Opioid-Induced Constipation and Associated Symptoms After Orthopedic Trauma.

PURPOSE: Opioid-induced constipation is an adverse effect often experienced among patients taking prescription opioid medication. Despite frequent opioid prescribing after orthopedic injury, there is a dearth of research examining opioid-induced constipation presentations in this population. This analysis examines the frequency of opioid-induced constipation manifestations and association with patient-reported outcomes among participants prescribed opioid medication following orthopedic injury. DESIGN: Secondary analysis of 86 clinical trial participants following orthopedic trauma. METHODS: Participants were assessed 2-weeks postoperatively with the following measures: Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference, PROMIS Physical Function, past 24-hour average pain intensity captured on the numeric pain rating scale, and the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire. Linear regressions examined the association between PAC-SYM scores and both pain intensity and PROMIS T-scores while accounting for injury severity and opioid medication dosage. RESULTS: Most participants (69%) reported experiencing opioid-induced constipation symptoms and 7% reported moderate to severe symptoms. Compared to those without symptoms, participants reporting opioid-induced constipation symptoms were found to have a 3-point increase in PROMIS Pain Interference (95% Confidence Interval [CI]: 0.28-5.90; p = .032), a 3-point decline in PROMIS Physical Function (95% CI: -6.57 to -0.02; p = .049), and a 1.7-point increase in average pain scores (95% CI: 0.50-3.01; p = .007) at 2-weeks following surgery. CONCLUSIONS: Opioid-induced constipation symptoms are common after orthopedic trauma and linked to increased pain interference and pain intensity as well as reduced physical function. CLINICAL IMPLICATIONS: Nurse-led assessments of opioid-induced constipation can support the timely delivery of interventions to alleviate symptoms and potentially improve patient-reported outcomes after injury.

Association between dietary intake of niacin and stroke in the US residents: evidence from national health and nutrition examination survey (NHANES) 1999-2018.

Objective: This study aims to explore the association between niacin intake and stroke within a diverse, multi-ethnic population. Methods: A stringent set of inclusion and exclusion criteria led to the enrollment of 39,721 participants from the National Health and Nutrition Examination Survey (NHANES). Two interviews were conducted to recall dietary intake, and the USDA's Food and Nutrient Database for Dietary Studies (FNDDS) was utilized to calculate niacin intake based on dietary recall results. Weighted multivariate logistic regression was employed to examine the correlation between niacin and stroke, with a simultaneous exploration of potential nonlinear relationships using restricted cubic spline (RCS) regression. Results: A comprehensive analysis of baseline data revealed that patients with stroke history had lower niacin intake levels. Both RCS analysis and multivariate logistic regression indicated a negative nonlinear association between niacin intake and stroke. The dose-response relationship exhibited a non-linear pattern within the range of dietary niacin intake. Prior to the inflection point (21.8 mg) in the non-linear correlation between niacin intake and stroke risk, there exists a marked decline in the risk of stroke as niacin intake increases. Following the inflection point, the deceleration in the decreasing trend of stroke risk with increasing niacin intake becomes evident. The inflection points exhibit variations across diverse populations. Conclusion: This investigation establishes a negative nonlinear association between niacin intake and stroke in the broader American population.

Influenza A virus infection activates caspase-8 to enhance innate antiviral immunity by cleaving CYLD and blocking TAK1 and RIG-I deubiquitination.

