Elucidating thoracic aortic dissection pathogenesis: The interplay of m1A-related gene expressions and miR-16-5p/YTHDC1 Axis in NLRP3-dependent pyroptosis.

The underlying molecular mechanisms of thoracic aortic dissection (TAD) remain incompletely understood. Recent insights into RNA methylation and microRNA-mediated gene regulation offer new avenues for exploring how these processes contribute to the pathophysiology of TAD, particularly through the modulation of pyroptosis and smooth muscle cell viability. This research aimed to elucidate the interplay of m1A-related gene expressions and miR-16-5p/YTHDC1 Axis in NLRP3-dependent pyroptosis, a mechanism implicated in the pathogenesis of TAD. We collected tissue samples from 28 human TAD patients and 8 healthy aortic group, as well as utilized a mouse model to replicate the disease. A combination of computational, in vitro, and in vivo methods was applied, including CIBERSORTx analysis, Pearson correlation, gene transfection using antagomiR-16-5p, siRNA, and several staining as well as cell culture techniques. Our analysis indicated two differentially expressed genes, ALKBH2 and YTHDC1. We found significant upregulation of has-miR-16-5p and downregulation of YTHDC1 at mRNA level in AD samples. Immune cell infiltration in TAD samples was examined using the CIBERSORTx database. We confirmed that YTHDC1 was a target of miR-16-5p, as evidenced by an inhibitory effect on luciferase activity. Inhibition of miR-16-5p enhanced SMC proliferation and promoted cell viability whilst downregulating NLRP3-pyroptosis. YTHDC1 expression was increased, and NLRP3-pyroptosis expressions were inhibited, suggesting miR-16-5p/YTHDC1 axis may involve the NLRP3-pyroptosis of the SMC. In vivo analyses confirmed the prevention of NLRP3-pyroptosis in middle layer of the thoracic aorta, implying that the miR-16-5p/YTHDC1 axis regulated SMC proliferation via NLRP3-pyroptosis signaling. Our findings underscored the anti-pyroptotic role of miR-16-5p/YTHDC1 axis in the pathogenesis of TAD, suggesting a potential therapeutic strategy via targeting YTHDC1 and suppressing miR-16-5p to inhibit NLRP3-dependent pyroptosis. Although further investigation is needed, these results relating to SMC proliferation are a significant step forward in understanding TAD.

Cell Membrane Hybrid Lipid Nanovesicles Enhance Innate Immunity for Synergistic Immunotherapy by Promoting Immunogenic Cell Death and cGAS Activation.

Immunotherapy shows great therapeutic potential for long-term protection against tumor relapse and metastasis. Innate immune sensors, such as cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), dissolve DNA and induce type I interferon. Through activation of the cGAS/STING pathway, chemotherapy drugs and reversine (REV) may provide synergetic anti-tumor effects. Here, we prepared drug-loaded cell membrane hybrid lipid nanovesicles (LEVs) (designated LEV@DOX@REV) by fusion of cell membranes, phospholipids, doxorubicin (DOX), and REV, to realize accurate delivery to tumors and chemo-immunotherapy. The cell membranes of LEVs confer "homing" abilities. DOX can induce immunogenic cell death as a result of its specific immunomodulatory effects, which promotes the maturation of immune cells and improves the microenvironment of the immune system. REV is proven to efficiently activate cGAS/STING signaling, thereby enhancing the immune system. The antitumor efficacy of LEV@DOX@REV was evaluated in a 4T1 subcutaneous tumor xenograft model, a distant metastatic tumor model, and a liver metastatic tumor model. LEV@DOX@REV facilitated the infiltration of cytotoxic T lymphocytes within tumors, increased the secretion of proinflammatory cytokines, and modified the tumor microenvironment. In conclusion, LEV@DOX@REV displayed favorable antitumor effects and extended the survival of tumor-bearing mice. We therefore successfully developed nanoparticles capable of enhancing immune activation that have potential therapeutic applications for cancer immunotherapy.

Could effective iodine-131 half-life be extended by lithium carbonate in Graves' disease patients: Results from a retrospective analysis.

