of 6 miRNAs (miR-92a, miR-21, miR-126, miR-122, miR-26a, and miR-185; all p < 0.04) during FU were identified. Overall apheresis treatment time influenced circulating miR-146a levels (p < 0.04). In LDLR mutation homozygotes (N = 5), compared to heterozygotes (N = 7), we found higher plasma levels of miR-181, miR-126, miR-155, and miR-92a (all p < 0.03). Treatment with PCSK9 inhibitors (N = 6) affected the plasma levels of 7 miRNAs (miR-126, miR-122, miR-26a, miR-155, miR-125a, miR-92a, and miR-27a; all p < 0.04). Long-term monitoring has shown that LA in patients with severe familial hypercholesterolemia influences plasma circulating miRNAs involved in endothelial dysfunction, cholesterol homeostasis, inflammation, and plaque development. The longer the treatment using LA, the better the miRNA milieu depicting the potential cardiovascular risk.

Post-therapeutic microRNA-146a in liquid biopsies may determine prognosis in metastatic gastrointestinal cancer patients receiving 90Y-radioembolization

PurposeThe role of microRNA-146a (miR-146a) in defining the tumor immune microenvironment (TIME) is well established. The aim of this study was to evaluate circulating miR-146a as an early prognostic marker of 90Y-radioembolization (90Y-RE) in metastatic liver cancer and to assess the correlation between circulating miR-146a and TIME cellular composition in distant, yet untreated metastases.MethodsTwenty-one patients with bilobar liver lesions from gastro-intestinal cancer underwent lobar 90Y-RE. Biopsy of contralateral lobe abscopal tumors was acquired at the onset of a second treatment session at a median of 21 days after initial RE, immediately prior to ablation therapy of the contralateral lobe tumor. miR-146a was measured by RT-qPCR in plasma collected 24 h before (T1) and 48 h after (T2) initial unilobar 90Y-RE. The level of miR-146a was correlated with the infiltration of CD4 + , CD8 + , FoxP3 T cells, CD163 + M2 macrophages and immune-exhausted T cells in the abscopal tumor tissue acquired before the second treatment session.ResultsPlasma samples collected at T2 showed a higher concentration of miR-146a with respect to T1 in 43% of the patients (p = 0.002). In these patients, tumors revealed a pro-tumorigenic immune composition with enrichment of Tim3 + immune exhausted cells (p = 0.021), in combination with a higher infiltration of CD163 + M2 macrophages and a lower infiltration of CD8 + T cells. Patients with a higher level of miR-146a after 90Y-RE showed a trend to shorter OS (p = 0.055).ConclusionmiR-146a may represent a novel prognostic biomarker for 90Y-radioembolization in metastatic liver cancer.

Matrine inhibits miR-181a-mediated chemoresistance in rectal cancer

Chemotherapy is widely used for treating rectal cancer, but the existence of drug resistance during chemotherapy hinders the therapeutic effect of chemotherapy. Studies have found that matrine inhibits miR-181a and PI3K-Akt and the expression of miR-181a affects PI3K-Akt activity. Therefore, this paper explores whether matrine can affect PI3K-Akt activity by regulating miR-181a via constructing a rat model of rectal cancer, and finally reduce the chemotherapy resistance of rectal cancer. The rat model of rectal cancer was constructed, treated with the chemotherapy drug pentafluorouracil (5-FU), and assigned into model group, chemotherapy-resistant group, low-dose and high-dose matrine group followed by analysis of the pathology by HE staining. Rectal cancer tissues were used to construct miR-181a silencing group and miR-181a overexpression group followed by measuring cell inhibition by MTT assay, cell proliferation and apoptosis by flow cytometry, and the levels of miR-181a, PI3K and Akt. (1) miR-181a expression was related to matrine’s inhibition of chemotherapy resistance in rectal cancer; (2) miR-181a expression induced PI3K-Akt signaling during matrine’s inhibition of chemotherapy resistance; (3) matrine can further inhibit PI3K-Akt activation by inhibiting miR-181a to enhance the sensitivity of chemotherapy resistance. Matrine can inhibit the expression of miR-181a to reduce PI3K-AKT signaling activity and decrease chemotherapy resistance of rectal cancer. It provides a new idea for clinical chemotherapy drugs to treat rectal cancer and increases the therapeutic effects.

