Muscone inhibits angiotensin II-induced cardiac hypertrophy through the STAT3, MAPK and TGF-ß/SMAD signaling pathways.

BACKGROUND: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear.The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiac hypertrophy. METHODS AND RESULTS: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Cardiac function was analyzed by echocardiography measurement, and the degree of cardiac fibrosis was determined by the quantitative real-time polymerase chain reaction (qRT-PCR), Masson trichrome staining and western blot assay. Secondly, qRT-PCR experiment showed that muscone attenuated cardiac injury by reducing the secretion of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, western blot analysis found that muscone exerted cardio-protective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-ß/SMAD pathways. In addition, CCK-8 and determination of serum biochemical indexes showed that no significant toxicity or side effects of muscone on normal cells and organs. CONCLUSIONS: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-ß/SMAD signaling pathways.

Clinical value of glucocorticoids for severe community-acquired pneumonia: A systematic review and meta-analysis based on randomized controlled trials.

BACKGROUND: Severe community-acquired pneumonia (sCAP) is characterized by severe symptoms and a poor prognosis, especially with the recent global impact of novel coronavirus in recent years. The use of glucocorticoids in sCAP is currently a subject of debate. To evaluate the clinical efficacy and safety of glucocorticoids and provide guidance for their rational use in clinical practice, we conducted this study. METHODS: We searched PubMed, Web of Science, and China National Knowledge Infrastructure using the following search terms: "pneumonia", "pneumonias", "Pulmonary Inflammation", "Pulmonary Inflammations", "Lung Inflammation", and "Lung Inflammations". The primary outcomes included mortality and the length of hospital stay. The secondary outcomes included the duration of mechanical ventilation, duration of vasoactive drug use, gastrointestinal bleeding, and multiple infections. The Cochrane Collaboration was used to assess the risk of bias of the included studies. Stata/MP14 was used for meta-analysis. RESULTS: These studies contained information on 1252 patients who received glucocorticoids and 1280 patients who did not. Meta-analysis showed that there was no difference in terms of mortality [risk ratio (RR) = 0.93, 95% confidence interval (CI): 0.81-1.07, P  > .05], gastrointestinal bleeding (RR = 1.38, 95% CI: 0.83-2.30, P  <  .05), multiple infections (RR = 1.17, 95% CI: 0.90-1.53, P  > .05) and length of hospital stay (mean difference [MD] = -0.87, 95% CI: -2.35 to 0.61, P  > .05) between the hormonal and nonhormonal groups. However, there was a significant difference in the duration of mechanical ventilation (MD = -1.54; 95% CI, -1.89 to -1.12, P  <  .05) and the duration of use of vasoactive drugs (MD = -14.09, 95% CI: -15.72 to -12.46, P < .05). CONCLUSION: Glucocorticoids reduced the duration of mechanical ventilation duration and vasoactive drug use in sCAP patients without increasing the risk of adverse events including hyperglycemia and multiple infections. However, there was no significant difference in mortality or length of hospital stay in sCAP patients between glucocorticoid and non-glucocorticoid groups. Glucocorticoids could be recommended for patients with sCAP with respiratory failure or hemodynamic instability.

Andrographolide attenuated MCT-induced HSOS via regulating NRF2-initiated mitochondrial biogenesis and antioxidant response.