The effective iodine-131 (I-131) half-life (EHL) plays an important role in the evaluation of radioactive iodine therapy for Graves' disease (GD) patients. It has been observed that the EHL of GD patients varies after taking lithium carbonate. The purpose of this study is to investigate whether EHL can be extended and to identify the predictive factors associated with this outcome. The clinical data of 225 GD patients were retrospectively reviewed. Patients were divided into two groups based on whether the ΔEHL was ≥ 0.5 days. EHL tested after lithium carbonate was defined as Li-EHL. In the univariate analysis, age, sex, thyrotropin receptor antibody (TRAb), thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), and baseline-EHL exhibited significant differences between the two groups (P < 0.05). Cutoff values of age and baseline-EHL to predict significant EHL extension were 40.5 years and 4.85 days, respectively, as determined by receiver operating characteristic (ROC) curve analysis. Multiple linear regression analysis further revealed that the regression equation, which included age, sex, baseline-EHL, and the FT3, free triiodothyronine (FT4)/free thyroxine(FT3) ratio, was statistically significant (P < 0.05). Li-EHL positively correlated with baseline-EHL and the FT4/FT3 ratio, but negatively correlated with age. Li-EHL was also increased in female individuals. In conclusion, age, sex, baseline-EHL and the FT4/FT3 ratio were associated with Li-EHL in GD patients.

Multiplex assays reveal anti-EBV antibody profile and its implication in detection and diagnosis of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) is detected in nearly 100% of nonkeratinizing nasopharyngeal carcinoma (NPC) and EBV-based biomarkers are used for NPC screening in endemic regions. Immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA), and recently identified anti-BNLF2b antibodies have been shown to be the most effective screening tool; however, the screening efficacy still needs to be improved. This study developed a multiplex serological assay by testing IgA and immunoglobulin G (IgG) antibodies against representative EBV antigens that are highly transcribed in NPC and/or function crucially in viral reactivation, including BALFs, BNLF2a/b, LF1, LF2, and Zta (BZLF1). Among them, BNLF2b-IgG had the best performance distinguishing NPC patients from controls (area under the curve: 0.951, 95% confidence interval [CI]: 0.913-0.990). Antibodies to lytic antigens BALF2 and VCA were significantly higher in advanced-stage than in early-stage tumors; in contrast, antibodies to latent protein EBNA1 and early lytic antigen BNLF2b were not correlated with tumor progression. Accordingly, a novel strategy combining EBNA1-IgA and BNLF2b-IgG was proposed and validated improving the integrated discrimination by 15.8% (95% CI: 9.8%-21.7%, p < .0001) compared with the two-antibody method. Furthermore, we found EBV antibody profile in patients was more complicated compared with that in healthy carriers, in which stronger correlations between antibodies against different phases of antigens were observed. Overall, our serological assay indicated that aberrant latent infection of EBV in nasopharyngeal epithelial cells was probably a key step in NPC initiation, while more lytic protein expression might be involved in NPC progression.

Intratumoral metabolic heterogeneity by 18F-FDG PET/CT to predict prognosis for patients with thymic epithelial tumors.

BACKGROUND: The aim of the present study was to evaluate the impact of intratumoral metabolic heterogeneity and quantitative 18F-FDG PET/CT imaging parameters in predicting patient outcomes in thymic epithelial tumors (TETs). METHODS: This retrospective study included 100 patients diagnosed with TETs who underwent pretreatment 18F-FDG PET/CT. The maximum and mean standardized uptake values (SUVmax and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on PET/CT were measured. Heterogeneity index-1 (HI-1; standard deviation [SD] divided by SUVmean) and heterogeneity index-2 (HI-2; linear regression slopes of the MTV according with different SUV thresholds), were evaluated as heterogeneity indices. Associations between these parameters and patient survival outcomes were analyzed. RESULTS: The univariate analysis showed that Masaoka stage, TNM stage, WHO classification, SUVmax, SUVmean, TLG, and HI-1 were significant prognostic factors for progression-free survival (PFS), while MTV, HI-2, age, gender, presence of myasthenia gravis, and maximum tumor diameter were not. Subsequently, multivariate analyses showed that HI-1 (p < 0.001) and TNM stage (p = 0.002) were independent prognostic factors for PFS. For the overall survival analysis, TNM stage, WHO classification, SUVmax, and HI-1 were significant prognostic factors in the univariate analysis, while TNM stage remained an independent prognostic factor in multivariate analyses (p = 0.024). The Kaplan Meier survival analyses showed worse prognoses for patients with TNM stages III and IV and HI-1 ≥ 0.16 compared to those with stages I and II and HI-1 < 0.16 (log-rank p < 0.001). CONCLUSION: HI-1 and TNM stage were independent prognostic factors for progression-free survival in TETs. HI-1 generated from baseline 18F-FDG PET/CT might be promising to identify patients with poor prognosis.

