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Specifically controlling cell pyroptosis is advantageous for oncotherapy as it allows simultaneous ablation of primary tumors and activation of immunogenicity of tumor environment. Herein, a facile and robust strategy is presented to construct efficient NIR-activated helical pyroptosis agents (PyroAs) with negligible dark cytotoxicity. It is demonstrated that the construction of four intramolecular B-X bonds (X = O or N) within the BODIPY chromophore enforces a significant twisting of its π-conjugation, yielding a variety of helical H BD molecules with desired high photosensitivity and negligible dark toxicity. A robust approach is established to extend H BD into the near-infrared (NIR) region through site-selective incorporation of an electron-withdrawing ester moiety. It is also proved that targeted delivery of the NIR-activated H BD-ER to the endoplasmic reticulum (ER) specifically activates pyroptosis pathway by equipping it with an ER-targeting moiety. Finally, the favorable biocompatibility, excellent antitumor efficacy, and remarkable systematic immune response of this unique NIR-activated helical PyroAs are shown in vivo, demonstrating its potential application in solid tumor immunotherapy., (© 2024 Wiley‐VCH GmbH.)

Background: Casticin (CAS), a natural flavonoid found in Viticis Fructus, Viticis Cannabifoliae Fructus, and Semen Euphorbiae, shows anti-inflammatory activity and efficacy against various cancers. However, its effect on stemness associated with self-renewal in cervical cancer (CC) cells remains unclear, as well as the underlying mechanism., Purpose: The primary objective of this study was to examine the effect of CAS on CC stemness and to explore the underpinning regulatory mechanism., Methods: HeLa cells underwent treatment with varying concentrations of CAS (0, 10, 30, 100 nM). To evaluate the impacts of CAS on CC stemness and tumorigenicity, sphere- and colony-formation assays and a xenograft model were employed. The study involved screening for changes in miRNAs and their target genes. The miRNA array identified an upregulation in miRNAs, whereas the mRNA array detected a downregulation of specific target genes. The latter genes were found to regulate stem cell-related genes through miR-342-3p in HeLa cells administered CAS. Next, whether miR-342-3p directly targets FOXM1 when upregulated by CAS was assessed by the luciferase reporter assay. qRT-PCR was performed to analyze miR-342-3p expression. Additionally, immunoblotting was conducted to assess the protein amounts of FoxM1 and stemness-related factors (CD133, CD49f, Nanog, and Sox2). Function rescue experiments were conducted to determine the mechanism of CAS in stemness regulation. These experiments involved utilizing a miR-342-3p inhibitor and overexpressing FOXM1 in HeLa cells., Results: CAS decreased in vitro stemness, suppressing sphere- and colony-formation capabilities of CC. It also dose-dependently downregulated the expression of stemness-associated proteins, including CD133, CD49f, Nanog, and Sox2. Moreover, CAS inhibited in vivo carcinogenesis, remarkably reducing tumor growth in mice bearing HeLa cell xenografts. Analysis revealed downregulated FOXM1 expression in HeLa cells treated with CAS. In the luciferase reporter assay, miR-342-3p was found to directly target FOXM1 in CAS-treated HeLa cells. Additionally, miR-342-3p inhibitor transfection successfully rescued CAS' suppressive impact on stemness. Furthermore, overexpression of FOXM1 did not induce changes in miR-342-3p expression. However, it effectively rescued CAS' suppressive effects on stemness. Moreover, CAS also inhibited stemness, upregulated miR-342-3p, and lowered FOXM1 expression in the SiHa cell line., Conclusion: CAS suppresses self-renewal-associated stemness by targeting FOXM1 via miR-342-3p upregulation. These findings suggest CAS is promising as a novel therapeutic candidate in CC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Although RNAi-based pest management holds great potential as an alternative to traditional chemical control, its efficiency is restricted by dsRNA instability and limited cellular uptake. Using nanomaterials to facilitate dsRNA delivery has shown promise in solving these challenges. In this study, we firstly used RNAi to investigate the role of the juvenile hormone and ecdysteroid signaling pathways genes in reproduction of Spodoptera frugiperda, the fall armyworm. Females in knocked-down treatments of any of the Met, EcR, and USP genes had greatly reduced fertility with the most pronounced inhibitory effects on oviposition observed following EcR knockdown, and thus the dsEcR could be a candidate target for RNAi-based oviposition inhibitory agency. Then a combinatorial spray-induced and nanocarrier-delivered gene silencing (SI-NDGS) approach that targeted EcR was conducted. At 72 h post-spay, the transcript levels of EcR and the oviposition were successfully reduced and inhibited. These findings support the groundwork for further developing novel RNAi-based pest management strategies for S. frugiperda., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

TRAF (Tumor necrosis factor receptor-associated factor) proteins are key mediators of signal transduction in cell signaling and immune regulation within the toll-like receptor (TLR) and tumor necrosis factor (TNFR) superfamily. Despite the importance of TRAF genes in teleost innate immunity, study on their functions in C. altivelis is limited. This study utilized bioinformatics methods to identify and named eight TRAF genes (CaTRAF2a, CaTRAF2a-like, CaTRAF2b, CaTRAF3, CaTRAF4a, CaTRAF5, CaTRAF6 and CaTRAF7) in C. altivelis. Phylogenetic, syntenic and molecular evolution revealed that all CaTRAF members were evolutionarily conserved in teleost. Domain analysis indicated the presence of a conserved N-terminal RING finger domain in all CaTRAF proteins. Most CaTRAF proteins also featured a MATH domain at the C-terminal, with the exception of CaTRAF7 which contained seven repeat WD40 domains. In addition, qRT-PCR was used to detect the expression patterns of nine different tissues and eight different embryonic development stages of healthy fish, and it was found that there were spatial and tissue specificities among the members. HE staining revealed evident pathological lesions in the tissues post V. harveyi infection. Atrophy and significant bending of the gill lamellae were observed in the gills, while irregular cell shapes, increased fat vacuoles, and enlarged cell volume were noted in the liver. Intestinal tissues displayed thickening of the muscle layer, elongation of intestinal villi, and increased folds. Moreover, the expression of TRAF gene changed significantly after V. harveyi infection. These results would help to clarify the molecular role of CaTRAF gene in the regulation of immune and inflammatory responses in C. altivelis., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Electronic switches have been considered to be one of the most important components of contemporary electronic circuits for processing and storing digital information. Fabricating functional devices with building blocks of atomic/molecular switches can greatly promote the minimization of the devices and meet the requirement of high integration. This review highlights key developments in the fabrication and application of molecular switching devices. This overview offers valuable insights into the switching mechanisms under various stimuli, emphasizing structural and energy state changes in the core molecules. Beyond the molecular switches, typical individual metal atomic switches are further introduced. A critical discussion of the main challenges for realizing and developing practical molecular/atomic switches is provided. These analyses and summaries will contribute to a comprehensive understanding of the switch mechanisms, providing guidance for the rational design of functional nanoswitch devices toward practical applications., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Adelphocoris suturalis is a destructive pest that attacks > 270 plants, including cotton, maize, soybean, and fruit trees. Adelphocoris suturalis can cause tremendous crop losses when the density exceeds economic thresholds, but because it can be both phytophagous and zoophytophagous it can serve as a natural enemy of other pests when the density is below the economic threshold. Effective control of its population is beneficial for maximizing yield and profits. RNA interference (RNAi) has potential to be a viable alternative to conventional pesticide-based pest management, but the lack of efficient double-stranded RNA (dsRNA) delivery systems and candidate genes are currently limiting factors for field applications., Results: In this study, RNAi of juvenile hormone (JH) receptor components methoprene-tolerant (Met)/Taiman (Tai) in Adelphocoris suturalis reduced fertility. Based on this reproductive role, we targeted Adelphocoris suturalis Met and Tai for knockdown by coupling nanomaterial-dsRNA complexes with a transdermal spray delivery system. Within 12 h of adult emergence, females were sprayed with star polycation (SPc)-dsRNA formulations and the RNAi effects were assessed over time. RNAi knockdown efficiencies of 39-58% were observed at 5 days post-treatment and abnormal ovarian development was apparent by 10 days post-treatment., Conclusion: Our results show that spray-induced and nanocarrier-delivered gene silencing (SI-NDGS) system targeting JH signal genes effectively impaired oviposition, thus developing a novel RNA fertility inhibitor to control Adelphocoris suturalis populations. These results give new perspective on pest management and suggest broad prospects for field applications. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

