Effect of inflammation on association between cancer and coronary artery disease.

BACKGROUND: Cancer and coronary artery disease (CAD) is reported to often co-exist in same individuals, however, whether cancer is directly associated with anatomical severity of CAD is rarely studied. The present study aimed to observe the relationship between newly diagnosed cancer and anatomical severity of CAD, moreover, to investigate effect of inflammation on the relationship of cancer with CAD. METHODS: 374 patients with newly diagnosed cancer who underwent coronary angiography (CAG) were enrolled. Through 1:3 propensity score matching (PSM) to cancer patients based on the age and gender among 51,106 non-cancer patients who underwent CAG, 1122 non-cancer patients were selected as control patients. Anatomical severity of CAD was assessed using SYNTAX score (SXscore) based on coronary angiographic image. SXscore ≤ 22 (highest quartile) was defined as SX-low, and SXscore > 22 as SX-high. The ratio of neutrophil to lymphocyte count (NLR) was used to describe inflammation level. Association between cancer and the anatomical severity of CAD was investigated using logistic regression. RESULTS: Univariate logistic regression analysis showed a correlation between cancer and anatomical severity of CAD (OR: 1.419, 95% CI: 1.083-1.859; P = 0.011). Cancer was associated with increased risk of SX-high after adjusted for common risk factors of CAD (OR: 1.598, 95% CI: 1.172-2.179, P = 0.003). Significant association between cancer and SX-high was revealed among patients with high inflammation (OR: 1.656, 95% CI: 1.099-2.497, P = 0.016), but not among patients with low inflammation (OR: 1.530, 95% CI: 0.973-2.498, P = 0.089). CONCLUSIONS: Cancer was associated with severity of CAD, however, the association between the two diseases was significant among patients with high inflammation rather than among patients with low inflammation.

The Teleost CXCL13-CXCR5 Axis Induces Inflammatory Cytokine Expression through the Akt-NF-κB, p38-AP-1, and p38-NF-κB Pathways.

The ancestors of chemokines originate in the most primitive of vertebrates, which has recently attracted great interest in the immune functions and the underlying mechanisms of fish chemokines. In the current study, we identified an evolutionarily conserved chemokine, CiCXCL13, from a teleost fish, grass carp. CiCXCL13 was characterized by a typical SCY (small cytokine CXC) domain and four cysteine residues (C34, C36, C61, C77), with the first two cysteines separated by a random amino acid residue, although it shared 24.2-54.8% identity with the counterparts from other vertebrates. CiCXCL13 was an inducible chemokine, whose expression was significantly upregulated in the immune tissues of grass carps after grass carp reovirus infection. CiCXCL13 could bind to the membrane of grass carp head kidney leukocytes and promote cell migration, NO release, and the expression of >15 inflammatory cytokines, including IL-1ß, TNF-α, IL-10 and TGF-ß1, thus regulating the inflammatory response. Mechanistically, CiCXCL13 interacted with its evolutionarily conserved receptor CiCXCR5 and activated the Akt-NF-κB and p38-AP-1 pathways, as well as a previously unrevealed p38-NF-κB pathway, to efficiently induce inflammatory cytokine expression, which was distinct from that reported in mammals. Zebrafish CXCL13 induced inflammatory cytokine expression through Akt, p38, NF-κB, and AP-1 as CiCXCL13. Meanwhile, the CiCXCL13-CiCXCR5 axis-mediated inflammatory activity was negatively shaped by grass carp atypical chemokine receptor 2 (CiACKR2). The present study is, to our knowledge, the first to comprehensively define the immune function of CXCL13 in inflammatory regulation and the underlying mechanism in teleosts, and it provides a valuable perspective on the evolution and biology of fish chemokines.

First in vitro and in vivo evaluation of recombinant IL-1ß protein as a potential immunomodulator against viral infection in fish.