Caspase-8, an aspartate-specific cysteine protease that primarily functions as an initiator caspase to induce apoptosis, can downregulate innate immunity in part by cleaving RIPK1 and IRF3. However, patients with caspase-8 mutations or deficiency develop immunodeficiency and are prone to viral infections. The molecular mechanism underlying this controversy remains unknown. Whether caspase-8 enhances or suppresses antiviral responses against influenza A virus (IAV) infection remains to be determined. Here, we report that caspase-8 is readily activated in A549 and NL20 cells infected with the H5N1, H5N6, and H1N1 subtypes of IAV. Surprisingly, caspase-8 deficiency and two caspase-8 inhibitors, Z-VAD and Z-IETD, do not enhance but rather downregulate antiviral innate immunity, as evidenced by decreased TBK1, IRF3, IκBα, and p65 phosphorylation, decreased IL-6, IFN-ß, MX1, and ISG15 gene expression; and decreased IFN-ß production but increased virus replication. Mechanistically, caspase-8 cleaves and inactivates CYLD, a tumor suppressor that functions as a deubiquitinase. Caspase-8 inhibition suppresses CYLD cleavage, RIG-I and TAK1 ubiquitination, and innate immune signaling. In contrast, CYLD deficiency enhances IAV-induced RIG-I and TAK1 ubiquitination and innate antiviral immunity. Neither caspase-3 deficiency nor treatment with its inhibitor Z-DEVD affects CYLD cleavage or antiviral innate immunity. Our study provides evidence that caspase-8 activation in two human airway epithelial cell lines does not silence but rather enhances innate immunity by inactivating CYLD.

The incidence and risk factors of perioperative recurrent stroke in elderly patients with previous ischemic stroke receiving hip fracture surgery.

BACKGROUND: Data are currently lacking regarding perioperative stroke recurrence in hip fracture patients with previous stroke. We aimed to analyze the incidence and risk factors of perioperative stroke recurrence in elderly patients with previous stroke who underwent hip fracture surgery. METHODS: We used 2019 and 2020 data from the United States National Inpatient Sample database. We identified elderly patients with previous ischemic stroke who had undergone hip fracture surgery to analyze the incidence of stroke recurrence. A 1:4 propensity score matching was used to balance confounding factors related to demographic data and matched the control group with the stroke recurrence group. Risk factors for stroke recurrence were determined using univariate and multivariate logistic analysis. RESULTS: The incidence of perioperative stroke recurrence in elderly patients with previous stroke who underwent hip fracture surgery was 5.7% (51/882). Multivariate logistic regression analysis showed that intertrochanteric fracture (odds ratio 2.24, 95% confidence interval 1.14-4.57; p = 0.021), hypertension (odds ratio 2.49, 95% confidence interval 1.26-5.02; p = 0.009), and postoperative pneumonia (odds ratio 4.35, 95% confidence interval 1.59-11.82; p = 0.004) were independently associated with stroke recurrence. CONCLUSIONS: The perioperative stroke recurrence rate in elderly hip fracture patients with previous stroke was 5.7%. Intertrochanteric fracture, hypertension, and postoperative pneumonia were identified as factors significantly associated with stroke recurrence in this study. Adequate systemic support post-fracture, effective blood pressure management, and proactive infection prevention may help reduce stroke recurrence, especially in patients with intertrochanteric fractures.

Step feature line extraction from large-scale point clouds of open-pit mine based on structural characteristics.

High-precision step feature lines play a crucial role in open-pit mine design, production scheduling, mining volume calculations, road network planning, and slope maintenance. Compared with the feature lines of the geometric model, step feature lines are more irregular, complex, higher in density, and richer in detail. In this study, a novel technique for extracting step feature line from large-scale point clouds of open-pit mine by leveraging structural attributes, that is, SFLE_OPM (Step Feature Line Extraction for Open-Pit Mine), is proposed. First, we adopt the k-dimensional tree (KD-tree) resampling method to reduce the point-cloud density while retaining point-cloud features and utilize bilateral filtering for denoising. Second, we use Point Cloud Properties Network (PCPNET) to estimate the normal, calculate the slope and aspect, and then filter them. We then apply morphological operations to the step surface and obtain more continuous and smoother slope lines. In addition, we construct an Open-Pit Mine Step Feature Line (OPMSFL) dataset and benchmarked SFLE_OPM, achieving an accuracy score of 89.31% and true positive rate score of 80.18%. The results demonstrate that our method yields a higher extraction accuracy and precision than most of the existing methods. Our dataset is available at https://github.com/OPMDataSets/OPMSFL .

