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Ischemic stroke (IS) is the predominant cause of morbidity and mortality worldwide. Ferroptosis, a new type of programmed cell death, has been shown to play a crucial role in IS pathogenesis. Traditionally, research focused on neurons did not uncover specific positive results for IS. However, glial cells have recently received interest as promising targets for IS treatment, not only for their structural function but also in the iron transfer between glia and neurons, which indicates a promising glia-neuron crosstalk in mediating the IS process and ischemia/reperfusion-associated neuropathology, showing their affiliation with ferroptosis. This review addresses the major phenomena of iron metabolism and the process and regulation of ferroptosis, with a particular focus on their impact on IS pathology. The review discusses iron homeostasis, the biology of reactive oxygen species, and lipid peroxidation for modulating the process of IS-induced ferroptosis in different glial cells. We then review recent therapies that leverage ferroptosis modulation for the treatment of IS. Extensive preclinical and clinical research is necessary to fully understand the roles of glia-neuron crosstalk and ferroptosis in IS., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common liver malignancy after hepatocellular carcinoma (HCC), with a dismal prognosis and high heterogeneity. The oncological advantages of anatomical resection (AR) and nonanatomical resection (NAR) in HCC have been studied, but surgical strategies for ICC remain controversial with insufficient investigations., Materials and Methods: From Jan 2013 to Dec 2016, 3880 consecutive patients were retrospectively reviewed from a single center. Patients with ICC undergoing AR or NAR have been enrolled according to inclusion and exclusion criteria. Propensity score matching (PSM) analysis was performed between two groups with a 1 : 1 ratio. The primary endpoint was overall survival (OS), and the secondary endpoints included disease-free survival (DFS), intraoperative patterns, postoperative morbidity, mortality, complications and recurrence. A prognostic nomogram was developed by a multivariate Cox proportion hazard model., Results: After PSM, 99 paired cases were selected from 276 patients enrolled in this study. Patients in the AR group achieved better 1-, 3-, and 5-year OS (70%, 46%, and 34%, respectively) and DFS (61%, 21%, and 10%, respectively) than patients in the NAR group with statistical significance after PSM analysis. The postoperative complications and recurrence patterns were comparable between the two groups. Multivariate analysis identified NAR, tumor size >5 cm, multiple tumors, and poor differentiation as independent risk factors for OS ( p < 0.05). Selected patients can benefit most from AR, according to subgroup analysis. A prognostic nomogram based on six independent risk factors for OS and factors with clinical significance was constructed to predict OS in ICC patients., Conclusion: AR improved the long-term survival of ICC with comparable postoperative complications and similar recurrence patterns. AR is suggested in ICC patients with sufficient remnant liver volume. In addition to surgery strategy, malignant characteristics of tumors are risk factors for ICC prognosis., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2022 Chao Wang et al.)

The association between blood urea nitrogen (BUN) and prognosis has been the focus of recent research. Therefore, the objective of this study was to investigate the association between BUN and hospital mortality in critically ill patients with cardiogenic shock (CS). This was a retrospective cohort study, in which data were obtained from the Medical Information Mart for Intensive Care III V1.4 database. Data from 697 patients with CS were analyzed. Logistic regression and subgroup analyses were used to assess the association between BUN and hospital mortality in patients with CS. The average age of the 697 participants was 71.14 years, and approximately 42.18% were men. In the multivariate logistic regression model, after adjusting for age, sex, diabetes, cardiac arrhythmias, urine output, simplified acute physiology score II, sequential organ failure assessment, creatinine, anion gap, and heart rate, high BUN demonstrated strong associations with increased in-hospital mortality (per standard deviation increase: odds ratio [OR] 1.47, 95% confidence interval [CI] 1.13-1.92). A similar result was observed in BUN tertile groups (BUN 23-37 mg/dL versus 6-22 mg/dL: OR [95% CI], 1.42 [0.86-2.34]; BUN 38-165 mg/dL versus 6-22 mg/dL: OR [95% CI], 1.99 [1.10-3.62]; P trend 0.0272). Subgroup analysis did not reveal any significant interactions among various subgroups, and higher BUN was associated with adverse clinical outcomes in patients with CS., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 En-qian Liu and Chun-lai Zeng.)