Hepatic sinusoidal obstruction syndrome (HSOS) is a death-dealing liver disease with a fatality rate of up to 67%. In the study present, we explored the efficacy of andrographolide (Andro), a diterpene lactone from Andrographis Herba, in ameliorating the monocrotaline (MCT)-induced HSOS and the underlying mechanism. The alleviation of Andro on MCT-induced rats HSOS was proved by biochemical index detection, electron microscope observation, and liver histological evaluation. Detection of hepatic ATP content, mitochondrial DNA (mtDNA) copy number, and protein expression of nuclear respiratory factor-1 (NRF1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) demonstrated that Andro strengthened mitochondrial biogenesis in livers from MCT-treated rats. Chromatin immunoprecipitation assay exhibited that Andro enhanced the occupation of nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) in the promoter regions of both PPARGC1A and NRF1. Andro also activated the NRF2-dependent anti-oxidative response and alleviated liver oxidative injury. In Nrf2 knock-out mice, MCT induced more severe liver damage, and Andro showed no alleviation in it. Furthermore, the Andro-activated mitochondrial biogenesis and anti-oxidative response were reduced in Nrf2 knock-out mice. Contrastingly, knocking out Kelch-like ECH-associated protein 1 (Keap1), a NRF2 repressor, reduced MCT-induced liver damage. Results from co-immunoprecipitation, molecular docking analysis, biotin-Andro pull-down, cellular thermal shift assay, and surface plasmon resonance assay showed that Andro hindered the NRF2-KEAP1 interaction via directly binding to KEAP1. In conclusion, our results revealed that NRF2-dependent liver mitochondrial biogenesis and anti-oxidative response were essential for the Andro-provided alleviation of the MCT-induced HSOS. Graphical Headlights: 1. Andro alleviated MCT-induced HSOS via activating antioxidative response and promoting mitochondrial biogenesis. 2. Andro-activated antioxidative response and mitochondrial biogenesis were NRF2-dependent. 3. Andro activated NRF2 via binding to KEAP1.

A new risk score for the assessment of outcomes for Chinese patients with peripartum cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a potentially life-threatening complication of pregnancy, but identifying patients at higher risk of this condition remains difficult. OBJECTIVES: We conducted a study to identify new risk factors associated with PPCM and predictors of poor outcomes. METHODS: This retrospective analysis included a total of 44 women with PPCM. As a control group, 79 women who gave birth around the same time as the PPCM patients and who did not have organic disease were included. A multivariate regression analysis was conducted to identify risk factors associated with PPCM and with delayed recovery. RESULTS: All PPCM patients were discharged within 28 days. In comparison to the control group, PPCM patients had higher rates of preeclampsia (20.4% vs. 1.27%, P<0.001), autoimmune disease (27.3% vs. 11.4%, P = 0.018), and cesarean delivery with preterm labor (31.8% vs. 17.7%, P = 0.037). The neonates of PPCM patients had lower birth weight (2.70±0.66 kg vs. 3.21±0.57 kg, P<0.001). PPCM patients had higher levels of C-reactive protein, d-dimer, brain natriuretic peptide (BNP), and serum phosphorus, but lower levels of albumin and serum calcium (all P<0.001). In all patients with PPCM, the left ventricular ejection fraction (LVEF) returned to normal (≥50%) within 28 days after admission. Subjects with early recovery (n = 34) had lower BNP than those with delayed recovery (n = 10) (649.7 ± 526.0 pg/mL vs. 1444.1 ± 1040.8 pg/mL, P = 0.002). Multivariate regression led to a three-point score system to predict PPCM (1 point each for the presence of pericardial effusion, left ventricular dilatation, and d-dimer level ≥0.5 µg/mL). At a cutoff of ≥2, this scoring system predicted delayed recovery with 95.5% sensitivity and 96.1% specificity. The negative predictive value was 97.4% and the positive predictive value was 93.3%. Binary logistic regression indicated that PPCM patients with pulmonary hypertension, lower hemoglobin, or worse LVEF tended to require longer hospital stay (minimum 14 days). CONCLUSIONS: A risk score that consists of pericardial effusion, left ventricular dilatation, and d-dimer level ≥ 0.5 µg/mL could help streamline the diagnosis of PPCM prior to confirmatory investigations. Moreover, a risk score that consists of pulmonary hypertension, lower hemoglobin and worse LVEF could help to predict poor outcomes in PPCM patients.

Construction and Analysis of Emotion Recognition and Psychotherapy System of College Students under Convolutional Neural Network and Interactive Technology.

