Exploring pharmacological active ingredients of traditional Chinese medicine by pharmacotranscriptomic map in ITCM.

With the emergence of high-throughput technologies, computational screening based on gene expression profiles has become one of the most effective methods for drug discovery. More importantly, profile-based approaches remarkably enhance novel drug-disease pair discovery without relying on drug- or disease-specific prior knowledge, which has been widely used in modern medicine. However, profile-based systematic screening of active ingredients of traditional Chinese medicine (TCM) has been scarcely performed due to inadequate pharmacotranscriptomic data. Here, we develop the largest-to-date online TCM active ingredients-based pharmacotranscriptomic platform integrated traditional Chinese medicine (ITCM) for the effective screening of active ingredients. First, we performed unified high-throughput experiments and constructed the largest data repository of 496 representative active ingredients, which was five times larger than the previous one built by our team. The transcriptome-based multi-scale analysis was also performed to elucidate their mechanism. Then, we developed six state-of-art signature search methods to screen active ingredients and determine the optimal signature size for all methods. Moreover, we integrated them into a screening strategy, TCM-Query, to identify the potential active ingredients for the special disease. In addition, we also comprehensively collected the TCM-related resource by literature mining. Finally, we applied ITCM to an active ingredient bavachinin, and two diseases, including prostate cancer and COVID-19, to demonstrate the power of drug discovery. ITCM was aimed to comprehensively explore the active ingredients of TCM and boost studies of pharmacological action and drug discovery. ITCM is available at http://itcm.biotcm.net.

Genome analysis of the mpox (formerly monkeypox) virus and characterization of core/variable regions.

Since smallpox was eradicated in 1980, the monkeypox virus (MPXV) has emerged as the most threatening orthopoxvirus in the world. In this study, we conducted a comprehensive analysis of the currently published complete genome sequences of the monkeypox virus. The core/variable regions were identified through core-pan analysis of MPXV. Besides single-nucleotide polymorphisms, our study also revealed that specific genes, multi-copy genes, repeat sequences, and recombination fragments are primarily distributed in the variable region. This result suggests that variable regions are not only more susceptible to single-base mutations, but also to events such as gene loss or gain, as well as recombination. Taken together, our results demonstrate the genomic characteristics of the core/variable regions of MPXV, and contribute to our understanding of the evolution of MPXV.

CD73/adenosine axis exerts cardioprotection against hypobaric hypoxia-induced metabolic shift and myocarditis in a sex-dependent manner.

BACKGROUND: Clinical and experimental studies have shown that the myocardial inflammatory response during pathological events varies between males and females. However, the cellular and molecular mechanisms of these sex differences remain elusive. CD73/adenosine axis has been linked to anti-inflammatory responses, but its sex-specific cardioprotective role is unclear. The present study aimed to investigate whether the CD73/adenosine axis elicits sex-dependent cardioprotection during metabolic changes and myocarditis induced by hypobaric hypoxia. METHODS: For 7 days, male and female mice received daily injections of the CD73 inhibitor adenosine 5'- (α, ß-methylene) diphosphate (APCP) 10 mg/kg/day while they were kept under normobaric normoxic and hypobaric hypoxic conditions. We evaluated the effects of hypobaric hypoxia on the CD73/adenosine axis, myocardial hypertrophy, and cardiac electrical activity and function. In addition, metabolic homeostasis and immunoregulation were investigated to clarify the sex-dependent cardioprotection of the CD73/adenosine axis. RESULTS: Hypobaric hypoxia-induced cardiac dysfunction and adverse remodeling were more pronounced in male mice. Also, male mice had hyperactivity of the CD73/adenosine axis, which aggravated myocarditis and metabolic shift compared to female mice. In addition, CD73 inhibition triggered prostatic acid phosphatase ectonucleotidase enzymatic activity to sustain adenosine overproduction in male mice but not in female mice. Moreover, dual inhibition prostatic acid phosphatase and CD73 enzymatic activities in male mice moderated adenosine content, alleviating glycolytic shift and proinflammatory response. CONCLUSION: The CD73/adenosine axis confers a sex-dependent cardioprotection. In addition, extracellular adenosine production in the hearts of male mice is influenced by prostatic acid phosphatase and tissue nonspecific alkaline phosphatase.

Cationic Polysaccharides Bind to the Endothelial Cell Surface Extracellular Matrix Involving Heparan Sulfate.

