CENPA promotes glutamine metabolism and tumor progression by up-regulating SLC38A1 in endometrial cancer.

Glutamine addiction is a significant hallmark of metabolic reprogramming in tumors and is crucial to the progression of cancer. Nevertheless, the regulatory mechanisms of glutamine metabolism in endometrial cancer (EC) remains elusive. In this research, we found that elevated expression of CENPA and solute carrier family 38 member 1 (SLC38A1) were firmly associated with worse clinical stage and unfavorable outcomes in EC patients. In addition, ectopic overexpression or silencing of CENPA could either enhance or diminish glutamine metabolism and tumor progression in EC. Mechanistically, CENPA directly regulated the transcriptional activity of the target gene, SLC38A1, leading to enhanced glutamine uptake and metabolism, thereby promoting EC progression. Notably, a prognostic model utilizing the expression levels of CENPA and SLC38A1 genes independently emerged as a prognostic factor for EC. More importantly, CENPA and SLC38A1 were significantly elevated and positively correlated, as well as indicative of poor prognosis in multiple cancers. In brief, our study confirmed that CENPA is a critical transcription factor involved in glutamine metabolism and tumor progression through modulating SLC38A1. This revelation suggests that targeting CENPA could be an appealing therapeutic approach to address pan-cancer glutamine addiction.

Comprehensive analysis based on glycolytic and glutaminolytic pathways signature for predicting prognosis and immunotherapy in ovarian cancer.

Background: Our study attempts to develop and identify an aerobic glycolysis and glutamine-related genes (AGGRGs) signature for estimating prognostic effectively of ovarian cancer (OV) patients. Materials & methods: OV related data were extracted from the multiple public databases, including TCGA-OV, GSE26193, GSE63885, and ICGC-OV. A consistent clustering approach was used to characterize the subtypes associated with AGGRGs. LASSO Cox regressions was utilized to construct the prognosis signatures of AGGRGs. In addition, GSE26193, GSE63885 and ICGC-OV served as independent external cohorts to assess the reliability of the model. In vitro and in vivo experiments were conducted to study the role of AAK1 in the malignant progression and glutamine metabolism of OV, and assessed its therapeutic potential for treating OV patients. Results: OV patients could be separated into four subtypes (quiescent, glycolysis, glutaminolytic, and mixed subtypes). The survival outcome of glutaminolytic subtype was notably worse than the glycolytic subtype. Besides, we identified eight AGGRGs (AAK1, GJB6, HMGN5, LPIN3, INTS6L, PPOX, SPAG4, and ZNF316) to establish a prognostic signature for OV patients. Comprehensive analysis revealed that the signature risk score served as an independent prognostic factor for OV. Additionally, high-risk OV patients were less sensitive to platinum and, conversely, were proved to be more responsive to immunotherapy than low-risk score. In cytological experiments, we found that AAK1 could promote cancer progression and glutamine metabolism via activating the Notch3 pathway in OV cells. Furthermore, knockdown of AAK1 significantly inhibited tumor growth and weight, decreased lung metastases, and ultimately extended the survival time of the nude mice. Conclusions: The prognostic signature of AGGRGs constructed could efficiently estimate the prognosis and immunotherapy effectiveness of OV patients. In addition, AAK1 may represent a promising therapeutic target for OV.

Leucine improves the growth performance, carcass traits, and lipid nutritional quality of pork in Shaziling pigs.

Leucine is involved in promoting fatty acid oxidation and lipolysis, mediating lipid metabolism and energy homeostasis, thus it has been widely used in livestock production. However, the effects of leucine on fat deposition and nutrition in Shaziling pigs remain unclear. A total of 72 Shaziling pigs (150 days old, weight 35.00 ± 1.00 kg) were randomly divided into 2 groups and fed with basal diet (control group) or basal diet containing 1% leucine (leucine group) for 60 days. The results showed that leucine significantly increased the average daily feed intake but decreased the ratio of feed to gain (P < 0.05), increased the loin muscle area and serum glucose content (P < 0.05) of Shaziling pigs. Besides, leucine regulated the re-distribution of fatty acids from adipose tissue to muscle as it significantly increased the contents of C18:1n-9 and C22:6n-3 (DHA) in the longissimus thoracis while decreased the contents of C22:5n-3 (DPA), C20:5n-3 (EPA), and DHA in the adipose tissue of Shaziling pigs (P < 0.05). Lipidomic analysis showed that the contents of phosphatidylethanolamines (PEs), cardiolipins (CLs), and phosphatidylglycerols (PGs) in the longissimus thoracis and the contents of lysophosphatidylethanolamines (LPEs), ceramides (Cers), phosphatidylinositols (PIs) in adipose tissue of Shaziling pigs were decreased in leucine group (P < 0.05). Collectively, this study clarified that dietary addition of 1% leucine have a better effect on growth performance and the deposition of beneficial fatty acids in the muscle of Shaziling pigs, which is conductive to the production of high quality and healthy pork. In addition, leucine altered the lipid composition of muscle and fat in Shaziling pigs. The related results provide a theoretical basis and application guidance for regulating fat deposition in Shaziling pigs, which is important for the healthy breeding of Shaziling pigs.

