Differentiated adaptative genetic architecture and language-related demographical history in South China inferred from 619 genomes from 56 populations.

BACKGROUND: The underrepresentation of human genomic resources from Southern Chinese populations limited their health equality in the precision medicine era and complete understanding of their genetic formation, admixture, and adaptive features. Besides, linguistical and genetic evidence supported the controversial hypothesis of their origin processes. One hotspot case was from the Chinese Guangxi Pinghua Han people (GPH), whose language was significantly similar to Southern Chinese dialects but whose uniparental gene pool was phylogenetically associated with the indigenous Tai-Kadai (TK) people. Here, we analyzed genome-wide SNP data in 619 people from four language families and 56 geographically different populations, in which 261 people from 21 geographically distinct populations were first reported here. RESULTS: We identified significant population stratification among ethnolinguistically diverse Guangxi populations, suggesting their differentiated genetic origin and admixture processes. GPH shared more alleles related to Zhuang than Southern Han Chinese but received more northern ancestry relative to Zhuang. Admixture models and estimates of genetic distances showed that GPH had a close genetic relationship with geographically close TK compared to Northern Han Chinese, supporting their admixture origin hypothesis. Further admixture time and demographic history reconstruction supported GPH was formed via admixture between Northern Han Chinese and Southern TK people. We identified robust signatures associated with lipid metabolisms, such as fatty acid desaturases (FADS) and medically relevant loci associated with Mendelian disorder (GJB2) and complex diseases. We also explored the shared and unique selection signatures of ethnically different but linguistically related Guangxi lineages and found some shared signals related to immune and malaria resistance. CONCLUSIONS: Our genetic analysis illuminated the language-related fine-scale genetic structure and provided robust genetic evidence to support the admixture hypothesis that can explain the pattern of observed genetic diversity and formation of GPH. This work presented one comprehensive analysis focused on the population history and demographical adaptative process, which provided genetic evidence for personal health management and disease risk prediction models from Guangxi people. Further large-scale whole-genome sequencing projects would provide the entire landscape of southern Chinese genomic diversity and their contributions to human health and disease traits.

The efficacy of different types of cerebral embolic protection device during transcatheter aortic valve implantation: a meta-analysis.

Aims: Perioperative stroke remains a devastating complication after transcatheter aortic valve implantation (TAVI), and using a cerebral embolic protection device (CEPD) during TAVI may reduce the occurrence of stroke according to some studies. Therefore, we conducted this meta-analysis to determine whether CEPD should be routinely used during TAVI. Methods and results: The inclusion criteria for this study were randomized controlled trials (RCTs) that examined the outcome of stroke with or without CEPD during TAVI, with a minimum follow-up period of 30 days. The primary endpoint was the occurrence of stroke (including both cerebrovascular accidents and death due to cerebrovascular accidents). The risk of stroke was lower in the CEPD group: RR 0.68, 95% CI 0.49-0.96, p = 0.03, I2 = 0%. A subgroup analysis was conducted according to the type of CEPD. The risk of stroke was lower in the I&LCCA (filter cover the innominate and the left common carotid arteries) type CEPD group: RR 0.66, 95% CI 0.49-0.96, p = 0.03, I2 = 36%. However, there was no statistically significant difference in the risk of stroke in the TMCA [filter cover the three major cerebral arteries (innominate, left common carotid, and subclavian arteries)] type CEPD group: RR 0.81, 95% CI 0.36-1.80, p = 0.60, I2 = 0%. Conclusions: In this meta-analysis, the I&LCCA-type CEPD can reduce the risk of stroke within 30 days following TAVI, but the TMCA type cannot.

Association between COVID-19 vaccination and hair cortisol concentrations.

