miR-495 promotes intestinal epithelial cell apoptosis through downregulation of Sphingosine-1-phosphate.

Many pathological conditions lead to defects in intestinal epithelial integrity and loss of barrier function; Sphingosine-1-phosphate (S1P) has been shown to augment intestinal barrier integrity, though the exact mechanisms are not completely understood. We have previously shown that overexpression of Sphingosine Kinase 1 (SphK1), the rate limiting enzyme for S1P synthesis, significantly increased S1P production and cell proliferation. Here we show that microRNA 495 (miR-495) upregulation led to decreased levels of SphK1 resultant from a direct effect at the SphK1 mRNA. Increasing expression of miR-495 in intestinal epithelial cells resulted in decreased proliferation and increased susceptibility to apoptosis. Transgenic expression of miR-495 inhibited mucosal growth, as well as decreased proliferation in the crypts. The intestinal villi also expressed decreased levels of barrier proteins and exaggerated damage upon exposure to cecal ligation-puncture. These results implicate miR-495 as a critical negative regulator of intestinal epithelial protection and proliferation through direct regulation of SphK1, the rate limiting enzyme critical for production of S1P.

Noncoding Vault RNA1-1 Impairs Intestinal Epithelial Renewal and Barrier Function by Interacting With CUG-binding Protein 1.

BACKGROUND & AIMS: Small noncoding vault RNAs (vtRNAs) are involved in many cell processes important for health and disease, but their pathobiological functions in the intestinal epithelium are underexplored. Here, we investigated the role of human vtRNA1-1 in regulating intestinal epithelial renewal and barrier function. METHODS: Studies were conducted in vtRNA1-1 transgenic (vtRNA1-1Tg) mice, primary enterocytes, and Caco-2 cells. Extracellular vesicles (EVs) were isolated from the serum of shock patients and septic mice. Intestinal organoids (enteroids) were prepared from vtRNA1-1Tg and littermate mice. Mucosal growth was measured by Ki67 immunostaining or BrdU incorporation, and gut permeability was assessed using the FITC-dextran assay. RESULTS: Intestinal tissues recovered from shock patients and septic mice evidenced mucosal injury and gut barrier dysfunction; vtRNA levels were elevated in EVs isolated from their sera. In mice, intestinal epithelial-specific transgenic expression of vtRNA1-1 inhibited mucosal growth, reduced Paneth cell numbers and intercellular junction (IJ) protein expression, and increased gut barrier vulnerability to lipopolysaccharide exposure. Conversely, in vitro silencing of vtRNA1-1 increased IJ protein levels and enhanced epithelial barrier function. Exposing enteroids to vtRNA1-1-rich EVs augmented paracellular permeability. Mechanistically, vtRNA1-1 interacted with CUG-binding protein 1 (CUGBP1) and increased CUGBP1 association with claudin-1 and occludin mRNAs, thereby inhibiting their expression. CONCLUSIONS: These findings indicate that elevated levels of vtRNA1-1 in EVs and mucosal tissues repress intestinal epithelial renewal and barrier function. Notably, this work reveals a novel role for dysregulation of the vtRNA1-1/CUGBP1 axis in the pathogenesis of gut mucosal disruption in critical illness.

Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation.

Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here, we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.NEW & NOTEWORTHY Our results indicate that intestinal epithelial tissue-specific transgenic miR-195 expression decreases the levels of SOX9 expression, along with reduced numbers of Paneth cells. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restores Paneth cell development ex vivo. miR-195 inhibits SOX9 translation by preventing binding of HuR to Sox9 mRNA. These findings suggest that interaction between miR-195 and HuR controls Paneth cell function via SOX9 in the intestinal epithelium.

Aromatherapy for the prevention of postoperative nausea and vomiting: A systematic review and meta-analysis.