Melatonin supplementation promotes muscle fiber hypertrophy and regulates lipid metabolism of skeletal muscle in weaned piglets.

Melatonin has been reported to play crucial roles in regulating meat quality, improving reproductive properties, and maintaining intestinal health in animal production, but whether it regulates skeletal muscle development in weaned piglet is rarely studied. This study was conducted to investigate the effects of melatonin on growth performance, skeletal muscle development, and lipid metabolism in animals by intragastric administration of melatonin solution. Twelve 28-d-old DLY (Duroc × Landrace × Yorkshire) weaned piglets with similar body weight were randomly divided into two groups: control group and melatonin group. The results showed that melatonin supplementation for 23 d had no effect on growth performance, but significantly reduced serum glucose content (P < 0.05). Remarkably, melatonin increased longissimus dorsi muscle (LDM) weight, eye muscle area and decreased the liver weight in weaned piglets (P < 0.05). In addition, the cross-sectional area of muscle fibers was increased (P < 0.05), while triglyceride levels were decreased in LDM and psoas major muscle by melatonin treatment (P < 0.05). Transcriptome sequencing showed melatonin induced the expression of genes related to skeletal muscle hypertrophy and fatty acid oxidation. Enrichment analysis indicated that melatonin regulated cholesterol metabolism, protein digestion and absorption, and mitophagy signaling pathways in muscle. Gene set enrichment analysis also confirmed the effects of melatonin on skeletal muscle development and mitochondrial structure and function. Moreover, quantitative real-time polymerase chain reaction analysis revealed that melatonin supplementation elevated the gene expression of cell differentiation and muscle fiber development, including paired box 7 (PAX7), myogenin (MYOG), myosin heavy chain (MYHC) IIA and MYHC IIB (P < 0.05), which was accompanied by increased insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 5 (IGFBP5) expression in LDM (P < 0.05). Additionally, melatonin regulated lipid metabolism and activated mitochondrial function in muscle by increasing the mRNA abundance of cytochrome c oxidase subunit 6A (COX6A), COX5B, and carnitine palmitoyltransferase 2 (CPT2) and decreasing the mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG), acetyl-CoA carboxylase (ACC) and fatty acid-binding protein 4 (FABP4) (P < 0.05). Together, our results suggest that melatonin could promote skeletal muscle growth and muscle fiber hypertrophy, improve mitochondrial function and decrease fat deposition in muscle.

Due to its extensive biological functions, melatonin has been widely used in animal production in recent years. The purpose of this study was to investigate the effects of melatonin on growth performance, muscle development, and lipid metabolism of weaned piglets. Twelve 28-d-old DLY (Duroc × Landrace × Yorkshire) weaned piglets were randomly divided into two groups: control group and melatonin group. The results showed that melatonin supplementation daily had no effect on growth performance, but increased muscle weight, eye muscle area, and decreased the liver weight in weaned piglets. Consistently, the cross-sectional area of myofiber increased, while triglyceride levels decreased in muscle. Melatonin induced the expression of genes related to skeletal muscle hypertrophy and fatty acid oxidation in muscle through transcriptome sequencing. Additionally, melatonin regulated cholesterol metabolism, protein digestion and absorption, and mitophagy signaling pathways in muscle. Gene set enrichment analysis also confirmed the effects of melatonin on skeletal muscle development and mitochondrial function. Moreover, melatonin supplementation elevated the gene expression of cell differentiation and muscle fiber development. Additionally, melatonin inhibited the mRNA expression related to fat synthesis while improved mitochondrial function in muscle. Together, our results suggest melatonin could promote skeletal muscle growth and muscle fiber hypertrophy, enhance mitochondrial function and decrease fat deposition in muscle.

Conjugated linoleic acids inhibit lipid deposition in subcutaneous adipose tissue and alter lipid profiles in serum of pigs.

