Color-Tunable Perovskite Nanomaterials with Intense Circularly Polarized Luminescence and Tailorable Compositions.

The ability to design halide perovskite nanocrystals (PNCs) with circularly polarized luminescence (CPL) offers exceptional potential in photonic technologies. Despite recent inspiring advances, the creation of PNCs with full-color tailorablity, outstanding CPL, and long-term stability remains a substantial challenge. Herein, a robust strategy to craft CPL-active PNCs is reported, exhibiting appealing full-color tunable wavelengths, enhanced CPL, and prolonged stability. In contrast to conventional methodologies, this strategy utilizes chiral nematic mesoporous silica (CNMS) as host to render in situ confined growth of diverse achiral PNCs. By strategically engineering photonic bandgap, adjusting loading amount of PNCs, and manipulating cations/anion compositions of PNCs, robust CPL responses with tunable wavelength and intensity are successfully obtained. The resulting PNCs-CNMS achieves stable CPL emissions with full-color tunability and impressive luminescent dissymmetric factors up to -0.17. Remarkably, silica-based hosts as a protective barrier confer exceptional resistance to humidity, photodegradation, and thermal stability, even up to 95 °C. Furthermore, the ability to achieve reversible CPL switching within PNCs-CNMS is attainable by leveraging the responsiveness of CNMS matrix or dynamic behavior of impregnated PNCs. Additionally, circularly polarized light-emitting diode devices based on PNCs-CNMS can be conveniently fabricated. This research affords a powerful platform for designing functional chiroptical materials.

Effects of low-tube voltage coronary CT angiography on plaque and pericoronary fat assessment: intraindividual comparison.

OBJECTIVES: To investigate the effects of low tube voltage on coronary plaques and pericoronary fat assessment, and to compare their extent among various levels of low voltage. MATERIALS AND METHODS: Patients were recommended for high-pitch low-tube voltage coronary computed tomography angiography (CCTA), and they were included if they had poor image quality and were referred to a conventional CCTA. The patients were classified into a low-voltage group (with 70-kV, 80-kV, and 90-kV subgroups) and a conventional group (100/120 kV). Their total plaque and subcomponent volumes and pericoronary fat attenuation index (FAI) were measured. RESULTS: A total of 1002 image slices (from 65 patients and 74 plaques) were included, including 21, 31, 13, 4, and 61 patients in the 70-kV, 80-kV, 90-kV, 100-kV, and 120-kV groups respectively. The CT values of noncalcified plaques in the conventional and low-voltage groups were 54.6 ± 21.3 HU and 31.5 ± 22.6 HU, respectively (p < 0.05). Compared with the conventional group, the necrotic core and calcification volume were increased, and the fibrolipid volume, periplaque, and right coronary artery FAI were decreased in the low-voltage group and its subgroups (p < 0.001). The magnitude of changes in fibrous and calcification volumes increased in the 70-kV subgroup compared with that in the 90-kV subgroup (p < 0.05). CONCLUSION: Low tube voltages, particularly of 70 kV, have a significant effect on coronary plaque and FAI. The effect of low voltage on plaque composition is characterized by a polarization pattern, i.e., a decrease in fibrolipid (medium density) and an increase in necrotic core (low density) and calcification (high density). CLINICAL RELEVANCE STATEMENT: Our results highlight the comparability and repeatability of plaque and pericoronary fat assessments facilitated by the same or a similar tube voltage. It is necessary to carry out studies on the specificity threshold of low tube voltage at each level. KEY POINTS: • Low tube voltage had a significant effect on coronary plaque and pericoronary fat, particularly 70 kV. • The effect of low tube voltage on plaque composition shows the shift from medium-density mixed components to low- and high-density components. • It is necessary to correct the specificity threshold or attenuation difference for low tube voltage at each level.

6-Shogaol prevents benzo (A) pyrene-exposed lung carcinogenesis via modulating PRDX1-associated oxidative stress, inflammation, and proliferation in mouse models.