This study's aim is to effectively establish a psychological intervention and treatment system for college students and discover and correct their psychological problems encountered in a timely manner. From the perspectives of pedagogy and psychology, the college students majoring in physical education are selected as the research objects, and an interactive college student emotion recognition and psychological intervention system is established based on convolutional neural network (CNN). The system takes face recognition as the data source, adopts feature recognition algorithms to effectively classify the different students, and designs a psychological intervention platform based on interactive technology, and it is compared with existing systems and models to further verify its effectiveness. The results show that the deep learning CNN has better ability to recognize student emotions than backpropagation neural network (BPNN) and decision tree (DT) algorithm. The recognition accuracy (ACC) can be as high as 89.32%. Support vector machine (SVM) algorithm is adopted to classify the emotions, and the recognition ACC is increased by 20%. When the system's K value is 5 and d value is 8, the ACC of the model can reach 92.35%. The use of this system for psychotherapy has a significant effect, and 45% of the students are very satisfied with the human-computer interaction of the system. This study aims to guess the psychology of students through emotion recognition and reduce human participation based on the human-computer interaction, which can provide a new research idea for college psychotherapy. At present, the mental health problems of college students cannot be ignored; especially every year, there will be news reports of college students' extreme behaviors due to depression and other psychological problems. An interactive college student emotion recognition and psychological intervention system based on convolutional neural network (CNN) is established. This system uses face recognition as the basic support technology and uses feature recognition algorithms to effectively classify different students. An interaction technology-based psychological intervention platform is designed and compared with existing systems and models to further verify the effectiveness of the proposed system. The results show that deep learning has better student emotion recognition ability than backpropagation neural network (BPNN) and decision tree algorithm. The recognition accuracy is up to 89.32%. Support vector machine algorithm is employed to classify emotions, and the recognition acceptability rate increases by 20%. When K is 5 and d is 8, the acceptability rate of the model can reach 92.35%. The effect of this system in psychotherapy is remarkable, and 45% of students are very satisfied with the human-computer interaction of this system. This work aims to speculate students' psychology through emotion recognition, reduce people's participation via human-computer interaction, and provide a new research idea for university psychotherapy.

Highly efficient thermal deformation optimization method for smart-cut mirrors over the entire photon energy range.

A method to optimize the notches of water-cooled white-beam mirrors over the entire photon energy range is proposed. A theoretical method is used to quantitatively evaluate the influence of the thermal load on the thermal deformation of a mirror. The result of theoretical calculations and finite-element analysis are consistent, which proves the feasibility of the method. The root mean square of the curvatures of the thermal deformation of the white-beam mirror over the entire photon energy range can be minimized. This method greatly simplifies the design work of water-cooled white-beam mirrors.

Rhein ameliorates transverse aortic constriction-induced cardiac hypertrophy via regulating STAT3 and p38 MAPK signaling pathways.

The progression from compensatory hypertrophy to heart failure is difficult to reverse, in part due to extracellular matrix fibrosis and continuous activation of abnormal signaling pathways. Although the anthraquinone rhein has been examined for its many biological properties, it is not clear whether it has therapeutic value in the treatment of cardiac hypertrophy and heart failure. In this study, we report for the first time that rhein can ameliorate transverse aortic constriction (TAC)-induced cardiac hypertrophy and other cardiac damage in vivo and in vitro. In addition, rhein can reduce cardiac hypertrophy by attenuating atrial natriuretic peptide, brain natriuretic peptide, and ß-MHC expression; cardiac fibrosis; and ERK phosphorylation and transport into the nucleus. Furthermore, the inhibitory effect of rhein on myocardial hypertrophy was similar to that of specific inhibitors of STAT3 and ERK signaling. In addition, rhein at therapeutic doses had no significant adverse effects or toxicity on liver and kidney function. We conclude that rhein reduces TAC-induced cardiac hypertrophy via targeted inhibition of the molecular function of ERK and downregulates STAT3 and p38 MAPK signaling. Therefore, rhein might be a novel and effective agent for treating cardiac hypertrophy and other cardiovascular diseases.

Injectable selenium-containing polymeric hydrogel formulation for effective treatment of myocardial infarction.