Conjugated linoleic acids (CLAs) have served as a nutritional strategy to reduce fat deposition in adipose tissues of pigs. However, the effects of CLAs on lipid profiles in serum and how these lipid molecules regulate fat deposition are still unclear. In this study, we explored the effects of CLAs on regulating lipid deposition in adipose tissues in terms of lipid molecules and microbiota based on a Heigai pig model. A total of 56 Heigai finishing pigs (body weight: 85.58 ±â€…10.39 kg) were randomly divided into two treatments and fed diets containing 1% soyabean oil or 1% CLAs for 40 d. CLAs reduced fat deposition and affected fatty acids composition in adipose tissues of Heigai pigs via upregulating the expression of the lipolytic gene (hormone-sensitive lipase, HSL) in vivo and in vitro. CLAs also altered the biochemical immune indexes including reduced content of total cholesterol (TChol), high-density lipoprotein (HDL-C), and low-density lipoprotein (LDL-C) and changed lipids profiles including decreased sphingolipids especially ceramides (Cers) and sphingomyelins (SMs) in serum of Heigai pigs. Mechanically, CLAs may decrease peroxisome proliferator-activated receptorγ (PPARγ) expression and further inhibit adipogenic differentiation in adipose tissues of pigs by suppressing the function of Cers in serum. Furthermore, Pearson's correlation analysis showed HSL expression was positively related to short-chain fatty acids (SCFAs) in the gut (P ≤ 0.05) but the abundance of Cers was negatively related to the production and functions of SCFAs (P ≤ 0.05). CLAs altered the distribution of the lipid in serum and inhibited adipogenic differentiation by suppressing the function of Cers and further decreasing PPARγ expression in adipose tissues of Heigai pigs. Besides, the HSL expression and the abundance of Cers are associated with the production and functions of SCFAs in the gut.

Meat quality is affected by fat deposition and conjugated linoleic acids (CLAs) have served as a nutritional strategy to reduce fat deposition in adipose tissues of pigs. We explored the effects of CLAs on lipid profiles in serum and how these lipid molecules regulate fat deposition based on a Heigai pig model. We found CLAs reduced fat deposition in vivo and in vitro and changed lipids profiles in serum including decreased sphingolipids especially cermides (Cers) and sphingomyelins in the serum of Heigai pigs. We also demonstrated CLAs inhibited adipogenic differentiation by suppressing the function of Cers and further decreasing peroxisome proliferator-activated receptorγ expression in adipose tissues. Furthermore, Pearson's correlation analysis showed hormone-sensitive lipase expression and the abundance of Cers are related to the production and functions of short-chain fatty acids in the gut. Our findings provide useful insights into the role of CLAs in regulating lipid composition in serum and lipid metabolism in adipose tissue and provide a new insight into producing high-quality pork in the pig industry by using nutritional strategies.

Single-nucleus and bulk RNA sequencing reveal cellular and transcriptional mechanisms underlying lipid dynamics in high marbled pork.

Pork is the most consumed meat in the world, and its quality is associated with human health. Intramuscular fat (IMF) deposition (also called marbling) is a key factor positively correlated with various quality traits and lipo-nutritional values of meat. However, the cell dynamics and transcriptional programs underlying lipid deposition in highly marbled meat are still unclear. Here, we used Laiwu pigs with high (HLW) or low (LLW) IMF contents to explore the cellular and transcriptional mechanisms underlying lipid deposition in highly-marbled pork by single-nucleus RNA sequencing (snRNA-seq) and bulk RNA sequencing. The HLW group had higher IMF contents but less drip loss than the LLW group. Lipidomics results revelled the changes of overall lipid classes composition (e.g., glycerolipids including triglycerides, diglycerides, and monoglycerides; sphingolipids including ceramides and monohexose ceramide significantly increased) between HLW and LLW groups. SnRNA-seq revealed nine distinct cell clusters, and the HLW group had a higher percentage of adipocytes (1.40% vs. 0.17%) than the LLW group. We identified 3 subpopulations of adipocytes, including PDE4D+/PDE7B+ (in HLW and LLW), DGAT2+/SCD+ (mostly in HLW) and FABP5+/SIAH1+ cells (mostly in HLW). Moreover, we showed that fibro/adipogenic progenitors could differentiate into IMF cells and contribute to 43.35% of adipocytes in mice. In addition, RNA-seq revealed different genes involved in lipid metabolism and fatty acid elongation. Our study provides new insights into the cellular and molecular signatures of marbling formation; such knowledge may facilitate the development of new strategies to increase IMF deposition and the lipo-nutritional quality of high marbled pork.

Fermented mixed feed regulates intestinal microbial community and metabolism and alters pork flavor and umami.

This study aimed to determine the effects of fermented mixed feed (FMF) supplementation (0%, 5% and 10%) on the intestinal microbial community and metabolism, and the compositions of volatile flavor compounds and inosine monophosphate (IMP) contents in the longissimus thoracis. In this study, 144 finishing pigs (Duroc × Berkshire × Jiaxing Black) were randomly allocated to 3 groups with 4 replicate pens per group and 12 pigs per pen. The experiment lasted 38 days after 4 days of acclimation. The 16S rRNA gene sequences and an untargeted metabolomics analysis showed FMF altered the profiles of microbes and metabolites in the colon. Heracles flash GC e-nose analysis showed that 10% FMF (treatment 3) had a greater influence on the compositions of volatile flavor compounds than 5% FMF (treatment 2). Compared to 0% FMF (treatment 1), the contents of total aldehydes, (E,E)-2,4-nonadienal, dodecanal, nonanal and 2-decenal were significantly increased by treatment 3, and treatment 3 increased IMP concentrations and gene expressions related to its synthesis. Correlations analysis showed significantly different microbes and metabolites had strong correlations with the contents of IMP and volatile flavor compounds. In conclusion, treatment 3 regulated intestinal microbial community and metabolism, that in turn altered the compositions of volatile compounds, which contributed to improving pork flavor and umami.