IL-1ß is an important proinflammatory cytokine with multifaceted modulatory roles in immune responses. In fish, recombinant IL-1ß has been employed in the control of bacterial diseases, while the antiviral mechanisms of IL-1ß remain largely unknown, and the efficacy of recombinant IL-1ß as an immunomodulator to prevent viral diseases is still not determined. This study evaluated the immunomodulatory effects of recombinant grass carp IL-1ß against grass carp reovirus (GCRV) in vitro and in vivo. Firstly, the mature form (Ser111-Lys270) of grass carp IL-1ß was identified, and its recombinant protein (designated as rgcIL-1ß) was prepared through prokaryotic expression. Then, an in vitro evaluation model for rgcIL-1ß activity was established in the CIK cells, with the appropriate concentration (600 ng/mL) and effect time (1 h). In vitro, rgcIL-1ß could not only induce the production of proinflammatory cytokines such as IL-1ß, IL-6, IL-8, and TNF-α but also a series of antiviral factors including IFN-1, IFN-2, IFN-γ, and ISG15. Mechanistically, transcriptome analysis and western blotting confirmed that rgcIL-1ß activated multiple transcriptional factors, including NF-κB, IRF1, IRF3, and IRF8, and the signal pathways associated with inflammatory cytokines and antiviral factors expression. Expectedly, rgcIL-1ß treatment significantly inhibited GCRV replication in vitro. In vivo administration of rgcIL-1ß via intraperitoneal pre-injection significantly aroused an antiviral response to restrict GCRV replication and intense tissue inflammation in grass carp, demonstrating the immunomodulatory effects of rgcIL-1ß. More importantly, rgcIL-1ß administrated with 10 ng/g and 1 ng/g could improve the survival rate of grass carp during GCRV infection. This study represents the first time to comprehensively reveal the immunomodulatory and antiviral mechanisms of IL-1ß in fish and may also pave the way for further developing recombinant IL-1ß as an immunotherapy for the prevention and control of fish viral diseases.

JunD functions as a transcription factor of IL-10 to regulate bacterial infectious inflammation in grass carp (Ctenopharyngodon idella).

IL-10 is a key anti-inflammatory mediator ensuring the protection of a host from excessive inflammation in response to pathogen infections, whose transcription or expression levels are tightly linked to the onset and progression of infectious diseases. An AP-1 family member called CiJunD was shown to be a transcription factor of IL-10 in grass carp (Ctenopharyngodon idella) in the current study. CiJunD protein harbored the conserved Jun and bZIP domains. Mutant experiments demonstrated that CiJunD bound to three specific sites on IL-10 promoter, i.e., 5'-ATTATTCATA-3', 5'-AGATGAGACATCT-3', and 5'-ATTATTCATC-3', mainly relying on the bZIP domain, and initiated IL-10 transcription. Expression data from the grass carp spleen infected by Aeromonas hydrophila and lipopolysaccharide (LPS) challenged spleen leukocytes indicated that the expressions of CiJunD and IL-10 were positively correlated, while the expression of pro-inflammatory cytokines, such as IL-1ß, IL-6, IL-8, IFN-γ, and TNF-α, showed an overall downward trend when CiJunD and IL-10 peaked. The ability of CiJunD to down-regulate the production of pro-inflammatory cytokines and up-regulate the expression of IL-10, both with and without LPS stimulation, was confirmed by overexpression experiments. Meanwhile, the subcellular fractionation assay revealed that the nuclear translocation of CiJunD was significantly enhanced after the LPS challenge. Moreover, in vivo administration of grass carp with Oxamflatin, a potent agonist of JunD activity, could promote IL-10 but suppress the expression of pro-inflammatory cytokines. Intriguingly, tissue inflammation lesions and the survival rates of grass carp infected with A. hydrophila were also significantly improved by Oxamflatin administration. This work sheds light on the regulation mechanism by JunD of IL-10 expression and bacterial infectious inflammation for the first time, and it may present a viable method for preventing infectious diseases in fish by regulating IL-10 expression and inflammatory response.

Lead helix winding tricuspid chordae tendineae: A case report.

BACKGROUND: As left bundle branch pacing (LBBP) is more like physiological pacing, LBBP has emerged as a novel pacing strategy that uses the native conduction system to improve ventricular synchronization with stable pacing parameters. LBBP has been revealed associated with a significantly reduced risk of new-onset atrial fibrillation and heart failure compared with conventional permanent pacemaker implantation. CASE SUMMARY: A 64-year-old man was admitted with a 24-h history of chest distress and shortness of breath, which continued unabated. The patient had no symptoms of chest pain, dizziness, syncope, nausea nor vomiting. There were no abnormalities found in routine examinations after admission. Twelve-lead electrocardiogram presented a result of 2:1 atrioventricular block. Coronary angiography was performed the next day and no abnormality was found. Finally, the patient agreed to received LBBP and signed the informed consent. During the process of withdrawing the Medtronic Model 3830 lead into sheath, we found the lead helix was wrapped around the chordae tendineae of the septal valve of tricuspid. Attempts to rotate the 3830 lead failed to release the lead helix from the chordae tendineae, and ultimately we used radiofrequency ablation to ablate the wrapped chordae tendineae. CONCLUSION: Radiofrequency ablation effectively solved this problem without complications. It is an effective and reliable method to resolve lead winding chordae.