BACKGROUND: Cortisol is a steroid hormone secreted mainly by the adrenal cortex and is associated with chronic stress levels in the body. Hair cortisol concentration (HCC) is a reliable index to assess human stress levels. So far, no study has reported whether COVID-19 vaccination is associated with the changes of HCC. METHODS: Hair samples were collected from 114 college students at Hangzhou City University and Zhejiang University. Among them, 57 cases completed COVID-19 vaccination and others did not. HCCs were measured by the chemiluminescence immunoassay (CLIA). The psychological stress levels were evaluated using the Chinese College Student Psychological Stress Scale (CCSPSS). General information and adverse reactions of the subjects were collected by questionnaire. RESULTS: Compared with the vaccinated college students, the unvaccinated students had higher HCC levels in both A and B hair segments respectively corresponding older or six weeks before and newer or six weeks after vaccination (p < 0.05), reflecting higher stress levels. Besides, the vaccinated group had significantly higher HCCs in segment B compared with segment A (p < 0.05). Further analysis showed that the value of ΔHCC (HCCseg.B - HCCseg.A) of the vaccinated group was strongly associated with COVID-19 vaccination (p < 0.05), but was not associated with age, gender, BMI, CCSPSS score, hormone use, exercise frequency, hair washing frequency, or hair treatment. Finally, the number of self-reported systemic adverse reactions in the vaccinated group was associated with ΔHCC (p < 0.01). CONCLUSION: The COVID-19 vaccination had an impact on the value of HCC, which might be linked to the occurrence of systemic adverse effects following vaccinations.

The Association between Four Common Polymorphisms in microRNA and Risk of Hepatocellular Carcinoma: An Updated Meta-Analysis.

Background: Many epidemiological studies have explored the relationship between single-nucleotide polymorphism and hepatocellular carcinoma (HCC). However, the results remain controversial. We performed a large-scale meta-analysis to draw a more precise estimation of the aforementioned association. Methods: Studies on the association between microRNA (MIR) polymorphisms and HCC risk that had been published up to Sep 30, 2021 were identified by searching the PubMed, Cochrane Library, Google Scholar, Web of Science, and Chinese Biomedical Literature electronic databases and the Excerpta Medical Database. The association between MIR polymorphisms and HCC risk was assessed using odds ratios (ORs) and their 95% confidence intervals (CIs). Results: Overall, 29 studies, with a total of 9,263 cases and 10,875 controls, were included in our meta-analysis. MicroRNA149 (MIR149) significantly decreased the risk of developing HCC on the overall population (homozygous model CC vs. TT: OR = 0.703, 95% CI = 0.549-0.899, P = 0.005), and microRNA 196 (MIR196) significantly decreased the risk of developing HCC on the overall population (recessive model TT vs. CT+CC: OR = 0.864, 95% CI = 0.751-0.993, P = 0.04) and on Caucasians (OR = 0.613, 95% CI = 0.414-0.907, P = 0.014). Conclusion: The MIR149 and MIR196 polymorphisms are the protect factors of developing HCC. The conduct of multi-center and multi-region studies with gene-gene, gene-environment should be considered.

Nanopore sequencing technology and its applications.

Since the development of Sanger sequencing in 1977, sequencing technology has played a pivotal role in molecular biology research by enabling the interpretation of biological genetic codes. Today, nanopore sequencing is one of the leading third-generation sequencing technologies. With its long reads, portability, and low cost, nanopore sequencing is widely used in various scientific fields including epidemic prevention and control, disease diagnosis, and animal and plant breeding. Despite initial concerns about high error rates, continuous innovation in sequencing platforms and algorithm analysis technology has effectively addressed its accuracy. During the coronavirus disease (COVID-19) pandemic, nanopore sequencing played a critical role in detecting the severe acute respiratory syndrome coronavirus-2 virus genome and containing the pandemic. However, a lack of understanding of this technology may limit its popularization and application. Nanopore sequencing is poised to become the mainstream choice for preventing and controlling COVID-19 and future epidemics while creating value in other fields such as oncology and botany. This work introduces the contributions of nanopore sequencing during the COVID-19 pandemic to promote public understanding and its use in emerging outbreaks worldwide. We discuss its application in microbial detection, cancer genomes, and plant genomes and summarize strategies to improve its accuracy.

Inhibition of hexokinase 2 with 3-BrPA promotes MDSCs differentiation and immunosuppressive function.

The adoptive transfer of ex vivo generated myeloid-derived suppressor cells (MDSCs) may be a promising therapeutic strategy for preventing allograft rejection after solid organ transplantation. Currently, the precise role of immune-metabolic pathways in the differentiation and function of MDSCs is not fully understood. Hexokinase 2 (HK2) is an isoform of hexokinase and is a key enzyme involved in the increased aerobic glycolysis of different immune cells during their activation and function. Here, we demonstrate that the addition of HK2 inhibitor 3-Bromopyruvic acid (3-BrPA) into traditional MDSCs induction system in vitro significantly promoted MDSCs production and enhanced their immunosuppressive function. Treatment with 3-BrPA increased the expression of MDSC-related immunosuppressive molecules, such as iNOS, Arg1, and CXCR2. Moreover, the adoptive transfer of 3-BrPA-treated MDSCs significantly prolonged the survival time of mouse heart allografts. This study provides a novel strategy to solve the problems of harvesting enough autologous cells for MDSC production from sick patients, and producing functionally enhanced MDSCs for preventing graft rejection and inducing tolerance.

