Circ-IP6K2 suppresses tumor progression by modulating the miR-1292-5p/CAMK2N1 signal in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is a malignant tumor originating from the epithelial cells of the renal tubules. The clear cell RCC subtype is closely linked to a poor prognosis due to its rapid progression. Circular RNA (circRNA) is a novel class of regulatory RNA molecules that play a role in the development of ccRCC, although their functions have not been fully elucidated. In this study, we identified a significant downregulation of circ-IP6K2 in ccRCC tissues based on data from the GSE100186 dataset. The decreased expression of circ-IP6K2 correlated with the progression of TNM stage and histological grade, and was also associated with decreased overall survival rates in ccRCC patients. Moreover, our findings revealed that circ-IP6K2 expression suppressed proliferation, migration, and invasion capabilities in vitro, and inhibited xenograft growth in vivo. Mechanistically, circ-IP6K2 acted as a sponge for miR-1292-5p in ccRCC cells, which in turn targeted the 3'UTR of CAMK2N1, leading to a decrease in its expression. CAMK2N1 was identified as a tumor suppressor that negatively regulated the ß-catenin/c-Myc oncogenic signaling pathway. Additionally, we confirmed a positive correlation between the expression of circ-IP6K2 and CAMK2N1 in ccRCC. Circ-IP6K2 functions to impede the progression of ccRCC by modulating the miR-1292-5p/CAMK2N1 axis. These findings shed new light on the molecular mechanisms driving ccRCC progression and suggest potential therapeutic targets for the treatment of ccRCC.

PDX1 Methylation, NGN3 and Pax6 Expression Levels in Pregnant Women with Gestational Diabetes Mellitus and their association with neonatal blood sugars and birth weight.

Objective: To investigate the correlation of maternal PDX1 methylation, NGN3 and Pax6 expression levels with neonatal blood sugars and birth weight in pregnant women with GDM and non GDM. Methods: This was a prospective cohort study. Total 80 pregnant women who were examined and delivered in the Department of Obstetrics of Affiliated Hospital of Hebei University from January 2019 to June 2022 were recruited and divided into two groups according to the results of oral glucose tolerance test (OGTT): the control group and the observation group, with 40 cases in each group. PDXl methylation rate was measured by the methylation-specific PCR method, whereas gene expression levels of PDX1, NGN3 and Pax6 were measured by RT-PCR meanwhile, neonatal blood glucose and hemoglobin A1c (HbA1c) levels were also measured. Results: In comparison with the control group, the observation group had higher levels of FBG, 2-hour postprandial blood glucose (2hPBG) and HbA1c (P<0.05). Neonatal birth weight and insulin levels in the observation group were significantly higher than those in the control group, while Apgar scores and blood glucose were lower than those in the control group(P<0.05). Moreover, the observation group had significantly lower gene expression levels of PDX1, NGN3 and Pax6, and a higher PDX1 methylation rate than the control group (P<0.05). Correlation analysis revealed a negative correlation between neonatal blood glucose levels and PDX1, NGN3 and Pax6 levels in the observation group, with statistical significance (P<0.05). Conclusion: Changes in maternal PDX1 methylation, NGN3 and Pax6 expression levels may lead to abnormal glucose metabolism in neonates, which has a close bearing on neonatal hypoglycemia and blood glucose levels caused by GDM.

Cation Substitution and Size Effects in Ca2ZnSb2 and Yb2MnSb2: Crystal and Electronic Structures and Thermoelectric Properties.

Zintl compounds often feature complex structural fragments and small band gaps, favoring promising thermoelectric properties. In this work, a new phase Ca2ZnSb2 is synthesized and characterized to be a LiGaGe-type structure. It is isotypic to Yb2MnSb2 with half vacancies at transition metal sites and undergoes a phase transition to Ca9Zn4+xSb9 after annealing. Interestingly, Ca2ZnSb2 and Yb2MnSb2 are amenable to diverse doping mechanisms at different sites. Here, by substituting smaller Li on cation sites, two novel layered compounds Ca1.84(1)Li0.16(1)Zn0.84(1)Sb2 and Yb1.82(1)Li0.18(1)Mn0.96(1)Sb2 with the P63/mmc space group are discovered, which can be viewed as derivatives of LiGaGe type. Despite having lower occupancy, the structural stability is improved compared with the prototype compounds owing to the reduced interlayered distances. Besides, the band structure analyses demonstrate that the bands near the Fermi level are mainly governed by the interlayered interaction. Due to the highly disordered structure, Yb1.82Li0.18Mn0.96Sb2 features ultralow thermal conductivity from 0.79 to 0.47 W·m-1·K-1 among the testing range; in addition, a remarkable Seebeck coefficient of 270.77 µV·K-1 at 723 K is observed. The discovery of the Ca2ZnSb2 phase enriches the 2-1-2 map, and the size effect induced by cations provides new ideas for material designing.