Continuous positive airway pressure therapy might be an effective strategy on reduction of atrial fibrillation recurrence after ablation in patients with obstructive sleep apnea: insights from the pooled studies.

Background: Obstructive sleep apnea (OSA) is an independent and modifiable risk factor in the initiation and maintenance of atrial fibrillation (AF). However, the effective of the continuous positive airway pressure (CPAP) on AF patients with OSA after ablation is elusive. Methods: Cochrane Library, PubMed, Embase, and Web of Science were systematically searched up to February 1, 2023. Studies comprising the AF recurrence rate between the CPAP therapy group and non-CPAP therapy group for the AF patients with OSA were included. Meanwhile, trial sequential analysis (TSA) was conducted to adjust the lower statistical power and random error in this study. Subgroup analysis identified the potential determinants for the AF recurrence rate with CPAP therapy. Results: A total of eight studies including 1,231 AF patients with OSA were eligible. Compared with non-CPAP treatment group, CPAP treatment group was statistically associated with a lower AF recurrence rate (risk ratio [RR], 0.58; p = 0.000). TSA indicated the firm evidence favoring CPAP group for AF recurrence risk. Three significant intervention-covariate interactions for AF recurrence was identified, including study design, non-paroxysmal AF (PAF) proportion, and CPAP treatment strategy. Conclusion: Our study suggests that CPAP therapy might be an effective strategy on reducing AF recurrence post-ablation for AF patients with OSA. The CPAP treatment strategy and the non-PAF proportion might be the possible determinants on AF recurrence for AF patients with OSA after ablation. Clinical trial registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023398588, identifier (CRD42023398588).

[Heterocyclic compounds and phenolic glycosides from flowers of Dendrobium officinale].

Eight heterocyclic compounds and twelve phenolic glycosides were separated from the water extract of Dendrobium officinale flowers through chromatographic techniques, such as Diaion HP-20 macroporous adsorption resin column chromatography(CC), silica gel CC, ODS CC, Sephadex LH-20 CC, and preparative high performance liquid chromatography(PHPLC). According to the spectroscopic analyses(MS, ~1H-NMR, and ~(13)C-NMR) and optical rotation data, the compounds were identified as dendrofurfural A(1), 2'-deoxyadenosine(2), 4-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanoic acid(3), 4-[2-formyl-5-(methoxymethyl)-1H-pyrrol-1-yl] butanoic acid(4), 1-(2-hydroxyethyl)-5-(methoxymethyl)-1H-pyrrole-2-carbaldehyde(5), 5-(methoxymethyl)-1H-pyrrole-2-carbaldehyde(6), methyl 5-(hydroxymethyl)-furan-2-carboxylate(7),(S)-5-hydroxymethyl-5H-furan-2-one(8), 2-methoxyphenyl-1-O-ß-D-glucopyranoside(9), arbutin(10), isotachioside(11), 2,6-dimethoxy-4-hydroxyphenol-1-O-ß-D-glucopyranoside(12), orcinol glucoside(13), tachioside(14), gastrodin(15), 4-O-ß-D-glucopyranosylvanillyl alcohol(16), 2,6-dimethoxy-4-hydroxymethylphenol-1-O-ß-D-glucopyranoside(17), icariside D_2(18), 4-formylphenyl-ß-D-glucopyranoside(19), and vanillin-4-O-ß-D-glucopyranoside(20). Among them, compound 1 is a new furfural benzyl alcohol condensate, with the skeleton first found in Dendrobium. Compounds 2-9, 11, 13, and 19 are reported from Dendrobium for the first time, and compounds 14 and 18 are reported for the first time from D. officinale. Compounds 11 and 14 showed moderate DPPH radical scavenging capacity, and compounds 11-14 demonstrated potent ABTS radical scavenging capacity, possessing antioxidant activity.