Triglyceride-glucose index (TyG index) is associated with type 2 diabetes mellitus (T2DM), but research on this relationship is limited in Japan. The purpose of this study was to evaluate the correlation between TyG index and the risk of T2DM in the Japanese population. Here, 12732 participants were selected from the NAGALA study (NAfld in the Gifu Area, Longitudinal Analysis) conducted between 2004 and 2015 for a retrospective cohort analysis. The association between TyG index and T2DM was assessed using the Cox proportional-hazard model. Subgroup analyses were conducted according to age, sex, smoking status, alcohol consumption, waist circumference, BMI, and follow-up duration. The formula for TyG index was expressed as ln [fasting triglyceride level (mg/dL) × fasting plasma glucose level (mg/dL)/2]. After follow-up, 150 (1.18%) patients developed T2DM. After adjusting for potential confounders, a linear relationship was observed between TyG and the risk of T2DM. After adjusting for age, sex, BMI, waist circumference, HDL-cholesterol, total cholesterol, systolic blood pressure, regular exercise, smoking status, and alcohol consumption, TyG index, as a continuous variable, was associated with an increased risk of T2DM (adjusted hazard ratio (aHR), 1.79; 95% confidence interval (95% CI), 1.25-2.57). Compared with the first quartile of TyG index, subjects in the fourth quartile were 2.33-fold more likely to develop T2DM (aHR 2.33, 95% CI 1.09-4.96; P for trend 0.0224). Subgroup analyses showed that the association between TyG index and incident T2DM stably existed in different subgroups according to the variables tested. Therefore, TyG index was linearly related to the risk of incident T2DM in the Japanese population and may be used as a monitoring tool., Competing Interests: All authors report that they have no conflicts of interest., (Copyright © 2020 En-qian Liu et al.)

Objective: High PM 2.5 concentration is the main feature of increasing haze in developing states, but information on its microbial composition remains very limited. This study aimed to determine the composition of microbiota in PM 2.5 in Guangzhou, a city located in the tropics in China., Methods: In Guangzhou, from March 5 th to 10 th , 2016, PM 2.5 was collected in middle volume air samplers for 23 h daily. The 16S rDNA V4 region of the PM 2.5 sample extracted DNA was investigated using high-throughput sequence., Results: Among the Guangzhou samples, Proteobacteria , Bacteroidetes , Firmicutes , Cyanobacteria , and Actinobacteria were the dominant microbiota accounting for more than 90% of the total microbiota, and Stenotrophomonas was the dominant gram-negative bacteria, accounting for 21.30%-23.57%. We examined the difference in bacterial distribution of PM 2.5 between Beijing and Guangzhou at the genus level; Stenotrophomonas was found in both studies, but Escherichia was only detected in Guangzhou., Conclusion: In conclusion, the diversity and specificity of microbial components in Guangzhou PM 2.5 were studied, which may provide a basis for future pathogenicity research in the tropics., (Copyright © 2020 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Background: Platelets in patients with type 2 diabetes mellitus (DM2) are characterized by increased activation and aggregation, which tends to be associated with a high morbidity and mortality due to cardiovascular disease (CVD). Moreover, a large proportion of DM2 patients show an inadequate response to standard antiplatelet treatments, contributing to recurrent cardiovascular events. In our previous study, we indicated that Salvianolic acid A (SAA) presents an antiplatelet effect in healthy volunteers. However, whether it can inhibit "activated platelets" with a pathologic status has not been explored. Therefore, this study was designed to investigate the antiplatelet effect of SAA and its diabetic complication-related difference in DM2., Methods: Forty patients diagnosed with DM2 from January 2018 to April 2018 were recruited. Fibrinogen-binding (PAC-1) and P-selectin (CD62p) flow cytometry reagents were measured under resting and stimulated conditions by flow cytometry, while agonist-induced platelet aggregation was conducted by light transmission aggregometry. Before all these measurements were conducted, all platelet samples were preincubated with a vehicle or SAA for 10 min. Additionally, the diabetic complication-related difference in the antiplatelet effect of SAA was further studied in enrolled patients., Results: The expressions of PAC-1 and CD62p were elevated in DM2, as well as the maximal platelet aggregation. In addition, SAA decreased the expressions of PAC-1 and CD62p, which were enhanced by ADP and thrombin (all P < 0.01). It also reduced the platelet aggregation induced by ADP (P < 0.001) and thrombin (P < 0.05). Comparing the antiplatelet effect of SAA on DM2, with and without diabetic complications, no statistically significant difference was found (all P > 0.05)., Conclusions: The present study demonstrated that SAA can inhibit platelet activation and aggregation in patients with DM2, and the inhibition did not abate for the existence of diabetic complications.