USP14-mediated NLRC5 upregulation inhibits endothelial cell activation and inflammation in atherosclerosis.

Atherosclerosis, a chronic inflammatory condition that leads to a variety of life-threatening cardiovascular diseases, is a worldwide public health concern. Endothelial cells (ECs), which line the inside of blood vessels, play an important role in atherogenic initiation. Endothelial activation and inflammation are indispensable for the early stage of atherosclerosis. Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme that regulates the stability and activity of target proteins, has been identified as a potential therapeutic target for many inflammatory diseases. However, the role of USP14 on ECs is undefined. In this study, we found that USP14 is downregulated in either atherosclerosis patient specimens or oxidized low-density lipoprotein (ox-LDL)-stimulated ECs as compared to the control group. Overexpression of USP14 in ECs restrains ox-LDL-stimulated nuclear transcription factor kappa B (NF-κB) activation and subsequent adhesion molecule production. USP14 inhibits endothelium proinflammatory activation by suppressing the degradation of the negative regulator of NF-κB signaling, nod-like receptor family caspase recruitment domain family domain containing 5 (NLRC5). Finally, our in vivo experiments confirmed that USP14 adenovirus injection in apolipoprotein E deficient (ApoE-/-) mice fed with a western diet reduced the atherosclerotic lesion size, inhibited macrophage accumulation in the intima, and restricted the progression of atherosclerosis. Our results reveal that USP14 may represent a new therapeutic target for atherosclerosis.

LysM protein BdLM1 of Botryosphaeria dothidea plays an important role in full virulence and inhibits plant immunity by binding chitin and protecting hyphae from hydrolysis.

Botryosphaeria dothidea infects hundreds of woody plants and causes a severe economic loss to apple production. In this study, we characterized BdLM1, a protein from B. dothidea that contains one LysM domain. BdLM1 expression was dramatically induced at 6 h post-inoculation in wounded apple fruit, strongly increased at 7 d post-inoculation (dpi), and peaked at 20 dpi in intact shoots. The knockout mutants of BdLM1 had significantly reduced virulence on intact apple shoots (20%), wounded apple shoots (40%), and wounded apple fruit (40%). BdLM1 suppressed programmed cell death caused by the mouse protein BAX through Agrobacterium-mediated transient expression in Nicotiana benthamiana, reduced H2O2 accumulation and callose deposition, downregulated resistance gene expression, and promoted Phytophthora nicotianae infection in N. benthamiana. Moreover, BdLM1 inhibited the active oxygen burst induced by chitin and flg22, bound chitin, and protected fungal hyphae against degradation by hydrolytic enzymes. Taken together, our results indicate that BdLM1 is an essential LysM effector required for the full virulence of B. dothidea and that it inhibits plant immunity. Moreover, BdLM1 could inhibit chitin-triggered plant immunity through a dual role, i.e., binding chitin and protecting fungal hyphae against chitinase hydrolysis.

Long Intergenic Non-Coding 00162 as Diagnostic Biomarker for Early-Stage Pancreatic Cancer.

OBJECTIVE: Pancreatic cancer (PC) is the fourth leading cause of cancer death due to insufficient diagnostic methods in early stage of PC. Growing evidence has shown that long intergenic non-coding RNAs (LINCRNAs) is a biomarker of the early-stage of PC. However, the expression level and diagnostic value of LINC00162 remains unclear. METHODS: LINC00162 expression was detected in peripheral blood samples from 155 subjects (52 healthy controls, 52 benign pancreatic disease (BPD) persons and 51 PC patients) by quantitative reverse transcription real-time polymerase chain reaction. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic value of LINC00162, carcinoembryonic antigen (CEA) and cancer antigen 199 (CA199). RESULTS: Our data indicated that the LINC00162 expression was upregulated in PC patients compared with healthy controls and BPD (all P<0.001). Furthermore, PC patients with advanced pathological grades, positive lymph node metastasis and positive distant metastasis showed higher LINC00162 levels (all P<0.001). In addition, the area under the ROC curve (AUC) found that the LINC00162 had higher diagnostic ability than CEA and CA199 in distinguishing the early-stage PC patients (AUC: LINC00162 versus(vs) CEA vs CA199=0.932 vs 0.669 vs 0.725). CONCLUSION: In summary, the LINC00162 may be a noninvasive and efficient marker for identifying patients with the early-stage PC. Further validation studies with a large number of patients and long-term follow-up patients are needed to confirm the potential diagnostic value and clinical utility of LINC00162 in patients with PC.

Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy.

Elesclomol is an anticancer drug that targets mitochondrial metabolism. In the past, elesclomol was recognized as an inducer of oxidative stress, but now it has also been found to suppress cancer by inducing cuproptosis. Elesclomol's anticancer activity is determined by the dependence of cancer on mitochondrial metabolism. The mitochondrial metabolism of cancer stem cells, cancer cells resistant to platinum drugs, proteasome inhibitors, molecularly targeted drugs, and cancer cells with inhibited glycolysis was significantly enhanced. Elesclomol exhibited tremendous toxicity to all three kinds of cells. Elesclomol's toxicity to cells is highly dependent on its transport of extracellular copper ions, a process involved in cuproptosis. The discovery of cuproptosis has perfected the specific cancer suppressor mechanism of elesclomol. For some time, elesclomol failed to yield favorable results in oncology clinical trials, but its safety in clinical application was confirmed. Research progress on the relationship between elesclomol, mitochondrial metabolism and cuproptosis provides a possibility to explore the reapplication of elesclomol in the clinic. New clinical trials should selectively target cancer types with high mitochondrial metabolism and attempt to combine elesclomol with platinum, proteasome inhibitors, molecularly targeted drugs, or glycolysis inhibitors. Herein, the particular anticancer mechanism of elesclomol and its relationship with mitochondrial metabolism and cuproptosis will be presented, which may shed light on the better application of elesclomol in clinical tumor treatment.

Performance evaluation between two automated biochemical analyzer systems: Roche Cobas 8000 and Mindray BS2000M.

Background: The values of biomarkers play a central role in routine clinical decision-making. Whereas the performance of different automated chemical analyzers remains unclear. To determine the performance of different platforms, we compared the consistency and accuracy between Roche Cobas 8000 and Mindray BS2000M. Methods: A total of 1869 remaining serum samples were collected. CK, LDH-1, RBP, Cys-C, IgA, IgM, and IgG were assessed using paired t-test, Passing-Bablok regression analysis, and Bland-Altman analysis according to CLSI EP5-A3. Results: There were significant differences in the average bias of all items between the two machines (P<0.001). Because the 95% confidence interval of intercept A included 0, CK, LDH-1, Cys-C and IgG did not show systematic error in Passing-Bablok regression analysis. The confidence interval of 95% of the slope B in IgM contained 1, and there was no difference in the two measurements in IgM. Except for IgA, the r values and correlation coefficient of all items were higher than 0.91, which showed that the correlation and consistency were good. The Bland-Altman analysis showed that two instruments had more than 95% of the points apart from CK, LDH-1, and IgA. Conclusions: It can be considered that the two instruments have good correlation and consistency in CK, LDH-1, RBP, Cys-C, IgM, and IgG, and the two instruments are interchangeable and can replace each other.

ZBTB20 regulates cardiac allograft rejection through NFкB-mediated inflammation in mouse heart transplantation.

Allograft rejection is a major obstacle for the long-term survival of heart transplantation (Htx) patients. The cardiac allograft rejection requires the activation of macrophages and effector T cells. In this study, we explored the role of zinc-finger and BTB domain containing protein 20 (ZBTB20) in the regulation of heart allograft rejection. Flow cytometry analysis of the spleen cells from mice undergoing an acute cardiac rejection revealed that the ZBTB20 protein expression was upregulated in both T and B cells(n = 4，P < 0.01). In addition, ZBTB20 gene knockdown significantly prolonged the survival of heart allografts in mice(n = 4，P < 0.01). Lack of ZBTB20 increased the expression of Foxp3 and limited the response of T helper 1 (Th1) cells(n = 4，P < 0.01). The ZBTB20-related regulation occurred through the activation of the NFкB pathway. In conclusion, our data suggest that ZBTB20 is involved in the regulation of T cells involved in acute heart allograft rejection. Hence, downregulation of ZBTB20 expression may inhibit T cells to prolong heart transplant survival.