In this study, we have investigated the chemopreventive role of 6-shogaol (6-SGL) on benzopyrene (BaP) exposed lung carcinogenesis by modulating PRDX1-associated oxidative stress, inflammation, and proliferation in Swiss albino mouse models. Mice were exposed to BaP (50 mg/kg b.wt) orally twice a week for four consecutive weeks and maintained for 16 weeks, respectively. 6-SGL (30 mg/kg b.wt) were orally administered to mouse 1 h before BaP exposure for 16 weeks. After the experiment's termination, 6-SGL (30 mg/kg b.wt) prevented the loss in body weight, increased lung weight, and the total number of tumors in the mice. Moreover, we observed that 6-SGL treatment reverted the activity of BaP-induced lipid peroxidation and antioxidants in mice. Also, 6-SGL impeded the phosphorylation of MAPK family proteins such as Erk1, p38, and Jnk1 in BaP-exposed mice. PRDX1 is an essential antioxidant protein that scavenges toxic radicals and enhances several antioxidant proteins. Overexpression of PRDX1 substantially inhibits MAPKs, proliferation, and inflammation signaling axis. Hence, PRDX1 is thought to be a novel targeting protein for preventing BaP-induced lung cancer. In this study, we have obtained the 6-SGL treatment in a mouse model that reverted BaP-induced depletion of PRDX1 expression. Moreover, pretreatment of 6-SGL (30 mg/kg b.wt) significantly inhibited enhanced proinflammatory cytokines (TNF-α, IL-6, IL-ß1, IL-10) and proliferative markers (Cyclin-D1, Cyclin-D2, and PCNA) in BaP-exposed mice. The histopathological studies also confirmed that 6-SGL effectively protected the cells with less damage. Thus, the study demonstrated that 6-SGL could be a potential phytochemical and act as a chemopreventive agent in BaP-induced lung cancer by enhancing PRDX1 expression.

Porous Organic Materials in Tissue Engineering: Recent Advances and Applications for Severed Facial Nerve Injury Repair.

The prevalence of facial nerve injury is substantial, and the restoration of its structure and function remains a significant challenge. Autologous nerve transplantation is a common treatment for severed facial nerve injury; however, it has great limitations. Therefore, there is an urgent need for clinical repair methods that can rival it. Tissue engineering nerve conduits are usually composed of scaffolds, cells and neurofactors. Tissue engineering is regarded as a promising method for facial nerve regeneration. Among different factors, the porous nerve conduit made of organic materials, which has high porosity and biocompatibility, plays an indispensable role. This review introduces facial nerve injury and the existing treatment methods and discusses the necessity of the application of porous nerve conduit. We focus on the application of porous organic polymer materials from production technology and material classification and summarize the necessity and research progress of these in repairing severed facial nerve injury, which is relatively rare in the existing articles. This review provides a theoretical basis for further research into and clinical interventions on facial nerve injury and has certain guiding significance for the development of new materials.

Apatinib combined with SOX regimen for conversion therapy in advanced gastric cancer patients: a retrospective cohort study.

BACKGROUND: Recently, many studies have shown that the progress of conversion therapy can provide surgical opportunities for patients with advanced gastric cancer (GC) and bring survival benefits. However, the results of the current study show that the regimen used in conversion therapy is still controversial. Apatinib, as the standard third-line treatment for GC, has an inconclusive status in conversion therapy. METHODS: This study retrospectively analyzed GC patients admitted to Zhejiang Provincial People's Hospital from June 2016 to November 2019. All patients were pathologically diagnosed, had unresectable factors, and received SOX regimen with or without apatinib as conversion therapy. RESULTS: A total of 50 patients were enrolled in the study. Altogether 33 patients (66%) received conversion surgery and 17 patients (34%) received conversion therapy without surgery. The median progression-free survival (PFS) between surgery group and non-surgery group were 21.0 versus 4.0 months (p < 0.0001), and the median overall survival (OS) were 29.0 versus 14.0 months (p < 0.0001). In conversion surgery group, 16 patients (16/33) were treated with SOX plus apatinib, and the R0 resection rate was 81.3%; 17 patients (17/33) were treated with SOX regimen along, and the R0 resection rate was 41.2% (p = 0.032). The PFS in the SOX combined with apatinib group was significantly longer than that of SOX group (25.5 versus 16 months, p = 0.045), and the median OS were 34.0 versus 23.0 months (p = 0.048). The addition of apatinib did not increase the incidence of serious adverse reactions throughout the preoperative therapy period. CONCLUSIONS: Patients with advanced inoperable gastric cancer could benefit probably from conversion chemotherapy and subsequence conversion surgery. Apatinib-targeted therapy combined with SOX chemotherapy may be a safe and feasible option for conversion therapy.