Nanomedicine compounds containing nanoparticles, such as iron oxides and gold, have been demonstrated to be effective in promoting different magnitudes of interaction with amyloid β fibrils, of which disintegrating or inhibiting effects are of great importance to treating fibrillary aggregation-induced neurological disorders such as Alzheimer's disease. This research herein studies the interaction between lysozyme amyloid fibrils, a type of fibers derived from hen egg white lysozyme, and Fe₃O₄ magnetic nanoparticles (MNPs) of an assorted diameter sizes of 5 nm, 10 nm and 20 nm, using atomic force microscopy (AFM). Specifically, the effects of the sizes of negatively charged MNPs on the resultant amyloid fibrillary mixture was investigated. Our results of AFM images indicated that the interaction between MNPs and the fibrils commences immediately after adding MNPs to the fibril solution, and the actions of such MNPs-doped fibrillary interplay, either integration or segmentation, is strongly dependent on the size and volume concentration of MNPs. In the cases of 5 nm and 20 nm particles of equivalent volume concentration, the adsorption and agglomeration of MNPs onto the fibrillary surfaces was observed, whereas, interestingly, MNPs with diameter size of 10 nm enables segmentation of the slender fibrils into debris when a proper implemented volume concentration was found, which signifies utter destruction of the amyloid fibrillary structure.

The miRNA processing genes play essential roles in the biosynthesis of mammalian miRNAs, and their genetic variants are involved in the development of various cancers. Our study aimed to determine the potential association between miRNA processing gene polymorphisms and cervical precancerous lesions. Five single nucleotide polymorphisms (SNPs), including Ran-GTP ( RAN ) rs14035, exportin-5 ( XPO5 ) rs11077, DICER1 rs3742330, DICER1 rs13078, and TARBP2 rs784567, were genotyped in a case-control study to estimate risk factors of cervical precancerous lesions. The gene-environment interactions and haplotype association were estimated. We identified a 27% decreased risk of cervical precancerous lesions for individuals with minor G allele in DICER1 rs3742330 (odds ratio (OR) = 0.73, 95% confidence interval (95% CI) = 0.58-0.92, P = 0.009). The AG and AG/GG genotypes in DICER1 rs3742330 were also found to decrease the risk of cervical precancerous lesions (AG compared with AA: OR = 0.51, 95% CI = 0.35-0.73, P <0.001; AG/GG compared with AA: OR = 0.54, 95% CI = 0.39-0.77, P = 0.001). The GT haplotype in DICER1 had a risk effect on cervical precancerous lesions compared with the AT haplotype (OR = 1.36, 95% CI = 1.08-1.73, P = 0.010). A two-factor ( DICER1 rs3742330 and human papillomavirus (HPV) infection) and two three-factor (model 1: rs3742330, passive smoking, and HPV infection; model 2: rs3742330, abortion history, and HPV infection) interaction models for cervical precancerous lesions were identified. In conclusion, the genetic variants in the miRNA processing genes and interactions with certain environmental factors might contribute to the risk of cervical precancerous lesions in southern Chinese women., (© 2018 The Author(s).)

In this research, the dynamic process of aggregation that forms microflower morphology in solution of lysozyme amyloid fibrils doped with spherical or spindle-like magnetic nanoparticles during the process of drying as well as their final microstructures were investigated. The prepared lysozyme amyloid fibrils as well as their mixtures with in-lab synthesized magnetic particles, which were prepared by adding the nanoparticles to the fibrils solution after the process of fibrillation was done, were characterized using brightfield trans-illumination-mode optical microscope, atomic force microscopy (AFM) and scanning electron microscope (SEM). Brightfield optical imaging bases upon photoabsorptive property of the fibrils-nanoparticle composites clearly reveals the morphological features in microscale, and additionally, for the in vivo, live action of the time-dependent process of self-assembly of such composites composed of fibrillary structure incorporated with magnetic particles was optically elucidated at ambient temperature. Moreover, while results of AFM reveal delicate and peculiar association of fibrils with magnetic nanoparticles of different shapes, SEM images illustrate a stark difference in fine detailed final morphology of microstructures associated with spherical and spindle-like nanoparticles. Our results indicated that the interaction between fibrils solution and the nanoparticles commence right after mixing, the dynamic process of forming dendritic structure resembling microflower morphology is on the order of minutes, and its final structure is highly dependent on the shape of magnetic nanoparticles., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Porphyromonas gingivalis is an oral opportunistic pathogen. Sequenced P. gingivalis laboratory strains display limited diversity in antigens that modulate host responses. Here, we present the genome sequence of A7A1-28, a strain possessing atypical fimbrillin and capsule types, with a single contig of 2,249,024 bp and a G+C content of 48.58%., (Copyright © 2017 Xie et al.)

