A novel indolylbenzoquinone compound HL-J6 suppresses biofilm formation and α-toxin secretion in methicillin-resistant Staphylococcus aureus.

Eradication of methicillin-resistant Staphylococcus aureus (MRSA) is challenging due to multi-drug resistance of strains and biofilm formation, the latter of which is an important barrier to the penetration of antibiotics and host defences. As such, there is an urgent need to discover and develop novel agents to fight MRSA-associated infection. In this study, HL-J6, a novel indolylbenzoquinone compound, was shown to inhibit S. aureus strains, with a minimum inhibitory concentration against MRSA252 of 2 µg/mL. Moreover, HL-J6 exhibited potent antibiofilm activity in vitro and was able to kill bacteria in biofilm. In the mouse models of wound infection, HL-J6 treatment reduced the MRSA load significantly and inhibited biofilm formation on the wounds. The potent targets of its antibiofilm activity were explored by real-time reverse transcriptase polymerase chain rection, which indicated that HL-J6 downregulated the transcription levels of sarA, atlAE and icaADBC. Moreover, Western blot results showed that HL-J6 reduced the secretion level of α-toxin, a major virulence factor. These findings indicate that HL-J6 is a promising lead compound for the development of novel drugs against MRSA biofilm infections.

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.

Transcriptome analyses reveal the effects of mixed saline-alkali stress on indoleacetic acid and cytokinins in Malus hupehensis Rehd. leaves.

Saline-alkali stress is a universal abiotic stress factor limiting fruit tree cultivation worldwide. Apple (Malus×domestica Borkh.) is one of the fruits with the largest yields worldwide. Tea crabapple (Malus hupehensis Rehd. var. pingyiensis Jiang) is a type of common apple rootstock in China. Because facultative apomixis occurs in this species, it is often used in molecular research. The present study investigated the molecular mechanism of the response of indoleacetic acid (IAA) and cytokinins [zeatin, trans-zeatin riboside (tZR), isopentenyladenine (iP), and isopentenyladenosine (iPA)] to mixed saline-alkali stress (MSAS) in tea crabapple leaves. The endogenous hormone content of tea crabapple leaves under MSAS was measured, and the expression of stress response-related genes was analyzed by RNA sequencing. The results showed that the concentration of IAA was initially higher and then lower than that in the control, whereas the concentration of zeatin, tZR, iP, and iPA was higher than that in the control. A total of 1262 differentially expressed genes were identified in the three comparison groups. Further analyses suggested that IAA and cytokinin biosynthetic genes were mostly upregulated in tea crabapple leaves, indicating that auxin and cytokinin signaling pathway regulation occurred in response to MSAS. These findings suggest that IAA and cytokinins play an important role in the response of tea crabapple to MSAS. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01275-4.

[Association of the ADCY9 gene and gene-environmental interaction with the susceptibility to childhood bronchial asthma]. / ADCY9åŸºå› ä¸Žå„¿ç«¥æ”¯æ°”ç®¡å“®å–˜çš„æ˜“æ„Ÿæ€§åŠçŽ¯å¢ƒäº¤äº’ä½œç”¨åˆ†æž.

OBJECTIVES: To study the association of the single nucleotide polymorphisms (SNPs) of the adenylyl cyclase IX (ADCY9) gene at rs1967309, rs2230739, rs2601814, rs2601825, rs2601796, and rs2283497 loci and gene-environment interaction with childhood bronchial asthma (asthma for short). METHODS: A total of 123 children with asthma who attended the hospital from March 2019 to September 2021 were enrolled as the asthma group, among whom 84 (68.3%) had mild-to-moderate attacks and 39 (31.7%) had severe attacks. A total of 124 healthy children were enrolled as the control group. The association of the SNPs and haplotypes of the ADCY9 gene at the above 6 loci with the susceptibility to childhood asthma was evaluated. The method of generalized multifactor dimensionality reduction was used to analyze gene-environment interaction. RESULTS: Polymorphisms were observed for the ADCY9 gene at the above six loci in both the asthma and control groups, and there were significant differences in genotype and allele frequencies at the rs1967309 locus between the two groups (P<0.05). There was no significant difference in the distribution frequency of haplotypes TA and GG between the asthma and control groups (P>0.05). The generalized multifactor dimensionality reduction analysis showed interaction between rs1967309 locus and allergen contact (P<0.05), which increased the risk of asthma (OR=1.585, P<0.05). CONCLUSIONS: The rs1967309 locus of the ADCY9 gene is associated with the susceptibility to childhood asthma, and the locus and allergen contact have a synergistic effect on the development of asthma.

