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Bovine herpes virus 1 (BoHV-1) causes a wide variety of diseases in wild and domestic cattle. The most widely used method for viral identification is real-time PCR, which can only be performed in laboratories using sophisticated instruments by expert personnel. Herein, we developed an ultrasensitive time-resolved fluorescence lateral flow immunochromatographic strip (ICS) assay for detecting BoHV-1 in bovine samples using a monoclonal antibody against BoHV-1 labelled with fluorescent microspheres, which can be applied in any setting. The intact process from sample collection to final result can be achieved in 15 min. The limit of detection of the assay for BoHV-1 was 102 TCID50/100 μL. The coincidence rate of the ICS method and real-time PCR recommended by the World Organization for Animal Health (WOAH) was 100% for negative, 92.30% for positive, and 95.42% for total, as evaluated by the detection of 131 clinical samples. This detection method was specifically targeted to BoHV-1, not exhibiting cross-reactivity with other bovine pathogens including BoHV-5. We developed an ICS assay equipped with a portable instrument that offers a sensitive and specific platform for the rapid and reliable detection of BoHV-1 in the field. The Point-of-Care test of BoHV-1 is suitable for the screening and surveillance of BoHV-1 in dairy herds.

ABSTRACTRuminal microbiota is gradually established after birth, while microbiota maturation could be highly diverse because of varied solid dietary accessibility. However, how the ruminal microbiota accreted from postnatal hay diets alters rumen epithelial development, and how this affects animal health remains largely unknown. Here, neonatal lambs were introduced to starchy corn-soybean starter or corn-soybean starter + alfalfa hay (AH) to investigate the influences of early life ruminal microbiome on rumen epithelial development using integrated 16s rRNA sequencing-metagenome-transcriptome approaches. The results showed that AH introduction elevated average daily weight gain, rumen weight and volume, rumen epithelial papillae length, and rumen muscle layer thickness. Meanwhile, the relative abundance of fibrolytic bacteria (Christensenellaceae R-7 group, Prevotellaceae UCG-001, and Succinivibrio), acetate producer (Acetitomaculum and Mitsuokella), and propionate producer Succiniclasticum was increased in the rumen content by AH supplementation (P < 0.05). Moreover, AH introduction decreased the relative abundance of total CAZymes, CBM, and GH and increased the abundance of KO genes related to volatile fatty acid (VFA) generation in the rumen content. AH lambs had a higher relative abundance of Succiniclasticum, Megasphaera, Succinivibrio, and Suttonella (P < 0.05), while a lower relative abundance of Cloacibacillus, Desulfovibrio, Dialister, Intestinimonas, Parabacteroides, and Pseudoscardovia (P < 0.05) in the rumen epithelial samples. Furthermore, these alterations in ruminal microbial structure and function resulted in ruminal epithelial cell proliferation and development pathways activation. In summary, AH introduction benefited ruminal fiber degradation and VFA generation bacteria colonization and promoted ruminal epithelial development. These findings provide new insights into ruminal microbial–host interactions in the early life.IMPORTANCEWhile it is established that a fiber-rich diet promotes rumen development in lambs, further research is needed to investigate the precise response of rumen microbiota and epithelium to high-quality alfalfa hay. Here, we observed that the inclusion of alfalfa hay led to a discernible alteration in the developmental trajectory of the rumen. Notably, there was a favorable shift in the rumen's volume, morphology, and the development of rumen papillae. Furthermore, ruminal microbial structure and function resulted in ruminal epithelial cell proliferation and development pathways activation, collectively provide compelling evidence supporting the capacity of alfalfa hay to enhance rumen development and health through ruminal micrbiota-host crosstalks. Our findings elucidate the functional response of the rumen to alfalfa hay introduction, providing new insights into strategies for promoting healthy development of the rumen in young ruminants.