Background: Lipoma preferred partner ( LPP ) and T-cell activation Rho GTPase activating protein ( TAGAP ) polymorphisms might influence the susceptibility to celiac disease. Therefore, we performed a meta-analysis by identifying relevant studies to estimate the risks of these polymorphisms on celiac disease. Methods: The PubMed, Web of Science and Embase databases were searched (up to October 2016) for LPP rs1464510 and TAGAP rs1738074 polymorphisms. Results: This meta-analysis included the same 7 studies for LPP rs1464510 and TAGAP rs1738074. The minor risk A allele at both rs1464510 and rs1738074 carried risks (odds ratios) of 1.26 (95% CI: 1.22-1.30) and 1.17 (95% CI: 1.14-1.21), respectively, which contributed to increased risks in all celiac disease patients by 10.72% and 6.59%, respectively. The estimated lambdas were 0.512 and 0.496, respectively, suggesting that a co-dominant model would be suitable for both gene effects. Conclusions: This meta-analysis provides robust estimates that polymorphisms in LPP and TAGAP genes are potential risk factors for celiac disease in European and American. Prospective studies and more genome-wide association studies (GWAS) are needed to confirm these findings, and some corresponding molecular biology experiments should be carried out to clarify the pathogenic mechanisms of celiac disease.

Introduction: The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infectious and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury., Methods: Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the 7-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated., Results: The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased the mortality (53.33% in Ad-shHepc1 treated mice versus 12.5% in Ad-shNeg treated mice, P <0.05). The knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. Moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice., Conclusions: Airway epithelial cell-derived hepcidin plays an important role in CLP induced acute lung injury. The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages.

Background: Information on polymorphic DNA in organelle genomes is essential for evolutionary and ecological studies. However, it is challenging to perform high-throughput investigations of chloroplast and mitochondrial DNA polymorphisms. In recent years, EcoTILLING stands out as one of the most universal, low-cost, and high-throughput reverse genetic methods, and the identification of natural genetic variants can provide much information about gene function, association mapping and linkage disequilibrium analysis and species evolution. Until now, no report exists on whether this method is applicable to organelle genomes and to what extent it can be used., Methodology/principal Findings: To address this problem, we adapted the CEL I-based heteroduplex cleavage strategy used in Targeting Induced Local Lesions in Genomes (TILLING) for the discovery of nucleotide polymorphisms in organelle genomes. To assess the applicability and accuracy of this technology, designated ORG-EcoTILLING, at different taxonomic levels, we sampled two sets of taxa representing accessions from the Brassicaceae with three chloroplast genes (accD, matK and rbcL) and one mitochondrial gene (atp6). The method successfully detected nine, six and one mutation sites in the accD, matK and rbcL genes, respectively, in 96 Brassica accessions. These mutations were confirmed by DNA sequencing, with 100% accuracy at both inter- and intraspecific levels. We also detected 44 putative mutations in accD in 91 accessions from 45 species and 29 genera of seven tribes. Compared with DNA sequencing results, the false negative rate was 36%. However, 17 SNPs detected in atp6 were completely identical to the sequencing results., Conclusions/significance: These results suggest that ORG-EcoTILLING is a powerful and cost-effective alternative method for high-throughput genome-wide assessment of inter- and intraspecific chloroplast and mitochondrial DNA polymorphisms. It will play an important role in evolutionary and ecological biology studies, in identification of related genes associated with agronomic importance such as high yield and improved cytoplasmic quality, and for identifying mitochondrial point mutations responsible for diseases in humans and other animals.