Efficacy and safety of bosentan in the treatment of persistent pulmonary hypertension of the newborn: a Metaanalysis. / æ³¢ç”Ÿå¦æ²»ç–—æ–°ç”Ÿå„¿æŒç»­æ€§è‚ºåŠ¨è„‰é«˜åŽ‹æœ‰æ•ˆæ€§åŠå®‰å ¨æ€§çš„Meta分析.

OBJECTIVES: To systematically evaluate the efficacy and safety of bosentan in the treatment of persistent pulmonary hypertension of the newborn (PPHN). METHODS: Chinese Journal Full-text Database, Weipu Database, Wanfang Data, China Biology Medicine disc, PubMed, Web of Science, Embase, and Cochrane Library were searched for literature on bosentan in the treatment of PPHN published up to August 31, 2021. RESULTS: A total of 8 randomized controlled trials were included for Meta analysis. The results of the Meta analysis showed that compared with the control group, the bosentan treatment group had a significantly lower treatment failure rate (RR=0.23, P<0.001), a significantly greater reduction in pulmonary artery pressure [mean difference (MD)=-11.79, P<0.001)], significantly greater increases in oxygen partial pressure (MD=10.21, P=0.006) and blood oxygen saturation (MD=8.30, P<0.001), and a significantly shorter length of hospital stay (MD=-1.35, P<0.001). The descriptive analysis showed that the bosentan treatment group had a lower degree of tricuspid regurgitation than the control group after treatment. The main adverse reactions of bosentan treatment included abnormal liver function, anemia and edema. The results of subgroup analysis based on treatment regimen, research area, and drug dose were consistent with those before stratification. CONCLUSIONS: Bosentan is effective in the treatment of PPHN. However, when using bosentan, attention should be paid to adverse reactions such as abnormal liver function.

Thioredoxin-1 regulates calcium homeostasis in MPP+ /MPTP-induced Parkinson's disease models.

Disturbance in calcium (Ca2+ ) homeostasis has been involved in a variety of neuropathological conditions including Parkinson's disease (PD). The Ca2+ channel, transient receptor potential channel 1 (TRPC1), plays a protective role in regulating entry of Ca2+ activated by store depletion of Ca2+ in endoplasmic reticulum (ER). We have showed that thioredoxin-1 (Trx-1) plays a role in suppressing ER stress in PD. However, whether Trx-1 regulates TRPC1 expression in PD is still unknown. In the present study, we demonstrated that treatment of 1-methyl-4-phenylpyridinum ion (MPP+ ) significantly reduced the expression of TRPC1 in PC12 cells, which was restored by Trx-1 overexpression, and further decreased significantly by Trx-1 siRNA. Moreover, we found that Ca2+ entered into the cells was decreased by MPP+ in PC 12 cells, which was restored by Trx-1 overexpression, and further decreased by Trx-1 siRNA. MPP+ significantly increased calcium-dependent cysteine protease calpain1 expression in PC12 cells, which was suppressed by Trx-1 overexpression. Calpain1 expression was increased by Trx-1 siRNA or SKF96365, an inhibitor of TRPC1. Moreover, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreased TRPC1 expression in the substantia nigra pars compacta region (SNpc), which was restored in mice overexpressing Trx-1, and further decreased in mice of knockdown Trx-1. Inversely, the expression of calpain1 was increased by MPTP, which was suppressed in mice overexpressing Trx-1, and further increased in mice of knockdown Trx-1. In conclusion, Trx-1 regulates the Ca2+ entry through regulating TRPC1 expression after treatment of MPP+ /MPTP.

Synthesis and anticancer activity evaluation of naphthalene-substituted triazole spirodienones.