Cationic polysaccharides have been extensively studied for drug delivery via the bloodstream, yet few have progressed to clinical use. Endothelial cells lining the blood vessel wall are coated in an anionic extracellular matrix called the glycocalyx. However, we do not fully comprehend the charged polysaccharide interactions with the glycocalyx. We reveal that the cationic polysaccharide poly(acetyl, arginyl) glucosamine (PAAG) exhibits the highest association with the endothelial glycocalyx, followed by dextran (neutral) and hyaluronan (anionic). Furthermore, we demonstrate that PAAG binds heparan sulfate (HS) within the glycocalyx, leading to intracellular accumulation. Using an in vitro glycocalyx model, we demonstrate a charge-based extent of association of polysaccharides with HS. Mechanistically, we observe that PAAG binding to HS occurs via a condensation reaction and functionally protects HS from degradation. Together, this study reveals the interplay between polysaccharide charge properties and interactions with the endothelial cell glycocalyx toward improved delivery system design and application.

NMR-Guided Isolation of Anti-inflammatory Carabranolides from the Fruits of Carpesium abrotanoides L.

Carabranolides present characteristic NMR resonances for the cyclopropane moiety, which distinctly differ from those of other compounds and were used for an NMR-guided isolation in this study. As a result, 11 undescribed carabranolides (1-11), along with five known ones (12-16), were isolated from the fruits of Carpesium abrotanoides L. Compounds 1-11 are new esters of carabrol at C-4 with different carboxylic acids. Their structures were elucidated by HRESIMS and NMR spectroscopic data analysis. The biological evaluation showed that compounds 2-4, 15, and 16 exhibited significant inhibitory activity against LPS-induced NO release with an IC50 value of 5.6-9.1 µM and dose-dependently decreased iNOS protein expression in RAW264.7 cells.

Effectiveness of a Triple Antiarrhythmic Drug Strategy for Arrhythmia Recurrence after Persistent Atrial Fibrillation Ablation.

BACKGROUND AND OBJECTIVE: Treating recurrent atrial arrhythmias after persistent atrial fibrillation (PeAF) ablation is often challenging. This single-center, prospective study aimed to observe the effectiveness of different combinations of oral antiarrhythmic drugs (AADs) in reverting to sinus rhythm (SR) in patients with recurrent atrial arrhythmias after PeAF ablation. METHODS: Forty-five patients who experienced recurrent atrial arrhythmias after PeAF ablation were included. Based on their medication regimens, patients were divided into two groups, with the study group being a triple-drug group (digoxin combined with amiodarone/ propafenone and ß-blocker), and the control group being a non-triple-drug group. RESULTS: The rate of reversion to SR was significantly higher in the study group (n = 29) than in the control group (n = 16) at 3 weeks (34.48% vs. 0%, p < 0.01) and 1 month (44.84% vs. 6.25%, p = 0.02) after initiating AADs. No patients with asymptomatic bradycardia were observed in either group. CONCLUSIONS: For patients with recurrent atrial arrhythmias after PeAF ablation, a regimen of low-dose digoxin combined with amiodarone/propafenone and ß-blocker may effectively improve short-term reversion rates.

Gender differences in GRK2 in cardiovascular diseases and its interactions with estrogen.

G protein-coupled receptor kinase 2 (GRK2) is a multifunctional protein involved in regulating G protein-coupled receptor (GPCR) and non-GPCR signaling in the body. In the cardiovascular system, increased expression of GRK2 has been implicated in the occurrence and development of several cardiovascular diseases (CVDs). Recent studies have found gender differences in GRK2 in the cardiovascular system under physiological and pathological conditions, where GRK2's expression and activity are increased in males than in females. The incidence of CVDs in premenopausal women is lower than in men of the same age, which is related to estrogen levels. Given the shared location of GRK2 and estrogen receptors, estrogen may interact with GRK2 by modulating vital molecules such as calmodulin (CaM), caveolin, RhoA, nitrate oxide (NO), and mouse double minute 2 homolog (Mdm2), via signaling pathways mediated by estrogen's genomic (ERα and ERß), and non-genomic (GPER) receptors, conferring cardiovascular protection in females. Highlighting the gender differences in GRK2 and understanding its interaction with estrogen in the cardiovascular system is pertinent in treating gender-related CVDs. As a result, this article explores the gender differences of GRK2 in the cardiovascular system and its relationship with estrogen during disease conditions. Estrogen's protective and therapeutic effects and its mechanism on GRK2-related cardiovascular diseases have also been discussed.