Abstract Background Modern dairy diets have shifted from being forage-based to grain and energy dense. However, feeding high-starch diets can lead to a metabolic disturbance that is linked to dysregulation of the gastrointestinal microbiome and systemic inflammatory response. Plant flavonoids have recently attracted extensive interest due to their anti-inflammatory effects in humans and ruminants. Here, multi-omics analysis was conducted to characterize the biological function and mechanisms of citrus flavonoids in modulating the hindgut microbiome of dairy cows fed a high-starch diet. Results Citrus flavonoid extract (CFE) significantly lowered serum concentrations of lipopolysaccharide (LPS) proinflammatory cytokines (TNF-α and IL-6), acute phase proteins (LPS-binding protein and haptoglobin) in dairy cows fed a high-starch diet. Dietary CFE supplementation increased fecal butyrate production and decreased fecal LPS. In addition, dietary CFE influenced the overall hindgut microbiota’s structure and composition. Notably, potentially beneficial bacteria, including Bacteroides, Bifidobacterium, Alistipes, and Akkermansia, were enriched in CFE and were found to be positively correlated with fecal metabolites and host metabolites. Fecal and serum untargeted metabolomics indicated that CFE supplementation mainly emphasized the metabolic feature “sphingolipid metabolism.” Metabolites associated with the sphingolipid metabolism pathway were positively associated with increased microorganisms in dairy cows fed CFE, particularly Bacteroides. Serum lipidomics analysis showed that the total contents of ceramide and sphingomyelin were decreased by CFE addition. Some differentially abundant sphingolipid species were markedly associated with serum IL-6, TNF-α, LPS, and fecal Bacteroides. Metaproteomics revealed that dietary supplementation with CFE strongly impacted the overall fecal bacterial protein profile and function. In CFE cows, enzymes involved in carbon metabolism, sphingolipid metabolism, and valine, leucine, and isoleucine biosynthesis were upregulated. Conclusions Our research indicates the importance of bacterial sphingolipids in maintaining hindgut symbiosis and homeostasis. Dietary supplementation with CFE can decrease systemic inflammation by maintaining hindgut microbiota homeostasis and regulating sphingolipid metabolism in dairy cows fed a high-starch diet. Video Abstract

The objectives of this study were to determine the effects of dietary supplementation with citrus flavonoid extracts (CFE) on milk performance, serum biochemistry parameters, fecal volatile fatty acids, fecal microbial community, and fecal metabolites in dairy cows. Eight multiparous lactating Holstein cows were used in a replicated 4 × 4 Latin square design (21-day period). Cows were fed a basal diet without addition (CON) or basal diet with added CFE at 50 (CFE50), 100 (CFE10), and 150 g/d (CFE150). Feeding CFE up to 150 g/d increased milk yield and milk lactose percentage. Supplementary CFE linearly decreased milk somatic cell count. Serum cytokines interleukin-1β (IL-1β), IL-2, IL-6, and tumor necrosis factor-α (TNF-α) concentrations decreased linearly as the levels of CFE increased. Cows in CFE150 had lower serum lipopolysaccharide and lipopolysaccharide binding protein compared with CON. These results indicate feeding CFE decreased systemic inflammation and endotoxin levels in dairy cows. Furthermore, feeding CFE linearly increased the concentrations of total volatile fatty acids, acetate, and butyrate in feces. The relative abundances of beneficial bacteria Bifidobacterium spp., Clostridium coccoides-Eubacterium rectale group, and Faecalibacterium prausnitzii in feces increased linearly with increasing CFE supplementation. The diversity and community structure of fecal microbiota were unaffected by CFE supplementation. However, supplementing CFE reduced the relative abundances of genera Ruminococcus_torques_group, Roseburia, and Lachnospira, but increased genera Bacteroides and Phascolarctobacterium. Metabolomics analysis showed that supplementary CFE resulted in a significant modification in the fecal metabolites profile. Compared with CON, fecal naringenin, hesperetin, hippuric acid, and sphingosine concentrations were greater in CFE150 cows, while fecal GlcCer(d18:1/20:0), Cer(d18:0/24:0), Cer(d18:0/22:0), sphinganine, and deoxycholic acid concentrations were less in CFE150 cows. Predicted pathway analysis suggested that ''sphingolipid metabolism'' was significantly enriched. Overall, these results indicate that citrus flavonoids could exert health-promoting effects by modulating hindgut microbiome and metabolism in lactating cows.