miRNA-142-3p aggravates hydrogen peroxide-induced human umbilical vein endothelial cell premature senescence by targeting SIRT1.

Vascular endothelial cell premature senescence plays an important part in stroke. Many microRNAs (miRNAs) are known to be involved in the pathological process of vascular endothelial cell premature senescence. The present study aimed to investigate the mechanism of hydrogen peroxide (H2O2)-induced premature senescence in human umbilical vein endothelial cells (HUVECs) and effect of miR-142-3p on hydrogen peroxide (H2O2)-induced premature senescence. HUVECs were exposed to H2O2 to establish a model premature senescence in endothelial cells. CCK-8 assay was performed to detect cell viability. Senescence-associated ß-galactosidase staining assay and senescence-related proteins p16 and p21 were used to detect changes in the degree of cell senescence. RT-qPCR and Western blot were conducted to measure mRNA and protein levels, respectively. The scratch wound-healing assay, transwell assay, and EdU assay were performed to evaluate the ability of migration and proliferation, respectively. miRNA-142-3p and silencing information regulator 2 related enzyme 1 (SIRT1) binding was verified using Targetscan software and a dual-luciferase assay. We found that miRNA-142-3p is abnormally up-regulated in HUVECs treated with H2O2. Functionally, miRNA-142-3p inhibition may mitigate the degree of HUVEC senescence and improve HUVEC migration and proliferation. Mechanistically, SIRT1 was validated to be targeted by miRNA-142-3p in HUVECs. Moreover, SIRT1 inhibition reversed the effects of miRNA-142-3p inhibition on senescent HUVECs exposed to H2O2. To our knowledge, this is the first study to show that miRNA-142-3p ameliorates H2O2-induced HUVECs premature senescence by targeting SIRT1 and may shed light on the role of the miR-142-3p/SIRT1 axis in stroke treatment.

A fast and efficient liquid chromatography-tandem mass spectrometry method for measuring l- and d-amino acids in the urine of patients with immunoglobulin A nephropathy.

Immunoglobulin nephropathy (IgAN) stands as the most prevalent primary glomerular nephropathy globally, typically diagnosed through an invasive renal biopsy. Emerging research suggests the significant involvement of chiral amino acids in kidney disease progression. This study introduces a nonderivative LC-tandem mass spectrometry approach, offering efficient separation outcomes within 15 min for identifying chiral amino acids in human urine samples. Subsequently, using this method, the analysis of l- and d-amino acids in the urine of both patients with IgAN and healthy individuals was conducted. Fourteen d-amino acids and 20 l-amino acids were identified in the urine samples obtained from 17 patients with IgAN and 21 healthy individuals. The results indicated notable variances in the concentrations of both l- and d-amino acids between the IgAN and healthy control groups. In contrast to the healthy group, the IgAN group exhibited higher mean urine concentrations of most l-amino acids and lower concentrations of d-amino acids. Furthermore, correlations between amino acids and clinical markers were investigated. These results propose a novel method for monitoring trace amino acids in urine samples and introduce a new concept for potential markers of IgAN.

Clinical efficacy of sodium aescinate administration following endovenous laser ablation for varicose veins.