Selenomethionine supplementation mitigates fluoride-induced liver apoptosis and inflammatory reactions by blocking Parkin-mediated mitophagy in mice.

As an environmental pollutant, fluoride-induced liver damage is directly linked to mitochondrial alteration and oxidative stress. Selenium's antioxidant capacity has been shown to alleviate liver damage. Emerging research proves that E3 ubiquitin ligase Park2 (Parkin)-mediated mitophagy may be a therapeutic target for fluorosis. The current study explored the effect of diverse selenium sources on fluoride-caused liver injury and the role of Parkin-mediated mitophagy in this intervention process. Therefore, this study established a fluoride-different selenium sources co-intervention wild-type (WT) mouse model and a fluoride-optimum selenium sources co-intervention Parkin gene knockout (Parkin-/-) mouse model. Our results show that selenomethionine (SeMet) is the optimum selenium supplementation form for mice suffering from fluorosis when compared to sodium selenite and chitosan nano­selenium because mice from the F-SeMet group showed more closely normal growth and development levels of liver function, antioxidant capacity, and anti-inflammatory ability. Explicitly, SeMet ameliorated liver inflammation and cell apoptosis in fluoride-toxic mice, accomplished through downregulating the mRNA and protein expression levels associated with mitochondrial fusion and fission, mitophagy, apoptosis, inflammatory signalling pathway of nuclear factor-kappa B (NF-κB), reducing the protein expression levels of PARKIN, PTEN-induced putative kinase1 (PINK1), SQSTM1/p62 (P62), microtubule-associated protein light chain 3 (LC3), cysteinyl aspartate specific proteinase 3 (CASPAS3), as well as restraining the content of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ). The Parkin-/- showed comparable positive effects to the SeMet in the liver of fluorosis mice. The structure of the mitochondria, mRNA, protein expression levels, and the content of proinflammatory factors in mice from the FParkin-/- and F + SeMetParkin-/- groups closely resembled those in the F + SeMetWT group. Overall, the above results indicated that SeMet could alleviate fluoride-triggered inflammation and apoptosis in mice liver via blocking Parkin-mediated mitophagy.

Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction.

Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.

A BODIPY-Ferrocene Conjugate for the Combined Photodynamic Therapy and Chemodynamic Therapy with Improved Antitumor Efficiency.

Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (•OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY-ferrocene conjugate with a balanced 1O2 and •OH generation capacity, which can serve as a high-efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as-prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY-ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT.

Screening of a Prognostic Gene Signature for Relapsed/Refractory Acute Myeloid Leukemia Based on Altered Circulating CircRNA Profiles.

Background: Relapsed/refractory acute myeloid leukemia (R/R-AML) has dismal prognosis due to chemotherapy resistance. Circular RNAs (circRNAs) have shown emerging roles in chemotherapy resistance in various cancers including hematologic malignancies. However, the potential roles of circRNAs in AML progression and drug resistance remain largely undetermined. Methods: In this study, circulating circRNAs expression profiles were analyzed among R/R-AML, de novo AML and healthy controls (HC) using a human circRNA Array. Bioinformatic analysis was carried out to explore the differentially expressed circRNAs (DE-circRNAs). GO, KEGG pathway analysis, along with circRNA-miRNA-mRNA network analysis, were conducted to identify the potential biological pathways involved in R/R-AML. Finally, the UALCAN database was used to assess the prognosis of different target DE-circRNAs-related mRNAs. Results: Forty-eight DE-circRNAs were upregulated, whereas twenty-seven DE-circRNAs were downregulated in R/R-AML samples. Up-regulated DE-circRNAs in R/R-AML samples were mainly enrichment in the biological processes and pathways of cell migration, microRNAs in cancers, Rap1 and Ras signaling pathways. Six DE-circRNAs were randomly selected to further explore their relationships with R/R-AML. GO and KEGG pathway analyses of the six candidate DE-circRNAs-related target mRNAs were mainly involved in the regulation of signal transduction and Ras signaling pathway. By overlapping our RNA-sequencing results of differentially expressed genes (DEGs) in R/R-AML samples with the candidate DE-circRNAs-predicted target mRNAs, we identified sixty-eight overlapping targeted mRNAs. Using UALCAN database analysis, we identified that AML patients with six upregulated DE-circRNA-related genes (ECE1, PI4K2A, SLC9A6, CCND3, PPP1R16B, and TRIM32) and one downregulated gene DE-circRNA-related genes (ARHGAP10) might have a poor prognosis. Conclusion: This study revealed the overall alterations of circRNAs in R/R-AML. DE-circRNAs and their related genes might be used as potential early, sensitive and stable biomarkers for AML diagnosis, R/R-AML monitoring, and even as novel treatment targets for R/R-AML.