An Ultra-Stable Electrode-Solid Electrolyte Composite for High-Performance All-Solid-State Li-Ion Batteries.

The low ionic and electronic conductivity between current solid electrolytes and high-capacity anodes limits the long-term cycling performance of all-solid-state lithium-ion batteries (ASSLIBs). Herein, this work reports the fabrication of an ultra-stable electrode-solid electrolyte composite for high-performance ASSLIBs enabled by the homogeneous coverage of ultrathin Mg(BH4 )2 layers on the surface of each MgH2 nanoparticle that are uniformly distributed on graphene. The initial discharge process of Mg(BH4 )2 layers results in uniform coverage of MgH2 nanoparticle with both LiBH4 as the solid electrolyte and Li2 B6 with even higher Li ion conductivity than LiBH4 . Consequently, the Li ion conductivity of graphene-supported MgH2 nanoparticles covered with ultrathin Mg(BH4 )2 layers is two orders of magnitude higher than that without Mg(BH4 )2 layers. Moreover, the thus-formed inactive Li2 B6 with strong adsorption capability toward LiBH4 , acts as a stabilizing framework, which, coupled with the structural support role of graphene, alleviates the volume change of MgH2 nanoparticles and facilitates the intimate contact between LiBH4 and individual MgH2 nanoparticles, leading to the formation of uniform stable interfaces with high ionic and electronic conductivity on each MgH2 nanoparticles. Hence, an ultrahigh specific capacity of 800 mAh g-1 is achieved for MgH2 at 2 A g-1 after 350 cycles.

Green Nanopesticide: pH-Responsive Eco-Friendly Pillar[5]arene-Modified Selenium Nanoparticles for Smart Delivery of Carbendazim to Suppress Sclerotinia Diseases.

Controlled-release delivery systems have been widely used to improve the efficacy and bioavailability of pesticides and minimize environmental risks. Herein, a fungicide carbendazim (CBZ)-loaded, a kind of nanovalve including trimethylammoniumpillar[5]arene (AP5), and methyl orange (MO)-functionalized mesoporous selenium (MSe) nanopesticides (CBZ@AP5/MSe⊃MO) were prepared. The nanovalve endowed CBZ@AP5/MSe⊃MO with a pH-responsive property, so the CBZ@AP5/MSe⊃MO can respond to the microenvironment of the pathogen Sclerotinia sclerotiorum (S. sclerotiorum). First, MO was shed due to protonation, and AP5-functionalized MSe gradually dissolved in an acid environment. Finally, CBZ was released rapidly. It is reported that AP5 and MO as the host and guest functionalized mesoporous selenium (MSe) have never been applied to agriculture. In vitro release experiments showed that the cumulative release rate of CBZ at pH 4.5 was 1.74 times higher than that in a neutral environment. In addition, we found that the contact angle of the CBZ@AP5/MSe⊃MO in maize and rape leaves was effectively decreased, which could retain more in the leaves after washout. It can also decrease the dry biomass and the reducing sugar of S.sclerotiorum. The CBZ@AP5/MSe⊃MO holds a good safety profile for plants, animal cells, and the environment owing to the targeted release properties. These results suggest that CBZ@AP5/MSe⊃MO is an environmentally friendly and effective drug-loaded system against S. sclerotiorum. It provides a new strategy for the design and development of nanopesticides and the control of S. sclerotiorum.

Cold exposure alters lipid metabolism of skeletal muscle through HIF-1α-induced mitophagy.

BACKGROUND: In addition to its contractile properties and role in movement, skeletal muscle plays an important function in regulating whole-body glucose and lipid metabolism. A central component of such regulation is mitochondria, whose quality and function are essential in maintaining proper metabolic homeostasis, with defects in processes such as autophagy and mitophagy involved in mitochondria quality control impairing skeletal muscle mass and function, and potentially leading to a number of associated diseases. Cold exposure has been reported to markedly induce metabolic remodeling and enhance insulin sensitivity in the whole body by regulating mitochondrial biogenesis. However, changes in lipid metabolism and lipidomic profiles in skeletal muscle in response to cold exposure are unclear. Here, we generated lipidomic or transcriptome profiles of mouse skeletal muscle following cold induction, to dissect the molecular mechanisms regulating lipid metabolism upon acute cold treatment. RESULTS: Our results indicated that short-term cold exposure (3 days) can lead to a significant increase in intramuscular fat deposition. Lipidomic analyses revealed that a cold challenge altered the overall lipid composition by increasing the content of triglyceride (TG), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE), while decreasing sphingomyelin (SM), validating lipid remodeling during the cold environment. In addition, RNA-seq and qPCR analysis showed that cold exposure promoted the expression of genes related to lipolysis and fatty acid biosynthesis. These marked changes in metabolic effects were associated with mitophagy and muscle signaling pathways, which were accompanied by increased TG deposition and impaired fatty acid oxidation. Mechanistically, HIF-1α signaling was highly activated in response to the cold challenge, which may contribute to intramuscular fat deposition and enhanced mitophagy in a cold environment. CONCLUSIONS: Overall, our data revealed the adaptive changes of skeletal muscle associated with lipidomic and transcriptomic profiles upon cold exposure. We described the significant alterations in the composition of specific lipid species and expression of genes involved in glucose and fatty acid metabolism. Cold-mediated mitophagy may play a critical role in modulating lipid metabolism in skeletal muscle, which is precisely regulated by HIF-1α signaling.