Single-shot technique of cryoablation for atrial fibrillation has comparable effective and safety outcomes compared to standard technique: insights from multiple clinical studies.

Background: Although there are many freezing protocols available, the optimal freezing dose is still not determined. We aimed to evaluate the effectiveness and safety of different freeze strategies of CBA in the treatment of AF. Methods: PubMed, Cochrane Library, Web of Science, and Embase were searched up to 1st December 2022. Studies comparing the outcomes between single-shot technique and standard technique of cryoablation were included. Subgroup analysis identified potential determinants for single-shot technique procedure. Results: Our search resulted in 3407 records after deduplication. A total of 17 qualified studies met our inclusion criteria. Compared with standard technique, single-shot technique of cryoablation has a comparable rate of freedom from AF/AT(RR 1.00; P = 0.968), a trend for lower rate of procedure complications (RR 0.80; P = 0.069), a lower rate in transient phrenic paralysis (t-PNP) (RR 0.67; P = 0.038), a similar rate in persistent phrenic paralysis (per-PNP) (RR 1.15; P = 0.645), as well as a comparable procedure parameters. Importantly, potentially significant treatment covariable interactions in procedure complications were found in freeze strategy subgroup, male proportion subgroup and age subgroup, including single-shot freeze (RR 1.02; P = 0.915) and TTI-guided (RR 0.63; P = 0.007) with interaction P = 0.051, high male proportion (RR 0.54; P = 0.005) and a low male proportion (RR 0.94; P = 0.759) with interaction P = 0.074, as well as age ≥ 65 (RR0.91; P = 0.642) and age <65 (RR 0.54; P = 0.006),interaction P = 0.090. Meanwhile, only one significant treatment covariable interactions in procedure complications was found in the hypertension subgroup, including HT > 60% (RR 0.89; P = 0.549) and HT ≤ 60% (RR 0. 46; P < 0.01) with interaction P = 0.043. Conclusions: Our study suggested that single-shot technique of cryoablation has comparable effective and safety outcomes for AF ablation compared to standard technique.

Correction: An aquatic virus exploits the IL6-STAT3-HSP90 signaling axis to promote viral entry.

[This corrects the article DOI: 10.1371/journal.ppat.1011320.].

Major depression disorder may causally associate with the increased atrial fibrillation risk: evidence from two-sample mendelian randomization analyses.

BACKGROUND: Observational studies have revealed a link between major depressive disorder (MDD) and a higher chance of developing atrial fibrillation (AF). It is still uncertain whether or not this correlation indicates a causal relationship. This research set out to evaluate the causal impact of MDD on AF. METHODS: To evaluate the causal relationship between MDD and AF, we employed a two-sample Mendelian randomization (MR) method. A new genome-wide association study (GWAS) with 500,199 participants was used to obtain an overview of the association of genetic variations with MDD. An additional GWAS incorporating 1,030,836 people provided data on the relationship between gene variants and AF. The inverse-variance weighted technique was utilized to assess the effect sizes. Sensitivity analysis included the use of other statistical approaches such as weighted median, Outlier, MR Pleiotropy Residual Sum, weighted mode, simple mode, and MR - Egger. RESULTS: By employing 47 single nucleotide polymorphisms (SNPs) as markers, MR analyses in random-effect inverse-variance weighted models found that genetically projected MDD was linked to an elevated incidence of AF (odds ratio [OR] = 1.098, 95% CI 1.000-1.206; P = 0.049). No gene pleiotropy was discovered as indicated by MR-Egger (intercept= -0.011, P = 0.169). Sensitivity analysis employing other MR techniques yielded reliable results. CONCLUSION: This MR study established a causal relationship between genetically predicted MDD and an elevated risk of AF.

An aquatic virus exploits the IL6-STAT3-HSP90 signaling axis to promote viral entry.