Structural Color Colloidal Photonic Crystals for Biomedical Applications.

Photonic crystals are a new class of optical microstructure materials characterized by a dielectric constant that varies periodically with space and features a photonic bandgap. Inspired by natural photonic crystals such as butterfly scales, a series of artificial photonic crystals are developed for use in integrated photonic platforms, biosensing, communication, and other fields. Among them, colloidal photonic crystals (CPCs) have gained widespread attention due to their excellent optical properties and advantages, such as ease of preparation and functionalization. This work reviews the classification and self-assembly principles of CPCs, details some of the latest biomedical applications of large-area, high-quality CPCs prepared using advanced self-assembly methods, summarizes the existing challenges in CPC construction and application, and anticipates future development directions and optimization strategy. With further advancements, CPCs are expected to play a more critical role in biosensors, drug delivery, cell research, and other fields, bringing significant benefits to biomedical research and clinical practice.

The prognostic value of the systemic immune inflammation index in patients with IgA nephropathy.

BACKGROUND: Immune and inflammatory factors are considered the basic underlying mechanisms of IgA nephropathy (IgAN). The systemic immune inflammation index (SII) is a new inflammatory biomarker and has been identified as a prognostic indicator for various diseases. However, limited studies have been conducted on the prognostic value of the SII in patients with IgAN, and we aimed to address this gap. METHODS: A total of 374 patients with IgAN confirmed by renal biopsy performed from 1 January 2015 to 1 April 2019, were retrospectively included. The follow-up period of all patients was at least 12 months after diagnosis, and the endpoint was defined as end-stage kidney disease (ESKD). Patients were further divided into a high-risk group (SII ≥ 456.21) and a low-risk group (SII < 456.21) based on the optimal cutoff value of the SII determined by receiver operating characteristic (ROC) curve analysis. Baseline clinicopathological parameters were compared between the groups, and Cox proportional hazards analyses and Kaplan-Meier analysis were performed to assess renal survival in IgAN patients. RESULTS: After a median follow-up period of 32.5 months, a total of 53 patients eventually reached ESKD. Patients in the high-SII group tended to have a lower hemoglobin level (p = 0.032) and eGFR (p < 0.001), a higher serum creatinine level (p = 0.023) and 24-hour total protein level (p = 0.004), more severe tubular atrophy and interstitial fibrosis (p = 0.002) and more crescents (p = 0.030) than did those in the low-SII group. Univariate and multivariate Cox regression analyses demonstrated that an SII ≥456.21 was an independent risk factor for poor renal survival in IgAN patients (HR 3.028; 95% CI 1.486-6.170; p = 0.002). Kaplan-Meier analysis revealed that a high SII was significantly associated with poor renal prognosis (p < 0.001) and consistently exhibited remarkable discriminatory ability across different subgroups in terms of renal survival. CONCLUSION: A high SII was associated with more severe baseline clinical and pathological features, and an SII ≥456.21 was an independent risk factor for progression to ESKD in IgAN patients.