Myocardial infarction (MI) is a serious threat to people's life and health, which is significantly hindered by effective treatment formulations. Interestingly, our recent endeavour of designing selenium-containing polymeric hydrogel has been experimentally proved to be helpful in combating inflammatory responses and treating MI. The design was inspired by selenium with anti-inflammatory and anti-fibrosis activities, and the formulation could also serve as a support of myocardial tissue upon the failure of this function. In details, an injectable selenium-containing polymeric hydrogel, namely, poly[di-(1-hydroxylyndecyl) selenide/polypropylene glycol/polyethylene glycol urethane] [poly(DH-SE/PEG/PPG urethane)], was synthesised by combining a thermosensitive PPG block, DH-Se (which has oxidation-reduction properties), and hydrophilic PEG segments. Based on the established mouse model of MI, this formulation was experimentally validated to effectively promote the recovery of cardiac function. At the same time, we confirmed by enzyme-linked immunosorbent assay, Masson staining and Western blotting that this formulation could inhibit inflammation and fibrosis, so as to significantly improve left ventricular remodelling. In summary, a selenium-containing polymeric hydrogel formulation analysed in the current study could be a promising therapeutic formulation, which can provide new strategies towards the effective treatment of myocardial infarction or even other inflammatory diseases.

Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury.

The precise control of cardiomyocyte viability is imperative to combat myocardial ischemia-reperfusion injury (I/R), in which apoptosis and pyroptosis putatively contribute to the process. Recent researches indicated that GSDMD is involved in I/R as an executive protein of pyroptosis. However, its effect on other forms of cell death is unclear. We identified that GSDMD and GSDMD-N levels were significantly upregulated in the I/R myocardium of mice. Knockout of GSDMD conferred the resistance of the hearts to reperfusion injury in the acute phase of I/R but aggravated reperfusion injury in the chronic phase of I/R. Mechanistically, GSDMD deficiency induced the activation of PARylation and the consumption of NAD+ and ATP, leading to cardiomyocyte apoptosis. Moreover, PJ34, a putative PARP-1 inhibitor, reduced the myocardial injury caused by GSDMD deficiency. Our results reveal a novel action modality of GSDMD in the regulation of cardiomyocyte death; inhibition of GSDMD activates PARylation, suggesting the multidirectional role of GSDMD in I/R and providing a new theory for clinical treatment.

Analysis of Students' Sports Exercise Behavior and Health Education Strategy Using Visual Perception-Motion Recognition Algorithm.

This study aims to explore the future development path of the college health education and health education's impact on students' sports exercise. Specifically, artificial intelligence (AI) algorithm is combined with intelligent robotics technology to acquire and analyze students' sports exercise behaviors. As a result, a new development model is formulated for college health education. First, it explores students' sports exercise and health education situation in Chinese higher institutions and uncovers the underlying problems. Then it puts forward the corresponding modification suggestions. Second, the AI algorithm and the Kinect sensor-mounted intelligent robot capture the human skeleton features to obtain smooth skeleton joint points data. At the same time, a visual perception human motion recognition (HMR) algorithm is established based on the Hidden Markov Model (HMM). Afterward, the proposed HMM-based HMR algorithm is used to recognize students' sports exercise motions by analyzing human motion skeleton images. The experimental outcomes suggest that the maximum reconstruction error of the HMR algorithm is 10 mm, and the compression ratio is between 5 and 10; the HMR rate is more than 96%. Compared with similar algorithms, the proposed visual perception HMR algorithm depends less on the number of training samples. It can achieve a high recognition rate given only a relatively few samples. Therefore, the proposed (AI + intelligent robot)-enabled HMM-based HMR algorithm can effectively identify the behavior characteristics of students in sports exercise. This study can provide a reference for exploring college students' health education development path.

Activation of transient receptor potential vanilloid 4 is involved in pressure overload-induced cardiac hypertrophy.