Background: Aortic dissection (AD) is a critical emergency in cardiovascular disease. AD occurs only in specific sites of the aorta, and the variation of shear stress in different aortic segments is a possible cause not reported. This study investigated the key molecules involved in shear stress-induced AD through quantitative bioinformatic analysis of a public RNA sequencing database and clinical tissue sample validation. Methods: Gene expression data from the GSE153434, GSE147026, and GSE52093 datasets were downloaded from the Gene Expression Omnibus. Next, differently expressed genes (DEGs) in each dataset were identified and integrated to identify common AD DEGs. STRING, Cytoscape, and MCODE were used to identify hub genes and crucial clustering modules, and Connectivity Map (CMap) was used to identify positive and negative agents. The same procedure was performed for the GSE160611 dataset to obtain shear stress-induced human aortic endothelial cell (HAEC) DEGs. After the integration of these two DEGs sets to identify shear stress-associated hub DEGs in AD, Gene Ontology Enrichment Analysis was performed. The common chemokine receptors and ligands in AD were identified by analyzing AD's three RNA sequencing datasets. Their origin was verified by analyzing AD single-cell sequencing data and validated by immunoblotting and immunofluorescence. Results: We identified 100 down-regulated and 50 up-regulated AD common DEGs. Enrichment results showed that common DEGs were closely related to blood vessel morphogenesis, muscle structure development, muscle tissue development, and chemotaxis. Among those DEGs, MYC, CCL2, and SPP1 are the three molecules with the highest degree. A crucial cluster of 15 genes was identified using MCODE, which contained inflammation-related genes with elevated expression and muscle cell-related genes with decreased expression, and CCL2 is central to immune-related genes. CMap confirmed MEK inhibitors and ALK inhibitors as possible therapeutic agents for AD. Moreover, 366 shear stress-associated DEGs in HAEC were identified in the GSE160611 dataset. After taking the intersection, we identified five shear stress-associated hub DEGs in AD (ANGPTL4, SNAI2, CCL2, GADD45B, and PROM1), and the enrichment analysis indicated they were related to the endothelial cell apoptotic process. Chemokine CCL2 was the molecule with a high degree in both DEG sets. Besides CCL2, CXCL5 was the only chemokine ligand differentially expressed in the three datasets. Additionally, immunoblotting confirmed the increased expression of CCL2 and CXCL5 in clinical tissue samples. Further research at the single-cell level revealed that CCL2 has multiple origins, and CXCL5 is macrophage-derived. Conclusion: Through integrative analysis, we identified core common AD DEGs and possible therapeutic agents based on these DEGs. We elucidated that the chemokine CCL2 and CXCL5-mediated “Endothelial-Monocyte-Neutrophil” axis may contribute to the development of shear stress-induced AD. These findings provide possible therapeutic targets for the prevention and treatment of AD.

Ruminant animals face multiple challenges during the rearing process, including immune disorders and oxidative stress. Green tea by-products have gained widespread attention for their significant immunomodulatory and antioxidant effects, leading to their application in livestock production. In this study, we investigated the effects of Dried Tea Residue (DTR) as a feed additive on the growth performance, blood biochemical indicators, and hindgut microbial structure and function of Hu sheep. Sixteen Hu sheep were randomly divided into two groups and fed with 0 and 100 g/d of DTR, respectively. Data were recorded over a 56-day feeding period. Compared to the control group, there were no significant changes in the production performance of Hu sheep fed with DTR. However, the sheep fed with DTR showed a significant increase in IgA (p

Citrus flavonoid extracts (CFE) have the potential to reduce rumen inflammation, improve ruminal function, and enhance production performance in ruminants. Our previous studies have investigated the effects of CFE on the structure and function of rumen microbiota in dairy cows. However, it remains unclear whether CFE affects the prevalence of antibiotic resistance genes (ARG) and virulence factors genes (VFG) in the rumen. Therefore, metagenomics was used to identify the rumen ARG and VFG in lactating dairy cows fed with CFE diets. The results showed that CFE significantly reduced the levels of Multidrug and Antiphagocytosis in the rumen (p

While solar-to-fuel conversion offers a renewable energy production strategy, photoelectrochemical water splitting requires further optimization. Here, authors examined nitrogen-doped NiFeOx catalysts to improve the oxygen evolution activity and stability of BiVO4 photoanodes.