Viral seasonality in the aquaculture industry is an important scientific issue for decades. While the molecular mechanisms underpinning the temperature-dependent pathogenesis of aquatic viral diseases remain largely unknown. Here we report that temperature-dependent activation of IL6-STAT3 signaling was exploited by grass carp reovirus (GCRV) to promote viral entry via increasing the expression of heat shock protein 90 (HSP90). Deploying GCRV infection as a model system, we discovered that GCRV induces the IL6-STAT3-HSP90 signaling activation to achieve temperature-dependent viral entry. Further biochemical and microscopic analyses revealed that the major capsid protein VP7 of GCRV interacted with HSP90 and relevant membrane-associated proteins to boost viral entry. Accordingly, exogenous expression of either IL6, HSP90, or VP7 in cells increased GCRV entry in a dose-dependent manner. Interestingly, other viruses (e.g., koi herpesvirus, Rhabdovirus carpio, Chinese giant salamander iridovirus) infecting ectothermic vertebrates have evolved a similar mechanism to promote their infection. This work delineates a molecular mechanism by which an aquatic viral pathogen exploits the host temperature-related immune response to promote its entry and replication, instructing us on new ways to develop targeted preventives and therapeutics for aquaculture viral diseases.

[A new bibenzyl derivative from stems of Dendrobium officinale].

Eleven compounds were isolated from the 95% ethanol extract of the stems of Dendrobium officinale after water extraction by various modern chromatographic techniques, such as silica gel column chromatography(CC), octadecyl-silica(ODS) CC, Sephadex LH-20 CC, preparative thin layer chromatography(PTLC) and preparative high performance liquid chromatography(PHPLC). According to spectroscopic analyses(MS, 1D-NMR, 2D-NMR) combined with optical rotation data and calculated electronic circular dichroism(ECD), their structures were identified as dendrocandin Y(1), 4,4'-dihydroxybibenzyl(2), 3-hydroxy-4',5-dimethoxybibenzyl(3), 3,3'-dihydroxy-5-methoxybibenzyl(4), 3-hydroxy-3',4',5-trimethoxybibenzyl(5), crepidatin(6), alternariol(7), 4-hydroxy-3-methoxypropiophenone(8), 3-hydroxy-4,5-dimethoxypropiophenone(9), auriculatum A(10) and hyperalcohol(11). Among them, compound 1 was a new bibenzyl derivative; compounds 2 and 7-11 have not been previously reported from Dendrobium plants; compound 6 was reported from D.officinale for the first time. Compounds 3-6 exhibited potent antioxidant activity with IC_(50) values of 3.11-9.05 µmol·L~(-1) in ABTS radical scavenging assay. Compound 4 showed significant inhibitory effect on α-glucosidase, with IC_(50) value of 17.42 µmol·L~(-1), indicating that it boasted hypoglycemic activity.

Functional and Expressional Analyses Reveal the Distinct Role of Complement Factor I in Regulating Complement System Activation during GCRV Infection in Ctenopharyngodon idella.

Complement factor I (CFI), a complement inhibitor, is well known for regulating the complement system activation by degrading complement component 3b (C3b) in animal serum, thus becoming involved in innate defense. Nevertheless, the functional mechanisms of CFI in the complement system and in host-pathogen interactions are far from being clarified in teleost fish. In the present study, we cloned and characterized the CFI gene, CiCFI, from grass carp (Ctenopharyngodon idella) and analyzed its function in degrading serum C3b and expression changes after grass carp reovirus (GCRV) infection. The open reading frame of CiCFI was found to be 2121 bp, encoding 706 amino acids with a molecular mass of 79.06 kDa. The pairwise alignments showed that CiCFI shared the highest identity (66.9%) with CFI from Carassius gibelio and the highest similarity (78.7%) with CFI from Danio rerio. The CiCFI protein was characterized by a conserved functional core Tryp_SPc domain with the catalytic triad and substrate binding sites. Phylogenetic analysis indicated that CiCFI and the homologs CFIs from other teleost fish formed a distinct evolutionary branch. Similar with the CFIs reported in mammals, the recombinant CiCFI protein could significantly reduce the C3b content in the serum, demonstrating the conserved function of CiCFI in the complement system in the grass carp. CiCFI mRNA and protein showed the highest expression level in the liver. After GCRV infection, the mRNA expressions of CiCFI were first down-regulated, then up-regulated, and then down-regulated to the initial level, while the protein expression levels maintained an overall downward trend to the late stage of infection in the liver of grass carps. Unexpectedly, the protein levels of CiCFI were also continuously down-regulated in the serum of grass carps during GCRV infection, while the content of serum C3b proteins first increases and then returns to the initial level, suggesting a distinct role of CiCFI in regulating complement activation and fish-virus interaction. Combining our previous results that complement factor D, a complement enhancer, shows continuously up-regulated expression levels in grass carps during GCRV infection, and this study may provide the further essential data for the full picture of complex complement regulation mechanism mediated by Df and CFI of the grass carp during pathogen infection.