Association between thyroid function and nonalcoholic fatty liver disease: a dose-response meta-analysis.

Background: Thyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research. Methods: The searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD. Results: Overall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2 = 0.0%, p<0.001) in the overall meta-analysis. The continuous variable meta-analysis indicated that individuals with high levels of TSH (SMD=1.32, 95% CI 0.660 to 1.970, p<0.001) had significantly higher levels of liver fibrosis than those with low levels. Conclusions: Our findings only validate that there is a correlation between the occurrence of NAFLD and abnormal levels of THs, and it is expected that more observational studies will still be conducted in the future to further demonstrate the relationship between thyroid hormones and NAFLD. Trial registration: Registered number in PROSPERO: CRD42023405052.

Effect of esketamine combined with dexmedetomidine on delirium in sedation for mechanically ventilated ICU patients: protocol for a nested substudy within a randomized controlled trial.

BACKGROUND: Use of sedatives and analgesics is associated with the occurrence of delirium in critically ill patients receiving mechanical ventilation. Dexmedetomidine reduces the occurrence of delirium but may cause hypotension, bradycardia, and insufficient sedation. This substudy aims to determine whether the combination of esketamine with dexmedetomidine can reduce the side effects and risk of delirium than dexmedetomidine alone in mechanically ventilated patients. METHODS: This single-center, randomized, active-controlled, superiority trial will be conducted at The First Affiliated Hospital of Nanjing Medical University. A total of 134 mechanically ventilated patients will be recruited and randomized to receive either dexmedetomidine alone or esketamine combined with dexmedetomidine, until extubation or for a maximum of 14 days. The primary outcome is the occurrence of delirium, while the second outcomes include the number of delirium-free days; subtype, severity, and duration of delirium; time to first onset of delirium; total dose of vasopressors and antipsychotics; duration of mechanical ventilation; ICU and hospital length of stay (LOS); accidental extubation, re-intubation, re-admission; and mortality in the ICU at 14 and 28 days. DISCUSSION: There is an urgent need for a new combination regimen of dexmedetomidine due to its evident side effects. The combination of esketamine and dexmedetomidine has been applied throughout the perioperative period. However, there is still a lack of evidence on the effects of this regimen on delirium in mechanically ventilated ICU patients. This substudy will evaluate the effects of the combination of esketamine and dexmedetomidine in reducing the risk of delirium for mechanically ventilated patients in ICU, thus providing evidence of this combination to improve the short-term prognosis. The study protocol has obtained approval from the Medical Ethics Committee (ID: 2022-SR-450). TRIAL REGISTRATION: ClinicalTrials.gov: NCT05466708, registered on 20 July 2022.

Cell fate decision by a morphogen-transcription factor-chromatin modifier axis.

Cell fate decisions remain poorly understood at the molecular level. Embryogenesis provides a unique opportunity to analyze molecular details associated with cell fate decisions. Works based on model organisms have provided a conceptual framework of genes that specify cell fate control, for example, transcription factors (TFs) controlling processes from pluripotency to immunity1. How TFs specify cell fate remains poorly understood. Here we report that SALL4 relies on NuRD (nucleosome-remodeling and deacetylase complex) to interpret BMP4 signal and decide cell fate in a well-controlled in vitro system. While NuRD complex cooperates with SALL4 to convert mouse embryonic fibroblasts or MEFs to pluripotency, BMP4 diverts the same process to an alternative fate, PrE (primitive endoderm). Mechanistically, BMP4 signals the dissociation of SALL4 from NuRD physically to establish a gene regulatory network for PrE. Our results provide a conceptual framework to explore the rich landscapes of cell fate choices intrinsic to development in higher organisms involving morphogen-TF-chromatin modifier pathways.