Cardiac dysfunction caused by sepsis is the predominant reason for death in patients with sepsis. However, the effective drugs for its prevention and the molecular mechanisms remain elusive. 1-Deoxynojirimycin (DNJ), a natural iminopyranose, exhibits various biological properties, such as hypoglycemic, antitumor, antiviral, and anti-inflammatory activities. However, whether DNJ can mediate biological activity resistance in sepsis-induced myocardial injury and the underlying mechanisms are unclear. Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling is an important pathway for the signal transduction of several key cytokines in the pathogenesis of sepsis, which can transcribe and modulate the host immune response. This study was conducted to confirm whether DNJ mediates oxidative stress, apoptosis, and inflammation in cardiomyocytes, thereby alleviating myocardial injury in sepsis via the JAK2/STAT6 signaling pathway. Septic cardiomyopathy was induced in mice using lipopolysaccharide (LPS), and they were then treated with DNJ. The results showed that DNJ markedly improved sepsis-induced cardiac dysfunction, attenuated reactive oxygen species generation, reduced cardiomyocyte apoptosis, and mitigated inflammation. Mechanistically, increased JAK2/STAT6 phosphorylation was observed in the mouse sepsis models, which decreased significantly after DNJ oral treatment. To further confirm whether DNJ mediates the JAK2/STAT6 pathway, the selective inhibitor fedratinib was used to block the JAK2 signaling pathway in vitro, which enhanced the protective effects of DNJ against the sepsis-induced cardiac damage. Collectively, these findings suggest that DNJ attenuates sepsis-induced myocardial injury by decreasing myocardial oxidative damage, apoptosis, and inflammation via the regulation of the JAK2/STAT6 signaling pathway.

Nutricines, the nutritionally active substances in feed, play a vital role in enhancing immune function, antioxidant activity, and feed efficiency in dairy cows. Identifying nutricines in total mixed ration (TMR) provides insights into feed quality and their impact on dairy cow health. However, due to the structural diversity of nutricines, data mining using multivariate variable models faces challenges in exploring their relationships. To address this, this study established a hierarchical clustering and optimization factor strategy for 13 common flavonoid peaks detected using apparent data and HPLC-DAD. The establishment of the flavonoid fingerprint of TMR diet in dairy cows detected 13 common peaks, five of which were found using standard products: p-coumaric acid, sinapic acid, tricin, and diosmetin. In vitro fermentation results using different TMR samples in substrate fermentation indicated that the dry matter disappearance rate, NH3-N, acetate, propionate, butyrate, isovalerate, and valerate changes varied significantly (p < 0.05). In spectrum–activity relationship studies, P2, P6, P8, P9, P10, and P11 were all considered possible factors causing this effect. In the analysis of optimization factor strategy, the peak spectrum model of four fermentation parameters, i.e., pH, dry matter digestibility, NH3-N, and acetate, was constructed after optimization (p < 0.05), and the data model is listed in the main text. In structure–activity relationship studies, ferulic acid, isoferulic acid, methyl sinapic acid, methyl 4-hydroxycinnamate, and p-hydroxybenzalacetone may serve as candidate references for compound 10 and may play an important role in affecting the digestibility of dry matter in in vitro fermentation. These findings highlight the role of flavonoids in TMR feed as key factors in maintaining dairy cow health and differentiating nutritional value. This study proposes a novel method for future TMR diet formulation and quality evaluation, with potential implications for improving dairy cow health and performance. Further research is needed to validate these findings and elucidate the mechanisms underlying nutricine effects on dairy cow nutrition and health.

Dendrobium officinale polysaccharide (DOP), which serves as a prebiotic, exhibits a variety of biological activities, including hypoglycemic activities. However, the effects of DOP on diabetes prevention and its hypoglycemic mechanisms are still unclear. In this study, the effects of DOP treatment on the prediabetic mice model were studied and the mechanism was investigated. The results showed that 200 mg/kg/d of DOP reduced the relative risk of type 2 diabetes mellitus (T2DM) from prediabetes by 63.7%. Meanwhile, DOP decreased the level of LPS and inhibited the expression of TLR4 by regulating the composition of the gut microbiota, consequently relieving the inflammation and alleviating insulin resistance. In addition, DOP increased the abundance of SCFA (short chain fatty acid)-producing bacteria in the intestine, increased the levels of intestinal SCFAs, promoted the expression of short-chain fatty acid receptors FFAR2/FFAR3, and increased the secretion of the intestinal hormones GLP-1 and PYY, which helped to repair islet damage, suppress appetite, and improve insulin resistance. Our results suggested that DOP is a promising functional food supplement for the prevention of T2DM.