Objectives: Postoperative nausea and vomiting (PONV) are common complications following surgical procedures. While drug-based treatments are standard, there is increasing interest in nonpharmacological alternatives, such as aromatherapy, due to potential benefits and minimal side effects. This study aimed to assess the effectiveness of aromatherapy in preventing PONV. Materials and Methods: A comprehensive systematic review and meta-analysis were conducted using PubMed, Cochrane Library, EMBASE, and CINAHL databases for studies published up to May 2023. The included studies were randomized controlled trials (RCTs) and nonrandomized studies of interventions that examined the impact of aromatherapy on PONV. The risk of bias was assessed, and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was employed to evaluate the certainty of the evidence. Results: Eleven studies were selected for review, with eight RCTs included in the meta-analysis. Aromatherapy effectively reduced postoperative nausea severity (standardized mean difference [SMD]: -0.93, 95% confidence interval [CI]: -1.64 to -0.22; P = 0.010), but the reduction in vomiting episodes was not statistically significant (SMD: -0.81, 95% CI: -1.98-0.37; P = 0.180). Subgroup analysis indicated that ginger essence, lavender, and peppermint oils were particularly effective in managing postoperative nausea. However, due to significant statistical heterogeneity and potential biases in the studies, the results should be interpreted with caution. The certainty of the evidence, as evaluated by the GRADE approach, was low. Conclusion: Preliminary evidence supports the potential benefit of aromatherapy in reducing the severity of postoperative nausea. However, given the low certainty of current evidence, more rigorous and standardized research is needed. The safety, affordability, and potential benefits to patient comfort make aromatherapy a promising area for further research in postoperative care.

Posttranscriptional Regulation of Intestinal Mucosal Growth and Adaptation by Noncoding RNAs in Critical Surgical Disorders.

The human intestinal epithelium has an impressive ability to respond to insults and its homeostasis is maintained by well-regulated mechanisms under various pathophysiological conditions. Nonetheless, acute injury and inhibited regeneration of the intestinal epithelium occur commonly in critically ill surgical patients, leading to the translocation of luminal toxic substances and bacteria to the bloodstream. Effective therapies for the preservation of intestinal epithelial integrity and for the prevention of mucosal hemorrhage and gut barrier dysfunction are limited, primarily because of a poor understanding of the mechanisms underlying mucosal disruption. Noncoding RNAs (ncRNAs), which include microRNAs (miRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and small vault RNAs (vtRNAs), modulate a wide array of biological functions and have been identified as orchestrators of intestinal epithelial homeostasis. Here, we feature the roles of many important ncRNAs in controlling intestinal mucosal growth, barrier function, and repair after injury-particularly in the context of postoperative recovery from bowel surgery. We review recent literature surrounding the relationships between lncRNAs, microRNAs, and RNA-binding proteins and how their interactions impact cell survival, proliferation, migration, and cell-to-cell interactions in the intestinal epithelium. With advancing knowledge of ncRNA biology and growing recognition of the importance of ncRNAs in maintaining the intestinal epithelial integrity, ncRNAs provide novel therapeutic targets for treatments to preserve the gut epithelium in individuals suffering from critical surgical disorders.

Circular RNA Cdr1as inhibits proliferation and delays injury-induced regeneration of the intestinal epithelium.

Circular RNAs (circRNAs) are highly expressed in the mammalian intestinal epithelium, but their functions remain largely unknown. Here, we identified the circRNA Cdr1as as a repressor of intestinal epithelial regeneration and defense. Cdr1as levels increased in mouse intestinal mucosa after colitis and septic stress, as well as in human intestinal mucosa from patients with inflammatory bowel disease and sepsis. Ablation of the Cdr1as locus from the mouse genome enhanced renewal of the intestinal mucosa, promoted injury-induced epithelial regeneration, and protected the mucosa against colitis. We found approximately 40 microRNAs, including miR-195, differentially expressed between intestinal mucosa of Cdr1as-knockout (Cdr1as-/-) versus littermate mice. Increasing the levels of Cdr1as inhibited intestinal epithelial repair after wounding in cultured cells and repressed growth of intestinal organoids cultured ex vivo, but this inhibition was abolished by miR-195 silencing. The reduction in miR-195 levels in the Cdr1as-/- intestinal epithelium was the result of reduced stability and processing of the precursor miR-195. These findings indicate that Cdr1as reduces proliferation and repair of the intestinal epithelium at least in part via interaction with miR-195 and highlight a role for induced Cdr1as in the pathogenesis of unhealed wounds and disrupted renewal of the intestinal mucosa.

The effects of incretin-based therapies on weight reduction and metabolic parameters in children with obesity: A systematic review and meta-analysis.