Optimization of Enzyme-Assisted Aqueous Extraction of Polysaccharide from Acanthopanax senticosus and Comparison of Physicochemical Properties and Bioactivities of Polysaccharides with Different Molecular Weights.

To obtain the optimal process for the enzyme-assisted aqueous extraction of polysaccharides from Acanthopanax senticosus, and study the physicochemical properties of polysaccharides of different molecular weights, the extraction of Acanthopanax polysaccharides was optimized using the BBD response surface test. The polysaccharides with different molecular weights were obtained by ethanol-graded precipitation at 40%, 60%, and 80%, which were presented as ASPS40, ASPS60, and ASPS80. The polysaccharides were analyzed by HPGPC, ion chromatography, FT-IR, UV, SEM, TGA, XRD, Congo red, and I2-KI tests. The antioxidant assay was used to evaluate their antioxidant properties in vitro. The findings demonstrated that the recovery rate of Acanthopanax polysaccharide was 10.53 ± 0.682%, which is about 2.5 times greater compared to the conventional method of hot water extraction. Based on FT-IR, TGA, polysaccharides with different molecular weights did not differ in their structure or thermal stability. The XRD suggests that the internal structure of ASPSs is amorphous. Congo red and I2-KI showed that all three polysaccharides had triple helix structures with longer branched chains and more side chains. Furthermore, the antioxidant results showed the antioxidant activity of polysaccharides is not only related to the molecular weight size but also can be related to its composition and structure. These studies developed a green, and scalable method to produce polysaccharides from Acanthopanax senticosus and evaluated the properties of Acanthopanax polysaccharides of different molecular weights.

Prospects for the application of traditional Chinese medicine network pharmacology in food science research.

There has always been a particular difficulty with in-depth research on the mechanisms of food nutrition and bioactivity. The main function of food is to meet the nutritional needs of the human body, rather than to exert a therapeutic effect. Its relatively modest biological activity makes it difficult to study from the perspective of general pharmacological models. With the popularity of functional foods and the concept of dietary therapy, and the development of information and multi-omics technology in food research, research into these mechanisms is moving towards a more microscopic future. Network pharmacology has accumulated nearly 20 years of research experience in traditional Chinese medicine (TCM), and there has been no shortage of work from this perspective on the medicinal functions of food. Given the similarity between the concept of 'multi-component-multi-target' properties of food and TCM, we think that network pharmacology is applicable to the study of the complex mechanisms of food. Here we review the development of network pharmacology, summarize its application to 'medicine and food homology', and propose a methodology based on food characteristics for the first time, demonstrating its feasibility for food research. © 2023 Society of Chemical Industry.

circSKA3 acts as a sponge of miR-6796-5p to be associated with outcomes of ischemic stroke by regulating matrix metalloproteinase 9 expression.