BackgroundThe Ankura II Thoracic Stent Graft System (Lifetech, Shenzhen, China) is an evolution of the Ankura stent graft. This study reports one-year outcomes of the Ankura II Thoracic Stent Graft System for endovascular treatment of Stanford type B aortic dissections.MethodsThe Ankura II Thoracic Aortic Endovascular Trial was a randomized, single-blinded, clinical trial conducted at 12 Chinese institutes. The enrolled patients diagnosed with Stanford type B aortic dissections (TBADs) were randomly assigned to the Ankura group or Ankura II group. Standard follow-up examinations were performed at 1, 6, and 12 months. Safety and efficacy data were analyzed.Results132 patients with TBADs were enrolled. The outcomes for the primary safety end points revealed that the Ankura II stent graft was statistically non-inferior compared to the Ankura stent graft. The 1-month device-related major adverse events (1.6 vs. 0%; p = 0.48), 1-month all-cause mortality (1.7 vs. 4.5%; p = 0.621), 12-month survival rate (95.2 ± 2.7% vs. 94.1 ± 2.9%; p = 0.769), and major adverse event (MAE) rate (5.1 vs. 4.7% at 1 month; p = 0.73 and 5.8 vs. 8.9% at 12 months; p = 0.718) of Ankura II group are all comparable to Ankura group. The two groups showed similar primary effectiveness and true lumen expansion effect, and false lumen remodeling was improved in Ankura II group (−100.0 vs. −48.5%; p = 0.08).ConclusionsThe one-year outcomes from this prospective, randomized, multicenter study demonstrate that Ankura II stent graft shows comparable results to Ankura for treating TBADs, resulting in low mortality rates, MAEs and reintervention rates.Clinical Trial RegistrationChiCTR-TRC-12002844.

BackgroundThe correlation between rhabdomyolysis and postoperative acute kidney injury has been reported in several surgical procedures. As a good predictor of rhabdomyolysis-related acute kidney injury, an elevated serum myoglobin level was often observed after total aortic arch replacement combined with frozen elephant trunk implantation. However, the correlation between serum myoglobin and acute kidney injury in such patients had not been established.MethodsTotally 398 stanford type A aortic dissection patients who underwent total aortic arch replacement combined with frozen elephant trunk implantation were enrolled in this retrospective study. The correlations between serum myoglobin and acute kidney injury as well as the 30-day mortality were assessed.ResultsOverall, 268(67.3%) patients had acute kidney injury (KDIGO stage 1 or higher) and 75(18.8%) had severe acute kidney injury (KDIGO stage 2&3). Patients who developed acute kidney injury had higher level of perioperative serum myoglobin than patients without acute kidney injury. After adjusting for known acute kidney injury risk factors, logarithmically transformed preoperative serum myoglobin [OR = 1.58 (95% CI, 1.26–1.95), P < 0.001] and postoperative day 1 serum myoglobin [OR = 3.47 (95%CI, 2.27–5.29), P < 0.001] were associated with severe acute kidney injury. These correlation persisted after adjustment for decline in filtration via change in serum creatinine (ΔCr) and biomarkers of cardiac and kidney injury, including N-terminal prohormone of brain natriuretic peptide, cardiac troponin I, creatine kinase-MB, serum creatinine and Cystatin C. Compared with the clinical model, sMb considerably improved the risk discrimination and reclassification for AKI.ConclusionFor stanford type A aortic dissection patients underwent total aortic arch replacement with frozen elephant trunk implantation, serum myoglobin can improve postoperative acute kidney injury risk classification. Rhabdomyolysis may be an important supplement to the existing knowledge on the mechanism of acute kidney injury.

The effects of dietary supplementation with citrus peel extract (CPE) on milk biochemical parameters, milk bacterial community, and milk metabolites were evaluated. Eight lactating cows were allocated to a replicated 4 × 4 Latin square. Experimental treatments included the control diet (CON), and CON supplemented with CPE at 50 g/d (CPE50), 100 g/d (CPE100), and 150 g/d (CPE150). Supplementing with CPE linearly decreased milk interleukin-6 and malondialdehyde concentrations and linearly increased lysozyme activity and 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity. Compared with CON, the milk of CPE150 cows had fewer abundances of several opportunistic pathogens and psychrotrophic bacteria, such as Escherichia-Shigella, Sphingobacterium, Alcaligenes, Stenotrophomonas, and Ochrobactrum. Supplementing with CPE significantly altered the metabolic profiling in the milk. The metabolites of flavonoids were enriched in the milk of cows fed CPE150, while some proinflammation compounds were decreased compared with CON. Correlation analysis showed that the change in the bacterial community might partly contribute to the alteration in the expression of milk cytokines. In conclusion, CPE exerts health-promoting effects (e.g., antioxidant, anti-microbial, and anti-inflammatory) in the mammary metabolism of cows due to its flavonoid compounds, which also provide additional value in terms of milk quality improvement.