Helicoverpa armigera GATAe transcriptional factor regulates the expression of Bacillus thuringiensis Cry1Ac receptor gene ABCC2 by its interplay with additional transcription factors.

Helicoverpa armigera is a worldwide pest that has been efficiently controlled by transgenic plants expressing Bt Cry toxins. To exert toxicity, Cry toxins bind to different receptors located in larval midgut cells. Previously, we reported that GATA transcription factor GATAe activates the expression of multiple H. armigera Cry1Ac receptors in different insect cell lines. Here, the mechanism involved in GATAe regulation of HaABCC2 gene expression, a key receptor of Cry1Ac, was analyzed. HaGATAe gene silencing by RNAi in H. armigera larvae confirmed the activation role of HaGATAe on the expression of HaABCC2 in the midgut. The contribution of all potential GATAe-binding sites was analyzed by site-directed mutagenesis using Hi5 cells expressing a reporter gene under regulation of different modified HaABCC2 promoters. DNA pull-down assays revealed that GATAe bound to different predicted GATA-binding sites and mutations of the different GATAe-binding sites identified two binding sites responsible for the promoter activity. The binding site B9, which is located near the transcription initiator site, has a major contribution on HaABCC2 expression. Also, DNA pull-down assays revealed that all other members of GATA TF family in H. armigera, besides GATAe, HaGATAa, HaGATAb, HaGATAc and HaGATAd also bound to the HaABCC2 promoter and decreased the GATAe dependent promoter activity. Finally, the potential participation in the regulation of HaABCC2 promoter of several TFs other than GATA TFs expressed in the midgut cells was analyzed. HaHR3 inhibited the GATAe dependent activity of the HaABCC2 promoter, while two other midgut-related TFs, HaCDX and HaSox21, also bound to the HaABCC2 promoter region and increased the GATAe dependent promoter activity. All these data showed that GATAe induces HaABCC2 expression by binding to HaGATAe binding sites in the promoter region and that additional TFs participate in modulating the HaGATAe-driven expression of HaABCC2.

Tumor-mutation burden as a marker for immunotherapy of pancreatic cancer: the case report and literature review.

Pancreatic cancer is digestive cancer with limited therapeutic options and a poor outcome. Pancreatic cancer has a high mortality rate, with a 5-year survival rate of less than 5%. The median survival after metastasis of the disease is less than 6 months. Studies have revealed that the standard treatment, including palliative chemotherapy or immunotherapy, is not significantly effective for pancreatic cancer. Herein, we report a case of pancreatic cancer who benefited from a combination of anti-PD-1 immunotherapy and chemotherapy.

Relationship between nosocomial infections and coronavirus disease 2019 in the neurosurgery unit: clinical characteristics and outcomes from a Chinese Tertiary-Care Hospital.

BACKGROUND: The COVID-19 pandemic has raised awareness of infection prevention and control. We found that the incidence of nosocomial infection in neurosurgery has changed. This study aimed to evaluate the impact of "coronavirus disease 2019 (COVID-19) prevention and control measures" on nosocomial infections in neurosurgery. METHODS: To explore changes in nosocomial infections in neurosurgery during the COVID-19 pandemic, the clinical data of inpatients undergoing neurosurgery at Taizhou Hospital of Zhejiang Province between January 1 and April 30, 2020 (COVID-19 era) were first analyzed and then compared with those from same period in 2019 (first pre-COVID-19 era). We also analyzed data between May 1 and December 31, 2020 (post-COVID-19 era) at the same time in 2019 (second pre-COVID-19 era). RESULTS: The nosocomial infection rate was 7.85% (54/688) in the first pre-COVID-19 era and 4.30% (26/605) in the COVID-19 era (P = 0.01). The respiratory system infection rate between the first pre-COVID-19 and COVID-19 eras was 6.1% vs. 2.0% (P < 0.01), while the urinary system infection rate was 1.7% vs. 2.0% (P = 0.84). Between the first pre-COVID-19 and COVID-19 eras, respiratory system and urinary infections accounted for 77.78% (42/54) vs. 46.15% (12/26) and 22.22% (12/54) vs. 46.15% (12/26) of the total nosocomial infections, respectively (P < 0.01). Between the second pre-COVID-19 and post-COVID-19 eras, respiratory system and urinary accounted for 53.66% (44/82) vs. 40.63% (39/96) and 24.39% (20/82) vs. 40.63% (39/96) of the total nosocomial infections, respectively (P = 0.02). CONCLUSIONS: The incidence of nosocomial infections in neurosurgery reduced during the COVID-19 pandemic. The reduction was primarily observed in respiratory infections, while the proportion of urinary infections increased significantly.