Peripheral blood parameters for predicting PICU admission and mechanical ventilation in pediatric inpatients with human parainfluenza virus-induced pneumonia.

Human parainfluenza viruses (hPIVs)-induced pneumonia is an important cause of pediatric hospitalization, and some develop severe pneumonias requiring pediatric intensive care unit (PICU) admission and mechanical ventilation (MV). The aim of this study is to investigate the value of peripheral blood (PB) parameters available on admission in predicting the need for PICU admission and MV due to pneumonia caused by hPIVs. A total of 331 cases including 277 (83.69%) on the general ward (GW) and 54 (16.31%) on the PICU were enrolled between January 2016 and June 2021. Of 54 patients admitted to the PICU, 24 patients (7.25%) received MV, whereas 30 (9.06%) did not. For both the PICU and GW groups, infants accounted for the highest proportion while school children had the lowest. Compared with the GW group, the PICU group had significantly higher rates of premature birth, fatigue, sore throat, headache, chest pain, tachypnea, dyspnea, and underlying diseases including congenital tracheal stenosis, congenital heart disease (CHD), metabolic disorder, and neurological disorder (ND), but significant lower proportion of exclusive breastfeeding and Z-scores for weight-for-height, weight-for-age, height-for-age, and body-mass-index (BMI)-for-age (BMIZ). Higher levels of some leukocyte differential counts (LDC)-related parameters including counts of neutrophil (N), ratios of neutrophil-to-lymphocyte ratio (NLR), derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR), and platelet-to-lymphocyte ratio (PLR), lower levels of some other LDC-related parameters including lymphocyte (L) and monocyte (M) counts, ratios of lymphocyte-to-monocyte ratio (LMR), lymphocyte-to-C-reactive protein ratio, and prognostic nutritional index (PNI), and lower levels of PB protein (PBP)-related parameters including red blood cell (RBC), hemoglobin, total protein (TP), and serum albumin were observed in the PB of patients in the PICU compared with those in the GW. Notably, higher PLR level and two comorbidities including CHD and ND were identified as independent risk factors for PICU admission, while lower PNI level as well as smaller numbers of RBC and L as good predictors. Low levels of TP might be a useful predictor of the need for MV. Overall, the relative contributions of LDC- and PBP-related factors for accurate identification of patients required PICU admission accounted for 53.69% and 46.31%, respectively. Thus, determination of whether a patient with hPIVs-induced pneumonia is admitted to PICU involves consideration of both the LDC- and PBP-related parameters.

Efficacy of granulocyte colony-stimulating factor for infertility undergoing IVF: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the effectiveness of granulocyte colony-stimulating factor (G-CSF) for infertility and recurrent spontaneous abortion. METHODS: Existing research was searched in PubMed, Embase and Cochrane Library till Dec 2021. Randomized control trials (RCTs) that compared G-CSF administration with the control group in infertility women undergoing IVF were included. The primary outcomes included clinical pregnancy rate; the secondary outcomes included live birth rate, abortion ratebiochemical pregnancy rate, embryo implantation rate, as well as endometrial thickness. RESULT(S): 20 RCTs were included in this study. G-CSF increased the clinical pregnancy rate (RR = 1.85; 95% CI: 1.07, 3.18) and the endometrial thickness (MD = 2.25; 95% CI: 1.58,2.92;) in patients with thin endometrium undergoing IVF. G-CSF increased the biochemical pregnancy rate (RR = 2.12; 95% CI: 1.54, 2.93), the embryo implantation rate (RR = 2.51; 95% CI: 1.82, 3.47) and the clinical pregnancy rate (RR = 1.93; 95% CI: 1.63, 2.29) in patients with a history of repeated implantation failure undergoing IVF. No differences were found in pregnancy outcomes of general IVF patients. CONCLUSIONS: Granulocyte colony-stimulating factor is likely to be a potential option for infertility women undergoing IVF with thin endometrium or recurrent implantation failure . TRIAL REGISTRATION: Retrospectively registered (The PROSPERO registration number: CRD42022360161).

Multivalent Interactions Enable the Natural Alkaline Amino Acids to Transmute into Macroscopic Adhesive Materials.