Building on our previous work that discovered 1,2,4-triazole-spirodienone as a promising pharmacophore for anticancer activity, we have further diversified 1,2,4-triazole- spirodienone derivatives and synthesized a series of novel naphthalene-substituted triazole spirodienones to explore their antineoplastic activity. Of these, compound 6a possesses remarkable in vitro cytotoxic activity by arresting cell cycle and inducing apoptosis in MDA-MB-231 cells. Subsequently, acute toxicity assay showed that 6a at 20 mg/kg has no apparent toxicity to the major organ in mice. In addition, compound 6ain vivo suppressed breast cancer 4T1 tumor growth. Taken together, these results indicate that compound 6a may be a potential anticancer agent for further development.

Effect of vitamin D on ventricular remodelling in heart failure: a meta-analysis of randomised controlled trials.

OBJECTIVES: The level of vitamin D is considered to be associated with the development and progression of heart failure (HF). However, it is still unclear whether supplementation of vitamin D could improve ventricular remodelling in patients with HF. This study aimed to systematically evaluate the influence and safety of additional vitamin D supplementation on ventricular remodelling in patients with HF. DESIGN: This study is a meta-analysis of randomised controlled trials (RCTs). SETTING: The PubMed, EMBASE, CNKI, Cochrane library, Web of Science databases and grey literature were searched for RCTs regarding the effect of vitamin D on ventricular remodelling in patients with HF (from database creation to October 2017). RevMan V.5.3 software was employed for data analysis. PARTICIPANTS: Seven RCTs with a total of 465 patients, including 235 cases in the vitamin D group and 230 cases in the control group, were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Left ventricular end-diastolic dimension (LVEDD), left ventricular ejection fraction (LVEF) and the incidence of adverse reactions. RESULTS: Compared with the control group, a decrease in the LVEDD (mean difference (MD)=-2.31 mm, 95% CI -4.15 to -0.47, p=0.01) and an increase in the LVEF (MD=4.18%, 95% CI 0.36 to 7.99, p=0.03) were observed in the vitamin D group. Subgroup analysis also revealed a reduced LVEDD in adults (>18 years) and adolescents (<18 years) of the vitamin D group relative to that in those of the control group. High-dose vitamin D (>4000 IU/day) was more effective at reducing the LVEDD than low-dose vitamin D (<4000 IU/day). Moreover, vitamin D supplementation was more effective at reducing the LVEDD and increasing the LVEF in patients with reduced ejection fraction than in patients without reduced ejection fraction. CONCLUSION: Vitamin D supplementation inhibits ventricular remodelling and improves cardiac function in patients with HF. TRIAL REGISTRATION NUMBER: CRD42017073893.

Combination Therapy with LXW7 and Ceria Nanoparticles Protects against Acute Cerebral Ischemia/Reperfusion Injury in Rats.

Ischemia/reperfusion is known to greatly increase oxidative stress in the penumbra, which results in brain damage. Integrin αvß3 is selectively up-regulated with ischemic injury to the brain and remains elevated throughout reperfusion. We determined whether or not a new compound biotinylated-LXW7-ceria nanoparticle (CeNP) (bLXW7-CeNP) plays a role in brain protection in the rat model of middle cerebral artery occlusion/reperfusion and shows better effects than CeNPs alone in improving the outcomes of focal oxidative stress and apoptosis more effectively. Male Sprague-Dawley rats were subjected to focal cerebral ischemia for 2 h followed by a 24-h reperfusion. Drug treatment was intravenously administered via the caudal vein 1 h after occlusion. Rats were randomly divided into the following 4 groups: bLXW7-CeNP treatment group (0.5 mg/kg); CeNP treatment group (0.5 mg/kg); control saline group; and sham group. Brains were harvested 24 h after reperfusion, and the neurologic deficit scores, infarction volume, blood-brain barrier (BBB) disruption, and the level of oxidative stress and apoptosis were determined. Results showed that the bLXW7-CeNP and CeNP treatments could improve neurologic deficit scores, infarction volume, BBB disruption, and the level of oxidative stress and apoptosis. Compound bLXW7-CeNP treatment exhibited better effects than CeNp treatment and showed remarkable statistical differences in the infarction volume, the degree of BBB breakdown, the apoptosis and oxidative stress, apart from neurologic deficit scores. Thus, we concluded that bLXW7-CeNP protects against acute cerebral ischemia/reperfusion injury. BLXW7, as a ligand of integrin αvß3, may be able to effectively localize the anti-oxidant CeNPs to the ischemic penumbra region, which may provide more adequate opportunities for CeNPs to exert anti-oxidative stress effects and subsequently reduce apoptosis in acute cerebral ischemia/reperfusion.