SOX4 induces drug resistance of colorectal cancer cells by downregulating CYLD through transcriptional activation of microRNA-17.

Exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells. Drug tolerance can reduce the benefits obtained from canonical treatment and reduce the survival rate of patients. Regulation of SRY-related HMG box transcription factor 4 (SOX4) has been proved to affect drug sensitivity. The current study aimed to explore the role of SOX4 in drug resistance of colorectal cancer (CRC) cells as well as the related molecular mechanisms. Expression patterns of SOX4, microRNA-17 (miR-17), and CYLD in both CRC tissues and cells were determined with their relationship analyzed by bioinformatics analysis, dual-luciferase reporter gene assay, and ChIP. Loss- and gain-function assays were performed to ascertain the effect of SOX4, miR-17, and CYLD on biological cellular processes and drug resistance to 5-FU. SOX4 and miR-17 were found to be highly expressed while CYLD was poorly expressed in CRC tissues and cells. Silencing of SOX4 resulted in the suppression of cellular proliferation, invasion, migration as well as a reduction in CRC drug resistance. Mechanically, CYLD was specifically targeted by miR-17, while SOX4 upregulated the expression of miR-17. Functionally, SOX4 triggered drug resistance of CRC cells to 5-FU through the miR-17/CYLD axis. Taken together, the key findings of the present study provides evidence suggesting that SOX4 elevates miR-17 to decrease CYLD, thus inducing chemotherapy resistance of CRC cells.

Hyperlipemia pancreatitis onset time affects the association between elevated serum triglyceride levels and disease severity.

BACKGROUND: The association of serum triglyceride (TG) levels with the severity of hypertriglyceridaemia-induced acute pancreatitis (HTG-AP) remains controversial. This study aimed to comprehensively assess the TG levels from the initial onset and their predictive value in the disease assessment of HTG-AP. METHODS: Data collected from January 2018 to July 2021 in one institute were assessed retrospectively. HTG-AP was defined as a TG level > 500 mg/dL in the absence of other common aetiologies of AP. The TG levels within 24 hours (24 h), 48 hours (48 h), 3-4 days (3-4 d), and 5-7 days (5-7 d) after symptom onset and their correlations with disease severity in HTG-AP patients were analysed by cross-sectional and longitudinal studies. RESULTS: In the cross-sectional study, 377 HTG-AP patients were included before lipid-lowering intervention: 216 subjects had their first TG levels measured within 24 h after onset, 91 within 48 h, 50 in 3-4 d, and 20 in 5-7 d. TG levels decreased in the 24 h, 48 h and 3-4 d groups (P < 0.001), however, the TG decline in the 5-7 d group had no difference compared with the 3-4 d group. HTG-AP patients with severe or moderately severe disease displayed higher TG levels than those with mild disease in the 24 h and 48 h groups (P < 0.050) but not in the 3-4 d or 5-7 d groups. Furthermore, the TG levels were correlated with the modified computed tomography severity index only in the 24 h and 48 h groups, while an association between serum calcium levels and C-reactive protein levels was only present in the 24 h group. Similarly, the TG levels were related to hospital days and ICU days in the 24 h and/or 48 h groups. In the longitudinal study, 165 patients with complete records of TG levels from 24 h to 5-7 d were enrolled. With supportive care and lipid-lowering treatment after admission, the TG levels declined rapidly (P < 0.001), and the correlations with disease severity weakened or even disappeared from 24 h to 5-7 d. CONCLUSION: TG levels decreased and attenuated the association with disease severity of HTG-AP over the time of onset. The TG levels within the initial 48 h after onset were most useful for the diagnosis and disease assessment of HTG-AP.