Efficacy and Tolerability of Ezetimibe/Atorvastatin Fixed-dose Combination Versus Atorvastatin Monotherapy in Hypercholesterolemia: A Phase III, Randomized, Active-controlled Study in Chinese Patients.

PURPOSE: The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins") and the cholesterol-lowering medication ezetimibe are widely used in the treatment of patients with high- and very high-risk atherosclerotic cardiovascular disease. This study compared the efficacy and tolerability of a fixed-dose combination (FDC) of ezetimibe/atorvastatin (EZ/AS) with those of escalating doses of atorvastatin monotherapy in Chinese patients with hypercholesterolemia uncontrolled with statin monotherapy. METHODS: This Phase III, 12-week, randomized, double-blind study included patients aged 18 to 80 years with hypercholesterolemia uncontrolled on atorvastatin 10 or 20 mg/d monotherapy. After a 5-week run-in period of treatment with atorvastatin 10 or 20 mg/d (cohorts A and B, respectively), or a bioequivalent dosage of another statin, patients were randomized in a 1:1 ratio within each cohort to receive EZ/AS 10/10 mg FDC (EZ10/AS10) or atorvastatin 20 mg (AS20), once daily (cohort A); or EZ/AS 10/20 mg FDC (EZ10/AS20) or atorvastatin 40 mg (AS40), once daily (cohort B). The primary end point was the percentage change from baseline in low-density lipoprotein cholesterol (LDL-C). Tolerability was also evaluated. FINDINGS: Of the 454 patients enrolled, 412 (90.7%) completed the study. The percentage change from baseline in LDL-C was statistically greater with EZ10/AS10 treatment (n = 88) compared with AS20 monotherapy (n = 89) (treatment difference, -19.5%; 95% CI, -26.7% to -12.3%; P < 0.001). The percentage change from baseline in LDL-C was statistically greater with EZ10/AS20 treatment (n = 137) compared with AS40 monotherapy (n = 140) (treatment difference, -15.9%; 95% CI, -21.0% to -10.7%; P < 0.001). The safety profile was comparable between the EZ/AS and atorvastatin groups in the two cohorts. IMPLICATIONS: The LDL-C level at week 12 was significantly improved with both FDCs compared with escalated doses of atorvastatin (20 or 40 mg/d) in these Chinese patients with hypercholesterolemia uncontrolled on atorvastatin 10 or 20 mg/d. Both FDCs were well tolerated, with no new tolerability-related findings. Chinadrugtrials.org.cn identifier: CTR20190172; ClinicalTrials.gov identifier: NCT03768427.

Efficacy and safety of hybutimibe in combination with atorvastatin for treatment of hypercholesteremia among patients with atherosclerotic cardiovascular disease risk equivalent: A multicenter, randomized, double-blinded phase III study.

