Genome-wide identification of walnut (Juglans regia) PME gene family members and expression analysis during infection with Cryptosphaeria pullmanensis pathogens.

Walnuts exhibit a higher resistance to diseases, though they are not completely immune. This study focuses on the Pectin methylesterase (PME) gene family to investigate whether it is involved in disease resistance in walnuts. These 21 genes are distributed across 12 chromosomes, with four pairs demonstrating homology. Variations in conserved motifs and gene structures suggest diverse functions within the gene family. Phylogenetic and collinear gene pairs of the PME family indicate that the gene family has evolved in a relatively stable way. The cis-acting elements and gene ontology enrichment of these genes, underscores their potential role in bolstering walnuts' defense mechanisms. Transcriptomic analyses were conducted under conditions of Cryptosphaeria pullmanensis infestation and verified by RT-qPCR. The results showed that certain JrPME family genes were activated in response, leading to the hypothesis that some members may confer resistance to the disease.

Effects of propranolol on glucose metabolism in hemangioma-derived endothelial cells.

Infantile hemangioma (IH) is the most common benign tumor in children. Propranolol is the first-line treatment for IH, but the underlying mechanism of propranolol treatment in IH is not completely understood. Integrated transcriptional and metabolic analyses were performed to investigate the metabolic changes in hemangioma-derived endothelial cells (HemECs) after propranolol treatment. The findings were then further validated through independent cell experiments using a Seahorse XFp analyzer, Western blotting, immunohistochemistry and mitochondrial functional assays. Thirty-four differentially expressed metabolites, including the glycolysis metabolites glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-bisphosphate, were identified by targeted metabolomics. A KEGG pathway enrichment analysis showed that the disturbances in these metabolites were highly related to glucose metabolism-related pathways, including the pentose phosphate pathway, the Warburg effect, glycolysis and the citric acid cycle. Transcriptional analysis revealed that metabolism-related pathways, including glycine, serine and threonine metabolism, tyrosine metabolism, and glutathione metabolism, were highly enriched. Moreover, integration of the metabolomic and transcriptomic data revealed that glucose metabolism-related pathways, particularly glycolysis, were altered after propranolol treatment. Cell experiments demonstrated that HemECs exhibited higher levels of glycolysis than human umbilical vein ECs (HUVECs) and that propranolol suppressed glycolysis in HemECs. In conclusion, propranolol inhibited glucose metabolism in HemECs by suppressing glucose metabolic pathways, particularly glycolysis.

Lifestyle effects on aging and CVD: A spotlight on the nutrient-sensing network.

Aging is widespread worldwide and a significant risk factor for cardiovascular disease (CVD). Mechanisms underlying aging have attracted considerable attention in recent years. Remarkably, aging and CVD overlap in numerous ways, with deregulated nutrient sensing as a common mechanism and lifestyle as a communal modifier. Interestingly, lifestyle triggers or suppresses multiple nutrient-related signaling pathways. In this review, we first present the composition of the nutrient-sensing network (NSN) and its metabolic impact on aging and CVD. Secondly, we review how risk factors closely associated with CVD, including adverse life states such as sedentary behavior, sleep disorders, high-fat diet, and psychosocial stress, contribute to aging and CVD, with a focus on the bridging role of the NSN. Finally, we focus on the positive effects of beneficial dietary interventions, specifically dietary restriction and the Mediterranean diet, on the regulation of nutrient metabolism and the delayed effects of aging and CVD that depend on the balance of the NSN. In summary, we expound on the interaction between lifestyle, NSN, aging, and CVD.

Toxic effects of sirolimus and everolimus on the development and behavior of zebrafish embryos.