CFTR Suppresses Neointimal Formation Through Attenuating Proliferation and Migration of Aortic Smooth Muscle Cells.

ABSTRACT: Cystic fibrosis transmembrane conductance regulator (CFTR) plays important roles in arterial functions and the fate of cells. To further understand its function in vascular remodeling, we examined whether CFTR directly regulates platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) proliferation and migration, as well as the balloon injury-induced neointimal formation. The CFTR adenoviral gene delivery was used to evaluate the effects of CFTR on neointimal formation in a rat model of carotid artery balloon injury. The roles of CFTR in PDGF-BB-stimulated VSMC proliferation and migration were detected by mitochondrial tetrazolium assay, wound healing assay, transwell chamber method, western blot, and qPCR. We found that CFTR expression was declined in injured rat carotid arteries, while adenoviral overexpression of CFTR in vivo attenuated neointimal formation in carotid arteries. CFTR overexpression inhibited PDGF-BB-induced VSMC proliferation and migration, whereas CFTR silencing caused the opposite results. Mechanistically, CFTR suppressed the phosphorylation of PDGF receptor ß, serum and glucocorticoid-inducible kinase 1, JNK, p38 and ERK induced by PDGF-BB, and the increased mRNA expression of matrix metalloproteinase-9 and MMP2 induced by PDGF-BB. In conclusion, our results indicated that CFTR may attenuate neointimal formation by suppressing PDGF-BB-induced activation of serum and glucocorticoid-inducible kinase 1 and the JNK/p38/ERK signaling pathway.

Associations of long-term physical activity trajectories with coronary artery calcium progression and cardiovascular disease events: results from the CARDIA study.

OBJECTIVE: The study aimed to assess the associations of physical activity (PA) trajectories across a 25-year span with coronary artery calcium (CAC) progression, and subsequent risk of cardiovascular disease (CVD) events. METHODS: We included 2497 participants from the Coronary Artery Disease Risk Development in Young Adults study who had computed tomography-assessment of CAC at baseline (year 15: 2000-2001) and follow-up (year 20 or 25) and at least three measures of PA from year 0 to year 25. Long-term PA trajectories were determined by latent class modelling using a validated questionnaire. RESULTS: Among the included participants, 1120 (44.9%) were men, 1418 (56.8%) were white, and the mean (SD) age was 40.4 (3.6) years. We identified three distinct PA trajectories based on PA average levels and change patterns: low (below PA guidelines, n=1332; 53.3%); moderate (meeting and slightly over PA guidelines, n=919; 36.8%) and high (about three times PA guidelines or more, n=246; 9.9%). During a mean (SD) follow-up of 8.9 (2.1) years, 640 (25.6%) participants had CAC progression. Participants in the high PA trajectory group had a higher risk of CAC progression than those in the low PA trajectory group after adjustment for traditional cardiovascular risk factors (HR 1.51; 95% CI 1.18 to 1.94). However, high PA trajectory was not associated with an increased risk of incident CVD events (HR 1.01; 95% CI 0.44 to 2.31) and the incidence of CVD events in participants with CAC progression was similar across all three PA trajectory groups (p=0.736). CONCLUSION: Long-term PA about three times the guidelines or more is independently associated with CAC progression; however, no additional risk of incident CVD events could be detected.

Diagnostic value of combined prealbumin-to-fibrinogen and albumin-to-fibrinogen ratios in Hp-negative gastric cancer.