Natural alkaline amino acids (aAAs) have been found to interact with tannic acid (TA) in aqueous solution via multiple noncovalent interactions, giving rise to the formation of water-immiscible supramolecular copolymers (aAAs/TA). The driving forces and the internal structures of the supramolecular copolymers were characterized by nuclear magnetic resonance (NMR), X-ray photoelectron spectroscopy (XPS), ζ-potential, elemental analysis (EA), and scanning electron microscopy (SEM). Rheological and lap shear adhesion measurements identify that the aAAs/TA soft materials exhibit wet and underwater adhesion, shear thinning, and self-healing behavior. This supramolecular adhesive can be utilized as both injectable materials and self-gelling powder. Another feature of the aAAs/TA adhesives is the acceptable cellular compatibility with L-929 cells, which enables the supramolecular copolymers to be potential soft materials for health care and bio-related applications. The work highlights that the cross-linked supramolecular polymerization strategy enables minimalistic biomolecules to emulate the functions of complicated proteins secreted by aquatic organisms.

Association of STAT3 gene polymorphisms with systemic lupus erythematosus in a Chinese Han population.

OBJECTIVE: Evidence supports the important role of STAT3 in SLE; however, association between STAT3 gene polymorphisms and SLE risk needs discussion. METHODS: Three hundred SLE patients and 380 healthy controls from Chinese Han population were included. DNA is extracted from peripheral blood mononuclear cells and the clinical characteristics of patients are collected. STAT3 gene polymorphisms (rs6503695, rs744166, rs9912773, and rs12601982) were genotyped by the Kompetitive Allele-Specific PCR (KASP) method. SPSS 26.0 was utilized to analyze the genetic susceptibility of SLE and STAT3 gene polymorphisms. RESULTS: Frequencies of genotypes CT, TT, and TT+CT were significantly lower in SLE patients compared with those in healthy controls with respect to rs6503695 (p = .007, p < .001, p = .001). Frequencies of rs744166 genotypes AG, AA, and AA+AG were decreased in SLE patients as compared to those in healthy controls (p = .034, p = .006, p = .009). The recessive models (CC vs GG+GC) for rs9912773 and (AA vs GG+GA) for rs12601982 were significantly related to SLE patients (p = .014, p = .035). Moreover, allele C of rs6503695 was related to optic nerve damage in SLE patients (p = .036). rs744166 allele G was correlated with positive rash and albuminuria in SLE patients (p = .006, p = .014). For rs9912773, SLE patients carrying genotype GG had higher serum C3 and C4 levels compared to genotype GC+CC (p = .029, p = .028). The rs12601982 allele G was strongly associated with positive hypocomplementemia in SLE patients (p = .034). SLE patients carrying genotypes GG, GC, and CC had different SLEDAI score for rs12601982 (GG vs GC vs CC, p = .003). CONCLUSION: STAT3 gene polymorphisms associated with SLE susceptibility.

Systemic lupus erythematosus with high disease activity identification based on machine learning.

OBJECTIVE: Clinical evaluation of systemic lupus erythematosus (SLE) disease activity is limited and inconsistent, and high disease activity significantly, seriously impacts on SLE patients. This study aims to generate a machine learning model to identify SLE patients with high disease activity. METHOD: A total of 1014 SLE patients with low disease activity and 453 SLE patients with high disease activity were included. A total of 94 clinical, laboratory data and 17 meteorological indicators were collected. After data preprocessing, we use mutual information and multisurf to evaluate and select the importance of features. The selected features are used for machine learning modeling. Performance of the model is evaluated and verified by a series of binary classification indicators. RESULTS: We screened out hematuria, proteinuria, pyuria, low complement, precipitation, sunlight and other features for model construction by integrated feature selection. After hyperparameter optimization, the LGB has the best performance (ROC: AUC = 0.930; PRC: AUC = 0.911, APS = 0.913; balance accuracy: 0.856), and the worst is the naive bayes (ROC: AUC = 0.849; PRC: AUC = 0.719, APS = 0.714; balance accuracy: 0.705). Finally, the selection of features has good consistency in the composite feature importance bar plot. CONCLUSION: We identify SLE patients with high disease activity by a simple machine learning pipeline, especially the LGB model based on the characteristics of proteinuria, hematuria, pyuria and other feathers screened out by collective feature selection.

Lupus nephritis or not? A simple and clinically friendly machine learning pipeline to help diagnosis of lupus nephritis.