Effects of five carbohydrate sources on cat diet digestibility, postprandial glucose, insulin response, and gut microbiomes.

Cat obesity has become a serious problem that affects cats' lives and welfare. Knowing how to control obesity in pet cats and its mechanism is urgently needed. Here, by feeding 30 cats different diets for 28 d, we explored the effects of 5 cat foods with potato, sweet potato, cassava, rice, and wheat as the main carbohydrate sources on the glycolipid metabolism of pet cats. The results showed that dietary carbohydrate sources did not affect the normal growth performance and stool scores of cats. Notably, we found that the starch gelatinization degree of sweet potato and cassava cat food were higher than those of other groups, while the rice diets had the highest digestibility, but the difference was not significant (P > 0.05). Furthermore, cats fed cassava diets had lower postprandial glucose responses. The mean glucose value, maximum glucose value, AUC0-360 min, AUC≤30 min, and AUC≥30 min in the cassava group were lower than those in other dietary groups (P > 0.05). In addition, we found that the carbohydrate source had a minimal effect on serum biochemical immune indices, but the blood lipid indices, such as TG, TC, HDL, and LDL of cats fed the cassava diet were maintained at a low level compared with other groups (P > 0.05). In addition, diets with different carbohydrate sources affect the gut microbial composition, and sweet potato and cassava diets tend to increase the diversity of gut microbiota with a higher Shannon index and Simpson index. The abundance of Fusobacterium, Veillonella, and Actinobacillus was significantly higher in sweet potato diet-fed cats (P < 0.05), while the abundance of Delftia, Shinella, Rothia, and Hydrogenophage was highest in cassava diet-fed cats (P < 0.05). Collectively, this study revealed that cassava and sweet potato diets have a better effect on feeding value, controlling blood glucose and blood lipids, and improving the intestinal flora of pet cats, which is worth developing dietary formulations to alleviate pet obesity.

Pet obesity is becoming increasingly common and may have a negative impact on pet health. The exploration of measures to alleviate pet obesity is urgently needed. Carbohydrates are an important component of pet food, and their digestion and absorption affect the levels of blood glucose and blood lipids and the procession of obesity. Therefore, the objective of this study was to evaluate the effects of different sources of carbohydrates on cat digestibility, postprandial glucose response, serum biochemical immune index, and microbiomes. The results showed that cat food with cassava and sweet potato as the main source of carbohydrates has a better effect on controlling blood glucose and blood lipids and improving the intestinal flora of pet cats. This provides a valuable reference for the research and development of pet food.

Prognostic nutritional index value in the prognosis of Kawasaki disease with coronary artery lesions.

Objectives: The prognostic nutritional index (PNI) is a purported predictor of intravenous immunoglobulin (IVIG) resistance and coronary artery aneurysm (CAA) development in patients with Kawasaki disease (KD). However, limited data exist on CAA regression. This study aimed to confirm whether the PNI is a predictor for CAA persistency in patients with KD. Methods: This retrospective study grouped 341 patients with KD based on the coronary artery status and time of aneurysm persistence. The clinical and laboratory parameters were compared, and multivariate logistic regression analysis was performed to identify the independent risk factors for persistent CAA. The receiver operating characteristic (ROC) curve was further used to assess the predictive values of the PNI in persistent CAA. Results: Among the study patients, 80 (23.5%) presented with CAA, including CAA persisting for 2 years in 17 patients (5.0%). Patients with CAA were more frequently treated with corticosteroids (p < 0.016). No statistically significant differences were found in the nutritional status and PNI among patients with or without coronary artery lesions, regardless of injury severity. Patients in the persistent CAA group presented with higher rates of overnutrition and showed lower PNI values and a higher incidence of thrombosis than those in the normal group (p < 0.05). The PNI and the maximum Z-score at 1 month of onset were significantly associated with CAA persisting for 2 years and may be used as predictors of persistent CAA. The area under the ROC curve was 0.708 (95% confidence interval, 0.569-0.847), and a 40.2 PNI cutoff yielded a sensitivity and specificity of 41 and 92%, respectively, for predicting CAA persisting for 2 years. Kaplan-Meier survival analysis revealed that the estimated median time of aneurysm persistence was significantly higher in patients with PNI values of ≤40 than in those with PNI values of >40 (hazard ratio, 2.958; 95% confidence interval, 1.601-5.464; p = 0.007). After sampling-time stratification, the PNI differed significantly between patients with and without persistent CAA when sampled on the second (p = 0.040), third (p = 0.028), and fourth days (p = 0.041) following disease onset. Conclusion: A lower PNI value is an independent risk factor for CAA persisting for 2 years in patients with KD, besides the maximum Z-score at 1 month after onset. Furthermore, the PNI obtained within 4 days from fever onset may possess greater predictive power for patients with persistent CAA.