Previous studies, including our own, have demonstrated that transient receptor potential vanilloid 4 (TRPV4) is expressed in hearts and implicated in cardiac remodeling and dysfunction. However, the effects of TRPV4 on pressure overload-induced cardiac hypertrophy remain unclear. In this study, we found that TRPV4 expression was significantly increased in mouse hypertrophic hearts, human failing hearts, and neurohormone-induced hypertrophic cardiomyocytes. Deletion of TRPV4 attenuated transverse aortic constriction (TAC)-induced cardiac hypertrophy, cardiac dysfunction, fibrosis, inflammation, and the activation of NFκB - NOD - like receptor pyrin domain-containing protein 3 (NLRP3) in mice. Furthermore, the TRPV4 antagonist GSK2193874 (GSK3874) inhibited cardiac remodeling and dysfunction induced by TAC. In vitro, pretreatment with GSK3874 reduced the neurohormone-induced cardiomyocyte hypertrophy and intracellular Ca2+ concentration elevation. The specific TRPV4 agonist GSK1016790A (GSK790A) triggered Ca2+ influx and evoked the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). But these effects were abolished by removing extracellular Ca2+ or GSK3874. More importantly, TAC or neurohormone stimulation-induced CaMKII phosphorylation was significantly blocked by TRPV4 inhibition. Finally, we show that CaMKII inhibition significantly prevented the phosphorylation of NFκB induced by GSK790A. Our results suggest that TRPV4 activation contributes to pressure overload-induced cardiac hypertrophy and dysfunction. This effect is associated with upregulated Ca2+/CaMKII mediated activation of NFκB-NLRP3. Thus, TRPV4 may represent a potential therapeutic drug target for cardiac hypertrophy and dysfunction after pressure overload.

Numerical iteration method to reduce the surface shape error of a bendable mirror in synchrotron radiation.

X-ray mirrors with high focusing performance are extensively used in the synchrotron radiation field. Especially for vertical reflecting bendable mirrors, many elements such as gravity, extended parts used for the bending mechanism, etc., usually affect the surface shape precision. There are no effective methods to remove all these errors at this point. However, an iteration method can be adopted to solve this problem. In this paper, a novel, to the best of our knowledge, iteration method on decreasing the error between the practice surface shape and the desired one is proposed. Not only can the precision of the surface shape be realized by this method, but also computational efficiency. Errors induced by gravity can be compensated for by an analytical method, while errors caused by the extended parts should be eliminated by a numerical method. Therefore, two main kinds of errors-gravity and parts of clamping-can be removed by iteration. Some examples are presented to illustrate the advantages of this method by comparison with the regular one.

Discovery and characterization of a monoclonal antibody targeting a conformational epitope of IL-6/IL-6Rα to inhibit IL-6/ IL-6Rα/gp130 hexameric signaling complex formation.

The functional interleukin 6 (IL-6) signaling complex is a hexameric structure composed of IL-6, IL-6Rα, and the signaling receptor gp130. There are three different modes of IL-6 signaling, classic signaling, trans-signaling, and trans-presentation, which are not functionally redundant and mediate pleiotropic effects on both physiological and pathophysiological states. Monoclonal antibodies against IL-6 or IL-6Rα have been successfully developed for clinical application. However, designing therapeutic interventions that block specific modes of IL-6 signaling in a pathologically relevant manner remains a great challenge. Here, we constructed a fusion protein Hyper-IL-6 (HyIL-6) composed of human IL-6 and IL-6Rα to develop specific blocking antibodies against the IL-6/IL-6Rα complex. We successfully screened the monoclonal antibody C14mab, which can bind to HyIL-6 with the binding constant 2.86 × 10-10 and significantly inhibit IL-6/IL-6Rα/gp130 complex formation. In vitro, C14mab effectively inhibited HyIL-6-stimulated signal transducer and activator of transcription 3 (STAT3) activation and related vascular endothelial growth factor (VEGF) induction. Moreover, C14mab efficaciously suppressed HyIL-6-induced acute phase response in vivo. Our data from hydrogen-deuterium exchange mass spectrometry demonstrate that C14mab mainly binds to site IIIa of IL-6 and blocks the final step in the interaction between gp130 and IL-6/IL-6Rα complex. Additionally, data from enzyme-linked immunosorbent assays and kinetics assays indicate that C14mab interacts simultaneously with IL-6 and IL-6Rα, while it does not interact with IL-6Rα alone. The unique features of C14mab may offer a novel alternative for IL-6 blockade and illuminate a better therapeutic intervention targeting IL-6.