OBJECTIVE: Diagnosis of lupus nephritis (LN) is a complex process, which usually requires renal biopsy. We aim to establish a machine learning pipeline to help diagnosis of LN. METHODS: A cohort of 681 systemic lupus erythematosus (SLE) patients without LN and 786 SLE patients with LN was established, and a total of 95 clinical, laboratory data and 17 meteorological indicators were collected. After tenfold cross-validation, the patients were divided into training set and test set. The features selected by collective feature selection method of mutual information (MI) and multisurf were used to construct the models of logistic regression, decision tree, random forest, naive Bayes, support vector machine (SVM), light gradient boosting (LGB), extreme gradient boosting (XGB), and artificial neural network (ANN), the models were compared and verified in post-analysis. RESULTS: Collective feature selection method screens out antistreptolysin (ASO), retinol binding protein (RBP), lupus anticoagulant 1 (LA1), LA2, proteinuria and other features, and the hyperparameter optimized XGB (ROC: AUC = 0.995; PRC: AUC = 1.000, APS = 1.000; balance accuracy: 0.990) has the best performance, followed by LGB (ROC: AUC = 0.992; PRC: AUC = 0.997, APS = 0.977; balance accuracy: 0.957). The worst performance is naive Bayes model (ROC: AUC = 0.799; PRC: AUC = 0.822, APS = 0.823; balance accuracy: 0.693). In the composite feature importance bar plots, ASO, RF, Up/Ucr, and other features play important roles in LN. CONCLUSION: We developed and validated a new and simple machine learning pathway for diagnosis of LN, especially the XGB model based on ASO, LA1, LA2, proteinuria, and other features screened out by collective feature selection.

'Single-shot' pulmonary vein isolation using a novel lotos pulsed field ablation catheter: a pre-clinical evaluation of feasibility, safety, and 30-day efficacy.

AIMS: Pulsed field ablation (PFA) is emerging as a non-thermal, tissue-specific technique for pulmonary vein isolation (PVI) in atrial fibrillation therapy. This pre-clinical study aims to investigate the feasibility and safety of PVI using a novel PFA system including a nanosecond-scale PFA generator, a novel lotos PFA catheter, and a customized 12 Fr steerable sheath. METHODS AND RESULTS: A total of 11 Yorkshire swine were included in this study, with 4 in the acute cohort and 7 in the chronic cohort. Under general anaesthesia, transseptal puncture and pulmonary vein (PV) angiography was initially performed. The PFA catheter was navigated to position at the right and left PV antrum after the electroanatomic reconstruction of the left atrium. Biphasic PFA applications were performed on PVs in both the spindle-shaped and the lotos-shaped poses. Pulmonary vein isolation and PFA-associated safety were assessed 30 min after ablation in both cohorts and 30 days later in the chronic cohort. Detailed necropsy and histopathology were performed. Additional intracardiac echocardiography and coronary angiogram were evaluated for safety. All target PVs (n = 20) were successfully isolated on the first attempt. No spasm of coronary artery or microbubble was seen during the procedure. Eleven of 12 PVs (91.6%) remained in isolation at the 30-day invasive study. No evidence of PV stenosis was observed in any targets. However, transient diaphragm capture occurred in 17.6%. Histopathological examinations showed no evidence of collateral injury. CONCLUSION: This study provides scientific evidence demonstrating the safety and efficacy of the novel PFA catheter and system for single-shot PVI, which shows great potential.

High density mapping of complex atrial tachycardia in patients after cardiac surgery.

To provide an overview of the current application of high-density mapping (HDM) in the mechanism of complex atrial tachycardias (ATs). Complex ATs are frequently scar-related, after history of previous cardiac surgery and large scars. These scar-related ATs are difficult to manage medically and frequently recur after electrical cardioversion. HDM technologies have enabled rigorous elucidation of AT mechanisms in patients post cardiac surgery. This article showed the application of HDM technology in complex ATs from the mechanisms of complex ATs, the development of HDM technology, and the identification of scars or critical isthmus from HDM. HDM-guided approach is highly effective for identifying the ATs mechanism and critical isthmus.

Predictors of pacing-induced cardiomyopathy detection and outcomes demonstration after conduction system pacing upgrade on patients with long-term persistent atrial fibrillation.