Background and Objective: Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia miltiorrhiza Bunge, a herb that is widely used for atherothrombotic disease treatment in Asian medicine. As platelets play pivotal roles in atherothrombogenesis, we studied the effect of SAA on platelet activation and its underlying mechanisms., Methods and Results: SAA dose-dependently inhibited platelet aggregation induced by ADP, thrombin, collagen and U46619. It reduced ADP-enhanced platelet P-selectin expression and fibrinogen binding, which consequently hampered ADP-induced platelet-leukocyte aggregation. SAA also inhibited platelet spreading on fibrinogen, a process mediated by outside-in signaling. Under an arterial shear rate of 1000 s(-1), SAA decreased platelet adhesion on collagen surfaces by approximately 40%. Western blot analysis showed that SAA, like the phosphoinositide 3-kinase (PI3K) inhibitors LY294002 and TGX-221, potently inhibited PI3K, as shown by reduced Akt phosphorylation. The in vitro findings were further evaluated in the mouse model of arterial thrombosis, in which SAA prolonged the mesenteric arterial occlusion time in wild-type mice (35 + or - 2 min without SAA and 56 + or - 4 min with SAA; P < 0.01). Interestingly, SAA could even counteract the shortened arterial occlusion time in Ldlr(tm1Her) mutant mice (21 + or - 2 min without SAA and 45 + or - 4 min with SAA; P < 0.01)., Conclusions: SAA inhibits platelet activation via the inhibition of PI3K, and attenuates arterial thrombus formation in vivo. Our data suggest that SAA may be developed as a novel therapeutic agent for the prevention of thrombotic disorders.

Background and Purpose: Recent studies have shown that resveratrol increased endothelial progenitor cells (EPCs) numbers and functional activity. However, the mechanisms remain to be determined. Previous studies have demonstrated that increased EPC numbers and activity were associated with the inhibition of EPC senescence, which involves activation of telomerase. Therefore, we investigated whether resveratrol inhibits the onset of EPC senescence through telomerase activation, leading to potentiation of cellular activity., Experimental Approach: After prolonged in vitro cultivation, EPCs were incubated with or without resveratrol. The senescence of EPCs were determined by acidic beta-galactosidase staining. The bromo-deoxyuridine incorporation assay or a modified Boyden chamber assay were employed to assess proliferative or migratory capacity, respectively. To further examine the underlying mechanisms of these effects, we measured telomerase activity and the phosphorylation of Akt by western blotting., Key Results: Resveratrol dose dependently prevented the onset of EPCs senescence and increased the proliferation and migration of EPCs. The effect of resveratrol on senescence could not be abolished by eNOS inhibitor or by an oestrogenic receptor antagonist. Resveratrol significantly increased telomerase activity and Akt phosphorylation. Pre-treatment with the PI3K inhibitor, LY294002, significantly attenuated resveratrol-induced telomerase activity., Conclusions and Implications: Resveratrol delayed the onset of EPC senescence and this effect was accompanied by activation of telomerase through the PI3K-Akt signalling pathway. The inhibition of EPCs senescence by resveratrol might protect EPCs against dysfunction induced by pathological factors in vivo and improve EPC functional activities in a way that may be important for cell therapy.

Background and Aims: Seed coat morphology is known to be an excellent character for taxonomic and evolutionary studies, thus understanding its structure and development has been an important goal for biologists. This research aimed to identify the developmental differences of seed coats between amphidiploids and their putative parents in Brassica., Methods: Scanning electron microscope (SEM) studies were carried out on six species (12 accessions), three amphidiploids and their three diploid parents., Key Results: Twelve types of basic ornamentation patterns were recognized during the whole developmental process of the seed coat. Six types of seed coat patterns appeared in three accessions of Brassica rapa, five types in B. oleracea, B. nigra and B. carinata, seven types in B. napus, and eight types in B. juncea. There was less difference among seed coat patterns of the three accessions of B. rapa. The reticulate and blister types were two of the most common patterns during the development of seeds in the six species, the blister-pimple and the pimple-foveate patterns were characteristic of B. rapa, and the ruminate of B. oleracea and B. nigra. The development of seed coat pattern in amphidiploids varied complicatedly. Some accessions showed intermediate patterns between the two putative parents, while others resembled only one of the two parents., Conclusions: The variation in the patterns of seed coat development could be used to provide a new and more effective way to analyse the close relationship among amphidiploids and their ancestral parents.