Genetic Characteristics and Transcriptional Regulation of Sodium Channel Related Genes in Chinese Patients With Brugada Syndrome.

Objective: To investigate the genetic characteristics and transcriptional regulation of the SCN5A gene of Brugada syndrome (BrS) patients in China. Methods: Using PubMed, Medline, China National Knowledge Internet (CNKI), and Wanfang Database, Chinese patients with BrS who underwent SCN5A gene testing were studied. Results: A total of 27 suitable studies involving Chinese BrS patients who underwent the SCN5A gene test were included. A total of 55 SCN5A gene mutations/variations were reported in Chinese BrS patients, including 10 from southern China and 45 from northern China. Mutations/variations of BrS patients from southern China mostly occurred in the regions of the α-subunit of Nav1.5, including DIII (Domain III), DIV, DIII-DIV, C-terminus regions, and the 3'UTR region. Furthermore, we analyzed the post-transcriptional modifications (PTMs) throughout the Nav1.5 protein encoded by SCN5A and found that the PTM changes happened in 72.7% of BrS patients from southern China and 26.7% from northern China. Conclusions: SCN5A mutations/variations of BrS patients in southern China mostly occurred in the DIII-DIV to C-terminus region and the 3'-UTR region of the SCN5A gene, different from northern China. PTM changes were consistent with the mutation/variation distribution of SCN5A, which might be involved in the regulation of the pathogenesis of BrS patients.

Loganin Inhibits Angiotensin II-Induced Cardiac Hypertrophy Through the JAK2/STAT3 and NF-κB Signaling Pathways.

Loganin is an iridoid glycoside extracted from Cornus officinalis, which is a traditional oriental medicine, and many biological properties of loganin have been reported. Nevertheless, it is not clear whether loganin has therapeutic effect on cardiovascular diseases. Hence, the aim of the present study was to investigate the effect of loganin on Ang II-induced cardiac hypertrophy. In the present study, we reported for the first time that loganin inhibits Ang II-provoked cardiac hypertrophy and cardiac damages in H9C2 cells and in mice. Furthermore, loganin can achieve cardioprotective effects through attenuating cardiac fibrosis, decreasing pro-inflammatory cytokine secretion, and suppressing the phosphorylation of critical proteins such as JAK2, STAT3, p65, and IκBα. Besides, the outstanding findings of the present study were to prove that loganin has no significant toxicity or side effects on normal cells and organs. Based on these results, we conclude that loganin mitigates Ang II-induced cardiac hypertrophy at least partially through inhibiting the JAK2/STAT3 and NF-κB signaling pathways. Accordingly, the natural product, loganin, might be a novel effective agent for the treatment of cardiac hypertrophy and heart failure.

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of HCC development. However, several HCC cell lines were recently noted to have HeLa cell contamination or to have been derived from non-hepatocellular origin, suggesting that functional validation of G9a in proper HCC models is still required. Herein, we first confirmed that higher G9a messenger RNA and protein expression levels were correlated with poor overall survival (OS) and disease-free survival (DFS) rates of HCC patients from The Cancer Genome Atlas (TCGA) dataset and our recruited HCC cohort. In an in vitro functional evaluation of HCC cells, HCC36 (hepatitis B virus-positive (HBV+) and Mahlavu (HBV-)) cells showed that G9a participated in promoting cell proliferation, colony formation, and migration/invasion abilities. Moreover, orthotopic inoculation of G9a-depleted Mahlavu cells in NOD-SCID mice also resulted in a significantly decreased tumor burden compared to the control group. Furthermore, after surveying microRNA (miRNA; miR) prediction databases, we identified the liver-specific miR-122 as a G9a-targeting miRNA. In various HCC cell lines, we observed that miR-122 expression levels tended to be inversely correlated to G9a expression levels. In clinical HCC specimens, a significant inverse correlation of miR-122 and G9a mRNA expression levels was also observed. Functionally, the colony formation and invasive ability were attenuated in miR-122-overexpressing HCC cells. HCC patients with low miR-122 and high G9a expression levels had the worst OS and DFS rates compared to others. Together, our results confirmed the importance of altered G9a expression during HCC progression and discovered that a novel liver-specific miR-122-G9a regulatory axis exists.