BACKGROUND: Growing evidence indicates that incretin-based therapies (IBTs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 inhibitors (DPP4is) are effective and safe for treating pediatric obesity patients with or without type 2 diabetes. Therefore, we aimed to perform a systematic review and meta-analysis for updating current evidence. METHODS: We searched the PubMed, the Cochrane Library, and the EMBASE database for articles published until September 15, 2023, and limited to randomized control trials. The primary outcomes were changed from baseline in weight metrics and the cardiometabolic profile. A random effects model will be used, as high heterogeneity is expected. All analyses were performed using STATA 17.0. RESULTS: Fifteen trials with a total number of 1286 participants were included in our meta-analysis. Overall, the mean difference in weight change between the IBTs group and the control group was -2.89 kg (95% confidence interval, -5.12 to -0.65, p = 0.011). Additionally, IBTs significantly reduced the HbA1c level and fasting plasma glucose by 0.37% and 6.99 mg/dl, compared with control groups. IBTs showed a little increased risk of GI side effects and hypoglycemia events, but none of the severe hypoglycemia events were occurred in IBTs group. CONCLUSIONS: Our study results have proved that GLP-1 RAs are safe, acceptable, and effective in weight reduction and sugar control for children with obesity. In addition, DPP-4is seems to have no effect on glycemic control and weight loss in childhood obesity. Further research is needed to confirm these findings, especially in younger children.

Corticosteroids for COVID-19-induced olfactory dysfunction: A comprehensive systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Olfactory dysfunction is a common manifestation in COVID-19 patients and can significantly impact their quality of life. Corticosteroids have been proposed as a potential treatment, but their efficacy remains controversial. This systematic review and meta-analysis aims to comprehensively analyze the efficacy of corticosteroid therapy for treating COVID-19-related olfactory dysfunction. METHODS: A literature search was conducted in PubMed, Cochrane Library, and Embase databases up to March 1, 2023. Randomized controlled trials investigating the effects of corticosteroids on olfactory dysfunction in patients with COVID-19 were included. The primary outcome was the olfactory score at the end of follow-up, and the secondary outcomes were the duration and the rate of recovery from olfactory dysfunction. RESULTS: Seven randomized controlled trials with 999 participants were included in the meta-analysis. Compared with the control group, corticosteroid treatment resulted in a statistically significant improvement in olfactory score with a standardized mean difference of 0.55 (95% CI: 0.15 to 0.95). Topical corticosteroids were found to be effective, but systemic corticosteroids were not. In addition, longer durations and higher dosages of corticosteroids treatment may also be associated with significant improvements in olfactory scores. No significant effect was observed on the duration or recovery rate of olfactory dysfunction. CONCLUSIONS: Our findings suggest that topical corticosteroid treatment is a viable option for improving COVID-19-related olfactory dysfunction, but further research is needed to investigate optimal treatment protocols and safety profiles.

HuR and Its Interactions with Noncoding RNAs in Gut Epithelium Homeostasis and Diseases.

The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body and its homeostasis is tightly controlled by numerous factors at multiple levels. The RNA-binding protein HuR (human antigen R) is intimately involved in many aspects of gut mucosal pathobiology and plays an important role in maintaining integrity of the intestinal epithelium by regulating stability and translation of target mRNAs. Nonetheless, deregulation of HuR expression and altered binding affinity of HuR for target transcripts occur commonly in various gut mucosal disorders. In this review, we highlight the essential role of HuR in the intestinal epithelium homeostasis and discuss recent results that interactions between HuR and noncoding RNAs (ncRNAs), including circular RNAs, long ncRNAs, small vault RNAs, and microRNAs, influence gut mucosal regeneration and regulate barrier function in various pathophysiological conditions. These exciting discoveries advance our knowledge of HuR biological function in the gut mucosa and also create a fundamental basis for developing novel therapies to protect intestinal epithelial integrity in critically ill patients.

Stabilization of Cx43 mRNA via RNA-binding protein HuR regulated by polyamines enhances intestinal epithelial barrier function.