OBJECTIVE: To identify the predictors of pacing-induced cardiomyopathy (PICM) and illustrate the safety and feasibility of conduction system pacing (CSP) upgrade on patients with long-term persistent atrial fibrillation (AF). METHODS: All patients with long-term persistent AF and normal left ventricular ejection fraction (LVEF) ≥50% were consecutively enrolled from January 2008 to December 2017, and all the patients with atrioventricular block (AVB) and high right ventricular pacing (RVP) percentage of at least 40%. The predictors of PICM were identified, and patients with PICM were followed up for at least 1 year regardless of CSP upgrade. Cardiac performances and lead outcomes were investigated in all patients before and after CSP upgrade. RESULTS: The present study included 139 patients, out of which 37 (26.62%) developed PICM, resulting in a significant decrease in the left ventricular ejection fraction (LVEF) from 56.11 ± 2.56% to 38.10 ± 5.81% (p< .01). The median duration for the development of PICM was 5.43 years. Lower LVEF (≤52.50%), longer paced QRS duration (≥175 ms), and higher RVP percentage (≥96.80%) were identified as independent predictors of PICM. Furthermore, the morbidity of PICM progressively increased with an increased number of predictors. The paced QRS duration (183.90 ± 22.34 ms vs. 136.57 ± 20.71 ms, p < .01), LVEF (39.35 ± 2.71% vs. 47.50 ± 7.43%, p < .01), and left ventricular end-diastolic diameter (LVEDD) (55.53 ± 5.67 mm vs. 53.20 ± 5.78 mm, p = .03) improved significantly on patients accepting CSP upgrade. CSP responses and complete reverse remodeling (LVEF ≥50% and LVEDD < 50 mm) were detected in 80.95% (17/21) and 42.9% (9/21) of patients. The pacing threshold (1.52 ± 0.78 V/0.4 ms vs. 1.27 ± 0.59 V/0.4 ms, p = .16) was stable after follow-up. CONCLUSION: PICM is very common in patients with long-term persistent AF, and CSP upgrade was favorable for better cardiac performance in this patient population.

Muscle quality index and cardiovascular disease among US population-findings from NHANES 2011-2014.

BACKGROUND AND OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. However, current evidence on the association between muscle quality and CVD is limited. This study investigates the potential association between the muscle quality index (MQI) and the prevalence of CVD and CVD-related mortality. METHODS: Participants were selected from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Data on mortality and causes of death were obtained from the National Death Index (NDI) records through December 31, 2019. Statistical analysis used in this study, including weighted multivariable linear and logistic regression, cox regression and Kaplan-Meier (K-M) analysis, to estimate the association between MQI and all-cause mortality as well as CVD mortality. In addition, subgroup analysis was used to estimate the association between MQI and CVD subtypes, such as heart attack, coronary heart disease, angina, congestive heart failure, and stroke. RESULTS: A total of 5,053 participants were included in the final analysis. Weighted multivariable linear regression models revealed that a lower MQI.total level was independently associated with an increased risk of CVD development in model 3, with t value =-3.48, 95%CI: (-0.24, -0.06), P = 0.002. During 5,053 person-years of 6.92 years of follow-up, there were 29 deaths from CVD. Still, the association between MQI.total and CVD mortality, as well as all-cause mortality did not reach statistical significance in the fully adjusted model (HR = 0.58, 95% CI: 0.21-1.62, P = 0.30; HR = 0.91, 95% CI:0.65,1.28, P = 0.59, respectively). Subgroup analysis confirmed that MQI.total was negatively associated with congestive heart failure (OR = 0.35, 95% CI = 0.18,0.68, P = 0.01). CONCLUSION: This study highlights the potential of MQI as a measure of muscle quality, its negative correlation with congestive heart failure (CHF). However, MQI was not very useful for predicting the health outcomes such as CVD and mortality. Therefore, more attention should be paid to the early recognition of muscle weakness progression in CHF. Further studies are needed to explore more effective indicator to evaluate the association between muscle quality and health outcomes.

Occurrence, Characteristics, and qPCR-Based Identification of Pectobacterium versatile Causing Soft Rot of Chinese Cabbage in China.

