Diosgenin improves post-myocardial infarction cardiac function via HAND2-induced angiogenesis.

While diosgenin has been demonstrated effective in various cardiovascular diseases, its specific impact on treating heart attacks remains unclear. Our research revealed that diosgenin significantly improved cardiac function in a myocardial infarction (MI) mouse model, reducing cardiac fibrosis and cell apoptosis while promoting angiogenesis. Mechanistically, diosgenin upregulated the Hand2 expression, promoting the proliferation and migration of endothelial cells under hypoxic conditions. Acting as a transcription factor, HAND2 activated the angiogenesis-related gene Aggf1. Conversely, silencing Hand2 inhibited the diosgenin-induced migration of hypoxic endothelial cells and angiogenesis. In summary, these findings provide new insights into the protective role of diosgenin in MI, validating its effect on angiogenic activity and providing a theoretical basis for clinical treatment strategies.

Potential contributions of keystone species to intestinal ecosystem in patients with Crohn's disease.

AIMS: Ravelling the central but poorly understood issue that potential contributions of keystone species to intestinal ecosystem functioning of patients with certain life-altering diseases including Crohn's disease (CD). METHODS AND RESULTS: In this study, a combination of 16S rRNA gene amplicon sequencing and amplicon-oriented metagenomic profiling was applied to gain insights into the shifts in bacterial community composition at different stages of CD course, and explore the functional roles of identified keystone species in intestinal microecosystem. Our results showed significant alterations in structure and composition of gut microbiota between CD patients and healthy control (HC) (P < 0.05), but was no difference at active and remission stages. Whole-community-based comprehensive analyses were employed to identify the differential species such as Escherichia coli, Anaerostipes hadrus, and Eubacterium hallii in CD patients, with healthy populations as the control. Metagenome-wide functional analyses further revealed that the relative abundance of specialized metabolism-related genes such as cynS, frdB, serA, and gltB from these bacterial species in CD group was significantly different (P < 0.05) from that in HC, and highlighted the potential roles of the keystone species in regulating the accumulation of important metabolites such as succinate, formate, ammonia, L-glutamate, and L-serine, which might have an effect on homeostasis of intestinal ecosystem. CONCLUSIONS: The findings identify several potential keystone species that may influence the intestinal microecosystem functioning of CD patients and provide some reference for future CD treatment.

Waist circumference prediction for epidemiological research using gradient boosted trees.

BACKGROUND: Waist circumference is becoming recognized as a useful predictor of health risks in clinical research. However, clinical datasets tend to lack this measurement and self-reported values tend to be inaccurate. Predicting waist circumference from standard physical features could be a viable method for generating this information when it is missing or mitigating the impact of inaccurate self-reports. This study determined the degree to which the XGBoost advanced machine learning algorithm could build models that predict waist circumference from height, weight, calculated Body Mass Index, age, race/ethnicity and sex, whether they perform better than current models based on linear regression, and the relative importance of each feature in this prediction. METHODS: We trained tree-based models (via XGBoost gradient boosting) and linear models (via regression) to predict waist circumference from height, weight, Body Mass Index, age, race/ethnicity and sex (n = 60,740 participants). We created 10 iterations of each model, each using 90% of the dataset for training and the remaining 10% for testing performance (this group was different for each iteration). We calculated model performance and feature importance as an average across 10 iterations. We then externally validated the ensembled version of the top model. RESULTS: The XGBoost model predicted waist circumference with a mean bias ± standard deviation of 0.0 ± 0.04 cm and a root mean squared error of 4.7 ± 0.05 cm, with performance varying slightly by sex and race/ethnicity. The XGBoost model showed varying degrees of improvement over linear regression models. The top 3 predictors were Body Mass Index, weight and race (Asian). External validation found that on average this model overestimated waist circumference by 4.65 cm in the United Kingdom population (mainly due to overprediction in females) and underestimated waist circumference by 1.7 cm in the Chinese population. The respective root mean squared errors were 7.7 cm and 7.1 cm. CONCLUSIONS: XGBoost-based models accurately predict waist circumference from standard physical features. Waist circumference prediction using this approach would be valuable for epidemiological research and beyond.