The development of the avian wing pattern has been the subject of heated debate due to its special shape. The Suppressor of cytokine signaling 2 (SOCS2) gene encodes a negative regulator of growth hormone (GH) signaling and bone growth and is known to be strongly expressed in the third digit of chicken forelimbs. These observations suggest that SOCS2 might regulate the morphology of the avian wing, however, the function of SOCS2 in avian limb development remains unknown. Here, we reexamined SOCS2 expression in successive developmental stages of chicken limb development by in situ hybridization (ISH) and describe extended expression from the posterior of the stypolod to the third digit of the forelimbs. We used the RCAS avian retrovirus to overexpress SOCS2 in the developing chicken limb buds, which resulted in reduced or malformed chicken wings while hindlimbs developed normally. Transcriptome sequencing (mRNA-Seq) revealed changes in expression of genes known to be associated with growth and development in forelimbs with overexpressed SOCS2. This study highlights a pivotal role for SOCS2 during the development of the wing in the chicken and provides new insight into molecular mechanisms regulating avian limb development., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

π-stacking interaction, as a fundamental type of intermolecular interaction, plays a crucial role in generating new functional molecules, altering the optoelectronic properties of materials, and maintaining protein structural stability. However, regulating intermolecular π-π interactions at the single-molecule level without altering the molecular conformation as well as the chemical properties remains a significant challenge. To this end, via conductance measurement with thousands of single molecular junctions employing a series of aromatic molecules, we demonstrate that the π-π coupling between neighboring aromatic molecules with rigid structures in a circuit can be greatly enhanced by increasing the bias voltage. We further reveal that this universal regulating effect of bias voltage without molecular conformational variation originates from the increases of the molecular dipole upon an applied electric field. These findings not only supply a non-destructive method to regulate the intermolecular interactions offering an approach to modulate the electron transport through a single molecular junction, but also deepen the understanding of the mechanism of π-π interactions.

A comprehensive understanding of carrier transport in photoisomeric molecular junctions is crucial for the rational design and delicate fabrication of single-molecule functional devices. It has been widely recognized that the conductance of azobenzene (a class of photoisomeric molecules) based molecular junctions is mainly determined by photoinduced conformational changes. In this study, it is demonstrated that the most probable conductance of amine-anchored azobenzene-based molecular junctions increases continuously upon UV irradiation. In contrast, the conductance of pyridyl-anchored molecular junctions with an identical azobenzene core exhibits a contrasting trend, highlighting the pivotal role that anchoring groups play, potentially overriding (even reversing) the effects of photoinduced conformational changes. It is further demonstrated that the molecule with cis -conformation cannot be fully mechanically stretched into the trans -conformation, clarifying that it is a great challenge to realize a reversible molecular switch by purely mechanical operation. Additionally, it is revealed that the coupling strength of pyridyl-anchored molecules is dramatically weakened when the UV irradiation time is prolonged, whereas it is not observed for amine-anchored molecules. The mechanisms for these observations are elucidated with the assistance of density functional theory calculations and UV-Vis spectra combined with flicker noise measurements which confirm the photoinduced conformational changes, providing insight into understanding the charge transport in photoisomeric molecular junctions and offering a routine for logical designing synchro opto-mechanical molecular switches.

This study introduces a modified DF2016 criterion to model a ductile fracture of sheet metals from shear to equibiaxial tension. The DF2016 criterion is modified so that a material constant is equal to the fracture strain at equibiaxial tension, which can be easily measured by the bulging experiments. To evaluate the performance of the modified DF2016 criterion, experiments are conducted for QP980 with five different specimens with stress states from shear to equibiaxial tension. The plasticity of the steel is characterized by the Swift-Voce hardening law and the pDrucker function, which is calibrated with the inverse engineering approach. A fracture strain is measured by the XTOP digital image correlation system for all the specimens, including the bulging test. The modified DF2016 criterion is also calibrated with the inverse engineering approach. The predicted force-stroke curves are compared with experimental results to evaluate the performance of the modified DF2016 criterion on the fracture prediction from shear to equibiaxial tension. The comparison shows that the modified DF2016 criterion can model the onset of the ductile fracture with high accuracy in wide stress states from shear to plane strain tension. Moreover, the calibration of the modified DF2016 criterion is comparatively easier than the original DF2016 criterion.

Background: The effect of inhaled nitric oxide (iNO) in neonates >34 weeks on improving respiration is well documented. However, the efficacy of iNO in preterm infants ≤34 weeks remains controversial. Objectives: The main purpose of this review is to assess the effectiveness and safety of iNO treatment in preterm infants ≤34 weeks. Search methods: We systematically searched PubMed, Embase and Cochrane Libraries from their inception to 1 June 2023. We also reviewed the reference lists of retrieved studies. Selection criteria: Our study involved randomized controlled trials on preterm infants ≤34 weeks, especially those receiving iNO treatment, and mainly assessed outcomes such as bronchopulmonary dysplasia (BPD) and mortality. Two authors independently reviewed these trials, extracted data, and evaluated study biases. Disagreements were resolved by consensus. We used the GRADE method to assess evidence quality. Results: Our research included a total of 17 studies involving 4,080 neonates and 7 follow-up studies. The synthesis of results showed that in neonates, iNO treatment reduced the incidence of BPD (RR: 0.92; 95% CI: 0.86-0.98). It also decreased the composite outcome of death or BPD (RR: 0.94; 95% CI: 0.90-0.98), without increasing the risk of short-term (such as intraventricular hemorrhage, periventricular leukomalacia) and long-term neurological outcomes (including Bayley mental developmental index <70, cerebral palsy and neurodevelopmental impairment). Furthermore, iNO did not significantly affect other neonatal complications like sepsis, pulmonary hemorrhage, necrotizing enterocolitis, and symptomatic patent ductus arteriosus. Subgroup analysis revealed that iNO significantly reduced BPD incidence in neonates at 36 weeks under specific intervention conditions, including age less than 3 days, birth weight over 1,000 g, iNO dose of 10 ppm or higher, or treatment duration exceeding 7 days ( p < 0.05). Conclusion: Inhaled NO reduced the incidence of BPD in neonates at 36 weeks of gestation, and the effect of the treatment depended on neonatal age, birth weight, duration and dose of iNO. Therefore, iNO can be considered a promising treatment for the potential prevention of BPD in premature infants. More data, however, would be needed to support nitric oxide registration in this specific patient population, to minimize its off-label use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Feng, Wu, Xu, Cui and Wu.)

The molecular binding orientation with respect to the electrode plays a pivotal role in determining the performance of molecular devices. However, accomplishing in situ modulation of single-molecule binding orientation remains a great challenge due to the lack of suitable testing systems and characterization approaches. To this end, by employing a developed STM-BJ technique, we demonstrate that the conductance of pyridine-anchored molecular junctions decreases as the applied voltage increases, which is determined by the repeated formation of thousands of gold-molecule-gold dynamic break junctions. In contrast, the static fixed molecular junctions (the distance between two electrodes is fixed) with identical molecules exhibit a reverse tendency as the bias voltage increases. Supported by flicker noise measurements and theoretical calculations, we provide compelling evidence that the orientation of nitrogen-gold bonds (a universal coordinate bond) in the pyridine-anchored molecular junctions can be manipulated to align with the electric field by the synergistic action of the mechanical stretching force and the electric fields, whereas either stimulus alone cannot achieve the same effect. Our study provides a framework for characterizing and regulating the orientation of a single coordinate bond, offering an approach to control electron transport through single molecular junctions., Competing Interests: The authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)

miR-124 is a miRNA predominantly expressed in the nervous system and accounts for more than a quarter of the total miRNAs in the brain. It regulates neurogenesis, neuronal differentiation, neuronal maturation, and synapse formation and is the most important miRNA in the brain. Furthermore, emerging evidence has suggested miR-124 may be associated with the pathogenesis of various neurodevelopmental and neuropsychiatric disorders. Here, we provide an overview of the role of miR-124 in neurodevelopment and the underling mechanisms, and finally, we prospect the significance of miR-124 research to the field of neuroscience., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The manipulation of single molecules has attracted extensive attention because of their promising applications in chemical, biological, medical, and materials sciences. Optical trapping of single molecules at room temperature, a critical approach to manipulating the single molecule, still faces great challenges due to the Brownian motions of molecules, weak optical gradient forces of laser, and limited characterization approaches. Here, we put forward localized surface plasmon (LSP)-assisted trapping of single molecules by utilizing scanning tunneling microscope break junction (STM-BJ) techniques, which could provide adjustable plasmonic nanogap and characterize the formation of molecular junction due to plasmonic trapping. We find that the plasmon-assisted trapping of single molecules in the nanogap, revealed by the conductance measurement, strongly depends on the molecular length and the experimental environments, i.e., plasmon could obviously promote the trapping of longer alkane-based molecules but is almost incapable of acting on shorter molecules in solutions. In contrast, the plasmon-assisted trapping of molecules can be ignored when the molecules are self-assembled (SAM) on a substrate independent of the molecular length.