Pectobacterium is one of the most important genera of phytopathogenic bacteria. It can cause soft-rot diseases on a wide range of plant species across the world. In this study, three Pectobacterium strains (KC01, KC02, and KC03) were isolated from soft-rotted Chinese cabbage in Beijing, China. These three strains were identified as Pectobacterium versatile based on phylogenetic analysis of Pectobacterium 16S ribosomal RNA, pmrA, and 504 Pectobacterium core genes, as well as a genomic average nucleotide identity analysis. Their biochemical characteristics were found to be similar to the P. versatile type strain ICMP9168T but differed in response to citric acid, stachyose, D-glucuronic acid, dextrin, and N-acetyl-ß-D-mannosamine. All of the tested P. versatile strains showed different carbohydrate utilization abilities compared with P. carotovorum and P. odoriferum, particularly in their ability to utilize D-arabitol, L-rhamnose, and L-serine. Under laboratory conditions, the maceration ability of P. versatile on Chinese cabbage was the highest at 28°C, compared with those at 13, 28, 23, and 33°C. Additionally, P. versatile could infect all of the 17 known Pectobacterium host plants, except for Welsh onion (Allium fistulosum). A SYBR Green quantitative PCR (qPCR) detection system was developed to distinguish P. versatile from other soft-rot bacteria based on the combined performance of melting curve (with a single melting peak at around 85°C) and fluorescence curve (with cycle threshold <30) when the bacterial genomic DNA concentration was in the range of 10 pg/µl to 10 ng/µl. This study is the first to report the presence of P. versatile on Chinese cabbage in China, as well as a specific and sensitive qPCR assay that can be used to quickly identify P. versatile. The work contributes to a better understanding of P. versatile and will facilitate the effective diagnosis of soft-rot disease, ultimately benefitting commercial crop production.

Nerve Injury-Induced γH2AX Reduction in Primary Sensory Neurons Is Involved in Neuropathic Pain Processing.

Phosphorylation of the serine 139 of the histone variant H2AX (γH2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether γH2AX is involved in neuropathic pain is still unclear. We found the expression of γH2AX and H2AX decreased in mice dorsal root ganglion (DRG) after spared nerve injury (SNI). Ataxia telangiectasia mutated (ATM), which promotes γH2AX, was also down-regulated in DRG after peripheral nerve injury. ATM inhibitor KU55933 decreased the level of γH2AX in ND7/23 cells. The intrathecal injection of KU55933 down-regulated DRG γH2AX expression and significantly induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. The inhibition of ATM by siRNA could also decrease the pain threshold. The inhibition of dephosphorylation of γH2AX by protein phosphatase 2A (PP2A) siRNA partially suppressed the down-regulation of γH2AX after SNI and relieved pain behavior. Further exploration of the mechanism revealed that inhibiting ATM by KU55933 up-regulated extracellular-signal regulated kinase (ERK) phosphorylation and down-regulated potassium ion channel genes, such as potassium voltage-gated channel subfamily Q member 2 (Kcnq2) and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in vivo, and KU559333 enhanced sensory neuron excitability in vitro. These preliminary findings imply that the down-regulation of γH2AX may contribute to neuropathic pain.

Sanguinarine inhibits melanoma invasion and migration by targeting the FAK/PI3K/AKT/mTOR signalling pathway.

CONTEXT: Sanguinarine (SAG) is the most abundant constituent of Macleaya cordata (Willd.) R. Br. (Popaceae). SAG has shown antimammary and colorectal metastatic effects in mice in vivo, suggesting its potential for cancer chemotherapy. OBJECTIVE: To determine the antimetastatic effect and underlying molecular mechanisms of SAG on melanoma. MATERIALS AND METHODS: CCK8 assay was used to determine the inhibition of SAG on the proliferation of A375 and A2058 cells. Network pharmacology analysis was applied to construct a compound-target network and select potential therapeutic targets of SAG against melanoma. Molecular docking simulation was conducted for further analysis of the selected targets. In vitro migration/invasion/western blot assay with 1, 1.5, 2 µM SAG and in vivo effect of 2, 4, 8 mg/kg SAG in xenotransplantation model in nude mice. RESULTS: The key targets of SAG treatment for melanoma were mainly enriched in PI3K-AKT pathway, and the binding energy of SAG to PI3K, AKT, and mTOR were -6.33, -6.31, and -6.07 kcal/mol, respectively. SAG treatment inhibited the proliferation, migration, and invasion ability of A375 and A2058 cells (p < 0.05) with IC50 values of 2.378 µM and 2.719 µM, respectively. It also decreased the phosphorylation levels of FAK, PI3K, AKT, mTOR and protein expression levels of MMP2 and ICAM-2. In the nude mouse xenograft model, 2, 4, 8 mg/kg SAG was shown to be effective in inhibiting tumour growth. CONCLUSIONS: Our research offered a theoretical foundation for the clinical antitumor properties of SAG, further suggesting its potential application in the clinic.