BACKGROUND: This study aimed to investigate the diagnostic value of prealbumin-to-fibrinogen ratio (PFR) and albumin-to-fibrinogen ratio (AFR) alone or in combination in Helicobacter pylori-negative gastric cancer (Hp-NGC) patients. METHODS: This study included 171 healthy controls, 180 Hp-NGC patients, and 215 Helicobacter pylori-negative chronic gastritis (HpN) patients. We compared the differences of various indicators and pathological characteristics between groups with Mann-Whitney U test and Chi-square test. The diagnostic value of PFR and AFR alone or in combination for Hp-NGC patients was assessed by the receiver operating characteristic (ROC) curve. RESULTS: PFR and AFR were related to the progression and clinicopathological characteristics of Hp-NGC. As the disease progressed, PFR and AFR values gradually decreased and were negatively related to the tumor size and depth of invasion. In addition, the area under the curves (AUCs) that resulted from combining PFR and AFR to distinguish Hp-NGC patients from healthy controls and HpN patients were 0.908 and 0.654, respectively. When combined with PFR and AFR in the differential diagnosis of tumors with a maximum diameter ≥ 5 cm and the T3 + T4 stage, the AUCs were 0.949 and 0.922; the sensitivity was 86.32% and 80.74%; and the specificity was 94.74% and 92.98%, respectively. CONCLUSIONS: PFR and AFR may be used as diagnostic biomarkers for Hp-NGC. The combination of PFR and AFR was more valuable than each indicator alone in the diagnosis of Hp-NGC.

Meningitis patients with pneumonia: correlation between blood parameters and clinical features.

Background: This research aimed to explore the possible relationship between the main experimental parameters and clinical status in meningitis patients with pneumonia infection. Methods: A retrospective analysis of the demographic characteristics, clinical features and laboratory parameters of meningitis patients was performed. Results: D-dimer, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) exhibited good diagnostic ability for meningitis complicated with pneumonia. Additionally, we observed a positive correlation between D-dimer and CRP in cases of meningitis with pneumonia infection. D-dimer, ESR and Streptococcus pneumoniae (S. pneumoniae) were independently associated with meningitis patients with pneumonia infection. Conclusion: D-dimer, CRP, ESR and S. pneumoniae infection may effectively anticipate disease progression and adverse consequences in meningitis patients with pneumonia infection.

D-dimer has an early and rapid diagnostic value for the hypercoagulation state. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have been widely used laboratory parameters for inflammatory diseases. In our study, we observed increased D-dimer, CRP and ESR levels in patients with meningitis, which were more pronounced in patients with meningitis complicated with pneumonia. It is worth noting that D-dimer and CRP showed a positive correlation in patients with meningitis. D-dimer, CRP and ESR in patients with meningitis can effectively monitor disease progression.

D-Dimer Combined With CRP Can Improve the Differential Value of Bacterial Meningitis and Tuberculous Meningitis.

OBJECTIVE: To explore the diagnostic value of the coagulation marker D-dimer and its combination with the traditional marker C-reactive protein (CRP) in distinguishing bacterial meningitis (BM) from tuberculous meningitis (TM). METHODS: We performed a retrospective study on specimens from 173 patients with meningitis who were hospitalized at the First Affiliated Hospital of Guangxi Medical University, Guangxi, China, from 2012 through 2020. The patient records were divided into the BM group and the TM group, and hematological parameters D-dimer and CRP were evaluated for the 2 groups. RESULTS: The levels of D-dimer and CRP in the BM group were significantly higher than those levels in the TM group (P ˂.001 for each), and the sensitivity and specificity of the combined detection of the 2 markers was 86.3% to 100%; the area under the receiver operating characteristic (ROC) curve reached 0.983 (95% confidence interval [CI], 0.966-0.999). CONCLUSION: D-dimer testing has high specificity in distinguishing between BM and TM; CRP testing also has high sensitivity. The combined diagnosis of the 2 biomarkers helps to distinguish TM from BM.

ZBTB20 Positively Regulates Oxidative Stress, Mitochondrial Fission, and Inflammatory Responses of ox-LDL-Induced Macrophages in Atherosclerosis.