Importance of general adiposity, visceral adiposity and vital signs in predicting blood biomarkers using machine learning.

INTRODUCTION: Blood biomarkers are measured for their ability to characterise physiological and disease states. Much is known about linear relations between blood biomarker concentrations and individual vital signs or adiposity indexes (eg, BMI). Comparatively little is known about non-linear relations with these easily accessible features, particularly when they are modelled in combination and can potentially interact with one another. METHODS: In this study, we used advanced machine learning algorithms to create non-linear computational models for predicting blood biomarkers (cells, lipids, metabolic factors) from age, general adiposity (BMI), visceral adiposity (Waist-to-Height Ratio, a Body Shape Index) and vital signs (systolic blood pressure, diastolic blood pressure, pulse). We determined the predictive power of the overall feature set. We further calculated feature importance in our models to identify the features with the strongest relations with each blood biomarker. Data were collected in 2018 and 2019 and analysed in 2020. RESULTS: Our findings characterise previously unknown relations between these predictors and blood biomarkers; in many instances the importance of certain features or feature classes (general adiposity, visceral adiposity or vital signs) differed from their expected contribution based on simplistic linear modelling techniques. CONCLUSIONS: This work could lead to the formation of new hypotheses for explaining complex biological systems and informs the creation of predictive models for potential clinical applications.

PM2.5 induces endothelial dysfunction via activating NLRP3 inflammasome.

PM2.5 (particulate matter <2.5 µm in diameter) is proven to contribute to the development of atherosclerosis. Endothelial cell dysfunction is the initial step of atherosclerosis. The underlying mechanisms of endothelial cell damage exposed to PM2.5 are still obscure. In our study, PM2.5 was administrated to C57BL/6 male mice by intranasal instillation for 2 weeks. Human umbilical vein endothelial cells (HUVECs) were also treated with PM2.5 to evaluate the adverse effect in vitro. The immunohistochemical staining of aortas showed that the expressions of proinflammatory cytokines and endothelial adhesion markers were significantly increased in PM2.5-exposed mice than that in saline-exposed mice. In vitro, PM2.5 could inhibit HUVECs viability and impair cell migration in a concentration-dependent manner. Besides, PM2.5 exposure downregulated eNOS expression while upregulated reactive oxygen species (ROS) levels. Mechanistically, PM2.5 activated the NLRP3 inflammasome in HUVECs while knockdown of NLRP3 could effectively reverse the downregulation of eNOS expression and production of ROS after PM2.5 exposure. In summary, our data showed that PM2.5 could cause endothelial dysfunction, and probably via NLRP3 inflammasome activation.

AMPK-mediated degradation of Nav1.5 through autophagy.

The voltage-gated cardiac sodium channel, Nav1.5, is the key component that controls cardiac excitative electrical impulse and propagation. However, the dynamic alterations of Nav1.5 during cardiac ischemia and reperfusion (I/R) are seldom reported. We found that the protein levels of rat cardiac Nav1.5 were significantly decreased in response to cardiac I/R injury. By simulating I/R injury in cells through activating AMPK by glucose deprivation, AMPK activator treatment, or hypoxia and reoxygenation (H/R), we found that Nav1.5 was down-regulated by AMPK-mediated autophagic degradation. Furthermore, AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5. This study highlights an instrumental role of AMPK in mediating the autophagic degradation of Nav1.5 during cardiac I/R injury.-Liu, X., Chen, Z., Han, Z., Liu, Y., Wu, X., Peng, Y., Di, W., Lan, R., Sun, B., Xu, B., Xu, W. AMPK-mediated degradation of Nav1.5 through autophagy.

Differential expression profile of long non-coding RNAs during differentiation of cardiomyocytes.