Long non-coding RNA ANRIL in gene regulation and its duality in atherosclerosis.

The antisense transcript long non-coding RNA (lncRNA) (antisense non-coding RNA in the INK4 locus, ANRIL) is an antisense of the cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on chromosome 9p21 that contains an overlapping 299-bp region and shares a bidirectional promoter with alternate open reading frame (ARF). In the context of gene regulation, ANRIL is responsible for directly recruiting polycomb group (PcG) proteins, including polycomb repressive complex-1 (PRC-1) and polycomb repressive complex-2 (PRC-2), to modify the epigenetic chromatin state and subsequently inhibit gene expression in cis-regulation. On the other hand, previous reports have indicated that ANRIL is capable of binding to a specific site or sequence, including the Alu element, E2F transcription factor 1 (E2F1), and CCCTC-binding factor (CTCF), to achieve trans-regulation functions. In addition to its function in cell proliferation, adhesion and apoptosis, ANRIL is very closely associated with atherosclerosis- related diseases. The different transcripts and the SNPs that are related to atherosclerotic vascular diseases (ASVD-SNPs) are inextricably linked to the development and progression of atherosclerosis. Linear transcripts have been shown to be a risk factor for atherosclerosis, whereas circular transcripts are protective against atherosclerosis. Furthermore, ANRIL also acts as a component of the inflammatory pathway involved in the regulation of inflammation, which is considered to be one of the causes of atherosclerosis. Collectively, ANRIL plays an important role in the formation of atherosclerosis, and the artificial modification of ANRIL transcripts should be considered following the development of this disease.

Impact of Physician-Coordinated Intensive Follow-Up on Long-Term Medical Costs in Patients with Unstable Angina Undergoing Percutaneous Coronary Intervention.

BACKGROUND: To investigate the impact of professional physician-coordinated intensive follow-up on long-term expenditures after percutaneous coronary intervention (PCI) in unstable angina (UA) patients. METHODS: In this study, there were 669 UA patients who underwent successful PCI and followed up for 3 years, then divided into the intensive follow-up group (N = 337), and the usual follow-up group (N = 332). Patients were provided with detailed discharge information and individualized follow-up schedules. The intensive group received the extra follow-up times and medical consultations, and all patients were followed up for approximately 3 years. RESULTS: At the 3-year mark after PCI, the cumulative major adverse cardiac events (MACE), recurrence of myocardial ischemia, cardiac death, all-cause death and revascularization in the intensive group were lower than in the usual group. Additionally, the proportion of good medication adherence was significantly higher than in the usual group (56.4% vs. 46.1%, p < 0.001). The hospitalization daytime, total hospitalization cost and total medical cost in the intensive group were lower. Multiple linear regression showed that diabetes, hypertension, intensive follow-up and good medication adherence were associated with emergency and regular clinical cost (p < 0.05), the re-hospitalization cost (p < 0.05) and the total medical cost (p < 0.05) of patient care. Intensive follow-up and good adherence were negatively correlated with the cost of re-hospitalization (standardized coefficients = -0.132, -0.128, p < 0.05) and total medical costs (standardized coefficients = -0.072, -0.086, p < 0.05). CONCLUSIONS: Intensive follow-up can reduce MACE, improve medication adherence and save long-term total medical costs, just by increasing the emergency and regular clinical visits cost in UA patients after PCI.