BACKGROUND AND PURPOSE: This study was undertaken to screen the circular RNAs (circRNAs) influencing matrix metalloproteinase 9 (MMP9) through the competing endogenous RNA (ceRNA) network and evaluate the prognostic value of these circRNAs for acute ischemic stroke. METHODS: A total of 220 ischemic stroke patients and 62 healthy subjects were included in this study. RNA was isolated from blood collected in PAXgene tubes. Illumina sequencing, quantitative real-time polymerase chain reaction (qRT-PCR) validation, and luciferase reporter assay were explored to construct and verify the existence of a circRNA-microRNA (miRNA)-matrix metalloproteinase-9 (MMP9) network. The 215 ischemic stroke patients were recruited in a prognostic cohort. They were prospectively followed up for 3 months after stroke onset, and a poor functional outcome was defined as a major disability or death. RESULTS: After Illumina sequencing, six circRNAs were predicted to bind miRNAs and then regulate MMP9 messenger RNA (mRNA). qRT-PCR showed that only circSKA3 was significantly increased in ischemic stroke patients compared to healthy controls and positively associated with MMP9 mRNA expression. Luciferase reporter assay further verified a direct interaction between circSKA3, MMP9, and hsa-miR-6796-5p. Patients in the top tertile of circSKA3 had a 2.672-fold (p < 0.05) risk of poor functional outcome, compared with those in the bottom tertile (p for trend = 0.016). The outcome was predicted by circSKA3 with area under the receiver operating characteristic curve at 0.614 (p = 0.004). CONCLUSIONS: circSKA3 functioned as a ceRNA for hsa-miR-6796-5p to aggravate the progression of ischemic stroke via targeting MMP9. Baseline circSKA3 was positively associated with poor outcomes of ischemic stroke. circSKA3 may be a potential biomarker or therapeutic target in ischemic stroke.

Elucidating the negatively influential and potentially toxic mechanism of single and combined micro-sized polyethylene and petroleum to Chlorella vulgaris at the cellular and molecular levels.

Although microplastics (MPs; <5 mm) may interact with co-contaminants (e.g., petroleum) in marine aquatic systems, little is known about their combined toxicity. Therefore, this study explored the toxicities and their mechanisms of micro-sized polyethylene (mPE) and their combination with petroleum to Chlorella vulgaris. The single MPs at various particle sizes, concentrations, and aging degree, single petroleum, and their combinations, were found to pose toxicities to C. vulgaris. This study also found the microcosm's microbial diversity changed. The microbial communities in the C. vulgaris biotopes were altered under exposure to mPE and petroleum, and were disturbed by external factors such as MPs particle size, concentration, aging time, and the combination with petroleum. Furthermore, as compared with the toxicity of petroleum on microalgal transcriptional function, mPE caused less toxic to C. vulgaris, and only impact the posttranslational modification, protein turnover, and signal transduction processes. Most importantly, mPE reduced petroleum toxicity in C. vulgaris via regulating the ABC transporter, eukaryotic ribosome synthesis, and the citrate cycle metabolic pathways. Overall, our findings could fundamentally provide insights into the joint ecotoxicological effects of MPs and petroleum, and highlight the potential risks of co-exsiting pollutants.

Near-miss organizational learning in nursing within a tertiary hospital: a mixed methods study.

BACKGROUND: Near-miss organizational learning is important for perspective and proactive risk management. Although nursing organizations are the largest component of the healthcare system and act as the final safety barrier, there is little research about the current status of near-miss organizational learning. Thus, we conducted this study to explore near-miss organizational learning in a Chinese nursing organization and offer suggestions for future improvement. METHODS: This was a mixed methods study with an explanatory sequence. It was conducted in a Chinese nursing organization of a tertiary hospital under the guidance of the 4I Framework of Organizational Learning. The quantitative study surveyed 600 nurses by simple random sampling. Then, we applied purposive sampling to recruit 16 nurses across managerial levels from low-, middle- and high-scored nursing units and conducted semi-structured interviews. Descriptive statistics, structured equation modelling and content analysis were applied in the data analysis. The Good Reporting of A Mixed Methods Study (GRAMMS) checklist was used to report this study. RESULTS: Only 33% of participants correctly recognized near-misses, and 4% of participants always reported near-misses. The 4I Framework of Organizational Learning was verified in the surveyed nursing organization (χ2 = 0.775, p = 0.379, RMSEA < 0.01). The current organizational learning behaviour was not conducive to near-miss organizational learning due to poor group-level learning (ßGG = 0.284) and poor learning absorption (ßMisalignment= -0.339). In addition, the researchers developed 13 codes, 9 categories and 5 themes to depict near-miss organizational learning, which were characterized by nurses' unfamiliarity with near-misses, preferences and the dominance of first-order problem-solving behaviour, the suspension of near-miss learning at the group level and poor learning absorption. CONCLUSION: The performance of near-miss organizational learning is unsatisfactory across all levels in surveyed nursing organization, especially with regard to group-level learning and poor learning absorption. Our research findings offer a scientific and comprehensive description of near-miss organizational learning and shed light on how to measure and improve near-miss organizational learning in the future.