Silencing integrin α6 enhances the pluripotency-differentiation transition in human dental pulp stem cells.

OBJECTIVES: Although integrins have been shown to be associated with proliferation and differentiation in some stem cells, the regulatory effect of integrin α6 (ITGα6) on the human dental pulp stem cells (hDPSCs) has not been reported. Here, we detected the roles of ITGα6 in hDPSCs. MATERIALS AND METHODS: Attached to Cytodex 3 microcarriers, hDPSCs grown under stimulated microgravity (SMG) or conventional culture conditions were measured the proliferation and different gene expression. Further, ITGα6 was silenced in hDPSCs, and its effect on proliferation, differentiation, and cytoskeletal organization was analyzed. RESULTS: SMG conditions increased the number of Ki67-positive hDPSCs and progression into S phase of cell cycle. WB analysis showed the expression of ITGα6 was upregulated in hDPSCs under SMG conditions. Knockdown of ITGα6 decreased the expression of stemness markers, CD105 and STRO-1 in hDPSCs, but promoted the osteogenic and odontogenic differentiation by increased ALP expression and Alizarin Red nodules. Moreover, RNA-seq demonstrated that RHO/ROCK signaling pathway upregulated silencing ITGα6-hDPSCs. Treatment with Y-27632 inhibited the effect of ITGα6 depletion on hDPSCs stemness, rearranged the cytoskeleton, promoted the pluripotency, proliferation ability, and inhibited the differentiation. CONCLUSION: ITGα6 promotes hDPSCs stemness via inhibiting RHO/ROCK and restoring cytoskeleton.

Determination of xanthine using a ratiometric fluorescence probe based on boron-doped carbon quantum dots and gold nanoclusters.

A dual-emission ratiometric fluorescent sensing system based on boron-doped carbon quantum dots (B-CQDs) and gold nanoclusters (AuNCs) has been developed for the determination of xanthine. The blue fluorescence of B-CQDs at 445 nm is then reduced by the AuNCs through the inner filter effect (IFE) under a single excitation wavelength of 370 nm. By the catalysis of xanthine oxidase (XOD), xanthine is oxidized by oxygen dissolved in the solution to produce H2O2. The horseradish peroxidase (HRP) catalyzes H2O2 to generate hydroxyl radicals, which can quench the fluorescence of AuNCs, leading to the recovery of the fluorescence of B-CQDs. Based on the relationship between the fluorescence intensity ratio (F445/F665) and the concentration of xanthine, the designed method exhibits a good linearity range of 1.2-500.0 µmol L -1 and a limit of detection of 0.37 µmol L -1. The ratiometric fluorescent is applied to determine xanthine in human urine samples. Good recoveries of spiked samples in the range 99.2-105.0% are obtained by the proposed assay, with relative standard deviations (RSD) ranging from 0.9 to 2.6%.

Hydrogen gas inhalation ameliorates cardiac remodelling and fibrosis by regulating NLRP3 inflammasome in myocardial infarction rats.

It is noteworthy that prolonged cardiac structural changes and excessive fibrosis caused by myocardial infarction (MI) seriously interfere with the treatment of heart failure in clinical practice. Currently, there are no effective and practical means of either prevention or treatment. Thus, novel therapeutic approaches are critical for the long-term quality of life of individuals with myocardial ischaemia. Herein, we aimed to explore the protective effect of H2 , a novel gas signal molecule with anti-oxidative stress and anti-inflammatory effects, on cardiac remodelling and fibrosis in MI rats, and to explore its possible mechanism. First, we successfully established MI model rats, which were then exposed to H2 inhalation with 2% concentration for 28 days (3 hours/day). The results showed that hydrogen gas can significantly improve cardiac function and reduce the area of cardiac fibrosis. In vitro experiments further proved that H2 can reduce the hypoxia-induced damage to cardiomyocytes and alleviate angiotensin II-induced migration and activation of cardiac fibroblasts. In conclusion, herein, we illustrated for the first time that inhalation of H2 ameliorates myocardial infarction-induced cardiac remodelling and fibrosis in MI rats and exert its protective effect mainly through inhibiting NLRP3-mediated pyroptosis.