BACKGROUND: Endovenous interventions and minimally invasive procedures are effective in the management of varicose veins. However, they can cause postoperative discomfort. OBJECTIVE: To evaluate the clinical efficacy of sodium aescinate (SA) in improving edema, pain, vein-specific symptoms, and quality of life in patients following endovenous laser ablation (EVLA) for varicose veins. METHODS: In this single-center randomized controlled trial (RCT), patients were allocated into two groups: in Group A, 60 mg SA was administered twice daily for 20 days, and in Group B (control), no venoactive drug was prescribed. The Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification system for chronic venous disorders was used to assess the varicose veins. The circumferences of the calf and ankle were recorded for evaluating edema. The 10-point Visual Analog Scale (VAS), Venous Clinical Severity Score (VCSS), and Aberdeen Varicose Veins Questionnaire (AVVQ) were used to measure the pain intensity, overall varicose vein severity, and patient's quality of life, respectively. RESULTS: The study included 87 patients (mean age, 59.9 ± 10.7 years; 54 men) with CEAP class C2-C5 varicose veins who underwent EVLA and phlebectomy or foam sclerotherapy. The calf circumference recovered quicker in Group A than in Group B by days 10, 21, and 30 (difference from baseline was 1.04 ± 0.35 vs 2.39 ± 1.15 [p < .001], 0.48 ± 0.42 vs1.73 ± 1.00 [p < .001], and 0.18 ± 0.64 vs 0.82 ± 0.96 [p < .001], respectively). The ankle circumference recovered quicker in Group A than in Group B by days 10 and 21 (the difference from baseline was 1.37 ± 0.52 vs 2.36 ± 0.93 [p < .001] and 0.58 ± 0.60 vs 1.14 ± 0.88 [p = .002], respectively). Pain relief was achieved quicker in Group A than in Group B (0.257 ± 1.097 [p = .0863] vs 0.506 ± 1.250 [p = .0168] by day 21). There were no significant differences in the VCSS and AVVQ scores between both groups. There were no drug-related adverse effects. CONCLUSIONS: SA, in combination with compression therapy, can relieve edema and alleviate pain in patients following EVLA for varicose veins.

Effects of Aloe Gel on Lactating Women with Nipple Trauma.

Background: To investigate the efficacy of aloe gel in reducing pain and promoting wound healing in postpartum women with nipple trauma. Method: There were 80 postpartum women who took part in this study having developed nipple trauma during breastfeeding in the obstetrics department of a tertiary grade A hospital in Suzhou from January to December 2021. Postpartum women with nipple trauma whose hospital bed numbers ranged between 15 and 33 were included in the test group, whereas those whose hospital bed numbers ranged between 35 and 53 were included in the control group. Both groups received health education and breastfeeding guidance. The control group applied lanolin cream to their nipple trauma, whereas the test group used aloe gel. We used a nipple trauma severity assessment table to determine the severity of nipple trauma in lactating women and a Visual Analogue Scale (VAS) to determine the level of nipple pain and referred to the Traditional Chinese Medicine Standard for Diagnosis and Therapeutic Efficacy for Diseases and Syndromes to determine the healing time of their wounds. Results: The test group scored 3.70 ± 1.24 and 1.65 ± 0.74 points on the VAS on the first and third days following the intervention, whereas the control group scored 4.30 ± 0.94 and 2.23 ± 1.07 points, respectively. It took 3.75 ± 1.08 days and 4.45 ± 1.15 days for the nipple pain to completely disappear in the test group and the control group, respectively. The healing period for nipple trauma was 5.28 ± 1.26 days for the test group and 6.03 ± 1.61 days for the control group. All of the aforementioned distinctions were statistically significant (p < 0.05). Conclusions: Aloe gel can significantly alleviate the pain associated with nipple trauma in lactating women, accelerate wound healing, and reduce the duration of nipple trauma.

Comprehensive identification and analysis of DUF640 genes associated with rice growth.