Sirolimus and everolimus have been widely used in children. These mammalian target of rapamycin (mTOR) inhibitors have shown excellent efficacy not only in organ transplant patients as immunosuppressive agents but also in patients with some other diseases. However, whether mTOR inhibitors can affect the growth and development of children is of great concern. In this study, using zebrafish models, we discovered that sirolimus and everolimus could slow the development of zebrafish, affecting indicators such as survival, hatching, deformities, body length, and movement. In addition to these basic indicators, sirolimus and everolimus had certain slowing effects on the growth and development of the nervous system, blood vessels, and the immune system. These effects were dose dependent. When the drug concentration reached or exceeded 0.5 µM, the impacts of sirolimus and everolimus were very significant. More interestingly, the impact was transient. Over time, the various manifestations of experimental embryos gradually approached those of control embryos. We also compared the effects of sirolimus and everolimus on zebrafish, and we revealed that there was no significant difference between these drugs in terms of their effects. In summary, the dose of sirolimus and everolimus in children should be strictly controlled, and the drug concentration should be monitored over time. Otherwise, drug overdosing may have a certain impact on the growth and development of children.

Erratum to "Protein Z modulates the metastasis of lung adenocarcinoma cells".

[This corrects the article DOI: 10.1515/biol-2022-0667.].

Protein Z modulates the metastasis of lung adenocarcinoma cells.

Protein Z (PZ), a vitamin-K-dependent anticoagulant glycoprotein, is reported to be highly expressed in various malignant tissues and correlated with a poor prognosis in patients with lung cancer. This study aimed to investigate the pathological activity of PZ on lung cancer cell migration, invasion, and metastasis. PZ was assessed by Western blot in three non-small-cell lung cancer cell lines (A549, H1299, and H1975). Meanwhile,western blot was used to detect the expression of EMT pathway-related proteins (Slug, Vimentin, and N-cadherin) in the A549 cells knocked down with siRNA. The cellular proliferation, migration, and invasion were detected by Cell Counting Kit (CCK)-8, wound healing, and Transwell assays in the A549 cells. The results showed that PZ expression was higher in A549, H1299, and H1975 cells, according to Western blot. CCK-8, wound healing, and Transwell assays showed that knockdown of PZ significantly decreased cellular proliferation, migration, and invasion, as well as the protein levels of Slug, Vimentin, and N-cadherin in the A549 cells. In conclusion, the pro-metastasis activity of PZ may modulate the epithelial-mesenchymal transition pathway in lung cancer A549 cells.

Oral antibiotic prophylaxis for infection in patients with vascular anomalies receiving sirolimus treatment: a multicenter retrospective study.

OBJECTIVES: Patients with vascular anomalies (VAs) who receive oral sirolimus may be at high risk of infectious complications. Antibiotic prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) has been advocated. However, there have been few evidence-based analyses on this topic. This study assessed the effect of prophylactic TMP-SMZ on the incidence of infections in VA patients receiving sirolimus monotherapy. METHODS: A retrospective, multicenter chart review was performed on all VA patients receiving sirolimus treatment from August, 2013 to January, 2021. RESULTS: Before January 2017, 112 patients were treated with sirolimus without antibiotic prophylaxis. In the subsequent period, 195 patients were treated with TMP-SMZ for at least 12 months during sirolimus therapy. The percentage of patients with at least one serious infection during the initial 12 months of sirolimus treatment did not differ between the groups (difference, 1.1%; 95% CI - 7.0-8.0%). We observed no difference in the incidence of individual infection or total adverse events between the groups. The rate of sirolimus discontinuation due to adverse events did not differ significantly between groups. CONCLUSIONS: We demonstrated that prophylactic TMP-SMZ does not decrease the incidence of infection or improve tolerance in VA patients receiving sirolimus monotherapy.

Integrated nontargeted and targeted metabolomics analyses amino acids metabolism in infantile hemangioma.