MiR-181a regulates mitophagy and improves cognitive function in vascular dementia via targeting PINK1/Parkin pathway

This study investigates the mechanism of miR-181a in cognitive function and mitophagy in vascular dementia. A rat model of vascular dementia was established by common carotid artery ligation and then divided into model group (n= 10), mimics group (n= 10), inhibitors group (n= 10), NC group (n= 10), and the remaining 10 rats were in sham operation group. The rats in mimics group were intravenously injected with miR-181a mimics and rats in inhibitors group were injected with miR-181a inhibitors. Model group and mimics group rats had a longer time on the 3rd to 4th day than sham operation group, and inhibitors group had a shorter time than model group and mimics group (allP&lt;0.05). Time in quadrant of the cylindrical platform in model group and mimics group was shortened while it was prolonged in inhibitors group (P&lt; 0.05). miR-181a mRNA level in model group, inhibitors group and NC group was lower. On the contrary, PINK1 and Parkin level was higher. miR-181a mRNA level was higher in mimics group with lower levels of PINK1 and Parkin (P&lt;0.05). miR-181a level in mimics group was significantly increased and PINK1 and Parkin mRNA was decreased. miR-181a mRNA level in inhibitors group decreased significantly, while PINK1 and Parkin mRNA was increased (P&lt;0.05). Parkin expression in mimics group and NC group was reduced. Up-regulation of miR-181 (mimics group) can target and inhibit PINK1/Parkin mRNA, thereby inhibiting mitophagy. miR-181a downregulation in mitochondria can promote PINK1/Parkin expression, thereby activating mitophagy in rats with vascular dementia, alleviating mitochondrial dysfunction, and improving the cognitive ability of rats.

The polymorphisms of miR-146a SNPs are associated with asthma in Southern Chinese Han population

Asthma, a prevalent disease characterized by innate and adaptive immune responses, has been associated with several risk factors including miR-146a. To better understand the potential impact of miR-146a SNPs on asthma susceptibility and clinical features in Southern Chinese Han population, we conducted a case-control to analyze two functional SNPs (rs2910164 and rs57095329) of the miR-146a (394 patients with asthma and 395 healthy controls). Our findings suggest that the rs2910164 C/G genotype may increase the risk for asthma in females, while the rs57095329 G/G genotype may be involved in the regulation of clinical characteristics of males with asthma. In addition, we demonstrated that the SNPs rs2910164 C/G and rs57095329 A/G variations functionally affected the miR-146a levels in patients with asthma, and may alter structure of miR-146a. Our data are the first to suggest that miR-146a SNPs may be significantly associated with onset asthma in Southern Chinese Han population. Our studies may provide new insight into the potential significance of miR-146a SNPs in asthma.

Terfezia boudieri and Terfezia claveryi inhibit the LPS/IFN-γ-mediated inflammation in RAW 264.7 macrophages through an Nrf2-independent mechanism

Desert truffles have been used as traditional treatments for numerous inflammatory disorders. However, the molecular mechanisms underlying their anti-inflammatory effects in RAW 264.7 macrophages have yet to be fully elucidated. The present study investigated the anti-inflammatory activities of two main desert truffles, Terfezia boudieri and T. claveryi, and the underlying mechanisms associated with their anti-inflammatory activities in RAW 264.7 macrophages stimulated with lipopolysaccharide/interferon-gamma (LPS/IFN-γ). Our results demonstrated that treatment with T. boudieri and T. claveryi extracts effectively suppressed the inflammatory response in LPS/IFN-γ-stimulated RAW 264.7 macrophages. Specifically, T. boudieri extract was found to reduce the production of nitric oxide and inhibit the expression of various pro-inflammatory markers, including inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor-α, and interleukin-6 (IL-6) at both the mRNA and protein levels. Similarly, T. claveryi extract exhibited comparable inhibitory effects, except for the expression of IL-6 and COX-2 at the protein level, where no significant effect was observed. Moreover, both studied extracts significantly downregulated the microRNA expression levels of miR-21, miR-146a, and miR-155, suggesting that T. boudieri and T. claveryi suppress the inflammatory response in LPS/IFN-γ-stimulated RAW 264.7 cells through an epigenetic mechanism. Furthermore, our study reveals a new mechanism for the anti-inflammatory properties of desert truffle extracts. We show for the first time that Terfezia extracts do not rely on the nuclear factor erythroid 2-related factor 2 pathway, previously linked to anti-inflammatory responses. This expands our understanding of natural product anti-inflammatory mechanisms and could have important implications for developing new therapies. To account for differences in truffle effects, extracts prepared were subjected to secondary metabolites profiling using UPLC-MS. UPLC-MS led to the annotation of 87 secondary metabolites belonging to various classes, including amino acids, carbohydrates, alkaloids, amides, fatty acids, sterols, and phenolic compounds. Therefore, these results indicate that T. boudieri and T. claveryi exhibit anti-inflammatory activities through suppressing multiple inflammatory mediators and cytokines and may be potential anti-inflammatory agents.