Metabolic syndrome (MS) is a metabolic disease with multiple complications. Mulberry leaf extract (MLE) is rich in flavonoids and has great potential in alleviating glucose and lipid metabolism disorders. This study evaluated the effect and mechanism of MLE on the alleviation of MS. The components of the MLE were analyzed, and then the regulation of lipid metabolism by MLE in vitro and in vivo was determined. In a hepatocyte model of oleic acid-induced lipid accumulation, it was found that MLE alleviated lipid accumulation and decreased the expression of genes involved in lipogenesis. Furthermore, MLE improved obesity, insulin resistance, plasma lipid profile, and liver function in MS mice after a 15-week intervention. MLE decreased the expression of SREBP1, ACC, and FAS through the AMPK signaling pathway to inhibit lipid synthesis and increase the level of CPT1A to promote lipid decomposition to achieve its hypolipidemic effect. Meanwhile, MLE was also shown to affect the composition of the gut microbiota and the production of short-chain fatty acids, which contributed to the alleviation of lipid accumulation. Our results suggest that MLE can improve MS by improving lipid metabolism through multiple mechanisms and can be developed into dietary supplements for the improvement of MS.

Disruption of the blood–brain barrier (BBB) has been considered as a major pathological change in stroke. eNOS/NO play a key role in maintain BBB function. Myricetin is one of the common flavones widely exists in food and fruit, show certain protective effect on the brain function. This experiment establishes oxygeneglucose deprivation and reoxygenation (OGD/R) brain cell model. The regulated effects of Myricetin on BBB function, eNOS/NO and eNOS uncoupling were evaluated. To investigate the molecular mechanism, Akt and Nrf2 inhibitor were also used. The result showed that Myricetin could significantly decreased the enhancement of endothelial permeability and inflammation in OGD/R model, in addition regulated eNOS/NO pathway. The regulate effect in endothelial permeability and eNOS activity by Myricetin were both decreased when combined with Akt inhibitor or Nrf2 inhibitor, and was abrogated when combined with Akt and Nrf2 inhibitor simultaneously. The regulated effect on eNOS uncoupling by Myricetin were abrogated when combined with Nrf2 inhibitor, but not with Akt inhibitor. In conclusion, Myricetin showed significant protect effect on ischemia/reperfusion-induced brain endothelial permeability, and related to simultaneously regulated Akt pathway and improvement of eNOS uncoupling through Nrf2 pathway. Keywords: Ischemia/reperfusion injury, eNOS/NO, eNOS uncoupling, Myricetin

Background Laboratory studies demonstrate glucose‐insulin‐potassium (GIK) as a potent cardioprotective intervention, but clinical trials have yielded mixed results, likely because of varying formulas and timing of GIK treatment and different clinical settings. This study sought to evaluate the effects of modified GIK regimen given perioperatively with an insulin‐glucose ratio of 1:3 in patients undergoing cardiopulmonary bypass surgery. Methods and Results In this prospective, randomized, double‐blinded trial with 930 patients referred for cardiac surgery with cardiopulmonary bypass, GIK (200 g/L glucose, 66.7 U/L insulin, and 80 mmol/L KCl) or placebo treatment was administered intravenously at 1 mL/kg per hour 10 minutes before anesthesia and continuously for 12.5 hours. The primary outcome was the incidence of in‐hospital major adverse cardiac events including all‐cause death, low cardiac output syndrome, acute myocardial infarction, cardiac arrest with successful resuscitation, congestive heart failure, and arrhythmia. GIK therapy reduced the incidence of major adverse cardiac events and enhanced cardiac function recovery without increasing perioperative blood glucose compared with the control group. Mechanistically, this treatment resulted in increased glucose uptake and less lactate excretion calculated by the differences between arterial and coronary sinus, and increased phosphorylation of insulin receptor substrate‐1 and protein kinase B in the hearts of GIK‐treated patients. Systemic blood lactate was also reduced in GIK‐treated patients during cardiopulmonary bypass surgery. Conclusions A modified GIK regimen administered perioperatively reduces the incidence of in‐hospital major adverse cardiac events in patients undergoing cardiopulmonary bypass surgery. These benefits are likely a result of enhanced systemic tissue perfusion and improved myocardial metabolism via activation of insulin signaling by GIK. Clinical Trial Registration URL: clinicaltrials.gov. Identifier: NCT01516138.