Many long non-coding RNAs (lncRNAs) are species specific and seem to be less conserved than protein-coding genes. Some of them are involved in the development of the lateral mesoderm in the heart and in the differentiation of cardiomyocytes. The purpose of the study was to investigate the expression profiles of lncRNAs during the differentiation of P19 cells into cardiomyocytes, with a view to studying the biological function of lncRNAs and their involvement in the mechanism of heart development. First, we observed the morphology of P19 cells during differentiation using an inverted microscope. Then, cardiac troponin T (cTnT) expression was detected to validate that the cells had successfully differentiated into cardiac myocytes by real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting. Lastly, the expression profile of lncRNA genes was obtained using an lncRNA microarray and real-time RT-PCR analyses. The microarray results showed that 40 lncRNAs were differentially expressed, of which 28 were upregulated and 12 were downregulated in differentiated cardiomyocytes. The differentially expressed lncRNAs were further validated. Our results illustrated a critical role of lncRNAs during the differentiation of P19 cells into cardiac myocytes, which will provide the foundation for further study of the biological functions of lncRNAs and the mechanism of heart development.

Half-dose ticagrelor versus standard-dose clopidogrel in a dual antiplatelet regimen for stent-assisted coiling or flow diversion of unruptured intracranial aneurysms: a cohort study.

BACKGROUND: Intracranial hemorrhage is the major safety concern of standard-dose ticagrelor (90 mg twice daily) based dual antiplatelet therapy (DAPT). The bleeding avoidance strategy through dose de-escalation has been investigated in interventional cardiology. However, the preserved antithrombotic efficacy and better safety of half-dose (45 mg twice daily) ticagrelor remains unverified in patients undergoing stent-assist coiling (SAC) or flow diversion (FD) treating unruptured intracranial aneurysms (UIA). METHODS: A single-center, prospective, cohort study was conducted to compare DAPT with aspirin 100 mg daily plus half-dose ticagrelor vs standard-dose clopidogrel (75 mg daily) in UIA patients. The adenosine diphosphate inhibition (ADPi) rate was utilized to quantify the antagonization of adenosine diphosphate (ADP)-induced platelet aggregation. The patients were followed-up at 6 month after discharge. The primary efficacy outcome was the major adverse cardiovascular and cerebrovascular events (MACCE), and the primary safety outcome was major bleeding. The secondary outcome was minor hemorrhage. RESULTS: Our study included 322 UIA patients, of which 254 patients were eventually enrolled after propensity score matching. The ADPi of half-dose ticagrelor (51.56%±31.46%) was comparable (P=0.089) to that of clopidogrel (57.44%±22.76%). The outcomes were also comparable. Five (3.94%) patients in the ticagrelor group and eight (6.30%) patients in the clopidogrel group reported MACCE (P=0.393). One patient in the ticagrelor group was diagnosed with asymptomatic intracranial hemorrhage 1 month after stenting. There were 36 (28.35%) minor hemorrhagic events in the ticagrelor group and 35 (27.56%) in the clopidogrel group, (P=0.889). CONCLUSION: Half-dose ticagrelor was effective and safe as a potential alternative to clopidogrel in the DAPT regimen for patients undergoing SAC/FD for UIA.

Construction of α-Acyloxy Ketones via Photoredox-Catalyzed O-H Insertion of Sulfoxonium Ylides with Carboxylic Acids.

Herein, a photoredox-catalyzed insertion of sulfoxonium ylides with carboxylic acids was advanced under mild and simple conditions, offering a practical approach for preparing α-acyloxy ketones with a broad scope of carboxylic acids. A combined experimental and computational study suggests that this reaction proceeds via a stepwise proton-assisted electron transfer mechanism.

Iron-catalyzed dual decarboxylative coupling of α-amino acids and dioxazolones under visible-light to access amide derivatives.

An iron-catalyzed decarboxylative C-N coupling of α-amino acids with dioxazolones is described herein to synthesize amide derivatives under visible-light. The desired products can be given in good to excellent yields under simple, mild, and oxidant-free conditions. This protocol provides a practical route for the transformation of α-amino acids to the corresponding amides. Computational studies were carried out to shed light on the mechanism of this reaction.

Acrylamide formation and aroma evaluation of fried pepper sauce under different exogenous Maillard reaction conditions.