Rapid and Accurate Detection of Lymph Node Metastases Enabled through Fluorescent Silicon Nanoparticles-Based Exosome Probes.

Sentinel lymph node (SLN) detection is of great significance for the prevention and treatment of cancer metastasis. Herein, we introduce silicon nanoparticles (SiNPs)-based exosome (SiNPs@EXO) probes for distinguishing normal and metastatic SLNs. Typically, SiNPs are suitable for stable and long-term tracking of exosomes, while cancer cell-driven exosomes with a tumor-homing effect allow targeting metastatic SLNs. Remarkably, the as-fabricated SiNPs@EXO has the ability to label metastatic SLNs, i.e., the fluorescence signal in SLNs reaches the peak within 0.5 h and remains up to 3 h. Comparatively, SLN tracers (e.g., indocyanine green) used clinically can illuminate SLNs 1 h post injection, whereas the signal witnesses a sharp fall then. Moreover, evaluations based on preclinical data confirm the negligible side effects of the SiNPs@EXO. Our results provide new tools for targeting SLNs and predicting lymphatic metastasis of tumor.

Aged microplastics decrease the bioavailability of coexisting heavy metals to microalga Chlorella vulgaris.

Environmental aging of ubiquitous microplastics (MP) occurs through the action of biotic and abiotic factors, and aged MP exhibit different physicochemical properties and environmental behavior from virgin MP. This study aimed to investigate the aged micro-sized polystyrene (mPS) and polyvinyl chloride (mPVC), and the heavy metals copper (Cu) and cadmium (Cd), and examine the effects of their combined toxicities on microalga Chlorella vulgaris. Results showed that the presence of MP inhibited cell growth as compared with the control, the inhibition rate (I) decreased as concentrations of MP rose and aged MP exhibited stronger inhibition of cells than did virgin MP. The largest I was achieved in each culture with the MP concentration of 0.01 g/L, in which aged mPS with the maximal of 36.84% (Iaged mPS) followed by aged mPVC (Iaged mPVC = 30.03%), virgin mPS (Ivirgin mPS = 29.10%) and virgin mPVC (Ivirgin mPVC = 16.72%). Addition of the heavy metals Cu2+ and Cd2+ significantly inhibited cell growth, and toxicity increased with concentrations in a range of 0.5-2.0 mg/L; the maximum I values were 19.50% (ICu) and 85.14% (ICd), respectively. The combined toxicity of aged MP + Cu or aged MP + Cd was less than that of individual heavy metals. In particular, as compared with the maximal ICd of 85.14% achieved by single Cd2+, the toxicity of Cd2+ was greatly reduced when combined with aged mPS and mPVC, with the I value decreased to 27.55% (Iaged mPS) and 32.51% (Iaged mPVC), respectively. Both single and combined treatments caused cell damage to the microalga, accompanied by increased superoxide dismutase (SOD) and intracellular malonaldehyde (MDA) content.

The protein kinase D1-mediated classical protein secretory pathway regulates the Ras oncogene-induced senescence response.

Senescent cells develop a senescence-associated secretory phenotype (SASP). The factors secreted by cells with a SASP have multiple biological functions that are mediated in an autocrine or paracrine manner. However, the status of the protein kinase D1 (PKD1; also known as PRKD1)-mediated classical protein secretory pathway, from the trans-Golgi network (TGN) to the cell surface, during cellular senescence and its role in the cellular senescence response remain unknown. Here, we show that the activities or quantities of critical components of this pathway, including PKD1, ADP-ribosylation factor 1 (ARF1) and phosphatidylinositol 4-kinase IIIß (PI4KIIIß), at the TGN are increased in senescent cells. Blocking of this pathway decreases IL-6 and IL-8 (hereafter IL-6/IL-8) secretion and results in IL-6/IL-8 accumulation in SASP-competent senescent cells. Inhibition of this pathway reduces IL-6/IL-8 secretion during Ras oncogene-induced senescence (OIS), retards Ras OIS and alleviates its associated ER stress and autophagy. Finally, targeting of this pathway triggers cell death in SASP factor-producing senescent cells due to the intracellular accumulation of massive amounts of IL-6/IL-8. Taken together, our results unveil the hyperactive state of the protein secretory pathway in SASP-competent senescent cells and its critical functions in mediating SASP factor secretion and the Ras OIS process, as well as in determining the fate of senescent cells.