Infantile hemangioma (IH) is the most common benign tumor in children. However, the exact pathogenesis of IH remains unclear. Integrated nontargeted and targeted metabolic analyses were performed to obtain insight into the possible pathogenic mechanism of IH. The results of nontargeted metabolic analysis showed that 216 and 128 differential metabolites (DMs) were identified between hemangioma-derived endothelial cells (HemECs) and HUVECs in positive-ion and negative-ion models, respectively. In both models, these DMs were predominantly enriched in pathways related to amino acid metabolism, including aminoacyl-tRNA biosynthesis and arginine and proline metabolism. Then, targeted metabolic analysis of amino acids was further performed to further clarify HemEC metabolism. A total of 22 amino acid metabolites were identified, among which only 16 metabolites, including glutamine, arginine and asparagine, were significantly differentially expressed between HemECs and HUVECs. These significant amino acids were significantly enriched in 10 metabolic pathways, including 'alanine, aspartate and glutamate metabolism', 'arginine biosynthesis', 'arginine and proline metabolism', and 'glycine, serine and threonine metabolism'. The results of our study revealed that amino acid metabolism is involved in IH. Key differential amino acid metabolites, including glutamine, asparagine and arginine, may play an important role in regulating HemEC metabolism.

Long-term outcomes of sirolimus treatment for kaposiform hemangioendothelioma: Continuing successes and ongoing challenges.

Treatment with sirolimus, an inhibitor of the mammalian target of rapamycin pathway, has improved the prognosis of patients with kaposiform hemangioendothelioma (KHE). However, the efficacy, durability and tolerability of long-term sirolimus treatment in patients with KHE have not been well elucidated. We performed efficacy and safety assessments based on more than 4.5 years of follow-up in patients receiving sirolimus therapy for KHE. One hundred sixty-seven patients were analyzed, including 102 (61.1%) patients with the Kasabach-Merritt phenomenon (KMP). Follow-up was conducted after a median of 56.0 months. A total of 154 (92.2%) patients had a durable response to sirolimus treatment. No difference in durable response was found between patients without KMP and patients with KMP (95.4% vs 90.2%; difference, 5.2%; 95% confidence interval [CI], -4.0% to 13.1%). Rebound growth occurred in 17.3% of patients upon sirolimus discontinuation. Early treatment discontinuation (odds ratio [OR]: 3.103; 95% CI: 1.529-6.299; P = .002) and mixed lesion type (OR: 2.271; 95% CI: 0.901-5.727; P = .047) were associated with tumor rebound growth. No KHE-related deaths occurred in this cohort. At the last follow-up, approximately 17.4% of patients had active disease and/or changes in body structures to a variable extent. Serious adverse events occurred most commonly during the first year of sirolimus therapy. Follow-up of almost 4.5 years demonstrated that the efficacy of sirolimus persisted over time and that long-term treatment with sirolimus was not associated with unacceptable cumulative toxicities. However, nonresponse, tumor relapse and long-term sequelae remained challenges despite intensified and prolonged sirolimus therapy.

Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma.

BACKGROUND: Infantile hemangioma (IH) is the most common tumor among infants, but the exact pathogenesis of IH is largely unknown. Our previous study revealed that glucose metabolism may play an important role in the pathogenesis of IH and that the inhibition of the glycolytic key enzyme phosphofructokinase-1 suppresses angiogenesis in IH. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a metabolic enzyme that converts fructose-6-bisphosphate to fructose-2,6-bisphosphate (F-2,6-BP), which is the most potent allosteric activator of the rate-limiting enzyme phosphofructokinase-1. This study was performed to explore the role of PFKFB3 in IH. METHODS: Microarray analysis was performed to screen the differentially expressed genes (DEGs) between proliferating and involuting IH tissues. PFKFB3 expression was examined by western blot and immunohistochemistry analyses. Cell migration, apoptosis and tube formation were analyzed. Metabolic analyses were performed to investigate the effect of PFKFB3 inhibition by PFK15. Mouse models were established to examine the effect of PFKFB3 inhibition in vivo. RESULTS: PFKFB3 was identified as one of the most significant DEGs and was more highly expressed in proliferating IH tissues and hemangioma-derived endothelial cells (HemECs) than in involuting IH tissues and human umbilical vein endothelial cells, respectively. PFKFB3 inhibition by PFK15 suppressed HemEC glucose metabolism mainly by affecting glycolytic metabolite metabolism and decreasing the glycolytic flux. Moreover, PFK15 inhibited HemEC angiogenesis and migration and induced apoptosis via activation of the apoptosis pathway. Treatment with the combination of PFK15 with propranolol had a synergistic inhibitory effect on HemECs. Moreover, PFKFB3 knockdown markedly suppressed HemEC angiogenesis. Mechanistically, inhibition of PFKFB3 suppressed the PI3K-Akt signaling pathway and induced apoptotic cell death. More importantly, the suppression of PFKFB3 by PFK15 or shPFKFB3 led to markedly reduced tumor growth in vivo. CONCLUSIONS: Our findings suggest that PFKFB3 inhibition can suppress IH angiogenesis and induce apoptosis. Thus, targeting PFKFB3 may be a novel therapeutic strategy for IH.