To explore the impact of the Maillard reaction on fried pepper sauce (FPS) flavor and safety quality, acrylamide and volatile organic compounds (VOCs) were measured in FPS. Acrylamide was detected in 10 Maillard treated groups and a total of 110 VOCs were identified, mainly aldehydes, ketones, alcohols, acids, etc., but the content of each group differed. Partial least squares discriminant analysis showed that acrylamide in white sugar-sodium glutamate group and xylose-soy peptide group processing accumulated most acrylamide and least VOCs; Lactose-glycine, lactose-cysteine, lactose-soy peptide, and white sugar-glycine groups were positively correlated with typical Maillard reaction product (2,3-Dihydro-3,5-dihydroxy-6-methyl-4(H)-pyran-4-One); Xylose-glycine, xylose-cysteine, and white sugar-cysteine groups were weakly correlated with typical products, but positively correlated with most VOCs, whereas white sugar-cysteine group lipids showed high oxidation levels. Although white sugar-soy peptide group is not harmful on acrylamide, it has little correlation with VOCs with large responses. Conventional excipient group aroma is relatively simple with a fresh fatty taste, whereas xylose-glycine, xylose-cysteine, xylose-soy peptide, lactose-glycine, and white sugar-cysteine groups all present basic fresh and fatty tastes; lactose-cysteine group has a fruity base note; and lactose-soybean peptide, white sugar-glycine, and white sugar-soybean peptide groups have a fruity base note on an unpleasant fatty aroma. Therefore, processing different exogenous Maillard reaction substrates can achieve FPS aroma regulation and reduce acrylamide harm.

Comprehensive metabolomic characterization of atrial fibrillation.

Background: Using human humoral metabolomic profiling, we can discover the diagnostic biomarkers and pathogenesis of disease. The specific characterization of atrial fibrillation (AF) subtypes with metabolomics may facilitate effective and targeted treatment, especially in early stages. Objectives: By investigating disturbed metabolic pathways, we could evaluate the diagnostic value of biomarkers based on metabolomics for different types of AF. Methods: A cohort of 363 patients was enrolled and divided into a discovery and validation set. Patients underwent an electrocardiogram (ECG) for suspected AF. Groups were divided as follows: healthy individuals (Control), suspected AF (Sus-AF), first diagnosed AF (Fir-AF), paroxysmal AF (Par-AF), persistent AF (Per-AF), and AF causing a cardiogenic ischemic stroke (Car-AF). Serum metabolomic profiles were determined by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Metabolomic variables were analyzed with clinical information to identify relevant diagnostic biomarkers. Results: The metabolic disorders were characterized by 16 cross-comparisons. We focused on comparing all of the types of AF (All-AFs) plus Car-AF vs. Control, All-AFs vs. Car-AF, Par-AF vs. Control, and Par-AF vs. Per-AF. Then, 117 and 94 metabolites were identified by GC/MS and LC-QTOF-MS, respectively. The essential altered metabolic pathways during AF progression included D-glutamine and D-glutamate metabolism, glycerophospholipid metabolism, etc. For differential diagnosis, the area under the curve (AUC) of specific metabolomic biomarkers ranged from 0.8237 to 0.9890 during the discovery phase, and the predictive values in the validation cohort were 78.8-90.2%. Conclusions: Serum metabolomics is a powerful way to identify metabolic disturbances. Differences in small-molecule metabolites may serve as biomarkers for AF onset, progression, and differential diagnosis.

Spinal macrophage migration inhibitory factor is a major contributor to rodent neuropathic pain-like hypersensitivity.

BACKGROUND: Neuropathic pain-like hypersensitivity evoked by peripheral nerve injury is a salient clinical feature of pathologic pain; however, the underlying mechanisms of this condition remain largely unknown. Previous work has confirmed that spinal macrophage migration inhibitory factor (MIF) contributes to the pathogenesis of formalin-induced inflammatory hyperalgesia, but the role for MIF in neuropathic pain is still not well defined. METHODS: After approval by the Ethical Committee of Animal Use and Care, the sciatic chronic constriction nerve injury-induced rodent model of neuropathic pain was built. The mechanical threshold with von Frey hairs and thermal latency with hot plate were measured, and the expression of spinal MIF, CD74, and downstream extracellular signal-regulated kinase 1/2 signaling cascade was detected. Finally, MIF gene mutation and exogenous recombinant MIF were used for further clarification. RESULTS: Intrathecal MIF tautomerase inhibitor reversed sciatic chronic constriction nerve injury-induced pain behaviors. The expression of MIF and CD74 up-regulated in a time-dependent manner in the ipsilateral spinal cord dorsal horn. These changes were associated with the activation of extracellular signal-regulated kinase 1/2 signaling by MIF/CD74 interaction, which subsequently led to up-regulation of interleukin-8 and N-methyl-D-aspartic acid receptor expression and additional production of prostaglandin E(2). Further, MIF gene mutation and exogenous recombinant MIF could desensitize and mimic sciatic chronic constriction nerve injury-evoked pain responses and cellular changes, respectively. CONCLUSIONS: MIF-associated extracellular signal-regulated kinase 1/2-N-methyl-D-aspartic acid receptor or prostaglandin E(2) cascade accounts for the changes in peripheral nerve injury-induced nociceptive responses.

Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate.

Embryo quality is strongly dependent on the in-vitro culture environment. Conventionally, IVF/intracytoplasmic sperm injection (ICSI) embryos are examined microscopically every morning (from day 1 to day 6) to assess fertilization, cleavage and embryo quality. Consequently, the frequent exposure to non-optimal conditions outside the incubator may adversely affect embryonic viability and quality. Hence, this study investigated whether reduction of observation frequency outside the incubator can enhance blastocyst formation rate. A total of 285 IVF/ICSI cycles were divided into two groups. Embryos in the control group (103 cycles) were assessed out-of-incubator every day after insemination (day 1 to day 6; six times). In the experimental group (182 cycles), embryos were assessed four times, on days 1, 3, 5 and 6. The total blastocyst formation rate, day-5 blastocyst formation rate, proportion of good blastocysts and number of cryopreserved blastocysts per patient were significantly lower for the control group compared with the experimental group (42.5%, 31.4%, 50.7%, 1.72+/-1.55 versus 52.6%, 40.7%, 60.1%, 2.64+/-2.59, respectively, P<0.05); although there were no significant differences in the proportions of good embryos on day 3, blastocyst formation rate on day 6, clinical pregnancy rate and implantation rate. Hence, reduction of the observation frequency of embryos outside the incubator can enhance embryo quality and blastocyst formation rate.

NYGGF4 homologous gene expression in 3T3-L1 adipocytes: regulation by FFA and adipokines.

NYGGF4 is a novel gene that is abundantly expressed in the adipose tissue of obese subjects and is involved in insulin resistance. In the present study, the mRNA expression of NYGGF4 homologous genes was examined in the 3T3-L1 cell line. The NYGGF4 mRNAs were expressed at low levels in the 3T3-L1 preadipocytes. During the conversion of 3T3-L1 preadipocytes to adipocytes, the expression of NYGGF4 mRNA was upregulated. On the 8th day after induction of differentiation, the NYGGF4 mRNA levels peaked and remained high. Free fatty acids (FFA) and tumor necrosis factor-α (TNFα) could upregulate NYGGF4 mRNA expression in 3T3-L1 adipocytes, while interleukin-6 (IL-6), leptin, and resistin exerted an inhibitory effect. The results suggest that the expression of NYGGF4 mRNA is affected by a variety of factors that are related to insulin sensitivity. It is likely that NYGGF4 may be an important mediator in the development of obesity-related insulin resistance.

Importance of timely management of patients in reducing fatality rate of coronavirus disease 2019.

The outbreak of coronavirus disease 2019 (COVID-19) characterized with pneumonia, firstly occurred in Wuhan city, China, in December 2019 has so far spread in over 200 countries and territories in the world. One of the important goals in facing outbreaks of COVID-19 is to reduce the case fatality rate. We reported here that the fatality rate of COVID-19 in other provinces of mainland China was 0.82% (121/14,708), significantly lower than 6.62% (4512/68,128) in Hubei province (p<0.0001). The main reason for the lower fatality rate was likely due to the timely management of the patients in other provinces, highlighting the importance of timely management of patients in reducing the fatality rate of COVID-19.

CCND1 G870A polymorphism contributes to breast cancer susceptibility: a meta-analysis.