Gut barrier dysfunction occurs commonly in patients with critical disorders, leading to the translocation of luminal toxic substances and bacteria to the bloodstream. Connexin 43 (Cx43) acts as a gap junction protein and is crucial for intercellular communication and the diffusion of nutrients. The levels of cellular Cx43 are tightly regulated by multiple factors, including polyamines, but the exact mechanism underlying the control of Cx43 expression remains largely unknown. The RNA-binding protein HuR regulates the stability and translation of target mRNAs and is involved in many aspects of intestinal epithelial pathobiology. Here we show that HuR directly bound to Cx43 mRNA via its 3'-untranslated region in intestinal epithelial cells (IECs) and this interaction enhanced Cx43 expression by stabilizing Cx43 mRNA. Depletion of cellular polyamines inhibited the [HuR/Cx43 mRNA] complex and decreased the level of Cx43 protein by destabilizing its mRNA, but these changes were prevented by ectopic overexpression of HuR. Polyamine depletion caused intestinal epithelial barrier dysfunction, which was reversed by ectopic Cx43 overexpression. Moreover, overexpression of checkpoint kinase 2 in polyamine-deficient cells increased the [HuR/Cx43 mRNA] complex, elevated Cx43 levels, and promoted barrier function. These findings indicate that Cx43 mRNA is a novel target of HuR in IECs and that polyamines regulate Cx43 mRNA stability via HuR, thus playing a critical role in the maintenance of intestinal epithelial barrier function.NEW & NOTEWORTHY The current study shows that polyamines stabilize the Cx43 mRNA via HuR, thus enhancing the function of the Cx43-mediated gap junction. These findings suggest that induced Cx43 by HuR plays a critical role in the process by which polyamines regulate intestinal epithelial barrier.

Pharmacokinetics, anti-rheumatoid arthritis activity, and active ingredient contents of Eucommia ulmoides Oliv.

Eucommia ulmoides Oliv. is a deciduous tree which contains various chemical ingredients. The main objective was to document the active chemical ingredients of Eucommia ulmoides Oliv. and their metabolic profiles in vivo, with a view to providing an experimental and theoretical basis for clarifying the mechanisms underlying the pharmacological activity of Eucommia ulmoides Oliv. against rheumatoid arthritis. Eight main active constituents of Eucommia ulmoides Oliv. bark (pinoresinol glucopyranoside, aucubin, geniposidic acid, geniposide, genipin, chlorogenic acid, quercetin and betulinic acid) were quantified using high-performance liquid chromatography (HPLC). This paper additionally identified and characterized prototype metabolites via ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with the Human Metabolome Database (HMDB) and literature comparisons. Ultra pressure liquid chromatography-mass spectrometry/ mass spectrometry (UPLC-MS/MS) was subsequently employed to quantify these components in blood over time and evaluate their pharmacokinetic characteristics. The anti-rheumatoid arthritis effects of genipin, pinoresinol glucopyranoside and their combinations were assessed using in vitro cellular assays. We identified and characterized a total of 53 ingredients from Eucommia ulmoides Oliv. bark and plasma samples, among which 20 were confirmed as prototype metabolites. Meanwhile, this paper derived and analyzed the metabolic cleavage pathway of 8 index ingredients. Six of these compounds displayed rapid entry into blood, with high plasma exposure and fast elimination rates. Data from the in vitro cellular assay showed that aucubin, pinoresinol glucopyranoside, genipin, and combinations of these compounds effectively inhibit MH7A cell proliferation, reduce NO release, and decrease inflammatory factor levels.

Suitable overwintering habitat simulation and the drivers of their population expansion for Siberian cranes (Grus leucogeranus) in China.

To gain a more comprehensive understanding of habitat preferences, potential wintering area distribution and drivers of population expansion of Grus leucogeranus, we selected 70 geographical distribution points and 11 environmental variables in its wintering period from 2015-2022. We modeled suitable habitat patterns for G. leucogeranus in China using MaxEnt model, and analyzed the relationship between suitable habitat distribution and environmental factors. The results showed that the dominant factors affecting the overwintering distribution of G. leucogeranus were distance to mudflats, elevation, average precipitation in February, distance to water sources, minimum temperature in December, and land use type, with a cumulative contribution rate of 94.6%. The wintering ground of G. leucogeranus in China was mainly distributed in the middle and lower reaches of the Yangtze Plain and the Yellow River Delta of the North China Plain. In these regions, the area of high-, medium- and low-suitability habitat were 17685, 60787 and 60747 km2, respectively. A total of 40 protected areas had been established in the high-suitability wintering range of G. leucogeranus in China, whereas 12 high-suitability wetlands such as Qili Lake in Anhui, Liangzi Lake in Hubei and Chenjia Lake in Jiangxi were still unprotected. The wintering grounds had shown a trend of expansion to the northeast and southeast since 2015. Considering the large-scale habitat shifts of G. leucogeranus in recent years and the frequent new wintering records in various places, we suggested that the shortage of food resources in natural habitats was the main factor driving the expansion of G. leucogeranus' wintering range. To protect G. leucogeranus more effectively, we should strengthen the restoration of natural habitats and the management of farmland habitats.