Protein domains with conserved amino acid sequences and uncharacterized functions are called domains of unknown function (DUF). The DUF640 gene family plays a crucial role in plant growth, particularly in light regulation, floral organ development, and fruit development. However, there exists a lack of systematic understanding of the evolutionary relationships and functional differentiation of DUF640 within the Oryza genus. In this study, 61 DUF640 genes were identified in the Oryza genus. The expression of DUF640s is induced by multiple hormonal stressors including abscisic acid (ABA), cytokinin (CK), ethylene (ETH), and indole-3-acetic acid (IAA). Specifically, OiDUF640-10 expression significantly increased after ETH treatment. Transgenic experiments showed that overexpressing OiDUF640-10 lines were sensitive to ETH, and seedling length was obstructed. Evolutionary analysis revealed differentiation of the OiDUF640-10 gene in O. sativa ssp. indica and japonica varieties, likely driven by natural selection during the domestication of cultivated rice. These results indicate that OiDUF640-10 plays a vital role in the regulation of rice seedling length.

miR396b/GRF6 module contributes to salt tolerance in rice.

Salinity, as one of the most challenging environmental factors restraining crop growth and yield, poses a severe threat to global food security. To address the rising food demand, it is urgent to develop crop varieties with enhanced yield and greater salt tolerance by delving into genes associated with salt tolerance and high-yield traits. MiR396b/GRF6 module has previously been demonstrated to increase rice yield by shaping the inflorescence architecture. In this study, we revealed that miR396b/GRF6 module can significantly improve salt tolerance of rice. In comparison with the wild type, the survival rate of MIM396 and OE-GRF6 transgenic lines increased by 48.0% and 74.4%, respectively. Concurrent with the increased salt tolerance, the transgenic plants exhibited reduced H2 O2 accumulation and elevated activities of ROS-scavenging enzymes (CAT, SOD and POD). Furthermore, we identified ZNF9, a negative regulator of rice salt tolerance, as directly binding to the promoter of miR396b to modulate the expression of miR396b/GRF6. Combined transcriptome and ChIP-seq analysis showed that MYB3R serves as the downstream target of miR396b/GRF6 in response to salt tolerance, and overexpression of MYB3R significantly enhanced salt tolerance. In conclusion, this study elucidated the potential mechanism underlying the response of the miR396b/GRF6 network to salt stress in rice. These findings offer a valuable genetic resource for the molecular breeding of high-yield rice varieties endowed with stronger salt tolerance.

[New perspective of anticoagulation in intensive care unit: basic and clinical advances in coagulation factor XII and XI inhibitors].

Anticoagulation therapy stands as a key treatment for thrombotic diseases. The consequential bleeding risk tied to existing anticoagulation methods significantly impacts patient prognosis. In the intensive care unit (ICU), patients often necessitate organ support, leading to the inevitable placement of artificial devices in blood vessels, thereby requiring anticoagulation treatment to avert clot formation that might impede organ support. Nevertheless, these patients commonly encounter a heightened risk of bleeding. Hemophilia B, identified in 1953, manifests as a deficiency in coagulation factor XI (FXI), which focused people's perspective on the endogenous coagulation pathway, that is, the contact pathway. Upon interaction between the surface of artificial devices and FXII, FXII activates, subsequently triggering FXI and initiating the "coagulation cascade" within the contact pathway. Inhibitors targeting the contact pathway encompass two primary categories: FXII inhibitors and FXI inhibitors, capable of impeding this process. This article reviews the role of FXII and FXI in activating the contact pathway, seeking to illuminate their contributions to thrombus formation. By listing the relatively mature drugs and their indications, clinicians are familiar with this new anticoagulant.

Drug-coated balloon therapy for in-stent restenosis in patients with iliofemoral deep vein thrombosis: A single-arm observational study.