Extracardiovascular injury complications in Kawasaki disease.

Importance: Patients with Kawasaki disease (KD) experience various extracardiovascular injury complications, which may affect their outcomes. Objective: To investigate the incidence and clinical characteristics of extracardiovascular complications in children with KD. Methods: The clinical data of patients diagnosed with KD in the First Affiliated Hospital of Guangxi Medical University from January 2003 to January 2021 were reviewed. The clinical characteristics and extracardiovascular complications were compared among patients stratified by age, intravenous immunoglobulin (IVIG) therapy responsiveness, and coronary status. Results: A total of 511 patients with KD were included, 357 (69.9%) were aged 1-5 years. Children aged <1 year (21.5%) and boys (70.8%) were more likely to have coronary artery lesions (CALs). The incidence of incomplete KD was lowest in 1-5-year-old patients (19.6%). Involvement of the hematological system gradually decreased with age (<1 year, 51.8%; 1-5 years, 36.7%; >5 years, 29.5%), whereas the involvement of the joints gradually increased with age (<1 year, 2.7%; 1-5 years, 6.2%; >5 years, 20.5%). Nervous system involvement was more common in IVIG non-responders (15.7% [13/83] vs. 5.4% [23/428], P = 0.001). However, there were no significant differences in extracardiovascular injury complications between patients with or without CALs. Interpretation: KD can involve multiple organ injuries as well as cardiovascular complications, and nervous systerm involvement may be more common in patients unresponsive to IVIG.

Thermo-responsive palladium-ruthenium nanozyme synergistic photodynamic therapy for metastatic breast cancer management.

Reactive oxygen species (ROS) have become an effective "weapon" for cancer therapy due to their strong oxidation and high anti-tumor activity. Photodynamic therapy (PDT) is one of the classical methods to induce reactive oxygen species. Therefore, an ultraminiature palladium ruthenium alloy (sPdRu) and Ru(II) were combined with thermally responsive phase change materials (PCMs). Polypyridyl-complex (RCE) co-encapsulation was performed to obtain thermally responsive nanoparticles (PdRu-RCE@PCMNPs) for multimodal synergistic anti-breast cancer therapy. On the one hand, the thermosensitive PCM protective layer can realize the slow release of sPdRu, and then catalyze the production of oxygen from tumor endogenous H2O2 to perform RCE-mediated PDT. At the same time, sPdRu further increased ROS levels through peroxidase (POD) activity. On the other hand, sPdRu has high photothermal conversion efficiency and can be effectively used for photothermal therapy and photodynamic therapy. Importantly, PdRu-RCE@PCM NPs not only can effectively inhibit primary tumor growth, but also can inhibit tumor metastasis. In addition, due to the effective accumulation of sPdRu and RCE, PdRu-RCE@PCM NPs also show excellent fluorescence and photothermal imaging capabilities of tumors, which can be used for tumor tracing and evaluation of treatment. Accordingly, PdRu-RCE@PCM NPs are useful in treating primary tumors and inhibiting tumor metastasis.

CLA improves the lipo-nutritional quality of pork and regulates the gut microbiota in Heigai pigs.

Conjugated linoleic acid (CLA) is a potential nutritional strategy to regulate meat quality in pigs and produce high-quality pork. However, the effects of CLA on nutritional quality, lipid dynamics, microbiota, and their metabolites in the gut of pigs remain unclear. Our study explored the effects of CLA on lipo-nutritional quality based on a Heigai pig model and investigated the regulatory mechanism using an integrated analysis of multiple omics. A total of 58 Heigai finishing pigs (body weight: 85.58 ± 10.39 kg) were randomly divided into 2 treatments and fed diets containing 1% soyabean oil and 1% CLA for 40 days. 1% CLA significantly decreased the backfat thickness (P < 0.05) and increased the intramuscular fat (IMF) content (P < 0.05). The expression of lipid metabolism-related genes was significantly changed (P < 0.05) and lipidome analysis showed the alternations of lipid dynamics in the longissimus dorsi muscle (LDM). In addition, based on the microbiome and metabolomic analyses, the relative abundances of Parabacteroides, Bacteroides, and Lachnospiraceae_UCG-010 increased and CLA changed the metabolome profiles and the short-chain fatty acid (SCFA) composition in the gut, which were significantly increased (P < 0.05). Additionally, Pearson's correlation analysis indicated that differential microbial genera and SCFAs induced by CLA had tight correlations with the backfat thickness, IMF content and lipids in the LDM. CLA enhances the lipid accumulation and metabolism in muscle and these changes are associated with the production and functions of the differential bacteria and SCFAs in the gut of pigs.