Background: To evaluate the safety and efficacy of hybutimibe plus atorvastatin for lipid control in hypercholesterolemia patients with atherosclerotic cardiovascular disease risk equivalent. Methods: In this double-blind phase III study, we 1:1 randomly assigned 255 hypercholesterolemia patients with atherosclerotic cardiovascular disease to receive hybutimibe plus atorvastatin or placebo plus atorvastatin. The primary endpoint was the rate of change of plasma low-density lipoprotein-cholesterol (LDL-C) level at 12 weeks from baseline. The secondary endpoints were plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), non-HDL-C, apoprotein (Apo) B, and 2-, 4-, 8-, and 12-week Apo A1 levels change rate and rates of change of plasma LDL-C levels at 2, 4, and 8 weeks from baseline. Results: From April 2016 to January 2018, 128 in the hybutimibe plus atorvastatin group and 125 in the atorvastatin group were included in modified intention-to-treat (mITT) analysis. After 12 weeks of treatment, LDL-C level changed from 2.61 mmol/L (±0.30) at baseline to 2.18 mmol/L (±0.45) in the hybutimibe plus atorvastatin group and from 2.58 (±0.31) mmol/L to 2.40 (± 0.46) mmol/L in the atorvastatin group (P < 0.0001), in mITT. The change rate in the hybutimibe plus atorvastatin group was significantly higher than that in the atorvastatin group (P < 0.0001); the estimated mean rates of change were -16.39 (95% confidence interval: -19.04, -13.74) and -6.75 (-9.48, -4.02), respectively. Consistently, in per-protocol set (PPS) analysis, the rate of change of LDL-C in the hybutimibe plus atorvastatin group was significantly higher than that in atorvastatin group. Significant decreases in the change rates of non-HDL-C, TC, and Apo B at 2, 4, 8, and 12 weeks (all P < 0.05) were observed for hybutimibe plus atorvastatin, while the differences were not significant for HDL-C, TG, and Apo-A1 (all P > 0.05). During the study period, no additional side effects were reported. Conclusions: Hybutimibe combined with atorvastatin resulted in significant improvements in LDL-C, non-HDL-C, TC, and Apo B compared with atorvastatin alone. The safety and tolerability were also acceptable, although additional benefits of hybutimibe plus atorvastatin were not observed compared with atorvastatin alone in HDL-C, TG, and Apo-A1.

Functional and expression analysis reveals the involvement of integrin αvß3 in antiviral immunity of grass carp (Ctenopharyngodon idella).

Integrins are α-ß heterodimeric cell receptors that can bind the protein components of pathogens, and play crucial roles in mammalian immune responses, but the immune functions mediated by integrins remains largely unknown in teleost fish. In this study, an integrin αvß3 (GCαvß3) originally assembled by αv (GCαv) and ß3 (GCß3) subunits, was identified from a teleost fish grass carp Ctenopharyngodon idella. The pairwise alignment analyses showed that the amino acid sequences of GCαv and GCß3 shared high similarity (75.2-95.1%) and identity (58.6-90.7%) with their homologs from other vertebrates. Both GCαv and GCß3 harbored the conserved protein domains and motifs, and were clustered in fish branch of the phylogenetic tree containing the counterparts from various vertebrates. Co-immunoprecipitation displayed that GCß3 could interact with the grass carp reovirus (GCRV) outer capsid protein VP5. Two incubation experiments revealed that the interaction of GCRV or VP5 proteins with GCß3 could induce the expressions of type I interferons (IFNs) including IFN2 and IFN3 in grass carp ovary cell line. The functional analysis demonstrated that GCαvß3 served as a receptor of viral protein components to be involved in antiviral immunity as human integrin αvß3 did. In addition, both GCαv and GCß3 were significantly upregulated in various tissues of grass carp after GCRV infection. This study might provide fundamental basis for understanding the molecular characteristics and immune functions of GCαvß3, and offer a new insight into the antiviral immune mechanism specific to the integrins in grass carp.

Mortality and Clinical Predictors After Percutaneous Mitral Valve Repair for Secondary Mitral Regurgitation: A Systematic Review and Meta-Regression Analysis.

Background: Percutaneous mitral valve repair (PMVR) provides an available choice for patients suffering from secondary mitral regurgitation (SMR), especially those whose symptoms persist after optimal, conventional, heart-failure therapy. However, conflicting results from clinical trials have created a problem in identifying patients who will benefit the most from PMVR. Objective: To pool mortality data and assess clinical predictors after PMVR among patients with SMR. To this end, subgroup and meta-regression analyses were additionally performed. Methods: We searched PubMed, EMBASE, and Cochrane databases, and 13 studies were finally included for meta-analysis. Estimated mortality and 95% confidence intervals (CIs) were obtained using a random-effects proportional meta-analysis. We also carried out a meta-regression analysis to clarify the potential influence of important covariates on mortality. Results: A total of 1,259 patients with SMR who had undergone PMVR were enrolled in our meta-analysis. The long-term estimated pooled mortality of PMVR was 19.3% (95% CI: 13.6-25.1). Meta-regression analysis showed that mortality was directly proportional to cardiac resynchronization therapy (CRT) (ß = 0.009; 95% CI: 0.002-0.016; p = 0.009), an effective regurgitant orifice (ERO) (ß = 0.009; 95% CI: 0.000-0.018; p = 0.047), and a mineralocorticoid receptor antagonist (MRA) use (ß = -0.015; 95% CI: -0.023--0.006; p < 0.001). Subgroup analysis indicated that patients with preexisting AF (ß = -0.002; 95% CI: -0.005- -0.000; p = 0.018) were associated with decreased mortality if they received a mitral annuloplasty device. Among the edge-to-edge repair device group, a higher left ventricular (LV) ejection fraction, or lower LV end-systolic diameter, LV end-systolic volume, and LV end-diastolic volume were proportional to lower mortality. Conclusion and Relevance: The pooled mortality of PMVR was 19.3% (95% CI: 13.6-25.1). Further meta-regression indicated that AF was associated with a better outcome in conjunction with the use of a mitral annuloplasty device, while better LV functioning predicted a better outcome after the implantation of an edge-to-edge repair device.