Atherosclerosis (AS) is one of the most serious and common cardiovascular diseases affecting human health. AS is featured by the accumulation of plaques in vessel walls. The pathophysiology of AS is relevant in the low-density lipoprotein (LDL) uptake by macrophages, as well as the conversion of macrophages to foam cells. However, the mechanisms about how macrophages regulate AS have not been fully elucidated. In this study, we aimed to illuminate the roles of ZBTB20 and to excavate the underlying regulative mechanisms of ZBTB20 in AS. The microarray analysis revealed that ZBTB20 was a hub gene in the oxidative stress and inflammatory responses induced by oxidized LDL (ox-LDL) in AS. Correspondingly, our validation studies showed that ZBTB20 increased in either the human atherosclerotic lesion or the ox-LDL-stimulated macrophages. Moreover, the knockdown of ZBTB20 decreased M1 polarization, suppressed the proinflammatory factors, inhibited mitochondrial fission, and reduced the oxidative stress level of macrophages induced by ox-LDL. The mechanistic studies revealed that the ZBTB20 knockdown suppressed NF-κB/MAPK activation and attenuated the mitochondrial fission possibly via regulating the nucleus translocation of NRF2, a pivotal transcription factor on redox homeostasis. Our in vivo studies showed that the sh-ZBTB20 adenovirus injection could reduce the progression of AS in apolipoprotein E-deficient (ApoE-/-) mice. All in all, these results suggested that ZBTB20 positively regulated the oxidative stress level, mitochondrial fission, and inflammatory responses of macrophages induced by ox-LDL, and the knockdown of ZBTB20 could attenuate the development of AS in ApoE-/- mice.

Warfarin Accelerates Aortic Calcification by Upregulating Senescence-Associated Secretory Phenotype Maker Expression.

Warfarin, a vitamin K antagonist (VKA), is known to promote arterial calcification (AC). In the present study, we conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis (MESA); 6655 participants were included. From MESA data, we found that AC was related to both age and vitamin K; furthermore, the score of AC increased with SASP marker including interlukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) rising. Next, a total of 79 warfarin users in our center developed significantly more calcified coronary plaques as compared to non-VKA users. We investigated the role of warfarin in phosphate-induced AC in different ages by in vitro experimental study. Furthermore, dose-time-response of warfarin was positively correlated with AC score distribution and plasma levels of the SASP maker IL-6 among patients < 65 years, but not among patients ≥ 65 years. In addition, in vitro research suggested that warfarin treatment tended to deteriorate calcification in young VSMC at the early stage of calcification. Our results suggested that aging and warfarin-treatment were independently related to increased AC. Younger patients were more sensitive to warfarin-related AC than older patients, which was possibly due to accumulated warfarin-induced cellular senescence.

Identification of Hub Genes Associated With Immune Infiltration and Predict Prognosis in Hepatocellular Carcinoma via Bioinformatics Approaches.

AIMS: In the cancer-related research field, there is currently a major need for a greater number of valuable biomarkers to predict the prognosis of hepatocellular carcinoma (HCC). In this study, we aimed to screen hub genes related to immune cell infiltration and explore their prognostic value for HCC. METHODS: We analyzed five datasets (GSE46408, GSE57957, GSE74656, GSE76427, and GSE87630) from the Gene Expression Omnibus database to screen the differentially expressed genes (DEGs). A protein-protein interaction network of the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes; then, the hub genes were identified. Functional enrichment of the genes was performed on the Metascape website. Next, the expression of these hub genes was validated in several databases, including Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and Human Protein Atlas. We explored the correlations between the hub genes and infiltrated immune cells in the TIMER2.0 database. The survival curves were generated in GEPIA2, and the univariate and multivariate Cox regression analyses were performed using TIMER2.0. RESULTS: The top ten hub genes [DNA topoisomerase II alpha (TOP2A), cyclin B2 (CCNB2), protein regulator of cytokinesis 1 (PRC1), Rac GTPase-activating protein 1 (RACGAP1), aurora kinase A (AURKA), cyclin-dependent kinase inhibitor 3 (CDKN3), nucleolar and spindle-associated protein 1 (NUSAP1), cell division cycle-associated 5 (CDCA5), abnormal spindle microtubule assembly (ASPM), and non-SMC condensin I complex subunit G (NCAPG)] were identified in subsequent analysis. These genes are most markedly enriched in cell division, suggesting their close association with tumorigenesis. Multi-database analyses validated that the hub genes were upregulated in HCC tissues. All hub genes positively correlated with several types of immune infiltration, including B cells, CD4+ T cells, macrophages, and dendritic cells. Furthermore, these hub genes served as independent prognostic factors, and the expression of these hub genes combing with the macrophage levels could help predict an unfavorable prognosis of HCC. CONCLUSION: In sum, these hub genes (TOP2A, CCNB2, PRC1, RACGAP1, AURKA, CDKN3, NUSAP1, CDCA5, ASPM, and NCAPG) may be pivotal markers for prognostic prediction as well as potentially work as targets for immune-based intervention strategies in HCC.