MiR-328-3p inhibits cell proliferation and metastasis in colorectal cancer by targeting Girdin and inhibiting the PI3K/Akt signaling pathway.

MiR-328-3p has been reported to be downregulated and serve as a tumor suppressor in several cancers. Previous studies only have reported the downregulation of miR-328-3p in CRC. However, the roles of miR-328-3p in CRC growth and metastasis were unknown. In this study, we demonstrated that miR-328-3p overexpression inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). The PI3K/Akt signaling pathway was also inactivated by miR-328-3p overexpression. MiR-328-3p knockdown showed the opposite effects. In addition, we confirmed that miR-328-3p directly bound to 3'UTR of Girdin and negatively regulated its expression. Girdin knockdown or treatment with PI3K inhibitor LY294002 blocked the effects of miR-328-3p inhibitor on cell proliferation, metastasis, and the PI3K/Akt signaling pathway. Moreover, pre-miR-328 decreased numbers of liver metastatic nodules, and reduced the levels of p-Akt, p-Girdin, and Girdin in metastatic tissues in liver. In conclusion, miR-328-3p may inhibit proliferation and metastasis of CRC cells by targeting Girdin and inactivating the PI3K/Akt signaling pathway. MiR-328-3p may be a novel target in cancer therapy.

A MnO2 nanosheet-assisted ratiometric fluorescence probe based on carbon quantum dots and o-phenylenediamine for determination of 6-mercaptopurine.

A MnO2 nanosheet-assisted ratiometric fluorescence probe based on carbon quantum dots (CQDs) and o-phenylenediamine (OPD) has been developed for the detection of the anticancer drug 6-mercaptopurine (6-MP). CQDs with strong fluorescence are synthesized via the one-step hydrothermal method. MnO2 nanosheets as an oxidase-mimicking nanomaterial directly oxidize OPD into 2,3-diaminophenazine (DAP) which has a fluorescence emission at 570 nm, whereas the fluorescence of CQDs at 445 nm is then reduced by the DAP through the inner filter effect (IFE) under a single excitation wavelength (370 nm). After adding 6-MP, MnO2 nanosheets can be reduced to Mn2+ and lose their oxidase-like property, blocking the IFE with the fluorescence decrease of DAP and fluorescence increase of CQDs. The novel ratiometric fluorescence probe exhibits considerable sensitivity toward 6-MP and linear response is in the 0.46-100.0 µmol L-1 concentration range with the detection limit of 0.14 µmol L-1. Furthermore, the probe shows good selectivity when exposed to a series of interfering other organic and inorganic compounds, and biomolecules and can be applied to the detection for 6-MP in human serum samples and pharmaceutical tablets. Satisfactory recoveries of 6-MP in human serum samples are in the range 96.1-110.9% with the RSD of 1.4 to 3.2%. The amount of 6-MP is successfully estimated as 49.3 mg in pharmaceutical tablet with the RSD of about  2.2%.

Large-Scale Rapid Positioning of Hierarchical Assemblies of Conjugated Polymers via Meniscus-Assisted Self-Assembly.

Rapid and deliberate patterning of nanomaterials over a large area is desirable for device manufacturing. We report a method for meniscus-assisted self-assembly (MASA)-enabled rapid positioning of hierarchically assembled dots and stripes composed of luminescent conjugated polymer over two length scales. Periodically arranged conjugated poly(9,9-dioctylfluorene) (PFO) polymers, yield dots, punch-holes and stripes at microscopic scale via MASA. Concurrent self-assembly of PFOs into two-dimensional lenticular crystals within each dot, punch-hole and stripe is realized at nanoscopic scale. Hierarchical assembly is achieved by constraining the evaporation of the PFOs solution in two approximately parallel plates via a MASA process. The three-phase contact line (TCL) of the liquid meniscus of the PFOs was printed using the upper plate, yielding an array of curved stripes. Rapid creation of hierarchical assemblies via MASA opens up possibilities for large-scale organization of a wide range of soft matters and nanomaterials.

MiR-144-5p limits experimental abdominal aortic aneurysm formation by mitigating M1 macrophage-associated inflammation: Suppression of TLR2 and OLR1.