Circ_0000140 restrains the proliferation, metastasis and glycolysis metabolism of oral squamous cell carcinoma through upregulating CDC73 via sponging miR-182-5p.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a more common cancer in the world. Emerging evidence suggests that circular RNAs (circRNAs) participate in the progression of OSCC. However, the role of circ_0000140 in OSCC is still unknown. METHODS: The expression of circ_0000140 and microRNA-182-5p (miR-182-5p) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Also, cell proliferation, migration and invasion were measured by colony formation and transwell assays, respectively. Western blot (WB) analysis was used to test the levels of proliferation, metastasis and glycolysis metabolism-related proteins as well as cell division cycle 73 (CDC73) protein. Further, the extracellular acidification rate (ECAR) of cells was detected by the Seahorse XF Extracellular Flux Analyzer. The lactate acid level of cells was tested by Lactate Assay Kit. Moreover, dual-luciferase reporter was used to verify the interaction between miR-182-3p and circ_0000140 or CDC73, and RNA immunoprecipitation (RIP) assay was employed to further confirm the relationship between miR-182-3p and circ_0000140. In addition, mice xenograft models were built to measure the effect of circ_0000140 on OSCC tumor growth in vivo. RESULTS: Circ_0000140 was lowly expressed in OSCC, and its overexpression hindered proliferation, migration, invasion and glycolysis metabolism in OSCC cells. MiR-182-5p could be sponged by circ_0000140, and its mimic could invert the suppression of circ_0000140 overexpression on OSCC progression. CDC73 could be targeted by miR-182-3p, and its silencing could reverse the inhibition of miR-182-3p inhibitor on OSCC progression. Further, overexpressed circ_0000140 reduced the OSCC tumor growth in vivo. CONCLUSIONS: Circ_0000140 might play an anti-cancer role in OSCC, which provided a novel target for clinical therapy of OSCC.

Dual-Amplification Strategy-Based SERS Chip for Sensitive and Reproducible Detection of DNA Methyltransferase Activity in Human Serum.

Herein, we present a dual-amplification sensing strategy-based surface-enhanced Raman scattering (SERS) chip, which combines rolling circle amplification (RCA) and polyadenine (PolyA) assembly for sensitive and reproducible determination of the activity of M.SssI, a cytosine-guanine dinucleotide (CpG) methyltransferase (MTase). Typically, in the presence of M.SssI, RCA process is triggered, resulting in long, single-stranded DNA (ssDNA) fragments that are hybridized with thousands of Raman reporters of Cy3. Afterward, the resultant ssDNA fragments are conjugated to SERS-active substrates made of silver core-gold satellite nanocomposites-modified silicon wafer (Ag-Au NPs@Si), with the SERS enhancement factor of ∼5 × 106. The core-satellite nanostructures are assembled relied on the strong affinity of PolyA toward gold/silver surface. Of particular significance, the developed SERS chip displays an ultrahigh sensitivity with a low limit of detection (LOD) of 2.8 × 10-3 U/mL, which is around 2 orders of magnitude higher than most reported methods. In addition, the constructed chip features a broad detection range covering from 0.05 to 50 U/mL. Besides for the ultrahigh sensitivity and broad dynamic range, the chip also features good reproducibility (e.g., the relative standard deviation (RSD) is less than ∼12%). Taking advantages of these merits, the developed chip is feasible for accurate discrimination of M.SssI with various concentrations spiked in human serum samples with good recoveries ranging from 99.6% to 107%.

Multifunctional Silicon-Carbon Nanohybrids Simultaneously Featuring Bright Fluorescence, High Antibacterial and Wound Healing Activity.