The ability to precisely regulate the size of a nanogap is essential for establishing high-yield molecular junctions, and it is crucial for the control of optical signals in extreme optics. Although remarkable strategies for the fabrication of nanogaps are proposed, wafer-compatible nanogaps with freely adjustable gap sizes are not yet available. Herein, two approaches for constructing in situ adjustable metal gaps are proposed which allow Ångstrom modulation resolution by employing either a lateral expandable piezoelectric sheet or a stretchable membrane. These in situ adjustable nanogaps are further developed into in-plane molecular break junctions, in which the gaps can be repeatedly closed and opened thousands of times with self-assembled molecules. The conductance of the single 1,4-benzenediamine (BDA) and the BDA molecular dimer is successfully determined using the proposed strategy. The measured conductance agreeing well with the data by employing another well-established scanning tunneling microscopy break junction technique provides insight into the formation of molecule dimer via hydrogen bond at single molecule level. The wafer-compatible nanogaps and in-plane dynamical break-junctions provide a potential approach to fabricate highly compacted devices using a single molecule as a building block and supply a promising in-plane technique to address the dynamical properties of single molecules., (© 2023 Wiley-VCH GmbH.)

Living creatures possess complex geometries, exceptional adaptability, and continuous growing and regenerating characteristics, which are difficult for synthetic materials to imitate simultaneously. A living polymer network with these features is reported. The polymer can be digitally printed into arbitrary 3D shapes and subsequently undergoes growth via living polymerization of a monomer as the nutrient. This leads to macroscopic dimensional growth and transforms the printed amorphous network into a crystallizable network, resulting in geometric adaptability via a shape-memory mechanism. By controlling the localized growth, an initial homogeneous structure can be converted into a geometrically different heterogeneous structure composed of materials with different properties (crystallization and mechanical properties). After growth, the original network can be chemically regenerated for regrowth. With this regenerative living 4D printing, one 3D-printed seed template can be turned into different derivatives with distinct geometries and mechanical properties when repeated regeneration is conducted in different localized regions and the degree of regrowth is varied., (© 2023 Wiley-VCH GmbH.)

Recent studies have shown that N 6 -methyladenosine (m 6 A) methylation, one of the most prevalent epigenetic modifications, is involved in diabetes mellitus. However, whether m 6 A regulates diabetic vascular endothelium injury is still elusive. Present research aimed to investigate the regulation and mechanism of m 6 A on vascular endothelium injury. Upregulation of METTL3 was observed in the high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs), following with the upregulation of m 6 A methylation level. Functionally, METTL3 silencing repressed the apoptosis and recovered the proliferation of HUVECs disposed by HG. Moreover, HG exposure upregulated the expression of suppressor of cytokine signaling3 (SOCS3). Mechanistically, METTL3 targeted the m 6 A site on SOCS3 mRNA, which positively regulated the mRNA stability of SOCS3. In conclusion, METTL3 silencing attenuated the HG-induced vascular endothelium cells injury via promoting SOCS3 stability. In conclusion, this research expands the understanding of m 6 A on vasculopathy in diabetes mellitus and provides a potential strategy for the protection of vascular endothelial injury., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Congenital heart disease/defect (CHD) is one of the most common congenital disabilities. Early diagnosis of CHD can improve the prognosis of newborns with CHD. The aim of this study was to evaluate the relationship between the factors and the onset of fetal congenital heart disease by measuring fetal umbilical artery (UA) Doppler index, maternal HCY, and Cys C levels during pregnancy. Methods: This retrospective study analyzed 202 fetuses with CHD, including 77 cases (39.1%) of simple CHD and 120 cases (60.9%) of complex CHD. Singleton pregnant women who were examined at the same time and whose malformation screening did not suggest any structural abnormalities in the fetus were assigned to the control group (n = 400). The UA Doppler index, plasma HCY, and Cys C levels were compared among the pregnant women across the three groups, and logistic regression analysis was performed on statistically significant markers. The ROC of UA S/D, PI, RI, HCY, and Cys C were plotted, and the area under the ROC (AUC) was calculated. Results: The UA S/D, PI, and RI in the complex CHD group were significantly higher than those in the control group (p < 0.05). The levels of HCY and Cys C in the CHD group were significantly higher than those in the control group (p < 0.05). HCY and S/D revealed a positive correlation (r = 0.157), and the difference was statistically significant (p < 0.001). Cys C and S/D were positively correlated (r = 0.131), and the difference was statistically significant (p < 0.05). The levels of UA Doppler indices, maternal plasma HCY, and Cys C were elevated in fetuses with CHD. The AUC of the combined test of the UA index, HCY, and Cys C was higher than that of each individual test. Conclusions: Elevated levels of the UA doppler indices, HCY, and Cys C during pregnancy are positively associated with the development of congenital heart disease in offspring. The combination of HCY and Cys C was the most efficient test for the diagnosis of CHD. We are the first to report that plasma Cys C levels of women pregnant with fetuses with CHD were higher than those of women pregnant with normal fetuses.

Background: The purpose of this study was to evaluate existing evidence in the field of long non-coding RNAs (lncRNAs) and prognosis of gastric cancer., Methods: A comprehensive literature search was performed through the electronic database. The combined hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of overall survival (OS), disease-free survival (DFS), or progression free survival (PFS) were calculated to assess the strength of the association. Kaplan-Meier (KM) plotter was used to verify lncRNA HOX transcript antisense RNA (HOTAIR) expression and OS., Results: Overall, a significant correlation between high lncRNAs expression and poor OS was explored in patients with gastric cancer (HR = 1.78, P < .001). Subgroup analysis based on statistical methods indicated the high expression of lncRNAs in log-rank (HR = 1.87, P < .001) and multivariate analysis (HR = 1.71, P < .001) were all significantly correlated with the poor OS. Clinicopathological parameters analysis showed the lncRNA expression were significantly associated prognosis, including TNM stage, tumor size, pathological differentiation, lymph nodes metastasis, distance metastasis, invasion depth and Lauren's classification. It was consistent with the verification results of bioinformatics database for lncRNA HOTAIR (P < .001)., Conclusion: Our study confirmed the expression of lncRNAs and clinicopathological features may serve as effective indicators of prognosis in patients with gastric cancer., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) is associated with prognosis in many cancers. The aim of this study was to systematically evaluate the potential correlation between AFAP1-AS1 and the prognosis of digestive system cancers (DSC)., Methods: EMBASE, Web of Science, Cochrane Library, PubMed, Wanfang Data (Chinese), and CNKI (Chinese) were comprehensively searched for literature published from the establishment of the database to September 2021.All case-control studies that met the inclusion criteria were retrieved; additionally manual retrieval and literature tracing was performed. After extracting the relevant data, Revman 5.3.5 software was used for meta-analysis., Results: Eighteen studies were included in analyses, high expression of AFAP1-AS1 was significantly correlated with poor prognosis in DSC, including overall survival (HR = 1.93, 95% CI: 1.72-2.17, P < .001) and disease-free survival/progression-free survival (HR = 1.87, 95% CI: 1.56-2.26, P < .001). In addition, the expression of AFAP1-AS1 was significantly correlated with tumor size, tumor stage, and lymph node metastasis., Conclusion: High expression of AFAP1-AS1 was associated with poor prognosis in DSC. Therefore, it could be used as a potential marker for evaluating prognosis in DSC., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Berberine (BER) is a natural isoquinoline alkaloid which extensively been applied to treat bacterial infection in TCM for a long time. Alginate is an important component of Pseudomonas aeruginosa biofilm. Herein, we investigated the effects of berberine and azithromycin (AZM) on alginate in the biofilm of P. aeruginosa PAO1., Methods: The MIC and synergistic activity of BER and AZM against PAO1 were determined using the micro broth dilution and checkerboard titration methods, respectively. The effect of BER on PAO1 growth was evaluated using a time-kill assay. Moreover, the effects of BER, AZM, and a combination of both on PAO1 biofilm formation, kinesis, and virulence factor expression were evaluated at subinhibitory concentrations. The alginate content in the biofilm was detected using ELISA, and the relative expression of alginate formation-related genes algD , algR , and algG was detected by qRT-PCR., Results: Simultaneous administration of berberine significantly reduced the MIC of azithromycin, and berberine at a certain concentration inhibited PAO1 growth. Moreover, combined berberine and azithromycin had synergistic effects against PAO1, significantly reducing biofilm formation, swarming, and twitching motility, and the production of virulence factors. The relative expression of alginate-related regulatory genes algG , algD , and algR of the combined treatment group was significantly lower than that of the control group., Conclusion: In summary, berberine and azithromycin in combination had a significant synergistic effect on the inhibition of alginate production by P. aeruginosa . Further molecular studies are in great need to reveal the mechanisms underlying the synergistic activity between berberine and azithromycin., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Zhijing Zhao et al.)