Cyclin D1 (CCND1), a key cell cycle regulatory protein that governs the cell cycle progression from G1 to S phase, can promote cell proliferation or induce growth arrest and apoptosis. Since the identification of a well-characterized functional polymorphism, G870A in exon 4 of CCND1, several molecular epidemiological studies were conducted in recent years to evaluate the association between G870A and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis on 5,371 cases with breast cancer and 5,336 controls from 7 published case-control studies showed that the variant allele 870A was associated with a significantly increased risk of breast cancer (AA vs. GG: OR = 1.18, 95% CI = 1.06-1.32; AG vs. GG: OR = 1.12, 95% CI = 1.01-1.23; AA/AG vs. GG: OR = 1.14, 95% CI = 1.04-1.25) without any between-study heterogeneity. In the stratified analysis by race, we found that the increased breast cancer risk associated with G870A polymorphism was more evident in Caucasians (OR = 1.14, 95% CI = 1.01-1.28, P = 0.88 for heterogeneity test), but not significant in Asians (OR = 1.10, 95% CI = 0.85-1.42, P = 0.05 for heterogeneity test). The results suggest that CCND1 G870A polymorphism may contribute to breast cancer development, especially in Caucasians. Additional well-designed large studies were required for the validation of this association in different populations.

A novel competitive fluorescent multiplex STR polymorphism assay for rapid, reliable and single-tube screening of 22q11.2 copy-number aberrations.

Copy-number aberrations of the 22q11.2 region can lead to varied resulting and complex phenotypes. Routine screening for these common constitutional chromosomal abnormalities requires powerful tools. A competitive fluorescent multiplex STR polymorphism assay (CFMSA) was built for detecting these aberrations. With the introduction of an internal reference and distinguishable STR polymorphism markers, this competitive fluorescent multiplex STR polymorphism assay provides complementary information about polymorphism and gene dosage in one tube simultaneously, thereby enhancing the assay sensitivity. It was first tested in 110 normal controls, and was proven to have highly polymorphic and reliable gene dosage information. Then, 476 subjects with congenital heart defect were screened according to the testing strategy of the American Heart Association, and 17 deletions and 1 duplication of 22q11.2 were correctly identified. It is expected that this assay will serve as a cost-effective alternative to existing assays for routine, large-scale screening in all at-risk individuals with either deletion or duplication in 22q11.2.

Epidural analgesia in the latent phase of labor and the risk of cesarean delivery: a five-year randomized controlled trial.

BACKGROUND: The optimal timing of epidural analgesia has been a controversial issue, and how early women can benefit from epidural analgesia is still debated. The objective of this trial was to test the hypothesis that patient-controlled epidural analgesia given at cervical dilation of 1.0 cm or more does not increase the risk of prolonged labor or Cesarean delivery. METHODS: After institutional review board approval and patient consent, 12,793 nulliparous patients requesting neuraxial analgesia were enrolled and randomized to an early epidural (cervical dilation at least 1.0 cm) or delayed epidural (cervical dilation at least 4.0 cm) group. A 15-ml epidural analgesic mixture consisting of 0.125% (1.25 mg/ml) ropivacaine plus 0.3 microg/ml sufentanil was given in a single bolus, followed by patient-controlled pump with a 10-ml bolus without background infusion. Repeatable meperidine (25 mg) was prescribed as being the rescue analgesic to patients in the delayed epidural group. The primary outcome was the rate of Cesarean section. RESULTS: The median diameters of cervical dilation were 1.6 cm and 5.1 cm in the early and delayed epidural groups, respectively (P < 0.0001). The duration of labor from analgesia request to vaginal delivery was equal in both groups (11.3 +/- 4.5 h for early epidural and 11.8 +/- 4.9 h for delayed epidural group women, P = 0.90). No statistically significant difference in the rate of Cesarean section was observed between the two groups on the intention-to-treat analysis (23.2% vs. 22.8% in the early and delayed epidural groups, respectively; P = 0.51). CONCLUSIONS: Epidural analgesia in the latent phase of labor at cervical dilation of 1.0 cm or more does not prolong the progression of labor and does not increase the rate of Cesarean in nulliparous women compared with the delayed analgesia at the cervical dilation of 4.0 cm or more.