Resveratrol protects against a high-fat diet-induced neuroinflammation by suppressing mitochondrial fission via targeting SIRT1/PGC-1α.

Various health issues have emerged due to consuming high-fat diets (HFD), particularly the detrimental impact they have on mitochondrial dynamics and subsequet cognition functions. Specially, mitochondrial fission can serve as an upstream signal in the regulation of cortical inflammation and neural pyroptosis. Our study was designed to verify the existence of neuroinflammation in the pathogenesis of HFD-induced cognitive dysfunction and demonstrated that resveratrol (RSV) attenuated neural deficits via regulation of cortical mitochondrial fission. A total of 50 male Sprague Dawley rats were randomly divided into five groups: control (Cont, 26 weeks on normal rodent diet); high-fat diet (HFD); dietary adjustments (HFD + ND); resveratrol intervention (HFD + R); joint intervention (HFD + ND + R) for 26 weeks. The spatial learning and memory function, spine density, NLRP3 inflammasome associated protein, mRNA and protein expression involved in mitochondrial dynamics and SIRT1/PGC-1α signaling pathway in brain were measured. Furthermore, reactive oxygen species (ROS) accumulation and resultant mitochondrial membrane potential (MMP) alteration in PC12 cells exposed to palmitic acid (PA) or Drp1 inhibitor (Mdivi-1) were detected to reflect mitochondrial function. The findings suggested that prolonged treatment of RSV improved cognitive deficits and neuronal damage induced by HFD, potentially attributed to activation of the SIRT1/PGC-1α axis. We further indicated that the activation of the NLRP3 inflammasome in PA (200 µM) treated PC12 cells could be inhibited by Mdivi-1. More importantly, Mdivi-1 (10 µM) reduced intracellular ROS levels and enhanced MMP by reversing Drp1-mediated aberrant mitochondrial fission. To summarize, those results clearly indicated that a HFD inhibited the SIRT1/PGC-1α pathway, which contributed to an imbalance in mitochondrial dynamics and the onset of NLRP3-mediated pyroptosis. This effect was mitigated by the RSV possibly through triggering the SIRT1/PGC-1α axis, prevented aberrant mitochondrial fission and thus inhibited the activation of the NLRP3 inflammatory pathway.

Engineering mouse cell fate controller by rational design.

Cell fate is likely regulated by a common machinery, while components of this machine remain to be identified. Here we report the design and testing of engineered cell fate controller NanogBiD, fusing BiD or BRG1 interacting domain of SS18 with Nanog. NanogBiD promotes mouse somatic cell reprogramming efficiently in contrast to the ineffective native protein under multiple testing conditions. Mechanistic studies further reveal that it facilitates cell fate transition by recruiting the intended Brg/Brahma-associated factor (BAF) complex to modulate chromatin accessibility and reorganize cell state specific enhancers known to be occupied by canonical Nanog, resulting in precocious activation of multiple genes including Sall4, miR-302, Dppa5a and Sox15 towards pluripotency. Although we have yet to test our approach in other species, our findings suggest that engineered chromatin regulators may provide much needed tools to engineer cell fate in the cells as drugs era.

METTL3-mediated N6-methyladenosine modification of STAT5A promotes gastric cancer progression by regulating KLF4.