Analysis of Therapeutic Decisions for Infantile Hemangiomas: A Prospective Study Comparing the Hemangioma Severity Scale with the Infantile Hemangioma Referral Score.

BACKGROUND: In view of the high incidence of infantile hemangioma (IH) in infants and young children, a comprehensive and reasonable evaluation scale for referral is urgently needed. This study compared the influence of the Hemangioma Severity Scale (HSS) and the Infantile Hemangioma Referral Score (IHReS) on treatment decisions for infantile hemangioma patients. OBJECTIVE: We aimed to establish a reliable and effective evaluation method for referral. METHODS: This was a prospective study to determine whether treatment was needed for IH patients after evaluation with the HSS and IHReS. RESULTS: A total of 266 consecutive referred IH patients were evaluated for the risk of IH, and the treatment rate was 80.8%. The area under the curve (AUC) of the subject receiver operating characteristic curve (ROC) of treatment decision making after referral by the HSS was 0.703 (95% CI: 0.634-0.772), and after referral by the IHReS was 0.892 (95% CI: 0.824-0.960). LIMITATIONS: This was a single-center study. CONCLUSIONS: For decisions regarding the treatment of IH patients, the IHReS has a higher efficiency and sensitivity than the HSS. However, the specificity of the IHReS is lower than that of the HSS.

Case Report: Bilateral symmetrical primary kaposiform hemangioendothelioma of the femur.

Kaposiform hemangioendothelioma (KHE) is a rare borderline vascular tumor that usually presents as a mass of skin or deep soft tissue. We report a unique case of an 8-year-old KHE patient with bilateral symmetrical sites involving both femurs. The laboratory, radiographic, and pathological findings of the patient were minutely described. During the 6-month follow-up, the symptoms of pain and dysfunction of this patient were relieved. This study aimed to arouse clinicians' concern about the symmetrical sites of KHE patients.

U-shaped association between serum albumin and pediatric intensive care unit mortality in critically ill children.

Introduction: The detailed association between albumin levels and mortality has not been studied in critically ill children. The aim of this study was to reveal an association between albumin levels in detail and mortality in critically ill children. Materials and methods: We retrospectively collected data from children admitted to four pediatric intensive care units (PICUs) in China between January 2015 and October 2020. Restricted cubic spline curves based on logistic regression models were generated to evaluate the detailed associations between serum albumin levels and PICU mortality. Threshold effect analysis was performed using two piecewise regression models. Results: The study included 9,123 children. The overall mortality was 5.3%. The detailed association between serum albumin levels and the risk of mortality followed a U-shape. The risk of mortality decreased with increasing serum albumin levels (OR = 0.919; 95% CI: 0.886, 0.954) in children with serum albumin levels < 43.2 g/L and increased with increasing serum albumin levels (OR = 1.174; 95% CI: 1.044, 1.316) in children with serum albumin levels ≥ 43.2 g/L. Conclusion: There was a U-shaped association between serum albumin levels and mortality in critically ill children in the PICU.

Performance of the PRISM I, PIM2, PELOD-2 and PRISM IV scoring systems in western China: a multicenter prospective study.