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity.

Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity. Targeted deletion of HuR in mice disrupted PC gene expression profiles, reduced PC-derived niche factors, and impaired ISC function, leading to inhibited renewal of the intestinal epithelium. Human intestinal mucosa from patients with critical surgical disorders exhibited decreased levels of tissue HuR and PC/ISC niche dysfunction, along with disrupted mucosal growth. HuR deletion led to mitochondrial impairment by decreasing the levels of several mitochondrial-associated proteins including prohibitin 1 (PHB1) in the intestinal epithelium, whereas HuR enhanced PHB1 expression by preventing microRNA-195 binding to the Phb1 mRNA. These results indicate that HuR is essential for maintaining the integrity of the PC/ISC niche and highlight a novel role for a defective PC/ISC niche in the pathogenesis of intestinal mucosa atrophy.

Iridoid from Eucommia ulmoides Oliv. Exerts Antiarthritis Effects by Inhibiting the JAK2/STAT3 Signaling Pathway In Vivo and In Vitro.

The purpose of this study was to investigate the anti-inflammatory effects of EU-Idd both in vivo and in vitro. In vivo, we used the collagen-induced arthritis (CIA) rat model to investigate the efficacy of EU-Idd on rheumatoid arthritis. Hematoxylin-eosin staining and Safranin O-fast green staining were used to evaluate the pathological status of the ankle joints in CIA rats. Micro-CT scanning was used to investigate bone erosion of the ankle joints. In vitro, the effect of EU-Idd on Th17 cell differentiation was identified by flow cytometry. TRAP staining was used to detect osteoclast cells. HFLS-RA model cells, induced by tumor necrosis factor-α(TNF-α), were used to evaluate the anti-inflammatory effects of EU-Idd while the levels of related inflammatory cytokines and JAK2/STAT3 proteins were detected by RT-qPCR and western blotting. EU-Idd alleviated joint inflammation in CIA rats and exerted protective effects on the ankle joints. EU-Idd also prevented the differentiation of CD4+ T cells into Th17 cells, reduced the number of osteoclasts, and improved the expression levels of bone metabolism-related proteins including OPG and RANKL. Moreover, EU-Idd inhibited the invasion and migration of HFLS-RA cells and downregulated the expression of related inflammatory cytokine genes and the protein expression levels of p-JAK2 and p-STAT3, both in vivo and in vitro. EU-Idd exerts anti-inflammatory and osteoprotective effects by regulating the JAK2/STAT3 pathway in rheumatoid arthritis. These results are beneficial to excavate new pharmaceutical ingredients for rheumatoid arthritis from iridoid.

Potential diagnostic markers and therapeutic targets for rheumatoid arthritis with comorbid depression based on bioinformatics analysis.

Background: Rheumatoid arthritis (RA) and depression are prevalent diseases that have a negative impact on the quality of life and place a significant economic burden on society. There is increasing evidence that the two diseases are closely related, which could make the disease outcomes worse. In this study, we aimed to identify diagnostic markers and analyzed the therapeutic potential of key genes. Methods: We assessed the differentially expressed genes (DEGs) specific for RA and Major depressive disorder (MDD) and used weighted gene co-expression network analysis (WGCNA) to identify co-expressed gene modules by obtaining the Gene expression profile data from Gene Expression Omnibus (GEO) database. By using the STRING database, a protein-protein interaction (PPI) network constructed and identified key genes. We also employed two types of machine learning techniques to derive diagnostic markers, which were assessed for their association with immune cells and potential therapeutic effects. Molecular docking and in vitro experiments were used to validate these analytical results. Results: In total, 48 DEGs were identified in RA with comorbid MDD. The PPI network was combined with WGCNA to identify 26 key genes of RA with comorbid MDD. Machine learning-based methods indicated that RA combined with MDD is likely related to six diagnostic markers: AURKA, BTN3A2, CXCL10, ERAP2, MARCO, and PLA2G7. CXCL10 and MARCO are closely associated with diverse immune cells in RA. However, apart from PLA2G7, the expression levels of the other five genes were associated with the composition of the majority of immune cells in MDD. Molecular docking and in vitro studies have revealed that Aucubin (AU) exerts the therapeutic effect through the downregulation of CXCL10 and BTN3A2 gene expression in PC12 cells. Conclusion: Our study indicates that six diagnostic markers were the basis of the comorbidity mechanism of RA and MDD and may also be potential therapeutic targets. Further mechanistic studies of the pathogenesis and treatment of RA and MDD may be able to identify new targets using these shared pathways.