The microRNA miR-30a has been reported to mitigate podocyte damage and resist injurious factors in lupus nephritis (LN), but the precise molecular mechanisms underlying these effects remain elusive. We hypothesized that miR-30a can ameliorate podocyte injury by downregulating the Notch1 signaling pathway and investigated the role of miR-30a in the pathogenesis of podocyte-treated with Immunoglobulin G from patients with LN (IgG-LN). The study enrolled 30 patients from new-onset systemic lupus erythematosus and 28 healthy individuals, then evaluated the levels of their serum miR-30a using RT-qPCR. Additionally, MPC5 cells were transfected with NICD-vector to overexpress Notch1, then with miR-30a mimics or inhibitors to determine miR-30a effects on Notch1. Analysis of function and regulatory mechanisms were performed with RT-qPCR, Western blotting, and CCK8 assays. Furthermore, we verified the candidate sequence targeted by miR-30a using a luciferase reporter gene assay. We observed a significant decrease in the serum miR-30a levels in patients with LN. Also, in IgG-LN-treated podocytes, miR-30a decreased and Notch1 expression was elevated. Bioinformatic analysis and transfection experiments revealed that Notch1 is a direct target of miR-30a. Further supporting this finding, miR-30a upregulation appeared to alleviate IgG-LN-treated podocyte injury, and Notch1 overexpression reversed this effect. To conclude, miR-30a can ameliorate podocyte injury via suppression of the Notch1 signaling pathway.

Background: To analyze the effect of multidisciplinary team (MDT) collaborative nursing model combined with mind mapping teaching method on postoperative complications and mental health of patients with advanced pancreatic cancer (APC)., Methods: The clinical data of 100 APC patients treated in Liaoning Cancer Hospital and Institute, Shenyang, China (Dec 2018 - Dec 2020) were retrospectively analyzed. They were randomly and equally split into group J and group Q. The patients of group J were nursed with mind mapping teaching method, while those of group Q were nursed with MDT collaborative nursing model combined with mind mapping teaching method to compare the incidence of complications, quality of life (QOL) and mental health between the two groups after nursing., Results: After nursing, the SAS, SDS and NRS scores decreased in both groups, with the notably lower scores in group Q compared with group J ( P < 0.05). After nursing, the QOL scores increased in both groups, with the notably higher scores in group Q compared with group J ( P < 0.05). Compared with group J, the nursing satisfaction in group Q was notably higher while the incidence of complications was notably lower ( P < 0.05)., Conclusion: The MDT collaborative nursing model combined with mind mapping teaching method in postoperative nursing of APC patients can improve negative emotions such as anxiety and depression, enhance the QOL, alleviate pain, reduce the incidence of postoperative complications and improve nursing satisfaction, worthy of application and promotion in clinic., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright © 2022 Ma et al. Published by Tehran University of Medical Sciences.)

Endometrial cancer (EC) is one of the most common gynecologic cancers in developed countries. Presently, it is imperative to develop a reliable, noninvasive, or minimally invasive detection method for EC. We explored the possibility of using DNA methylation marker from endometrial brush samples (with a "Tao brush") and cervical scrapes (with a "Pap brush") for early detection of EC. We analyzed the methylation data of EC and normal endometrial tissues from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data sets. An optimized methylation-sensitive restriction enzyme combined with real-time fluorescent quantitative PCR (MSRE-qPCR) was used for methylation detection. Included in the training set were 143 endometrial tissues, 103 Tao, and 109 Pap brush samples. The validation set included 110 Tao and 112 Pap brush samples. PCDHGB7 was significantly hypermethylated in EC compared with normal endometrial tissues in the TCGA and GEO data sets (AUC >0.95), which was verified in clinical samples. In the Pap brush samples, the AUC was 0.86 with 80.65% sensitivity and 82.81% specificity, whereas the Tao brush samples exhibited higher specificity (95.31%). The combination of Tao and Pap brush samples significantly increased the sensitivity to 90.32%. In the validation set, the final model yielded a sensitivity of 98.61%, specificity of 60.53%, positive predictive value of 82.56%, and negative predictive value of 95.83%. These results demonstrate the potential application of the novel methylation marker, hypermethylated PCDHGB7 , in cervical scrapings and endometrial brush, which provides a viable, noninvasive, or minimally invasive method for early endometrial cancer detection across different clinical features and histologies to supplement current hysteroscopy diagnosis., Competing Interests: SD is one of the co-founders and the R & D director of Shanghai Epiprobe Biotechnology Co., Ltd. ZM and CW are employed by Epiprobe. WY serves on the scientific advisory boards of Epiprobe. SD has pending patents related to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yuan, Mao, Lu, Xu, Wang, Xu, Zhou, Zhang, Yu, Dong, Wang and Cheng.)

The objective of this study was to construct a novel strategy for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants using multiplex PCR-mass spectrometry minisequencing technique (mPCR-MS minisequencing). Using the nucleic acid sequence of a SARS-CoV-2 nonvariant and a synthetic SARS-CoV-2 variant-carrying plasmid, a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) method based on the single-base mass probe extension of multiplex PCR amplification products was established to detect 9 mutation types in 7 mutated sites (HV6970del, N501Y, K417N, P681H, D614G, E484K, L452R, E484Q, and P681R) in the receptor-binding domain of the spike protein of SARS-CoV-2 variants. Twenty-one respiratory tract pathogens (9 bacteria and 12 respiratory viruses) and nucleic acid samples from non-COVID-19 patients were selected for specific validation. Twenty samples from COVID-19 patients were used to verify the accuracy of this method. The 9 mutation types could be detected simultaneously by triple PCR amplification coupled with MALDI-TOF MS. SARS-CoV-2 and six variants, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.429 (Epsilon), B.1.526 (Iota), P.1 (Gamma) and B.1.617.2 (Delta), could be identified. The detection limit for all 9 sites was 1.5 × 10 3 copies. The specificity of this method was 100%, and the accuracy of real-time PCR cycle threshold ( C T ) values less than 27 among positive samples was 100%. This method is open and extensible, and can be used in a high-throughput manner, easily allowing the addition of new mutation sites as needed to identify and track new SARS-CoV-2 variants as they emerge. mPCR-MS minisequencing provides a new detection option with practical application value for SARS-CoV-2 and its variant infection. IMPORTANCE The emergence of SARS-CoV-2 variants is the key factor in the second wave of the COVID-19 pandemic. An all-in-one SARS-CoV-2 variant identification method based on a multiplex PCR-mass spectrometry minisequencing system was developed in this study. Six SARS-CoV-2 variants (Alpha, Beta, Epsilon, Iota, Gamma, and Delta) can be identified simultaneously. This method can not only achieve the multisite simultaneous detection that cannot be realized by PCR coupled with first-generation sequencing technology and quantitative PCR (qPCR) technology but also avoid the shortcomings of time-consuming, high-cost, and high technical requirements of whole-genome sequencing technology. As a simple screening assay for monitoring the emergence and spread of SARS-CoV-2 and variants, mPCR-MS minisequencing is expected to play an important role in the detection and monitoring of SARS-CoV-2 infection as a supplementary technology.