In this work, a class of multifunctional silicon-carbon nanohybrids (designated as SiCNs), which simultaneously possess aqueous dispersibility, bright fluorescence (photoluminescence quantum yield [PLQY]: ≈28%), as well as high antibacterial and wound healing activity, is presented. Taking advantage of these unique merits, cell distribution and pharmacological behavior of the SiCNs is first investigated through tracking their strong and stable fluorescence. The high bacteria inhibition ability (≈82.9% killing rate toward S. aureus) and hemostatic effects (shorten the bleeding time from ≈60 to ≈15 s) of the resultant SiCNs are then demonstrated. Moreover, the wound closure promotion activity (10% lead in wound contraction) is systematically demonstrated in vivo, which is especially suitable for wound healing applications. The results suggest the SiCNs as a new kind of high-performance multifunctional nanoagents suitable for various biological and biomedical utilizations.

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis (HS), insulin resistance (IR), and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here, we report that USP4 expression was dramatically down-regulated in livers from NAFLD patients and different NAFLD mouse models induced by high-fat diet (HFD) or genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes. Hepatocyte-specific USP4 depletion exacerbated HS, IR, and inflammatory response in HFD-induced NAFLD mice. Conversely, hepatic USP4 overexpression notably alleviated the pathological alterations in two different NAFLD models. Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-ß activated kinase 1 (TAK1), leading to a suppression of the activation of downstream nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) cascades, which, in turn, reversed the disruption of insulin receptor substrate/protein kinase B/glycogen synthase kinase 3 beta (IRS-AKT-GSK3ß) signaling. In addition, USP4-TAK1 interaction and subsequent TAK1 deubiquitination were required for amelioration of metabolic dysfunctions. Conclusion: Collectively, the present study provides evidence that USP4 functions as a pivotal suppressor in NAFLD and related metabolic disorders. (Hepatology 2018; 00:000-000).

Biomimetic preparation of core-shell structured surface-enhanced Raman scattering substrate with antifouling ability, good stability, and reliable quantitative capability.

The fouling and stability are two most critical limiting factors for practical applications of surface-enhanced Raman scattering (SERS)-based microfluidic electrophoresis device. Herein, we present a novel biomimetic nanoengineering strategy to achieve a SERS substrate featuring antifouling ability, good stability, and reliable quantitative capability. Typically, by employing tea polyphenol as the reducing agent, the substrate made of silver core-gold shell nanostructures in situ grown on silicon wafer surface is fabricated. The core-shell nanostructures are further embedded with internal standard molecules. Remarkably, the fabricated substrate preserves distinct SERS effects, adaptable reproducibility, and reliable quantitative ability even if the substrate is incubated with 15% H2 O2 , 13% HNO3 , or 108  CFU/mL bacteria, or suffered from 12-day continuous vibration at 250 rpm/min in PBS buffer. As a proof-of-concept application, the DNA-functionalized substrate is capable of precise quantification of Hg2+ with a limit of detection down to ca. 1 pM even in sewage water.

Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling.

Exercise-induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease-induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming-induced physiological hypertrophy and pressure overload-induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid-related orphan nuclear receptor-α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming-induced physiological hypertrophic murine hearts. In vivo and in vitro loss-of-function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti-hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese-dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro-hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti-hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti-hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a RORα-dependent manner.

Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα-dependent manner.

Rupture of vulnerable plaques is the main trigger of acute cardio-cerebral vascular events, but mechanisms responsible for transforming a stable atherosclerotic into a vulnerable plaque remain largely unknown. Melatonin, an indoleamine hormone secreted by the pineal gland, plays pleiotropic roles in the cardiovascular system; however, the effect of melatonin on vulnerable plaque rupture and its underlying mechanisms remains unknown. Here, we generated a rupture-prone vulnerable carotid plaque model induced by endogenous renovascular hypertension combined with low shear stress in hypercholesterolemic ApoE-/- mice. Melatonin (10 mg/kg/d by oral administration for 9 weeks) significantly prevented vulnerable plaque rupture, with lower incidence of intraplaque hemorrhage (42.9% vs. 9.5%, P = 0.014) and of spontaneous plaque rupture with intraluminal thrombus formation (38.1% vs. 9.5%, P = 0.029). Mechanistic studies indicated that melatonin ameliorated intraplaque inflammation by suppressing the differentiation of intraplaque macrophages toward the proinflammatory M1 phenotype, and circadian nuclear receptor retinoid acid receptor-related orphan receptor-α (RORα) mediated melatonin-exerted vasoprotection against vulnerable plaque instability and intraplaque macrophage polarization. Further analysis in human monocyte-derived macrophages confirmed the role of melatonin in regulating macrophage polarization by regulating the AMPKα-STATs pathway in a RORα-dependent manner. In summary, our data provided the first evidence that melatonin-RORα axis acts as a novel endogenous protective signaling pathway in the vasculature, regulates intraplaque inflammation, and stabilizes rupture-prone vulnerable plaques.