Bidirectional anisotropic palladium nanozymes reprogram macrophages to enhance collaborative chemodynamic therapy of colorectal cancer.

In the complex tumor microenvironment (TME), tumor-associated macrophages (TAMs) play an important role in immunosuppression and tumor growth; hence, tumor cells are no longer the only target during tumor treatment. However, how to simultaneously target both tumor cells and TAMs to effectively eliminate the tumor remains a challenge. Herein, based on the specific receptors for cancer cells and TAMs, we prepared bidirectional anisotropic palladium nanoclusters (Pd-HA+Pd-M@R NPs) to simultaneously target tumor cells and TAMs for enhancing the therapeutic effect. In these nanoclusters, the Pd-HA part was obtained by modifying hyaluronic acid (HA) on the surface of ultra-small Pd nanozymes that could target CT26 cells. Moreover, with the high peroxidase (POD) and catalase (CAT) activity of Pd nanozymes, Pd-HA NPs directly caused cancer cell death by producing H2O2 and highly toxic reactive oxygen therapy (ROS) through chemodynamic therapy (CDT). The other part of Pd NPs functioned as a carrier that linked mannose (Man) and the imiquimod molecule (R837) to obtain Pd-M@R NPs, which could specifically connect the mannose receptor of TAMs and perform targeted reprogramming of TAMs to M1 phenotype to reverse immunosuppression and further activate immunotherapy to form "double therapy". Therefore, the strategy of "double therapy" provides new sights for treating malignant tumors. STATEMENT OF SIGNIFICANCE: The bidirectional anisotropic Pd nanoclusters (Pd-HA+Pd-M@R NPs) that can simultaneously target the tumor cells and TAMs with the modification of HA and mannose, respectively. Under the biodirectional anisotropic effect, the Pd nanozymes in Pd-HA can directly kill CT 26 cells through catalyze producing toxic ROS. The Pd-M@R exhibited effectively delivery the imiquimod molecule (R837) to TAMs and specifically induced it transformed into M1 phenotype to reverse tumor immunosuppression to form the "double therapy".

Clinical Efficacy and In Vitro Drug Sensitivity Test Results of Azithromycin Combined With Other Antimicrobial Therapies in the Treatment of MDR P. aeruginosa Ventilator-Associated Pneumonia.

Objective: The aim of the research was to study the effect of azithromycin (AZM) in the treatment of MDR P. aeruginosa VAP combined with other antimicrobial therapies. Methods: The clinical outcomes were retrospectively collected and analyzed to elucidate the efficacy of different combinations involving azithromycin in the treatment of MDR-PA VAP. The minimal inhibitory concentration (MIC) of five drugs was measured by the agar dilution method against 27 isolates of MDR-PA, alone or in combination. Results: The incidence of VAP has increased approximately to 10.4% (961/9245) in 5 years and 18.4% (177/961) caused by P. aeruginosa ranking fourth. A total of 151 cases of MDR P. aeruginosa were included in the clinical retrospective study. Clinical efficacy results are as follows: meropenem + azithromycin (MEM + AZM) was 69.2% (9/13), cefoperazone/sulbactam + azithromycin (SCF + AZM) was 60% (6/10), and the combination of three drugs containing AZM was 69.2% (9/13). The curative effect of meropenem + amikacin (MEM + AMK) was better than that of the meropenem + levofloxacin (MEM + LEV) group, p = 0.029 (p < 0.05). The curative effect of cefoperazone/sulbactam + amikacin (SCF + AMK) was better than that of the cefoperazone/sulbactam + levofloxacin (SCF + LEV) group, p = 0.025 (p < 0.05). There was no significant difference between combinations of two or three drugs containing AZM, p > 0.05 (p = 0.806). From the MIC results, the AMK single drug was already very sensitive to the selected strains. When MEM or SCF was combined with AZM, the sensitivity of them to strains can be significantly increased. When combined with MEM and AZM, the MIC50 and MIC90 of MEM decreased to 1 and 2 ug/mL from 8 to 32 ug/mL. When combined with SCF + AZM, the MIC50 of SCF decreased to 16 ug/mL, and the curve shifted obviously. However, for the combination of SCF + LEV + AZM, MIC50 and MIC90 could not achieve substantive changes. From the FIC index results, the main actions of MEM + AZM were additive effects, accounting for 72%; for the combination of SCF + AZM, the additive effect was 40%. The combination of AMK or LEV with AZM mainly showed unrelated effects, and the combination of three drugs could not improve the positive correlation between LEV and AZM. Conclusion: AZM may increase the effect of MEM or SCF against MDR P. aeruginosa VAP. Based on MEM or SCF combined with AMK or AZM, we can achieve a good effect in the treatment of MDR P. aeruginosa VAP.