Bacteria play an important role in the formation of primary Common Bile Duct (CBD) stones. However, the composition and function of the microbiota of bile duct in patients with primary CBD stones remained to be explored. We utilized the 16S rRNA gene high-throughput sequencing technology to analyze the microbial diversity and community composition of biliary and duodenal microbiota in 15 patients with primary CBD stones and 4 patients without biliary tract diseases. Alpha diversity analysis showed that the microbiota richness was similar in bile and intestinal fluid; Beta diversity analysis showed that there were differences in the composition between biliary microbiota and the duodenal microbiota, but the abundance of the main groups showed similarities. The composition of the biliary microbiota from gallstone patients was more complex, as was the duodenal microbiota. Proteobacteria and Firmicutes were the dominant bacteria at phylum level, accounting for at least 75% of the total reads in each subgroup. Pseudomonas and Escherichia-Shigella were the major genus among subgroups, but Escherichia-Shigella had increased abundance in duodenal microbiota with primary choledocholithiasis, which may play an important role in stone formation. It is noteworthy that Clostridium sensu&#95;stricto, Lachnospiraceae &#95;UCG-008, Butyrivibrio and Roseburia which could produce short chain fatty acids (SCFAs), were significantly decreased in biliary microbiota with primary CBD stones (p < 0.05). Our study provided new insights into the compositional of normal biliary microbiota. The micro-ecology of biliary and duodenal in patients with stones is complex and closely related, and there is a potential for dysbacteriosis. The decrease in abundance of certain major acid-producing bacteria affects the health of the biliary tract and thus leads to the formation of stones., Competing Interests: The authors have no conflict of interest and competing Interests to declare., (© 2021 The Authors.)

Adipose tissue macrophages (ATMs) represent the most abundant leukocytes in adipose tissue (AT). An increase in number and a phenotypical switch of ATMs during the development of obesity contribute to chronic inflammation and metabolic disorders, which have been regarded as potential therapeutic targets to restore AT homeostasis. Emodin has been shown to exert strong anti-inflammatory property via acting on macrophages in a range of disease models. However, whether emodin exerts a beneficial effect on obesity via modulating ATMs has not been reported. In high-fat diet (HFD)-induced obese mice, emodin significantly inhibited the increase of body weight and lipid accumulation in ATs. Emodin apparently reduced glucose and insulin levels and ameliorated serum lipid profiles in HFD-fed mice. Moreover, the local and systemic inflammation was dramatically alleviated by emodin. We next discovered that M2 macrophage percentage was greatly increased by emodin although total ATMs was not altered, which resulted in a net increase of M2 macrophages in AT. In vitro studies confirmed that emodin promoted the polarization of macrophages towards M2. Gene ontology (GO) analysis showed that myeloid leukocyte differentiation and activation were among the most significant biological processes in emodin-treated ATMs. We further identified that TREM2 was the most dramatically upregulated molecule by emodin and emodin-induced M2 macrophage polarization was dependent on TREM2. Furthermore, silencing TREM2 apparently abrogated the effect of emodin on AT inflammation and adipogenesis. We, for the first time, disclosed that emodin inhibited obesity by promoting M2 macrophage polarization via TREM2, suggesting that emodin may be explored as a clinical and translational candidate in preventing obesity and its related metabolic diseases., (© 2021 Federation of American Societies for Experimental Biology.)

Objective: Abnormal signaling pathways play a crucial role in the mechanisms of podocyte injury in diabetic nephropathy. They also affect the recovery of podocytes after islet transplantation (IT). However, the specific signaling abnormalities that affect the therapeutic effect of IT on podocytes remains unclear. The purpose of this study was to assess whether the RhoA/ROCK/NF- κ B signaling pathway is related to podocyte restoration after IT., Methods: A mouse model of diabetic nephropathy was established in vivo using streptozotocin. The mice were then subsequently reared for 4 weeks after islet transplantation to determine the effect of IT. Islet cells, CCG-1423 (RhoA Inhibitor), and fasudil (ROCK inhibitor) were then cocultured with podocytes in vitro to assess their protective effects on podocyte injury induced by high glucose (HG). Protein expression levels of RhoA, ROCK1, synaptopodin, IL-6, and MCP-1 in kidney tissues were then measured using immunohistochemistry and Western blotting techniques., Results: Islet transplantation reduced the expression levels of RhoA/ROCK1 and that of related inflammatory factors such as IL-6 and MCP-1 in the kidney podocytes of diabetic nephropathy. In the same line, islet cells reduced the expression of RhoA, ROCK1, and pp65 in immortalized podocytes under high glucose (35.0 mmol/L glucose) conditions., Conclusions: Islet transplantation can reverse podocyte injury in diabetes nephropathy by inhibiting the RhoA/ROCK1 signaling pathway. Islet cells have a strong protective effect on podocytes treated with high glucose (35.0 mmol/L glucose). Discovery of signaling pathways affecting podocyte recovery is helpful for individualized efficacy evaluation and targeted therapy of islet transplantation patients., Competing Interests: The authors have no competing interests., (Copyright © 2021 Chongchu Huang et al.)

Aims: To assess the expression and epigenetic regulation of Syncoilin, intermediate filament protein ( SYNC ) in gastric cancer tissues, and to determine its associations with clinicopathological features; immune infiltration of macrophages in tumors; and patient survival. Materials and Methods: Clinicopathological features, expression profiles, and methylation data of the SYNC gene were obtained from multi-institutional real-world public datasets. A total of 1601 samples from patients with gastric cancer were examined. The associations between clinicopathological features and SYNC expression levels were assessed by the chi-square test; survival was assessed using the Kaplan-Meier analysis. The infiltration levels of M1, 2-polarized tumor-associated macrophages (TAMs) in a gastric tumor immune microenvironment were quantified using deconvolution, and the correlation between SYNC expression level and M1, 2-polarized macrophages' infiltration was examined using the Pearson correlation test. SYNC gene methylation data were analyzed to investigate epigenetic control of its expression. Results: SYNC expression was elevated in gastric cancer tissues ( p  < 0.01), and was associated with a poorer overall survival ( p  < 0.01) and poorer postprogression survival ( p  = 0.01). Higher SYNC levels were significantly associated with more aggressive clinicopathological features in gastric cancer patients ( p  < 0.05). SYNC was also associated with the infiltration of M2-polarized TAMs in the gastric tumor immune microenvironment ( p  < 0.001). Hypomethylation was shown to be associated with SYNC' s upregulation ( p  < 0.05). Conclusion: SYNC is highly expressed in gastric cancer tissues and has the potential to be a therapeutic target and to serve as a prognostic marker.

Aims: High-fat diet (HFD)-induced insulin resistance (IR) impairs skeletal muscle mitochondrial biogenesis and functions, adversely affecting human health and lifespan. Vitamin K2 (VK2) has a beneficial role in improving insulin sensitivity and glucose metabolism. However, the underlying molecular mechanisms of VK2 on insulin sensitivity have not been well established. We investigated VK2's modulation of mitochondrial function to protect against IR in mice and cell models. Results: VK2 supplementation could effectively ameliorate the development of IR by improving mitochondrial function in both HFD-fed mice and palmitate acid-exposed cells. We revealed for the first time that HFD-caused mitochondrial dysfunction could be reversed by VK2 treatment. VK2 enhanced the mitochondrial function by improving mitochondrial respiratory capacity, increasing mitochondrial biogenesis and the enzymatic activities of mitochondrial complexes through SIRT1 signaling. The benefits of VK2 were abrogated in C 2 C 12 transfected with SIRT1 siRNA but not in C 2 C 12 transfected with AMPK siRNA. VK2 and SRT1720, a specific agonist of SIRT1, had the same effect on improving mitochondrial function via SIRT1 signaling. Thus, SIRT1 is required for VK2 improvement in skeletal muscle. Further, the beneficial effects of both VK2 and geranylgeraniol contribute to inhibited IR in skeletal muscle via SIRT1. Innovation and Conclusion: These studies demonstrated a previously undiscovered mechanism by which VK2 alleviates IR in skeletal muscle by improving mitochondrial function via SIRT1. Naturally occurring VK2 prevents IR by improving mitochondrial function through SIRT1 signaling. These results could provide a foundation to identify new VK2-based preventive and therapeutic strategies for IR.