BACKGROUND: Iliofemoral deep vein thrombosis (IFDVT) causes severe symptoms and affect the quality of life to a great extent. Endovascular thrombectomy and stent implantation have been a feasible strategie to alleviate the signs and symptoms of IFDVT. However, venous in-stent restenosis (ISR) has become an emerging non-negligible problem. METHODS: To evaluate the histological characteristics of venous ISR, neointima of arterial and venous ISR patients were collected and examed. To explore the effect of drug-coated balloon (DCB) on venous ISR lesions, we conducted a single-center retrospective case series study involving IFDVT patients with ISR after venous stenting who were treated with paclitaxel-coated balloon dilatation. RESULTS: We found a collagen-rich matrix but not elastin, as well as fewer cells and less neovascularization in venous intimal hyperplasia compared with neointima in arteries. Thirteen IFDVT patients were involved in the study, with average preoperative stenosis degree of 87.69% ± 13.48%. After intervention, the stenosis degree was significantly reduced to 14.6% ± 14.36% immediately (p < 0.0001) and to 16.54% ± 15.73% during follow-up (p < 0.0001). During follow-up, the VEINES-QOL scores (p < 0.0001), VEINES-Sym scores (p < 0.0001), and Villalta scores (p = 0.04) of patients was improved significantly compared with those before intervention. No major adverse events were observed. CONCLUSIONS: The use of DCB may have a positive effect in the treatment of venous ISR by targeting intimal hyperplasia. Moreover, the application of DCB dilatation in IFDVT stenting patients with ISR is deemed safe and effective.

Surgical management of abdominal aortic graft infection: network meta-analysis.

BACKGROUND: A paucity of evidence exists regarding the optimal management for abdominal aortic graft infection. The aim of this paper was to assess short- and long-term outcomes following different surgical options in aortic graft infection patients. METHODS: Medline, Embase and the Cochrane Library were searched from inception to February 2023. Network meta-analysis was performed using a frequentist method. Patients were divided into four treatment groups: complete graft removal with in situ repair, complete graft removal with extra-anatomic repair, partial graft removal with in situ repair and partial graft removal with extra-anatomic repair. The mortality rate at 30-days and 1-year was the primary outcome. Secondary outcomes were longer-term mortality rate, primary patency and reinfections. For included RCTs, the Cochrane risk-of-bias tool was utilized to assess the risk of bias. The methodological quality of cohort studies was evaluated using the Newcastle-Ottawa scale. RESULTS: Among 4559 retrieved studies, 22 studies with 1118 patients (11 multi-arm and 11 single-arm studies) were included. Patients received complete graft removal with in situ repair (N = 852), partial graft removal with in situ repair (N = 36), complete graft removal with extra-anatomic repair (N = 228) and partial graft removal with extra-anatomic repair (N = 2). Both network meta-analysis results and pooled results of multi- and single-arm cohorts indicated that partial graft removal with in situ repair has the lowest 30-day and 1-year mortality rates (0% and 6.1% respectively), followed by complete graft removal with in situ repair (11.9% and 23.8% respectively) and complete graft removal with extra-anatomic repair (16.6% and 41.4% respectively). In addition, complete graft removal with in situ repair had a lower 3-year (complete graft removal with in situ repair versus complete graft removal with extra-anatomic repair: 32.1% versus 90%) and 5-year (complete graft removal with in situ repair versus complete graft removal with extra-anatomic repair: 45.6% versus 67.9%) mortality rate when compared with complete graft removal with extra-anatomic repair. Patients in the complete graft removal with in situ repair group had the lowest reinfections (8%), followed by partial graft removal with in situ repair (9.3%) and complete graft removal with extra-anatomic repair (22.4%). CONCLUSION: Partial graft removal with in situ repair was associated with lower 30-day and 1-year mortality rates when compared with complete graft removal with in situ repair and complete graft removal with extra-anatomic repair. Partial graft removal with in situ repair might be a feasible treatment for specific aortic graft infection patients.

NOP14-mediated ribosome biogenesis is required for mTORC2 activation and predicts rapamycin sensitivity.