N6-methyladenosine (m6A) is the predominant post-transcriptional RNA modification in eukaryotes and plays a pivotal regulatory role in various aspects of RNA fate determination, such as mRNA stability, alternative splicing, and translation. Dysregulation of the critical m6A methyltransferase METTL3 is implicated in tumorigenesis and development. Here, this work showed that METTL3 is upregulated in gastric cancer tissues and is associated with poor prognosis. METTL3 methylates the A2318 site within the coding sequence (CDS) region of STAT5A. IGF2BP2 recognizes and binds METTL3-mediated m6A modification of STAT5A through its GXXG motif in the KH3 and KH4 domains, leading to increased stability of STAT5A mRNA. In addition, both METTL3 and IGF2BP2 are positively correlated with STAT5A in human gastric cancer tissue samples. Helicobacter pylori infection increased the expression level of METTL3 in gastric cancer cells, thereby leading to the upregulation of STAT5A. Functional studies indicated that STAT5A overexpression markedly enhances the proliferation and migration of GC cells, whereas STAT5A knockdown has inhibitory effects. Further nude mouse experiments showed that STAT5A knockdown effectively inhibits the growth and metastasis of gastric cancer in vivo. Moreover, as a transcription factor, STAT5A represses KLF4 transcription by binding to its promoter region. The overexpression of KLF4 can counteract the oncogenic impact of STAT5A. Overall, this study highlights the crucial role of m6A in gastric cancer and provides potential therapeutic targets for gastric cancer.

The circular RNA hsa_circ_0045800 serves as a favorable biomarker in pathogenesis of sjögren's syndrome.

BACKGROUND: Circular RNAs (circRNAs) play various roles in the development of many autoimmune diseases. However, their expression profiles and specific function in Sjögren's Syndrome remains largely unknown. OBJECTIVES: We aimed to investigate circRNAs potential diagnostic value in primary Sjögren's syndrome (pSS) and contribution to the pathogenesis of pSS. METHODS: This study included 102 subjects, 51 pSS patients and 51 healthy controls. The concentration of hsa_circ_0045800 was analyzed in peripheral blood mononuclear cells obtained from 51 pSS patients and 51 healthy controls by qRT-PCR. We established a receiver operating characteristic curve (ROC) to assess the biological diagnostic value of hsa_circ_0045800 for pSS. In addition, we analyzed the correlation between hsa_circ_0045800 and disease activity in Sjogren's syndrome. A differential analysis was also conducted on the concentration of hsa_circ_0045800 in patients in pSS patients before and after treatment. We studied the downstream mechanism of hsa_circ_0045800 through bioinformatics analysis and confirmed it using luciferase reporter gene assay. RESULTS: We confirmed that the concentration of hsa_circ_0045800 was elevated 10.4-fold in peripheral blood mononuclear cells of pSS patients than in healthy controls (p = 0.00). In the pSS active disease group, the concentration of hsa_circ_0045800 is 2.5-fold higher compared to the pSS non-active disease group (p = 0.04). The concentration of hsa_circ_0045800 after treatment was decreased by 80% compared with that before treatment (p = 0.037), suggesting its utility as a potential marker for monitoring treatment efficacy. ROC curve analysis showed that the diagnostic value of hsa_circ_0045800 in pSS patients was significantly higher than that in healthy controls, with an area under the curve of 0.865, a sensitivity of 74%, and a specificity of 92%. The concentration of hsa_circ_0045800 is correlated with various clinical factors: the concentration of hsa_circ_0045800 is positively associated with age (r = 0.328, P = 0.019), oral dryness (r = 0.331, P = 0.017), while it is negatively correlated with HGB (r = -0.435, P = 0.001) and and hypothyroidism (r = -0.318, P = 0.023). Bioinformatics predictions and luciferase assays indicated that hsa_circ_0045800 acts as a molecular sponge for miR-1247-5p, with SMAD2 being a target gene of miR-1247-5p. CONCLUSION: Our study results show that hsa_circ_0045800 potentially contributes to the development and progression of pSS via the miR-1247-5p/SMAD2 pathway. Peripheral blood mononuclear cells are directly involved in the pathogenesis of pSS, and the discovery of hsa_circ_0045800 in peripheral blood mononuclear cells highlights its potential as a novel biomarker for disease activity and diagnosis in patients with pSS. Key Points • The concentration of hsa_circ_0045800 was higher in peripheral blood mononuclear cells of pSS patients. • Hsa_circ_0045800 promoted pSS progression through miR-1247-5p-SMAD2 axis. • Hsa_circ_0045800 is a potential biomarker for pSS.