Objective: Decompression sickness (DCS) causes serious brain hypoxic-ischemic injury. This experiment was designed to observe whether hyperbaric oxygen (HBO2) pretreatment played a neuroprotective effect in decompression sickness rat models and to explore the mechanism of protective effects., Methods: Sprague-Dawley (SD) male rats were pretreated with HBO2 and then underwent decompression to establish the DCS rat model. Antioxidant capacities were evaluated by detecting peroxides (GPx), superoxide dismutase (SOD), catalase (CAT) activity and malondialdehyde (MDA) content in brains. The levels of metal elements manganese (Mn), zinc (Zn), iron (Fe) and magnesium (Mg) in brain tissues were assessed by flame atomic absorption spectrometry. Necrosis and apoptosis of neurons were assessed by H-E staining and immunohistochemical staining., Results: HBO2 pretreatment reduced the degree of necrosis and apoptosis in brain tissues of decompression sickness rat models. In addition, HBO2 pretreatment increased GPx, SOD and CAT activities and reduced MDA accumulation. It also increased the content of Mn, Zn, Fe and Mg in brain tissue, which are all related to free radical metabolism., Conclusion: These results suggested that HBO2 pretreatment has protective effects on brain injury of rats with decompression sickness. The mechanism of the protective effects may be related to reducing oxidative damage by affecting metal elements in vivo., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Purpose: Atrial remodeling takes part in the pathogenesis of atrial fibrillation (AF). Aliskiren, as a direct renin inhibitor, has been shown to exert protective effects against arrhythmia. The aim of this study was to investigate the potential role of aliskiren in atrial remodeling in a chronic intermittent hypoxia (CIH) rat model., Methods: A total of 45 Sprague-Dawley rats were randomly assigned into three groups (n=15 per group): control group; CIH group; and CIH with aliskiren (CIH-A) group. CIH and CIH-A rats were subjected to CIH for 6 h per day for 4 weeks. Atrial fibrosis was evaluated using Masson's trichrome staining. Electrophysiological tests were conducted in the isolated perfused hearts to assess the atrial effective refractory period and inducibility of AF. Atrial ionic remodeling was measured using the whole-cell patch-clamp technique, and Western blotting and real-time quantitative polymerase chain reactionwere performed to evaluate changes in ion channels., Results: CIH induced obvious collagen deposition, and the abnormal fibrosis was significantly attenuated by aliskiren. The inducibility of AF was increased significantly in the CIH group compared with the control and CIH-A groups (23±24.5% vs 2.0±4.2% vs 5.0±7.0%, respectively; P <0.05). Compared with the control group, the densites of the calcium current ( I CaL ) and sodium current ( I Na ) were reduced significantly in the CIH group ( I CaL : -3.16±0.61 pA/pF vs -7.13±1.98 pA/pF; I Na : -50.97±8.71 pA/pF vs -132.58±25.34 pA/pF, respectively; all P <0.05). Following intervention with aliskiren, the reductions in I CaL and I Na were significantly improved, and the ionic modeling changes assessed at the mRNA and protein levels were also significantly improved., Conclusion: CIH could alter atrial modeling and subsequently promote the occurrence and development of AF, which could be attenuated by treatment with aliskiren., Competing Interests: The authors declare no conflicts of interest for this work., (© 2020 Miao et al.)

Dose-limiting nephrotoxicity is a significant side effect of polymyxin B treatment. Only limited clinical studies describe the pharmacodynamics of polymyxin B, with little guidance existing for treatment optimisation against multidrug-resistant Gram-negative bacteria. In this study, differences in the likelihood of achieving efficacious and toxic exposures of polymyxin B for critically ill, general ward and cystic fibrosis (CF) patients were evaluated. The following dosing regimens were tested: maintenance doses of 1, 1.25, 1.5 and 2 mg/kg every 12 h (q12h); and loading doses of 2 mg/kg followed by 1.25 mg/kg q12h and 2.5 mg/kg followed by 1.5 mg/kg q12h. Patient weight notably influenced exposure and the required patient dose. To achieve an optimised exposure with minimal toxicity risk, an empirical polymyxin B dose of 2 mg/kg q12h was required for critically ill patients weighing 50 kg, whereas doses of 1.25 mg/kg q12h and 1 mg/kg q12h were required for those weighing 75 kg and 100 kg, respectively. Conversely, 2 mg/kg q12h was required for general ward patients weighing 75 kg. For general ward and CF patients weighing 50 kg, the target exposure could not be achieved with any regimen. Furthermore, the likelihood of toxicity was always high for bacteria with minimum inhibitory concentrations (MICs) of ≥2 mg/L. These findings support the use of a loading dose to increase the achievement of polymyxin B target exposures. To improve efficacy, doses should be optimised according to the patient population., (Copyright © 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

We report a novel solid-state molecular device structure based on double self-assembled monolayers (D-SAM) incorporated into the suspended nanowire architecture to form a "Au|SAM-1||SAM-2|Au" junction. Using commercially available thiol molecules that are devoid of synthetic difficulty, we constructed a "Au|S-(CH 2 ) 6 -ferrocene||SAM-2|Au" junction with various lengths and chemical structures of SAM-2 to tune the coupling between the ferrocene conductive molecular orbital and electrode of the junction. Combining low noise and a wide temperature range measurement, we demonstrated systematically modulated conduction depending on the length and chemical nature of SAM-2. Meanwhile, the transport mechanism transition from tunneling to hopping and the intermediate state accompanied by the current fluctuation due to the coexistence of the hopping and tunneling transport channels were observed. Considering the versatility of this solid-state D-SAM in modulating the electrode-molecule interface and electroactive groups, this strategy thus provides a novel facile strategy for tailorable nanoscale charge transport studies and functional molecular devices.

Objective: Atrial fibrillation (AF) represents the most common arrhythmia encountered in cardiology department. The purpose of this study was designed to investigate whether cilostazol, an oral phosphodiesterase 3 inhibitor (PDE3) could have protective effects on atrial remodeling in a canine model of AF and explore the potential molecular mechanisms., Methods: Dogs were randomly assigned to Sham, Paced, Paced + cilostazol group, 7 dogs in each group. In Sham group, pacemaker was instrumented but without pacing. Rapid atrial pacing (RAP) at 600 or 500 bpm/min was maintained in Paced group and Paced + cilo group for 2 h or 2 weeks in acute or chronic experiment, respectively. The Paced + cilo group of dogs were pretreated with cilostazol orally (10 mg·kg -1 ·d -1 , cilo) for 1 h or 2 days prior RAP induction and served as treatment group. Atrial effective refractory periods (AERP) at different basic cycle lengths (BCLs), inducibility, and duration time of AF were measured after pacing for 2 h. The blood sample, echocardiography, histopathology, inflammation and oxidative stress makers, protein and mRNA expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected after 2 weeks pacing in each group., Results: Significant changes in electrophysiological parameters were observed in the acute RAP canine model, the AERPs shortened with increased inducibility and duration of AF, which was attenuated by cilostazol (P < 0.05). The serum inflammation makers as interleukin-8 (IL-8) and toll like receptor 4 (TLR 4) levels and oxidative stress indicators like xanthine oxidative (XO) and reactive oxygen species (ROS) in the Paced group was significantly higher than that in Sham group (P < 0.01), and was significantly reduced by cilostazol treatment (P < 0.01). The level of mean platelet volume (MPV) which is one of the platelet indices was significantly elevated in Paced group (P < 0.01). While after cilostazol treated for 2 weeks, the level of MPV was obviously decreased than Paced group (P < 0.01). Pathology and echocardiography studies showed that cilostazol can also prevent RAP induced cardiac fibrosis and structural remodeling. The MPV level has close correlations with IL-8, TLR4, XO and ROS (all P < 0.01). MMP-2 and MMP-9 expression were significantly increased in Paced group (all P < 0.01), which can be attenuated by cilostazol., Conclusions: Cilostazol may have protective effects on RAP-induced atrial remodeling by anti-inflammatory, anti-oxidative stress action and regulate the extracellular collagen matrix in a canine model. Moreover, MPV level is associated with inflammation and oxidative stress response of RAP, which might be an important predictors of new-onset and recurrent AF., Competing Interests: Financial disclosures None. Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