Effects of farnesoid-X-receptor SUMOylation mutation on myocardial ischemia/reperfusion injury in mice.

Myocardial ischemia/reperfusion (MI/R) injury induces excessive cellular apoptosis and contributes significantly to final infarct size. We previously demonstrated that a nuclear receptor, Farnesoid X receptor (FXR), plays a crucial role in mediating myocardial apoptosis. The FXR functions are regulated by post translational modifications (PTM). However, whether the proapoptotic effect of FXR in MI/R injury is regulated by PTM remains unclear. Here, we aimed to study the effect of SUMOylation, a PTM involved in the pathogenesis of MI/R injury per se, on the proapoptotic effect of FXR in MI/R injury. We observed that FXR could be SUMOylated in heart tissues, and FXR SUMOylation levels were downregulated in ischemia reperfused myocardium. By overexpression of SUMOylation-defective FXR mutant, it was demonstrated that decreased SUMOylation augmented the detrimental effect of FXR, via activation of mitochondrial apoptosis pathway and autophagy dysfunction in MI/R injury. Further mechanistic studies suggested that decreased SUMOylation levels increased the transcription activity of FXR, and the subsequently upregulated FXR target gene SHP mediated the proapoptotic effects of FXR. Taken together, we provided the first evidence that the cardiac effects of FXR could be regulated by SUMOylation, and that manipulating FXR SUMOylation levels may hold therapeutic promise for constraining MI/R injury.

[Core prescription excavation of launched Chinese patent medicines for treating different syndromes of angina pectoris].

To analyze the medication features and regularity of prescriptions of traditional Chinese medicines in treating patients with coronary heart disease angina pectoris based on the launched Chinese patent medicines. In the article,we collected all of the launched Chinese patent medicines for treating coronary heart disease and angina pectoris from the Chinese patent medicine value assessment information database,and set up a medical record normalized database,then carried out the classification of syndromes. The medication features and prescription rules for angina pectoris were analyzed by frequency statistics and association rules(IBM SPSS Modeler 14. 1 Premiums software,Apriori algorithm). Finally,a total of 170 prescriptions were selected,and 197 Chinese herbs were included,involving to totally 11 syndrome types,in which blood stasis syndrome,Qi stagnation and blood stasis syndrome,Qi deficiency and blood stasis syndrome,Qi-Yin deficiency and blood stasis syndrome were the main syndrome types. The frequency of single-herb medicines for the four main syndrome types,the combination of commonly used medicines,and the core prescriptions were summarized. After comparing the core prescriptions of the four syndrome types,we could analyze the medication features and prescription rules. In conclusion,the therapeutic principle is blood-activating and stasis-dissolving,and consideration was also given to promoting Qi,invigorating Qi and resuscitation and invigorating Qi-Yin. The main medicines include Danshen(Salvia Miltiorrhizae Radix et Rhizoma) and Chuan-xiong(Chuanxiong Rhizoma). According to different types of syndromes,Chinese herbal medicines are added,such as Jiangxiang(Dalbergiae Odoriferae Lignum), Chishao(Paeoniaeradix Rubra), Sanqi(Notoginseng Radix et Rhizoma), Honghua(Carthami Flos),Bingpian(Borneolum Syntheticum),Renshen(Ginseng Radix et Rhizoma). Frequency statistics and association rules are combined to explore the medication features and core prescriptions,which provide ideas for the treatment of angina pectoris and the development of new drugs.