BACKGROUND: The aim of this study was to evaluate the performance of the four scoring tools in predicting mortality in pediatric intensive care units (PICUs) in western China. METHODS: This was a multicenter, prospective, cohort study conducted in six PICUs in western China. The performances of the scoring systems were evaluated based on both discrimination and calibration. Discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUC) for each model. Calibration was measured across defined groups based on mortality risk using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: A total of 2034 patients were included in this study, of whom 127 (6.2%) died. For the entire cohort, AUCs for Pediatric Risk of Mortality Score (PRISM) I, Pediatric Index of Mortality 2 (PIM2), Pediatric Logistic Organ Dysfunction Score-2 (PELOD-2) and PRISM IV were 0.88 [95% confidence interval (CI) 0.85-0.92], 0.84 (95% CI 0.80-0.88), 0.80 (95% CI 0.75-0.85), and 0.91 (95% CI 0.88-0.94), respectively. The Hosmer-Lemeshow goodness-of-fit Chi-square value was 12.71 (P = 0.12) for PRISM I, 4.70 (P = 0.79) for PIM2, 205.98 (P < 0.001) for PELOD-2, and 7.50 (P = 0.48) for PRISM IV [degree of freedom (df) = 8]. The standardized mortality ratios obtained with the PRISM I, PIM2, PELOD-2, and PRISM IV models were 0.87 (95% CI, 0.75-1.01), 0.97 (95% CI, 0.85-1.12), 1.74 (95% CI, 1.58-1.92), and 1.05 (95% CI, 0.92-1.21), respectively. CONCLUSIONS: PRISM IV performed best and can be used as a prediction tool in PICUs in Western China. However, PRISM IV needs to be further validated in NICUs.

Safety Evaluation of Oral Sirolimus in the Treatment of Childhood Diseases: A Systematic Review.

Background: Sirolimus, a mammalian target of rapamycin inhibitor, has been widely used in pediatric patients, but the safety of sirolimus in pediatric patients has not been well determined. Objective: The objective of this study was to systematically evaluate prospective studies reporting the safety of sirolimus in the treatment of childhood diseases. Methods: The following data were extracted in a standardized manner: study design, demographic characteristics, intervention, and safety outcomes. Results: In total, 9 studies were included, encompassing 575 patients who received oral sirolimus for at least 6 months. Various adverse events occurred. The most common adverse event was oral mucositis (8.2%, 95% CI: 0.054 to 0.110). Through comparative analysis of the subgroups based on the targeted concentration range, we discovered that many adverse events were significantly higher in the high concentration group (≥10 ng/mL) than in the low concentration group (<10 ng/mL) (p < 0.01). More interestingly, we found that oral mucositis was more frequently reported in children with vascular anomalies than tuberous sclerosis complex. Conclusions: This study shows that oral sirolimus in the treatment of childhood diseases is safe and reliable. However, sirolimus treatment in the pediatric population should be strictly monitored to reduce the occurrence of serious or fatal adverse events.

Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy.

Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection in the central nervous system or structural brain damage. Microglia are thought to be macrophages of the central nervous system, devouring bits of neuronal cells and dead cells in the brain. They are activated in various ways, and microglia-mediated neuroinflammation is characteristic of central nervous system diseases, including SAE. Here, we systematically described the pathogenesis of SAE and demonstrated that microglia are closely related to the occurrence and development of SAE. Furthermore, we comprehensively discussed the function and phenotype of microglia and summarized their activation mechanism and role in SAE pathogenesis. Finally, this review summarizes recent studies on treating cognitive impairment in SAE by blocking microglial activation and toxic factors produced after activation. We suggest that targeting microglial activation may be a putative treatment for SAE.

Infantile hepatic hemangiomas: looking backwards and forwards.

Infantile hepatic hemangiomas (IHHs) are common benign tumors seen in the liver of infants. IHHs are true infantile hemangiomas (IHs) and have phases of proliferation and involution parallel to those of cutaneous IHs. The definition and classification of IHH are still confusing in the literature. The mechanisms during the pathogenesis of IHH have yet to be discovered. The clinical manifestations of IHH are heterogeneous. Although most IHH lesions are asymptomatic, some lesions can lead to severe complications, such as hypothyroidism, consumptive coagulopathy, and high-output congestive cardiac failure. Consequently, some patients can possibly encounter a fatal clinical condition. The heterogeneity of the lesions and the occurrence of disease-related comorbidities can make the treatment of IHH challenging. Oral propranolol is emerging as an effective systemic approach to IHH with obvious responses in tumor remission and symptom regression. However, the precise clinical characteristics and treatment strategies for patients with severe IHH have not yet been well established. Here, we summarize the epidemiology, pathogenic mechanism, clinical manifestations, diagnosis, and treatment of IHH. Recent updates and future perspectives for IHH will also be elaborated.