One of the most globally prevalent supraventricular arrhythmias is atrial fibrillation (AF). Knowledge of the structures and functions of messenger RNA (mRNA) has recently increased. It is no longer viewed as solely an intermediate molecule between DNA and proteins but has come to be seen as a dynamic and modifiable gene regulator. This new perspective on mRNA has led to rising interest in it and its presence in research into new therapeutic schemes. This paper, therefore, focuses on microRNAs (miRNAs), which are small noncoding RNAs that regulate posttranscriptional gene expression and play a vital role in the physiology and normative development of cardiovascular systems. This means they play an equally vital role in the development and progression of cardiovascular diseases. In recent years, multiple studies have pinpointed particular miRNA expression profiles as being associated with varying histological features of AF. These studies have been carried out in both animal models and AF patients. The emergence of miRNAs as biomarkers and their therapeutic potential in AF patients will be discussed in the body of this paper., Competing Interests: The authors declare there is no conflict of interest to report., (Copyright © 2020 Xiaona Xu et al.)

Ulvan was the polysaccharide (U) from a large edible green algae Ulva pertusa. In this study, phosphorylated ulvan (PU) was prepared by the sodium trimetaphosphate -sodium tripolyphosphate method. Antioxidant and antihyperlipidemic effects of U and PU were investigated employing in vivo systems. The PU was confirmed by IR, 31 P NMR and 13 C NMR spectra. And in addition, we found that the PU3 group at the dose of 500 mg/kg showed stronger antioxidant activity. Compared with hyperlipidemia group, it significantly increased GSH-Px (34.29%; P < 0.01), SOD (20.04%; P < 0.01) and CAT (37.49%; P < 0.01). Treatment of hyperlipidemia mice with PU resulted in a significant decrease in TC, TG and LDL-C, and significant increase in HDL-C. The PU3 significantly increased HDL-C (33.70%; P < 0.01), decreased LDL-C (52.73%; P < 0.01) and TG (33.58%; P < 0.01) compared with hyperlipidemia group. The result showed that phosphorylation could improve hypolipidaemic and antioxidant activities in vivo. PU may be used as a drug for hyperlipidaemia treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Vascular calcification is an independent risk factor for plaque instability and is associated with endothelial cell function. Here, we investigated the role of endothelial cell function in the calcification of atherosclerotic plaques. We hypothesized that atherosclerosis would be associated with endothelial dysfunction and that bosentan (Tracleer®), a dual endothelin-receptor antagonist, would preserve endothelial cell function in an apolipoprotein E-deficient (ApoE -/- ) mouse model of atherosclerosis. Accordingly, 4-6-week-old ApoE -/- mice were fed a high-fat diet and treated with bosentan, and the effects of this treatment on body weight and blood lipid concentrations was evaluated. Endothelial damage in the aortic arch was assessed immunohistochemically to detect the proapoptotic proteins PDCD4, caspase-3, and Bax and the antiapoptotic protein Bcl-2. Notably, bosentan treatment was associated with decreased concentrations of these proteins and of blood lipids in ApoE -/- mice. Consistent with these findings, we observed increased concentrations of miRNA-21 and PDCD4 mRNA expression in the aortic arch endothelium after bosentan treatment. We conclude that bosentan can prevent endothelial cell death and protect against atherosclerosis in ApoE-deficient mice by upregulating miRNA-21., Competing Interests: The authors declare there are no conflicts of interest to report., (Copyright © 2019 Xiaona Xu et al.)

Papillary thyroid carcinoma (PTC) is a common endocrine tumor. This study found that different iodine concentrations affected the proliferation, apoptosis, and migration of PTC. For this study, we collected clinical information from PTC patients and monitored the levels of urinary iodine, LC3-II, and caspase-3 in cancer tissue, and BRAF kinase in peripheral blood from PTC patients. We also monitored the proliferation, apoptosis and migration ability of human papillary-thyroid carcinoma (BCPAP) cells at different iodine concentrations and their association with changes in autophagy and BRAF kinase activity of BCPAP cells at high iodine levels (10 -3 mol/l). We found that the proportion of tumor diameters ≥ 1 cm in the iodine excess group were lower than that in the iodine non-excess group. The proportion of PTC patients with infiltration in the iodine excess group was higher than that in the iodine non-excess group. Levels of the autophagy-related protein LC3-II and the apoptosis-related protein caspase-3 in cancer tissues, and activity of BRAF kinase in peripheral blood, were positively correlated with urinary iodine concentrations from PTC patients. At high iodine levels, the proliferation rate decreased, and apoptosis percentage and migration rates increased compared with the no-iodine group. At high iodine levels, the frequencies of autophagosomes (Aph) and autophagosome-lysosomes (Apl) in BCPAP cells increased significantly, and activities of LC3-II and BRAF kinase increased, respectively. The activity of LC3-II decreased when BRAF kinase was inhibited. The activity of LC3-II and the proliferation and migration rates of BCPAP cells decreased, and the apoptosis percentage increased when autophagy was inhibited at high iodine concentrations. Our results demonstrated that, in the presence of excessive iodine, the mean tumor size of PTC patients was smaller and easier to invade than tumors in patients not supplied with excessive iodine. The levels of autophagy and apoptosis in PTC cancer tissues, and activities of BRAF kinase in peripheral blood increased with increasing urinary iodine concentrations. High iodine levels inhibited cell proliferation and promoted apoptosis and migration of PTC cells. Autophagy induced by BRAF kinase in PTC cells was involved in anti-apoptosis, and promoted proliferation and migration at high iodine concentrations. This study provides a rationale for iodine supplementation in PTC patients., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Circulating follicular helper T (cTfh) cells are a novel subset of cluster of differentiation (CD)4+ helper T cells. Interleukin (IL)-21 and C-X-C motif chemokine ligand (CXCL)13 are the principal effectors and chemotactic regulatory factors of Tfh. However, the roles of IL-21 and CXCL13 in gastric cancer have not yet been completely elucidated. The aim of the present study was to investigate the distribution of cTfh cells, and the expression of IL-21 and CXCL13 in patients with gastric cancer was evaluated in order to ascertain the significance and potential mechanisms of these effectors in gastric cancer. A total of 50 patients with gastric cancer were enrolled as the study subjects, with 30 healthy individuals selected as controls. The percentage of cTfh cells (cTfh%) in the peripheral blood was calculated using flow cytometry. They are identified in the present study as CD4+ chemokine C-X-C receptor (CXCR)5+ inducible T cell co-stimulator (ICOS)+ cells. The serum levels of IL-21 and CXCL13 were determined by ELISA. The cTfh% in the peripheral blood and the concentration of IL-21 and CXCL13 in the serum were significantly higher in patients with gastric cancer compared with the control group. cTfh% was significantly higher in patients with lymph node metastasis, Tumor-Node-Metastasis (TNM) stage III-IV and low differentiation. The concentrations of IL-21 and CXCL13 in patients with lymph node metastasis and/or TNM III-IV were significantly higher than in those without lymph node metastasis or with TNM I-II. There was a positive correlation between cTfh%/CXCL13 and IL-21/CXCL13, while there was no correlation between cTfh%/IL-21. cTfh cells and associated factors (IL-21/CXCL13) may be involved in the development and progression of gastric cancer. There may be mutual regulation among cTfh cells, IL-21 and CXCL13.

[This corrects the article DOI: 10.18632/oncotarget.14712.].