A neutrophil cell membrane-biomimetic nanoplatform based on L-arginine nanoparticles for early osteoarthritis diagnosis and nitric oxide therapy.

Osteoarthritis (OA) is a common debilitating disease affecting articular joints for which no effective disease-modifying early diagnosis or medical therapy tools are currently available. The inefficient delivery of drugs into inflamed chondrocytes has restricted the development of anti-OA medication. Evidence has shown that inflammatory neutrophils possess the property of targeting inflammation via inflammatory tissue recruiting. Herein, we report neutrophil-cell-membrane-based biomimetic nanoparticles (NM-LANPs@Ru) as an OA theranostic nanoplatform; they act as a NO delivery system, coating neutrophil cell membrane onto the surface of self-assembled PEGylated L-arginine nanoparticles (LANPs) to act as a NO donor and loading a Ru complex to act as a ROS inducer. NM-LANPs@Ru demonstrated the specific targeting of inflamed OA with low toxicity, good NO release, and excellent fluorescence/photoacoustic (FL/PA) imaging properties. We showed that NM-LANPs@Ru exhibited enhanced cellular association in inflamed chondrocyte cells (C28/I2), much higher than NO release from ROS oxidized LA, and it improved the inhibition of the apoptosis of inflamed C28/I2 cells compared with control treatments. In vivo studies demonstrated that NM-LANPs@Ru effectively targeted inflamed OA, based on real-time dual-modal FL/PA imaging, eventually exhibiting its excellent anti-inflammatory activity. Our study may provide a new approach for the early diagnosis and treatment of osteoarthritis using a neutrophil-cell-membrane-based biomimetic nanoplatform for NO or drug delivery.

A temperature-responsive selenium nanohydrogel for strawberry grey mould management.

Grey mould is a fungal disease caused by Botrytis cinerea (B. cinerea), which can cause serious damage to a variety of crops. Herein, we developed iprodione (Ipr) reagent-loaded mesoporous selenium nanoparticles (MSe NPs), combined them with low-melting agarose (LA), and obtained a temperature-responsive selenium particle nanogel (Ipr@MSe@LA NPs) using a simple method. Importantly, Ipr@MSe@LA could capture B. cinerea and quickly be softened to realize the controlled release of Ipr, and effectively inhibit and kill B. cinerea. Plate-based antibacterial tests showed that the colony area of the Ipr@MSe@LA NPs was 4.27 cm-2, which was much smaller than that of the control (25 cm-2). In addition, the Ipr@MSe@LA NPs showed good biocompatibility, and they could improve the photosynthetic efficiency of plants and promote plant growth. Measurement of the fluorescence parameters showed that the maximum photochemical efficiency (Fv/Fm) of the plant leaves of the inoculated group (B. cinerea) is 0.58, but the Fv/Fm value of the Ipr@MSe@LA group is higher than 0.8. In particular, Ipr@MSe@LA NPs could prolong the storage time of strawberries, thereby preserving their freshness. Overall, Ipr@MSe@LA NPs exhibit excellent effects in terms of controlling strawberry gray mould and prolonging the fruit storage time, and this is expected to become a promising strategy for developing intelligent pesticide formulations.

Bioinformatic analysis of dysregulated circular RNAs in pediatric pulmonary hypertension linked congenital heart disease.

Background: Circular RNAs (circRNAs) may play important roles in the progression of pulmonary arterial hypertension. However, the potential roles they play in childhood pulmonary arterial hypertension associated congenital heart disease (CHD) progression remains unclear. Methods: Thirteen human plasma samples including eight from pulmonary arterial hypertension secondary to CHD patients and five from a control group were analyzed using the Arraystar Human circRNA array. The relative expression levels of five differentially expressed circRNAs in pulmonary arterial hypertension were detected using real-time polymerase chain reaction (PCR) analysis. In parallel, these levels were also taken on control samples from 32 CHD patients. We used miRanda and TargetScan software packages to predict potential microRNA (miRNA)targets, which were then combined into a circRNA-miRNA-messenger RNA (mRNA) network. Results: Twenty-seven circRNAs (three upregulated and 24 downregulated) were differentially expressed between the pulmonary arterial hypertension and control groups. Compared to control group levels, circ_003416 expression in the pulmonary arterial hypertension group was significantly downregulated, while circ_005372 expression, in contrast, was significantly upregulated. The differential expression of these circRNAs was mainly linked to variation in levels of oxidative phosphorylation and tight junction signaling. Conclusions: We identified one overexpressed and one underexpressed circRNA in plasma samples from children with CHD associated pulmonary arterial hypertension. Bioinformatic analysis indicated these dysregulated circRNAs might be associated with the occurrence and regulation of pulmonary arterial hypertension.