Statin Use and Delirium Risk: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Findings on the association of statin use with delirium risk are inconsistent. THE STUDY QUESTION: Is statin use associated with delirium risk? STUDY DESIGN: We searched PubMed, the Cochrane Library, and the EMBASE database, limiting the search to human patients and articles in English published until December 31, 2021. The effect size and 95% confidence interval (CI) were defined as the odds ratio (OR) and 95% CI, respectively, to indicate the difference in the incidence of delirium between statin use and nonuse groups. A random-effects model was selected in the case of high heterogeneity of study populations. We used funnel plots, Egger test, Duval and Tweedie trim-and-fill approach, and the classic fail-safe N to assess publication bias. RESULTS: Of a total of 264 identified studies, 13 were selected for the qualitative review-4 RCTs and 9 observational cohort studies. Statin use was not associated with low delirium risk (pooled OR, 0·82; 95% CI, 0·64-1·04; P = 0·09). Substantial statistical heterogeneity was observed ( I2 , 90%). Visual inspection of the funnel plot of ORs from the studies revealed symmetry. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, we assigned the evidence a rating of C and a weak recommendation for this review. CONCLUSIONS: Statin use is not associated with delirium risk. More comprehensive RCTs are required to confirm the results.

miR-542-5p targets c-myc and negates the cell proliferation effect of SphK1 in intestinal epithelial cells.

Intestinal epithelial barrier defects occur commonly during a variety of pathological conditions, though their underlying mechanisms are not completely understood. Sphingosine-1-phosphate (S1P) has been shown to be a critical regulator of proliferation and of maintenance of an intact intestinal epithelial barrier, as is also sphingosine kinase 1 (SphK1), the rate-limiting enzyme for S1P synthesis. SphK1 has been shown to modulate its effect on intestinal epithelial proliferation through increased levels of c-myc. We conducted genome-wide profile analysis to search for differential microRNA expression related to overexpressed SphK1 demonstrating adjusted expression of microRNA 542-5p (miR-542-5p). Here, we show that miR-542-5p is regulated by SphK1 activity and is an effector of c-myc translation that ultimately serves as a critical regulator of the intestinal epithelial barrier. miR-542-5p directly regulates c-myc translation through direct binding to the c-myc mRNA. Exogenous S1P analogs administered in vivo protect murine intestinal barrier from damage due to mesenteric ischemia reperfusion, and damaged intestinal tissue had increased levels of miR-542-5p. These results indicate that miR-542-5p plays a critical role in the regulation of S1P-mediated intestinal barrier function, and may highlight a novel role in potential therapies.

Small noncoding vault RNA2-1 disrupts gut epithelial barrier function via interaction with HuR.

Vault RNAs (vtRNAs) are small noncoding RNAs and highly expressed in many eukaryotes. Here, we identified vtRNA2-1 as a novel regulator of the intestinal barrier via interaction with RNA-binding protein HuR. Intestinal mucosal tissues from patients with inflammatory bowel diseases and from mice with colitis or sepsis express increased levels of vtRNAs relative to controls. Ectopically expressed vtRNA2-1 decreases the levels of intercellular junction (IJ) proteins claudin 1, occludin, and E-cadherin and causes intestinal epithelial barrier dysfunction in vitro, whereas vtRNA2-1 silencing promotes barrier function. Increased vtRNA2-1 also decreases IJs in intestinal organoid, inhibits epithelial renewal, and causes Paneth cell defects ex vivo. Elevating the levels of tissue vtRNA2-1 in the intestinal mucosa increases the vulnerability of the gut barrier to septic stress in mice. vtRNA2-1 interacts with HuR and prevents HuR binding to claudin 1 and occludin mRNAs, thus decreasing their translation. These results indicate that vtRNA2-1 impairs intestinal barrier function by repressing HuR-facilitated translation of claudin 1 and occludin.

[Effects of triterpenoid and iridoid of Eucommiae Cortex on collagen-induced arthritis in rats].