BACKGROUND: It has been noted that dysregulation of microRNAs (miRNAs) contributes to the formation of abdominal aortic aneurysm (AAA), a vascular disease associated with progressive aortic dilatation and degradation, and pathological infiltration and activation of inflammatory cells, such as macrophages. Our microarray data revealing that miR-144-5p was the top 1 downregulated miRNA in mouse AAA tissues as compared to normal aortas motivated us to explore its role in AAA development. METHODS: We profiled miRNA and mRNA expression in Angiotensin II (Ang II)- (n = 3) and saline-infused abdominal aortas (n = 4) via Agilent microarrays, and further validated the data with real-time QPCR. In vivo, miR-144-5p or control agomirs were given to Apoe-/- mice with Ang II infusion-induced AAA. In vitro, mouse RAW 264.7 macrophages and human THP-1 macrophage-like cells were transfected with miR-144-5p or control agomirs/antagomirs, and oxidized Low Density Lipoprotein (ox-LDL) was used to stimulate M1 macrophage polarization. RESULTS: Based on the microarray and real-time QPCR validation data, we identified miR-144-5p as a novel downregulated miRNA in AAA tissues. Overexpression of miR-144-5p by utilizing its specific agomirs in vivo significantly attenuated Ang II-induced aortic dilatation and elastic degradation in Apoe-/- mice and improved their survival. AAA incidence was reduced by miR-144-5p as well. MiR-144-5p polarized macrophages to M2 type in Ang II-infused aortas. Further, the expression levels of two predictive targets for miR-144-5p, Toll Like Receptor 2 (TLR2) and ox-LDL Receptor 1 (OLR1), were higher in AAA specimens, and negatively correlated to miR-144-5p (Pearson correlation coefficient r < -0.9, P < .01). These two molecules were then confirmed as novel miR-144-5p targets via dual-luciferase assay. MiR-144-5p agomirs suppressed ox-LDL-induced upregulation of M1 macrophage markers, including interleukin 1ß (IL1ß), tumor necrosis factor α (TNFα), prostaglandin-endoperoxide synthase 2 (PTGS2) and nitric oxide synthase 2 (NOS2), in macrophages probably by targeting TLR2. MiR-144-5p also inhibited the signaling transduction of pathways downstream to TLR2 and OLR1, including NF-κB and ERK1/2 pathways, whose abnormal activation contributed AAA formation. CONCLUSION: Our work suggests miR-144-5p as a novel regulator for AAA pathology. Management of miR-144-5p and its targets TLR2 and OLR1 provides therapeutic potential for limiting AAA formation.

MiR-126a-5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS-4 expression.

Abdominal aortic aneurysm (AAA) is a serious vascular disease featured by inflammatory infiltration in aortic wall, aortic dilatation and extracellular matrix (ECM) degradation. Dysregulation of microRNAs (miRNAs) is implicated in AAA progress. By profiling miRNA expression in mouse AAA tissues and control aortas, we noted that miR-126a-5p was down-regulated by 18-fold in AAA samples, which was further validated with real-time qPCR. This study was performed to investigate miR-126a-5p's role in AAA formation. In vivo, a 28-d infusion of 1 µg/kg/min Angiotensin (Ang) II was used to induce AAA formation in Apoe-/- mice. MiR-126a-5p (20 mg/kg; MIMAT0000137) or negative control (NC) agomirs were intravenously injected to mice on days 0, 7, 14 and 21 post-Ang II infusion. Our data showed that miR-126a-5p overexpression significantly improved the survival and reduced aortic dilatation in Ang II-infused mice. Elastic fragment and ECM degradation induced by Ang II were also ameliorated by miR-126a-5p. A strong up-regulation of ADAM metallopeptidase with thrombospondin type 1 motif 4 (ADAMTS-4), a secreted proteinase that regulates matrix degradation, was observed in smooth muscle cells (SMCs) of aortic tunica media, which was inhibited by miR-126a-5p. Dual-luciferase results demonstrated ADAMTS-4 as a new and valid target for miR-126a-5p. In vitro, human aortic SMCs (hASMCs) were stimulated by Ang II. Gain- and loss-of-function experiments further confirmed that miR-126-5p prevented Ang II-induced ECM degradation, and reduced ADAMTS-4 expression in hASMCs. In summary, our work demonstrates that miR-126a-5p limits experimental AAA formation and reduces ADAMTS-4 expression in abdominal aortas.