Long Non-coding RNA ANRIL in Gene Regulation and Its Duality in Atherosclerosis / 华中科技大学学报（医学）（英德文版）

The antisense transcript long non-coding RNA (1ncRNA) (antisense non-coding RNA in the INK4 locus,ANRIL) is an antisense of the cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on chromosome 9p21 that contains an overlapping 299-bp region and shares a bidirectional promoter with alternate open reading frame (ARF).In the context of gene regulation,ANRIL is responsible for directly recruiting polycomb group (PcG) proteins,including polycomb repressive complex-1 (PRC-1) and polycomb repressive complex-2 (PRC-2),to modify the epigenetic chrornatin state and subsequently inhibit gene expression in cis-regulation.On the other hand,previous reports have indicated that ANRIL is capable of binding to a specific site or sequence,including the Alu element,E2F transcription factor 1 (E2F1),and CCCTC-binding factor (CTCF),to achieve trans-regulation functions.In addition to its function in cell proliferation,adhesion and apoptosis,ANRIL is very closely associated with atherosclerosis-related diseases.The different transcripts and the SNPs that are related to atherosclerotic vascular diseases (ASVD-SNPs) are inextricably linked to the development and progression of atherosclerosis.Linear transcripts have been shown to be a risk factor for atherosclerosis,whereas circular transcripts are protective against atherosclerosis.Furthermore,ANRIL also acts as a component of the inflammatory pathway involved in the regulation of inflammation,which is considered to be one of the causes of atherosclerosis.Collectively,ANRIL plays an important role in the formation of atherosclerosis,and the artificial modification of ANRIL transcripts should be considered following the development of this disease.

Association between left ventricular end-diastolic pressure and coronary artery disease as well as its extent and severity.

Patients with myocardial ischemia exhibit increased left ventricular end-diastolic pressure (LVEDP). The study was to evaluate the relationship between LVEDP measured by left cardiac catheterization and coronary artery disease (CAD) as well as its extent and severity evaluated by coronary angiography (CAG). 912 patients who underwent CAG and left cardiac catheterization were enrolled. There were 313 patients without CAD and 599 with CAD according to CAG. The extent and severity of coronary artery was evaluated by number of vessels and Gensini score. Analyze the correlation of LVEDP and CAD as well as its extent and severity. LVEDP was significantly higher in CAD patients than non-CAD (9.58±5.78 mmHg vs 10.9±5.46 mmHg, P<0.001), and was correlated independently with the presence of CAD (OR = 0.11, per 5 mmHg increase, 95% CI 1.02-1.29, P = 0.02). LVEDP was increased with an increase of number of vessels. By linear regression analysis, LVEDP was significantly associated with Gensini score (standardized ß = 0.034, P = 0.001). In non-CAD group, LVEDP was only correlated with age (r = 0.123, P = 0.030). In conclusion, our findings suggest that elevated LVEDP was significantly associated with CAD as well as its extent and severity. LVEDP was only correlated with age in non-CAD patients. LVEDP measurement provides incremental clinical value for CAD and non-CAD patients.

1-[2-(Pyrazin-2-ylsulfan-yl)eth-yl]pyrazine-2(1H)-thione.

The title multifunctional twisted organic ligand, C(10)H(10)N(4)S(2), contains a short C=S bond [1.671 (2) Å]. The dihedral angle between the two pyrazine rings is 39.83 (6)°. In the crystal, inter-molecular C-H⋯N and C-H⋯S hydrogen bonds result in the formation of a supra-molecular network.

Two novel sulfur compounds from the seeds of Raphanus sativus L.

The seeds of Raphanus sativus L., known as Lai-fu-zi in traditional Chinese Medicine, are always roasted before clinical use for avoiding nausea. During an investigation of the chemical difference between roasted and pre-roasted products, two novel sulfur-containing compounds, which mainly existed in the pre-roasted products, were isolated. Their structures and absolute configurations were established by spectroscopic and X-ray diffraction analysis.

Piperazine-2,3,5,6-tetra-one.

The mol-ecule of the title compound, C(4)H(2)N(2)O(4), is located around an inversion center and the four O atoms are in the 2,3,5,6-positions of the piperazine ring. In the crystal, bifurcated N-H⋯O hydrogen bonds link the mol-ecules into a corrugated layer parallel to (101).