Maternal and Perinatal Risk Factors for Infantile Hemangioma: A Matched Case-Control Study with a Large Sample Size.

INTRODUCTION: Infantile hemangioma (IH) is the most common benign tumor in infancy, but information about its pathogenesis is limited. The aim of this study was to determine maternal and perinatal risk factors for IH. METHODS: A total of 1033 IH patients were enrolled in the study between 2017 and 2020. IH patients were matched with controls by sex. Trained investigators collected detailed information from the participants. Logistic regression models were used for multivariate analysis. RESULTS: The statistical analysis demonstrated that miscarriage history (odds ratio [OR] = 4.275; 95% confidence interval [CI] [3.195, 5.720]), anemia in pregnancy (OR = 4.228; 95% CI [3.083, 5.799]), preterm premature rupture of membranes (PPROM) (OR = 3.182; 95% CI [1.359, 7.454]), placenta previa (OR = 2.440; 95% CI [1.787, 3.333]), threatened miscarriage (OR = 2.290; 95% CI [1.726, 3.039]), premature rupture of membranes (PROM) (OR = 1.785; P < 0.05), progesterone use (OR = 1.614; P < 0.001) and abnormal amniotic fluid volume (OR = 1.499; P < 0.05) were independent risk factors for IH. Gestational diabetes mellitus (GDM) (OR = 0.607; 95% CI [0.464, 0.794]), multiple gestations (OR = 0.407; 95% CI [0.232, 0.713]), hypothyroidism (OR = 0.407; 95% CI [0.227, 0.730]) and uterine fibroids (OR = 0.393; 95% CI [0.250, 0.618]) may reduce the risk of IH. CONCLUSIONS: Maternal and perinatal factors are closely associated with IH occurrence. Our study provides reliable clues to guide further exploration of the pathogenesis of IH. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03331744. Infantile hemangioma is the most common benign tumor in children, which seriously affects appearance and function and even threatens life. The pathogenesis is not clear, a detailed case-control study of the maternal and perinatal periods with a large sample size will facilitate the development of individualized and precise treatment, early and timely interventions for high-risk children and improvement of prognosis. Our study found that miscarriage history, anemia in pregnancy, preterm premature rupture of membranes (PPROM), placenta previa, threatened miscarriage, premature rupture of membranes (PROM), progesterone use and abnormal amniotic fluid volume were independent risk factors for IH.

Exosomes in atherosclerosis: Convergence on macrophages.

As the primary cells of atherosclerotic plaques, macrophages play a central role in the occurrence and progression of atherosclerosis (AS). In recent years, macrophages have received extensive attention as therapeutic targets. Exosomes, as natural nanoparticles, have high biocompatibility and strong targeting ability and have been widely studied as imaging agents and drug carriers. Studies on the relationship between atherosclerotic macrophages and exosomes have been focused on for the past few years. Nevertheless, no complex review has been undertaken in this area. In this review, we summarize in detail the role of macrophages in atherosclerosis, especially their plasticity and phenotypic and distributional heterogeneity. Based on the high correlation between macrophages and the pathological process of atherosclerosis, as well as the targeting of exosomes, we further review the clinical application of targeting macrophage-associated exosomes. We focus on the role of macrophage-associated exosomes in the phenotypic transformation of cells in atherosclerosis, providing a new idea for the clinical application of targeting macrophage-associated exosomes. Finally, we specifically summarize and prospect the diagnosis of macrophage-associated exosomes, such as imaging agent delivery, biomarkers and therapeutic strategies.