It is a consensus that the hydrogen economy has come to a standstill due to the lack of feasible hydrogen storage solutions, especially, the suitable hydrogen storage materials. In this work, the potential of a new kind of two-dimensional (2D) AXenes, Na _2 N and K _2 N, as hydrogen storage materials are evaluated by the first-principles calculations. In particular, we find that Na _2 N in T phase indicates a hydrogen storage capacity as high as 6.25 wt% with a desirable hydrogen adsorption energy of –0.167 eV per H _2 molecule and a desorption temperature of 216 K, identifying T-phase Na _2 N to be a very promising reversible hydrogen storage material. In accordance to our results, H _2 –Na _2 N interaction causes H _2 charge polarization, which is responsible for the moderate binding strength. In addition, Gibbs adsorption free energy reveals that the system will be more stable as more H _2 molecules are loaded on the surface.

Congenital heart disease (CHD) is the most common form of congenital human birth anomalies and a leading cause of perinatal and infant mortality. Some studies including our published genome-wide association study (GWAS) of CHD have indicated that genetic variants may contribute to the risk of CHD. Recently, Cordell et al. published a GWAS of multiple CHD phenotypes in European Caucasians and identified 3 susceptibility loci (rs870142, rs16835979 and rs6824295) for ostium secundum atrial septal defect (ASD) at chromosome 4p16. However, whether these loci at 4p16 confer the predisposition to CHD in Chinese population is unclear. In the current study, we first analyzed the associations between these 3 single nucleotide polymorphisms (SNPs) at 4p16 and CHD risk by using our existing genome-wide scan data and found all of the 3 SNPs showed significant associations with ASD in the same direction as that observed in Cordell's study, but not with other subtypes- ventricular septal defect (VSD) and ASD combined VSD. As these 3 SNPs were in high linkage disequilibrium (LD) in Chinese population, we selected one SNP with the lowest P value in our GWAS scan (rs16835979) to perform a replication study with additional 1,709 CHD cases with multiple phenotypes and 1,962 controls. The significant association was also observed only within the ASD subgroup, which was heterogeneous from other disease groups. In combined GWAS and replication samples, the minor allele of rs16835979 remained significant association with the risk of ASD (OR = 1.22, 95% CI = 1.08-1.38, P = 0.001). Our findings suggest that susceptibility loci of ASD identified from Cordell's European GWAS are generalizable to Chinese population, and such investigation may provide new insights into the roles of genetic variants in the etiology of different CHD phenotypes.

In this study, we evaluated the effect of astragaloside IV (Ast IV) post-ischemia treatment on myocardial ischemia-reperfusion (IR) injury (IRI). We also examined whether hypoxia inducible factor-1α (HIF-1α) and its downstream gene-inducible nitric oxide (NO) synthase (iNOS) play roles in the cardioprotective effect of Ast IV. Cultured cardiomyocytes and perfused isolated rat hearts were exposed to Ast IV during reperfusion in the presence or absence of the HIF-1α inhibitor 2-methoxyestradiol (2-MeOE2). The post-ischemia treatment with Ast IV protected cardiomyocytes from the apoptosis and death induced by simulated IRI (SIRI). Additionally, in cardiomyocytes, 2-MeOE2 and HIF-1α siRNA treatment each not only abolished the anti-apoptotic effect of post-ischemia treatment with Ast IV but also reversed the upregulation of HIF-1α and iNOS expression. Furthermore, after treatment with Ast IV, post-ischemic cardiac functional recovery and lactate dehydrogenase (LDH) release in the coronary flow (CF) were improved, and the myocardial infarct size was decreased. Moreover, the number of apoptotic cells was reduced, and the upregulation of the anti-apoptotic protein Bcl2 and downregulation of the pro-apoptotic protein Caspase3 were reversed. 2-MeOE2 reversed these effects of Ast IV on IR-injured hearts. These results suggest that post-ischemia treatment with Ast IV can attenuate IRI by upregulating HIF-1α expression, which transmits a survival signal to the myocardium.

