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.

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.

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.

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.

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.

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.

miR-30c regulates proliferation, apoptosis and differentiation via the Shh signaling pathway in P19 cells.

MicroRNAs (miRNAs) are small, non-coding single-stranded RNAs that suppress protein expression by binding to the 3' untranslated regions of their target genes. Many studies have shown that miRNAs have important roles in congenital heart diseases (CHDs) by regulating gene expression and signaling pathways. We previously found that miR-30c was highly expressed in the heart tissues of aborted embryos with ventricular septal defects. Therefore, this study aimed to explore the effects of miR-30c in CHDs. miR-30c was overexpressed or knocked down in P19 cells, a myocardial cell model that is widely used to study cardiogenesis. We found that miR-30c overexpression not only increased cell proliferation by promoting cell entry into S phase but also suppressed cell apoptosis. In addition, we found that miR-30c inhibited dimethyl sulfoxide-induced differentiation of P19 cells. miR-30c knockdown, in contrast, inhibited cell proliferation and increased apoptosis and differentiation. The Sonic hedgehog (Shh) signaling pathway is essential for normal embryonic development. Western blotting and luciferase assays revealed that Gli2, a transcriptional factor that has essential roles in the Shh signaling pathway, was a potential target gene of miR-30c. Ptch1, another important player in the Shh signaling pathway and a transcriptional target of Gli2, was downregulated by miR-30c overexpression and upregulated by miR-30c knockdown. Collectively, our study revealed that miR-30c suppressed P19 cell differentiation by inhibiting the Shh signaling pathway and altered the balance between cell proliferation and apoptosis, which may result in embryonic cardiac malfunctions.

Effect of miR-20b on Apoptosis, Differentiation, the BMP Signaling Pathway and Mitochondrial Function in the P19 Cell Model of Cardiac Differentiation In Vitro.

OBJECTIVE: To explore the effect of miR-20b on apoptosis, differentiation, the BMP signaling pathway and mitochondrial function in the P19 cell model of cardiac differentiation in vitro. METHODS: A miR-20b over-expression vector, a miR-20b silencing vector and their corresponding empty vectors were constructed and transfected into P19 cells, separately. Stably miR-20b overexpressing and silenced P19 cell lines were successfully selected by blasticidin and puromycin, separately. The cells were induced to undergo apoptosis in FBS-free-α-MEM. The induced cells were examined by flow cytometry and measurement of their caspase-3 activities. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate the relative expression of marker genes of cardiomyocytes during differentiation, such as cTnT, GATA4 and ANP. QRT-PCR was also used to detect the mitochondrial DNA (mtDNA) copy number. We investigated the cellular ATP production using a luciferase-based luminescence assay. The reactive oxygen species (ROS) was determined by DCFDA (2', 7'-Dichlorofluorescein diacetate) and the mitochondrial membrane potential (MMP) was elucidated by a JC-1 fluorescent probe, both using fluorescence microscopy and flow cytometer. The expression of BMP signaling pathway-related proteins were analyzed by Western blotting. RESULTS: Stably miR-20b overexpressing and silenced P19 cell lines were successfully obtained. MiR-20b overexpression increased apoptosis and promoted differentiation in P19 cells by promoting the activation of the BMP signaling pathway. In addition, miR-20b overexpression induced mitochondrial impairment in P19 cells during differentiation, which was characterized by lower MMP, raised ATP synthesis and increased ROS levels. The effects of miR-20b silencing were the exact opposite to those of overexpression. CONCLUSION: Collectively, these results suggested that miR-20b was very important in apoptosis, differentiation and mitochondrial function of P19 cells. MiR-20b may represent a new therapeutic target for congenital heart diseases and provide new insights into the mechanisms of cardiac diseases.

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.

Genetic variants in epoxide hydrolases modify the risk of oligozoospermia and asthenospermia in Han-Chinese population.

OBJECTIVES: Epoxide hydrolases are involved in detoxifying and excreting the environmental chemicals, which are associated with decreased semen quality and male infertility. We hypothesized that polymorphisms in epoxide hydrolases may be associated with risk of oligozoospermia and asthenospermia. DESIGN AND METHODS: In this study, 468 fertile controls and 672 idiopathic male infertile patients were recruited. SNPstream and TaqMan assay were used to genotype four single nucleotide polymorphisms in EPHX1 and EPHX2. The semen analysis was performed by computer-assisted semen analysis system. RESULTS: Our results demonstrated that rs1042064 of EPHX2 was significantly associated with decreased risk of oligozoospermia (OR=0.65, 95% CI: 0.44-0.98) and asthenospermia (OR=0.66, 95% CI: 0.46-0.94). CONCLUSIONS: Our results provided evidence that genetic variants in epoxide hydrolases may modify the risk of oligozoospermia and asthenospermia in Han-Chinese population.

Endocrine disruptors, polychlorinated biphenyls-induced gC1qR-dependent apoptosis in human trophoblast cell line HTR-8/SVneo.

Although an association exists between exposure to polychlorinated biphenyls (PCBs) and spontaneous miscarriage, the mechanisms underlying this phenomenon remain unclear. In this study, PCBs content in plasma was detected by gas chromatography-mass spectrometry (GC-MS) and decidua tissues were examined for the expression of globular heads of C1q receptor (gC1qR) using Western blot in patients who underwent induced abortion and spontaneous abortion. Results showed increased PCBs content and gC1qR expression in patients who experienced spontaneous abortion. In vitro, Western blot analysis demonstrated significantly higher caspase 3 expression and apoptotic cell counts in green fluorescent protein (GFP)-gC1qR vector group. Additionally, gC1qR and caspase 3 showed decreased expression following PCBs plus gC1qR small interfering RNA (siRNA) treatment. The percentage of apoptotic cells increased in cells treated with PCBs alone or PCB plus negative siRNA. These data suggest that maternal exposure to PCBs is associated with adverse pregnancy outcomes and that upregulation of gC1qR is important for PCBs-mediated trophoblast cell apoptosis.

The role of gC1qR in regulating survival of human papillomavirus 16 oncogene-transfected cervical cancer cells.

Human papillomavirus 16 (HPV-16) is strongly associated with the development of 50% of cervical cancers. The E6 and E7 proteins encoded by high-risk HPV types are associated with the immune evasion of cervical cancer cells, but the mechanism is poorly understood. The purpose of this study was to investigate whether cells transfected with E6 and E7 expression constructs reduce the expression of the globular heads of the C1q receptor (gC1qR), a mitochondrial surface protein overexpressed in certain cancer cells. First, C-33A cells were transiently transfected with the HPV-16 E6 and E7 oncogenes which resulted in gC1qR inhibition and a reduction in apoptosis. Second, gC1qR overexpression in cells showed that caspase-3 activation and mitochondrial dysfunction were involved in gC1qR-induced apoptosis. Cells transfected with a GFP-gC1qR vector resulted in upregulated gC1qR protein and a gradual increase in the generation of reactive oxygen species (ROS). Additionally, ROS generation and increased Ca2+ influx in mitochondria resulted in the loss of the mitochondrial transmembrane potential. Interestingly, when gC1qR was overexpressed in C-33A cells, apoptosis was significantly inhibited when cells were treated with metformin, which may protect mitochondrial function. These data suggest that gC1qR could play an important role in HPV-16-induced cervical cancer immune evasion depending on its level of expression and subcellular localisation.

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.