MiR-126-5p promotes contractile switching of aortic smooth muscle cells by targeting VEPH1 and alleviates Ang II-induced abdominal aortic aneurysm in mice.

Abdominal aortic aneurysm (AAA) is a potential lethal disease that is defined by an irreversible dilatation (>50%) of the aorta. During AAA expansion, the aortic wall is often remodeled, which is featured by extracellular matrix (ECM) degeneration, medial and adventitial inflammation, depletion and phenotypic switching of vascular smooth muscle cells (SMCs). Recent studies have suggested microRNAs as vital regulators for vascular SMC function. Our earlier work demonstrated an anti-AAA role of miR-126-5p in ApoE-/- mice infused with angiotensin (Ang) II. The present study aimed to further elucidate its role in AAA pathogenesis with a focus on aortic SMC phenotypic switching. Ventricular zone expressed PH domain containing 1 (VEPH1) was identified as a novel negative regulator for vascular SMC differentiation by our group, and its expression was negatively correlated to miR-126-5p in mouse abdominal aortas based on the present microarray data. In vivo, in addition attenuating Ang II infusion-induced aortic dilation and elastin degradation, miR-126-5p agomirs also significantly reduced the expression of VEPH1. In vitro, to induce synthetic transition of human aortic smooth muscle cells (hAoSMCs), cells were stimulated with 1 µM Ang II for 24 h. Ectopic overexpression of miR-126-5p restored the differentiation of hAoSMCs-the expression of contractile/differentiated SMC markers, MYH11, and α-SMA, increased, whilst that of synthetic/dedifferentiated SMC markers, PCNA and Vimentin, decreased. Both mus and homo VEPH1 genes were validated as direct targets for miR-126-5p. VEPH1 re-expression impaired miR-126-5p-induced differentiation of hAoSMCs. In addition, Ang II-induced upregulation in matrix metalloproteinase (MMP)-9 and MMP2, two key proteases responsible for ECM degradation, in mouse aortas and hAoSMCs was reduced by miR-126-5p overexpression as well. Collectively, these results reveal an important, but previously unexplored, role of miR-126-5p in inhibiting AAA development-associated aortic SMC dedifferentiation.

Xanthoplanine attenuates macrophage polarization towards M1 and inflammation response via disruption of CrkL-STAT5 complex.

Monocyte infiltration and macrophage polarization are widely considered as pivotal steps for the initiation and progression of atherosclerosis. Previous studies suggested that zanthoxylum piperitum had strong analgesic and anti-inflammatory effects. However, it remains unclear whether zanthoxylum piperitum inhibits inflammation via macrophage function. In the present study, we investigated the effects of xanthoplanine (the total alkaloid extract of zanthoxylum piperitum) on macrophage function. CCK-8 kit was performed to determine cell viability and the preferred concentration of xanthoplanine. We assayed the effects of xanthoplanine on markers of macrophage polarization and inflammation via quantitative PCR and enzyme-linked immunosorbent assay, and measured the production of reactive oxygen species (ROS) by flow cytometry. Immunoblots, co-immunoprecipitation, immunofluorescence and Luciferase activity were performed to investigate the molecular mechanism of STAT signaling pathway in response to xanthoplanine. We found that xanthoplanine (50 and 100 µM) significantly reduced M1 polarization and promoted M2 polarization. The contents of inflammatory cytokines measured by ELISA were markedly decreased in macrophages pretreated with xanthoplanine, compared with those induced by LPS and IFN-γ. In parallel, xanthoplanine alleviated the production of ROS in macrophages induced by LPS and IFN-γ. Moreover, xanthoplanine alleviated STAT5 phosphorylation and blocked STAT5 nuclear translocation without alterations in CrkL expression, subsequently interrupting the interaction between p-STAT5 and CrkL. Likewise, xanthoplanine prominently attenuated the transcription activity of STAT5 induced by LPS and IFN-γ but did not affect the transcription activity of STAT1 and STAT3. Xanthoplanine attenuated M1 phenotypic switch and macrophage inflammation via blocking the formation of CrkL-STAT5 complex.