Background. Insulin resistance and systemic inflammation frequently occur in infants undergoing cardiac surgery with cardiopulmonary bypass, while adiponectin has been demonstrated to have insulin-sensitizing and anti-inflammatory properties in obesity and type 2 diabetes mellitus. In this prospective study, we aimed to investigate the association of adiponectin with insulin resistance and inflammatory mediators in infants undergoing cardiac surgery with cardiopulmonary bypass. Methods and Results. From sixty infants undergoing open cardiac surgery, blood samples were taken before anesthesia, at the initiation of cardiopulmonary bypass and at 0, 6, 12, 24, and 48 hours after the termination of cardiopulmonary bypass. Plasma interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and adiponectin levels were assessed in blood samples. Insulin resistance was measured by assessment of the insulin requirement to maintain euglycaemia and repeated measurements of an insulin glycaemic index. Insulin glycaemic index, IL-6, and TNF-α increased up to 3–8-fold 6 h after the operation. Adiponectin is negatively correlated with markers of systemic inflammation 6 h after CPB. Conclusions. Although the level of serum adiponectin decreased significantly, there was a significant inverse association of adiponectin with markers of systemic inflammation and insulin resistance in infants undergoing open cardiac surgery.

BACKGROUND: Ghrelin has been reported to protect the cardiovascular system; however, the cardioprotective effect of ghrelin against cardiopulmonary bypass (CPB) induced myocardial injury are unclear. In this study, the protective effect of ghrelin on CPB induced myocardial injury and the underlying mechanisms were investigated. METHODS AND RESULTS: Adult male rats were subjected to CPB and randomly to receive vehicle (n = 8), ghrelin (n = 8), ghrelin plus [D-Lys3]-GHRP-6, a GHSR-1a inhibitor (n = 8), or ghrelin plus wortmannin, a phosphoinositide 3'-kinase (PI3K) inhibitor (n = 8). In vitro study was performed on cultured cardiomyocytes subjected to simulated cardiopulmonary bypass (SCPB). Ghrelin attenuated the inflammatory response, as evidenced by reduced induction of TNF-α, IL-6 and myocardial myeloperoxidase activity and concurrent reduction in apoptosis, oxidative stress, and levels of myocardial injury markers following CPB. Moreover, ghrelin significantly increased cardiac function after CPB. In cultured cardiomyocytes subjected to simulated CPB, ghrelin increased cell viability and decreased the percentage of apoptotic myocytes. Inhibition of ghrelin downstream signaling blocked the cardioprotective effects both in vivo and vitro. CONCLUSIONS: Ghrelin could provide an effective approach to the attenuation of CPB induced myocardial injury. The cardioprotective effects elicited by ghrelin may contribute to the inhibition of inflammatory response through the Akt-activated pathway.

Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.

Previous studies have shown that the JAK2/STAT3 signaling pathway plays a regulatory role in cellular oxidative stress injury (OSI). In this study, we explored the role of the JAK2/STAT3 signaling pathway in hydrogen peroxide (H2O2)-induced OSI and the protective effect of melatonin against (H2O2)-induced injury in human umbilical vein endothelial cells (HUVECs). AG490 (a specific inhibitor of the JAK2/STAT3 signaling pathway) and JAK2 siRNA were used to manipulate JAK2/STAT3 activity, and the results showed that AG490 and JAK2 siRNA inhibited OSI and the levels of p-JAK2 and p-STAT3. HUVECs were then subjected to H2O2 in the absence or presence of melatonin, the main secretory product of the pineal gland. Melatonin conferred a protective effect against H2O2, which was evidenced by improvements in cell viability, adhesive ability and migratory ability, decreases in the apoptotic index and reactive oxygen species (ROS) production and several biochemical parameters in HUVECs. Immunofluorescence and Western blotting showed that H2O2 treatment increased the levels of p-JAK2, p-STAT3, Cytochrome c, Bax and Caspase3 and decreased the levels of Bcl2, whereas melatonin treatment partially reversed these effects. We, for the first time, demonstrate that the inhibition of the JAK2/STAT3 signaling pathway results in a protective effect against endothelial OSI. The protective effects of melatonin against OSI, at least partially, depend upon JAK2/STAT3 inhibition.