The ethyl acetate fraction of ethanol extract of Eucommiae Cortex can effectively inhibit joint inflammation and bone destruction in rats with collagen-induced arthritis(CIA) and has a potential therapeutic effect on rheumatoid arthritis. The triterpenoid(EU-Tid) and iridoid(EU-Idd) of Eucommiae Cortex are derivatives isolated from the ethyl acetate fraction of the ethanol extract of Eucommiae Cortex, and it is not clear whether they have inhibitory effects on joint inflammation and bone erosion in CIA rats. Therefore, based on the CIA model, the effects of EU-Tid, EU-Idd, and their combination(EU-TP) on arthritis in rats were observed, and the material basis of Eucommiae Cortex against arthritis was further clarified. The samples were collected two and four weeks after administration to observe the pathological changes in different stages of arthritis in CIA rats. For the rats in the model control group, with the prolongation of the disease course, the paw volume and arthritis score increased and histopathological lesions aggravated. Compared with the model control group, the drug administration groups showed reduced paw volumes and arthritis scores, and improved joint lesions and cartilage destruction. Additionally, the mRNA expression levels of tumor necrosis factor-α(TNF-α), interleukin-17(IL-17), and interleukin-23(IL-23) in the spleen were down-regulated in the drug administration groups. EU-TP and EU-Tid at concentrations of 160 and 320 µg·mL~(-1) could significantly inhibit the proliferation of human fibroblast-like synoviocytes-RA(HFLS-RA) and nitric oxide(NO) release in the supernatant of RAW264.7 cells induced by lipopolysaccharide(LPS) at the concentration range of 10-80 µg·mL~(-1) in vitro. EU-Idd had no effect on the proliferation of HFLS-RA but could reduce the NO release at concentrations of 40 and 80 µg·mL~(-1). The results indicated that the terpenoids of Eucommiae Cortex had great potential in the treatment of rheumatoid arthritis.

c-Jun-mediated miR-19b expression induces endothelial barrier dysfunction in an in vitro model of hemorrhagic shock.

BACKGROUND: Our previous data demonstrated that miR-19b expression was increased in human lung microvascular endothelial cells in-vitro-, in-vivo and in patients with hemorrhagic shock, leading to a decrease in syndecan-1 mRNA and protein and resulting in loss of endothelial barrier function. However, the mechanism underlying increased miR-19b expression remains unclear. The objective of the current study was to determine if c-Jun mediates the early responsive microRNA, miR-19b, to cause endothelial barrier dysfunction. METHOD: Human lung microvascular endothelial cells (HLMEC) or HEK293T cells were transfected with c-Jun overexpressing vector, c-Jun siRNA, miR-19b promoter vector, miR-19b mutated promoter vector, miR-19b oligo inhibitor, then subjected to hypoxia/reoxygenation as in-vitro model of hemorrhagic shock. Levels of protein, miRNA, and luciferase activity were measured. Transwell permeability of endothelial monolayers were also determined. Plasma levels of c-Jun were measured in injured patients with hemorrhagic shock. RESULT: Hypoxia/reoxygenation induced primary (pri-)miR-19b, mature miR-19b, and c-Jun expression over time in a comparable timeframe. c-Jun silencing by transfection with its specific siRNA reduced both pri-miR-19b and mature miR-19b levels. Conversely, c-Jun overexpression enhanced H/R-induced pri-miR-19b. Studies using a luciferase reporter assay revealed that in cells transfected with vectors containing the wild-type miR-19b promoter and luciferase reporter, c-Jun overexpression or hypoxia/ reoxygenation significantly increased luciferase activity. c-Jun knockdown reduced the luciferase activity in these cells, suggesting that the miR-19b promoter is directly activated by c-Jun. Further, chromatin immunoprecipitation assay confirmed that c-Jun directly bound to the promoter DNA of miR-19b and hypoxia/reoxygenation significantly increased this interaction. Additionally, c-Jun silencing prevented cell surface syndecan-1 loss and endothelial barrier dysfunction in HLMECs after hypoxia/reoxygenation. Lastly, c-Jun was significantly elevated in patients with hemorrhagic shock compared to healthy controls. CONCLUSION: Transcription factor c-Jun is inducible by hypoxia/reoxygenation, binds to and activates the miR-19b promoter. Using an in-vitro model of hemorrhagic shock, our findings identified a novel cellular mechanism whereby hypoxia/ reoxygenation increases miR-19b transcription by inducing c-Jun and leads to syndecan-1 decrease and endothelial cell barrier dysfunction. This finding supports that miR-19b could be a potential therapeutic target for hemorrhage shock.