This study was to investigate the effects of microRNA-21 (miR-21) on ox-LDL-induced HUVECs apoptosis. MTT assay was performed to evaluate the proliferation of HUVECs. Quantitative RT-PCR was conducted to quantify the expression of miR-21. Western blotting was used to determine protein expression. Annexin V/propidium iodide double staining was adopted to detect cell apoptosis. We found that ox-LD significantly induced HUVECs apoptosis and reduced miR-21 expression. MiR-21 mimic attenuated the apoptosis of HUVECs under ox-LDL treatment compared with the NC groups while miR-21 inhibitors promoted that of HUVECs. MiR-21 directly targeted PDCD4 in HUVECs. Moreover, miR-21 significantly regulated the downstream apoptotic proteins like bax, bad, bcl-2 and caspase3, meanwhile it enhanced the phosphorylation of ERK., Competing Interests: None., (IJCEP Copyright © 2017.)

Background: The current study aims to elucidate the role of miRNA-338-3p (miR-338-3p) in the invasion of renal cell carcinoma (RCC)., Methods: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-338-3p in human RCC cell lines with high metastatic potential (Caki-1) and low metastatic potential (786-O), respectively. The Caki-1 and 786-O cells were transfected with miR-338-3p mimic or inhibitor. Wound healing assay, Transwell assay and western blotting were performed to analyze the invasive ability and expression of activin receptor-like kinase 5 (ALK5) in the RCC cell lines. During the 36-month follow-up, we detected the expressions of miR-338-3p and ALK5 in 22 RCC cases with metastasis and 60 cases achieving a remission., Results: miR-339-3p was significantly downregulated in the Caki-1 cells as compared with the 786-O cells. The transfection with miR-338-3p inhibitor caused an increased invasive ability of both two cell lines. However, the transfection with miR-338-3p mimic caused a reduction of the invasiveness. In RCC cells, the expression of ALK5 was negatively correlated to miR-338-3p. Upregulation of ALK5 partially counteracted the miR-338-3p-induced invasiveness of RCC cells. We subsequently found the negative correlations between miR-338-3p and metastasis/ALK5 expression could be also observed in human RCC tissues., Conclusion: Taken together, these results indicate that miR-338-3p acts as a novel tumor suppressor to inhibit the invasion of RCC by regulating ALK5 expression., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Sporadic colorectal cancer (sCRC) is one of the most commonly diagnosed cancers worldwide, but few genetic markers have been identified and used for its early detection. MicroRNAs are diverse cellular regulators in cancer pathogenesis that bind to the 3'-untranslated region (3'-UTR) of their target mRNAs, and variants within the miRNA target sites on sCRC-related genes may influence its pathogenesis. To investigate this possibility, we used a bioinformatical method to screen SNPs for putative changes in miRNA recognition sites within the 3'-UTR of sCRC-related genes. The rs11466537 single nucleotide polymorphism was predicted to modify the regulation of hsa-miR-1193 on the Transforming Growth Factor β Receptor II (TGFBR2) gene. Additionally, luciferase reporter assays indicated that hsa-miR-1193 bound the T allele more strongly than the A allele of rs11466537 (with A being the less frequent variant), and real time-polymerase chain reaction and western blot analysis showed that TGFBR2 is significantly repressed by hsa-miR-1193. Furthermore, overexpression of hsa-miR-1193 promoted HT-29 cell proliferation, while the loss of hsa-miR-1193 inhibited the process. Finally, the rs11466537 genotyping result revealed that the frequency of A allele carriers was 1.5% in the control blood samples, but 0 in the sCRC patients' normal colon tissue samples. Our results demonstrated that hsa-miR-1193 may be involved in sCRC tumourigenesis at least in part by suppression of TGFBR2, and the A allele of rs11466537 disturbed the regulation of hsa-miR-1193 on TGFBR2.

Fibulin-3 has emerged as a promising novel biomarker in conforming or monitoring malignant pleural mesothelioma (MPM). This study sought to evaluate the diagnostic and prognostic efficacies of humoral fibulin-3 for MPM. Seven eligible publications comprising 468 MPM cases for diagnosis, and 138 for prognosis were identified. Results manifested that humoral fibulin-3 sustained a pooled sensitivity of 0.62 (95% CI: 0.45-0.77) and specificity of 0.82 (95% CI: 0.73-0.89) in discriminating MPM patients from cancer-free individuals, corresponding to an AUC (area under the curve) of 0.81. For the survival analysis, fibulin-3 expression was not markedly associated with overall survival (OS) time of the MPM patients [HR (hazard ratio): 1.84, 95% CI: 0.75-4.56, P = 0.185]. In the subgroup analyses stratified by test matrix and ethnicity, data revealed that serum-based fibulin-3 examination achieved superior accuracy than plasma-based analysis (sensitivity: 0.77 versus 0.54; specificity: 0.85 versus 0.77; AUC: 0.92 versus 0.69); additionally, testing of fibulin-3 in Europeans retained higher efficacy than those in Americans and Australians. Taken together, fibulin-3 confers a relatively high diagnostic efficacy and is acceptable to be an auxiliary biomarker to aid in MPM identification.

Nanoscale metal organic frameworks (NMOFs) have shown great potential in biomedicine owing to their structural/chemical diversities, high molecular loading capacities, and intrinsic biodegradability. Herein, we report the rational design of a NMOF composed by hafnium (Hf(4+)) and tetrakis (4-carboxyphenyl) porphyrin (TCPP). In such Hf-TCPP NMOFs, while TCPP is a photosensitizer to allow photodynamic therapy (PDT), Hf(4+) with strong X-ray attenuation ability could serve as a radio-sensitizer to enhance radiotherapy (RT). Those NMOFs with polyethylene glycol (PEG) coating show efficient tumor homing upon intravenous injection, and thus could be used for in vivo combined RT & PDT, achieving a remarkable anti-tumor effect. Importantly, Hf-TCPP NMOFs show efficient clearance from the mouse body, minimizing concerns regarding their possible long-term toxicity. Our work thus presents a new concept of developing multifunctional NMOFs as a biodegradable carrier-free system, in which both metal ions and organic ligands are fully utilized to exert their therapeutic functions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The common carp (Cyprinus carpio) as one of the most important aquaculture fishes produces over 3 million metric tones annually, approximately 10% the annual production of the all farmed freshwater fish worldwide. However, the tetraploidy genome and long generation-time of the common carp have made its breeding and genetic studies extremely difficult. Here, TALEN and CRISPR-Cas9, two versatile genome-editing tools, are employed to target common carp bone-related genes sp7, runx2, bmp2a, spp1, opg, and muscle suppressor gene mstn. TALEN were shown to induce mutations in the target coding sites of sp7, runx2, spp1 and mstn. With CRISPR-Cas9, the two common carp sp7 genes, sp7a and sp7b, were mutated individually, all resulting in severe bone defects; while mstnba mutated fish have grown significantly more muscle cells. We also employed CRISPR-Cas9 to generate double mutant fish of sp7a;mstnba with high efficiencies in a single step. These results demonstrate that both TALEN and CRISPR-Cas9 are highly efficient tools for modifying the common carp genome, and open avenues for facilitating common carp genetic studies and breeding.

A sensitive and reliable LC-ESI-MS method for the determination of salvianolic acid C in rat plasma has been developed and validated. Plasma samples were prepared by liquid-liquid extraction with ethyl acetate and separated on a Zorbax SB-C18 column (3.5 µm, 2.1 × 100 mm) at a flow rate of 0.3 mL/min using acetonitrile-water as mobile phase. The detection was carried out by a single quadrupole mass spectrometer with electrospray ionization source and selected ion monitoring mode. Linearity was obtained for salvianolic acid C ranging from 5 to 1000 ng/mL. The intra- and inter-day precisions (RSD, %) didn't exceed 9.96%, and the accuracy (RE, %) were all within ±3.64%. The average recoveries of the analyte and internal standard were >89.13%. Salvianolic acid C was proved to be stable during all sample storage, preparation and analytic procedures. The validated method was successfully applied to pharmacokinetic study after oral and intravenous administration of salvianolic acid C to rats. The absolute oral bioavailability of salvianolic acid C was 0.29 ± 0.05%. This method was further applied to simultaneous determination of salvianolic acid A, salvianolic acid B and salvianolic acid C in rat plasma and showed good practicability., (Copyright © 2015 John Wiley & Sons, Ltd.)