Metal/metalloid levels in hair of Shenzhen residents and the associated influencing factors.

129 Shenzhen residents' hair samples were collected and the metal/metalloid concentrations of Hg, As, Pb, Cd, Cr, Cu, Mn, Zn, Fe and Ni were detected. Meanwhile, the relationships between metal/metalloid contents in human hair and gender, age, seafood diet habit, smoking habit, as well as the housing type (dwelling environment) were analyzed. Results showed that the average content of Hg, As, Pb, Cd, Cr, Cu, Mn, Zn, Fe and Ni in human hair of Shenzhen residents was 0.76 ± 0.96, 0.10 ± 0.04, 5.25 ± 4.88, 0.25 ± 0.33, 0.60 ± 0.31, 13.84 ± 3.67, 2.82 ± 2.01, 196.90 ± 145.01, 12.20 ± 5.10 and 0.34 ± 0.32 µg/g, respectively. Compared with other regions at home and abroad, most metal/metalloids in Shenzhen residents were at a moderate level, and the highly toxic elements (i.e. Pb, Cd, As and Hg) didn't exceed the upper limit of normal values in China. Statistical analysis showed that the young male people contained significantly higher (p < 0.05) level of Pb (in age group of 20-30 years old) and Fe (in age group of 20-40 years old) in hair than the female people. Smokers had significantly (p < 0.05) higher level of Cd (0.35 µg/g) but lower level of Zn (101.24 µg/g) than non-smokers (Cd: 0.17 µg/g; Zn: 252.63 µg/g). Hg and Pb contents in hair of Shenzhen people were positively related with the frequencies of seafood consumption and the age, respectively. Moreover, residents lived in private buildings (well decorated house) accumulated significantly higher (p < 0.05) levels of Pb, Cr, Fe and Ni as compared with those lived in public rental house and village house (no decoration or simple decoration), suggesting that decoration material was also an important way for human exposure to heavy metals.

Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B.

Based on NH2-(AEEA)5-amphotericin B (DMR005; AEEA is 8-amino-3,6-dioxaoctanoic acid), a series of novel esterified and acylated derivatives of DMR005 were synthesized. These derivatives were evaluated for their antifungal activities using the broth dilution method, for their hemolytic toxicity with sterile defibrinated sheep blood, and for their self-association through UV-visible spectroscopy. The preliminary screening tests indicated that NH2-(AEEA)5-amphotericin B methyl ester (DMR031) was an ideal compound. The results of minimum inhibitory concentration and time-kill assays showed that antifungal activities of DMR031 (4 µg ml-1) against Candida albicans ATCC10231 and ATCC90028 were reduced by four times compared to these of amphotericin B (AmB) (1 µg ml-1). DMR031 (142 ± 1 mg ml-1) significantly improved the water solubility of AmB as DMR005 did. Preliminary safety assessments of DMR031 were carried out via cell toxicity assay of HEK293T in vitro, which turned out to be much better than AmB. AmB had good efficacy in vivo at a dose of 1 mg ml-1. However, DMR031 still had no efficacy in vivo even at a dose of 16 mg ml-1, merely prolonged the survival time of mice.

The synthesis and activity evaluation of N-acylated analogs of echinocandin B with improved solubility and lower toxicity.

Presently, echinocandins have been recommended as the first-line drugs for the treatment of invasive candidiasis. However, low oral bioavailability and solubility limit their application. To improve this situation, this study chose amino acid and fatty acid as raw materials to modify the nucleus of echinocandin B. Six N-acylated analogs were screened from the derivatives that possessed potent antifungal activity and good water solubility. Based on antifungal susceptibility and hemolytic toxicity, compound 5 as the candidate had good antifungal activity and no hemolytic effect. Moreover, compared with anidulafungin, compound 5 showed a comparable fungicidal effect, much higher solubility, and lower toxicity. In conclusion, compound 5 has the potential for further research and development on account of reserved antifungal activity, high solubility, and low toxicity.