The mechanistic target of rapamycin (mTOR) forms two distinct complexes: rapamycin-sensitive mTOR complex 1 (mTORC1) and rapamycin-insensitive mTORC2. mTORC2 primarily regulates cell survival by phosphorylating Akt, though the upstream regulation of mTORC2 remains less well-defined than that of mTORC1. In this study, we show that NOP14, a 40S ribosome biogenesis factor and a target of the mTORC1-S6K axis, plays an essential role in mTORC2 signaling. Knockdown of NOP14 led to mTORC2 inactivation and Akt destabilization. Conversely, overexpression of NOP14 stimulated mTORC2-Akt activation and enhanced cell proliferation. Fractionation and coimmunoprecipitation assays demonstrated that the mTORC2 complex was recruited to the rough endoplasmic reticulum through association with endoplasmic reticulum-bound ribosomes. In vivo, high levels of NOP14 correlated with poor prognosis in multiple cancer types. Notably, cancer cells with NOP14 high expression exhibit increased sensitivity to mTOR inhibitors, because the feedback activation of the PI3K-PDK1-Akt axis by mTORC1 inhibition was compensated by mTORC2 inhibition partly through NOP14 downregulation. In conclusion, our findings reveal a spatial regulation of mTORC2-Akt signaling and identify ribosome biogenesis as a potential biomarker for assessing rapalog response in cancer therapy.

Bone Marrow Mesenchymal Stem Cell Extracellular Vesicle-derived miR-27b- 3p activates the Wnt/Β-catenin Pathway by Targeting SMAD4 and Aggravates Hepatic Ischemia-reperfusion Injury.

BACKGROUND: To investigate the roles of extracellular vesicles (EVs) secreted from bone marrow mesenchymal stem cells (BMSCs) and miR-27 (highly expressed in BMSC EVs) in hepatic ischemia‒ reperfusion injury (HIRI). APPROACHES AND RESULTS: We constructed a HIRI mouse model and pretreated it with an injection of agomir-miR-27-3p, agomir-NC, BMSC-EVs or control normal PBS into the abdominal cavity. Compared with the HIRI group, HIRI mice preinjected with BMSC-EVs had significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and alleviated liver necrosis (P<0.05). However, compared with HIRI+NC mice, HIRI+miR-27b mice had significantly increased ALT and AST levels, aggravated liver necrosis, and increased apoptosis-related protein expression (P<0.05). The proliferation and apoptosis of AML-12 cells transfected with miR-27 were significantly higher than the proliferation and apoptosis of AML-12 cells in the mimic NC group (P<0.01) after hypoxia induction. SMAD4 was proven to be a miR-27 target gene. Furthermore, compared to HIRI+NC mice, HIRI+miR-27 mice displayed extremely reduced SMAD4 expression and increased levels of wnt1, ß-catenin, c-Myc, and Cyclin D1. CONCLUSION: Our findings reveal the role and mechanism of miR-27 in HIRI and provide novel insights for the prevention and treatment of HIRI; for example, EVs derived from BMSCs transfected with antimiR- 27 might demonstrate better protection against HIRI.

Association between phthalates and sleep problems in the U.S. adult females from NHANES 2011-2014.

There is little research on the relationship between phthalates exposure and sleep problems in adult females, with existing studies only assessing the association between exposure to individual phthalates with sleep problems. We aimed to analyse the relationship between phthalates and sleep problems in 1366 US females aged 20 years and older from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) by age stratification. Multivariate logistic regression showed that the fourth quartile of MECPP increased the risk of sleep problems in females aged 20-39 compared with the reference quartile (OR: 1.87, 95% CI: 1.14, 3.08). The WQS index was significantly associated with the sleep problems in females aged 20-39. In the BKMR, a positive overall trend between the mixture and sleep problems in females aged 20-39. In this study, we concluded that phthalates might increase the risk of sleep problems in females aged 20-39.

Aberrant accumulation of ceramides in mitochondria triggers cell death by inducing autophagy in Arabidopsis.