Transcriptomics analysis provides new insights into the fish antiviral mechanism and identification of interferon-stimulated genes in grass carp (Ctenopharyngodon idella).

Grass carp is an economically important freshwater fish in China, and haemorrhagic disease caused by GCRV has seriously restricted its farming scale. To understand the host molecular basis for antiviral defence and explore the effector molecules, a global transcriptional profiling of four major immune tissues (liver, spleen, head kidney, and trunk kidney) of GCRV-infected grass carp was established. A total of 192.65 Gb clean data was obtained with 6.11 Gb per sample and stored in the NCBI Sequence Read Archive (with accession number PRJNA759556). Based on the GO and KEEG analyses, 108 unique GO terms were enriched in the four tissues. Thirty-five enriched pathways were obtained, with 21 metabolism-related pathways mainly gained in the liver and trunk kidney, and 14 immune response pathways were enriched in the spleen and head kidney. Also demonstrated was that GCRV stimulates not only the expression of interferon-stimulated genes (ISGs) but also proinflammatory cytokines. 27 ISGs were screened from the candidate DEGs, and eight ISGs were identified for the first time in grass crap. These ISGs were classified into three categories by their function found in mammals: (i) positively regulates the IFN signalling pathway (RIG-I, MDA5, IRF7, IRF9, STAT2, and TRIM25); (ii) negatively regulates the IFN signalling pathway (usp18 and SOCS1); and (iii) exerts direct antiviral activity such as Mx1, ISG15, ISG56, ISG58, viperin, and PKR. Eight major ISGs and four typical differentially inflammatory cytokines were used for further expression analysis with prominent expression in the liver, spleen and kidney. The onset time of IFN-mediated antiviral response was trunk kidney (12-24 h) > liver (48 h) > spleen (96-120 h), and the intensity was liver > spleen > trunk kidney. Notably, the inflammatory reaction occurs early in the liver and trunk kidney. This result implies that ISGs may act synergistically and that the IFN response is closely related to the inflammatory response against GCRV infection. The transcriptomic profiles obtained and the function of ISGs predicted in this study provide new insights into fish antiviral mechanisms and developing effective therapeutic directions.

Deciphering mechanism of the herbal formula WuShen in the treatment of postinfarction heart failure.

BACKGROUND: Numerous clinical studies reported the effectiveness of herbal formula WuShen (WS) in treating cardiovascular diseases, yet relevant basic research was rarely conducted. METHODS AND RESULTS: Twelve main bioactive compounds of WS decoction were identified using the ultra-performance liquid chromatography-LTQ-Orbitrap mass spectrometer. A total of 137 active compounds with 613 targets were predicted by network pharmacology; their bioinformatic annotation and human microarray data suggested that wounding healing, inflammatory response, and gap junction were potentially the major therapeutic modules. A rat model of post-myocardial infarction (MI) heart failure (HF) was used to study the effects of WS on cardiac function, adverse cardiac remodeling, and experimental arrhythmias. Rats treated with WS led to a significantly improved pump function and reduced susceptibility to both ventricular tachycardia and atrial fibrillation, and restricted adverse cardiac remodeling partly via inhibiting TGFß1/SMADs mediated extracellular matrix deposition and Rac1/NOX2/CTGF/Connexin43 -involved gap junction remodeling. CONCLUSIONS: The present study highlights that WS can be applied to the treatment of heart failure and the upstream therapy for atrial fibrillation and ventricular tachycardia through its preventive effect on adverse cardiac remodeling.