Sphingolipids are membrane lipids and play critical roles in signal transduction. Ceramides are central components of sphingolipid metabolism that are involved in cell death. However, the mechanism of ceramides regulating cell death in plants remains unclear. Here, we found that ceramides accumulated in mitochondria of accelerated cell death 5 mutant (acd5), and expression of mitochondrion-localized ceramide kinase (ACD5) suppressed mitochondrial ceramide accumulation and the acd5 cell death phenotype. Using immuno-electron microscopy, we observed hyperaccumulation of ceramides in acer acd5 double mutants, which are characterized by mutations in both ACER (alkaline ceramidase) and ACD5 genes. The results confirmed that plants with specific ceramide accumulation exhibited localization of ceramides to mitochondria, resulting in an increase in mitochondrial reactive oxygen species production. Interestingly, when compared with the wild type, autophagy-deficient mutants showed stronger resistance to ceramide-induced cell death. Lipid profiling analysis demonstrated that plants with ceramide accumulation exhibited a significant increase in phosphatidylethanolamine levels. Furthermore, exogenous ceramide treatment or endogenous ceramide accumulation induces autophagy. When exposed to exogenous ceramides, an increase in the level of the autophagy-specific ubiquitin-like protein, ATG8e, associated with mitochondria, where it directly bound to ceramides. Taken together, we propose that the accumulation of ceramides in mitochondria can induce cell death by regulating autophagy.

Gastrodin alleviates premature senescence of vascular endothelial cells by enhancing the Nrf2/HO-1 signalling pathway.

Endothelial dysfunction is an independent risk factor for stroke. The dysfunction of endothelial cells (EC) is closely concerned with EC senescence. Gastrodin (GAS) is an organic compound extracted from the dried root mass of the Orchidaceae plant Gastrodiae gastrodiae. It is used clinically to treat diseases such as vertebrobasilar insufficiency, vestibular neuronitis and vertigo. In the present study, we used hydrogen peroxide (H2 O2 )-induced human umbilical vein endothelial cells (HUVECs) to establish an in vitro EC senescence model and to investigate the role and mechanism of GAS in EC senescence. It's found that H2 O2 -treated HUVECs increased the proportion of senescence-associated ß-galactosidase (SA ß-gal) positive cells and the relative protein expression levels of senescence-associated cyclin p16 and p21. In addition, GAS reduced the proportion of SA ß-gal positive cells and the relative protein expression levels of p16 and p21, and increased the proliferation and migration ability of HUVECs. Meanwhile, GAS increased the expression of the anti-oxidative stress protein HO-1 and its nuclear expression level of Nrf2. The anti-senescence effect of GAS was blocked when HO-1 expression was inhibited by SnPPIX. Furthermore, absence of HO-1 abolished the effect of GAS on HUVEC proliferation and migration. In conclusion, GAS ameliorated H2 O2 -induced cellular senescence and enhanced cell proliferation and migration by enhancing Nrf2/HO-1 signalling in HUVECs. These findings of our study expanded the understanding of GAS pharmacology and suggested that GAS may offer a potential therapeutic agent for stroke.

Identification and characterization of BES1 genes involved in grain size development of Oryza sativa L.

BES1 (BRI1-EMS-SUPPRESSOR1) defines a unique class of plant-specific transcription factors that plays an essential role in response to Brassinosteroids (BRs) signal induction pathways. In our study, we conducted genome-wide scanning and comprehensive characterization of the BES1 gene family in rice and other eukaryotes, leading to valuable findings. Molecular docking experiments showed that all OsBES1 genes in rice could directly bind to BR small molecules. Among the identified genes, OsBES1-4 exhibited a remarkable response as it consistently showed induction upon exposure to various phytohormones after treatment. Further functional verification of OsBES1-4 revealed its impact on grain size. Overexpression of OsBES1-4 resulted in increased grain size, as confirmed by cytological observations showing an increase in cell length and cell number. Moreover, we identified that OsBES1-4 plays a role in rice grain size development by binding to the BR response element in the promoter region of the OsBZR1 gene. Evolutionary analysis indicated differentiation of OsBES1-4 between indica and japonica rice varieties, suggesting natural selection during the domestication process of cultivated rice. Therefore, we conclude that OsBES1-4 plays a crucial role in regulating rice grain size and has the potential to be an important target in rice breeding programs, and haplotype analysis found that all OsBES1 genes were associated with grain size development, either thousand-grain weight, grain length, or grain width. Overall, these findings suggest that the BES1 genes are involved in the regulation of grain size development in rice, and the utilization of SNPs in the OsBES1-4 gene promoter could be a favorable option for distinguishing indica and japonica.