The synthesis and biological evaluation of a novel series of compounds based on suberoylanilide hydroxamic acid ( SAHA ) had been designed as potential histone deacetylase inhibitors ( HDAC is). Molecular docking studies indicated that our derivatives had better fitting in the binding sites of HDAC 8 than SAHA . Compounds 1–5 were synthesized through the synthetic routes. In biological test, compounds also showed good inhibitory activity in HDAC enzyme assay and more potent growth inhibition in human glioma cell lines ( MGR 2, U251, and U373). A representative compound, N3F, exhibited better inhibitory effect ( HDAC , IC 50 = 0.1187 μ m ; U251, IC 50 = 0.8949 μ m ) and lower toxicity for human normal cells ( LO 2, IC 50 = 172.5 μ m and MRC 5, IC 50 = 213.6 μ m ) compared with SAHA ( HDAC , IC 50 = 0.8717 μ m ; U251, IC 50 = 8.938 μ m ; LO 2, IC 50 = 86.52 μ m and MRC 5, IC 50 = 81.02 μ m ). In addition, N3F obviously increased Beclin‐1 and Caspase‐3 and 9 as well as inhibited Bcl‐2 in U251 cells. All of our results indicated that these SAHA cap derivatives could serve as potential lead compounds for further optimization. In addition, N3F and N2E both displayed promising profile as antitumor candidates for the treatment of human glioma.
The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infection makes it as an important pathogen for hospital-and community-acquired infections. MRSA spreads fast and widely with multi-site infection and multi-drug resistance. MRSA, hepatitis B and AIDS are called the three leading refractory infections in the world nowadays. The formation of MRSA biofilm makes the infection to be chronic and difficult to control and brings great difficulties for clinical treatment. The formation process of MRSA biofilm, the quorum sensing system, pathogenicity and resistance mechanisms of MRSA,and control strategies are discussed in the article. It is of great significance to fully understand the evolution nature, the therapeutic strategies and be alert of its increasing clinical importance.
Key words:
Methicillin-resistant Staphylococcus aureus; Biofilm; Infection; Therapeutic strategies
Abstract Background Long non-coding RNA H19 was demonstrated to be significantly correlated with tumor metastasis. However, the specific functions of H19 in colorectal cancer (CRC) metastasis and the underlying mechanism are still largely unclear. Methods Use public database to screen the potential lncRNA crucial for metastasis in colorectal cancer. The expression of H19 in clinical CRC specimens was detected by qRT-PCR. The effect of H19 on the metastasis of CRC cells was investigated by transwell, wound healing assays, CCK-8 assays and animal studies. The potential proteins binding to H19 were identified by LC-MS and verified by RNA immunoprecipitation (RIP). The expression of indicated RNA and proteins were measured by qRT-PCR or western blot. Results We found the expression of lncRNA H19 was significantly upregulated in primary tumor and metastatic tissues, correlated with poor prognosis in CRC. Ectopic H19 expression promoted the metastasis of colorectal cancer cells in vitro and in vivo, and induced epithelial-to-mesenchymal transition (EMT). Mechanistically, H19 directly bound to hnRNPA2B1. Knockdown of hnRNPA2B1 attenuated the H19-induce migration and invasion in CRC cells. Furthermore, H19 stabilized and upregulated the expression of Raf-1 by facilitated the interaction between hnRNPA2B1 and Raf-1 mRNA, resulting in activation of Raf-ERK signaling. Conclusions Our findings demonstrate the role of H19/hnRNPA2B1/EMT axis in regulation CRC metastasis, suggested H19 could be a potential biomarker to predict prognosis as well as a therapeutic strategy for CRC.
Four suberoylanilide hydroxamic acid (SAHA) derivatives (N34, N4I, N4B, N24) were designed and synthesized on the basis of our previous studies on N25. Assays for anti-proliferative activity and histone deacetylase (HDAC) activity were performed against human lung cancer (SPC-A-1, LTEP-a-2, NCI-H1650) and normal lung cells (MRC-5), which were compared with those of SAHA. Molecular docking was used to theoretically confirm the receptor-binding ability of N34. Ultimately, N34 was validated as the best HDAC inhibitor candidate. Furthermore, the effects of N34 on the levels of apoptosis- and autophagy-associated proteins caspase-3, caspase-9, Bcl-2 and Beclin-1 in SPC-A-1 cells were evaluated. N34 exerted more evident effects on human lung cancer than the other three SAHA derivatives did. Keywords: Anti-proliferative activity, apoptosis- and autophagy-associated protein, HDAC activity assay, suberoylanilide hydroxamic acid (SAHA) derivaties, synthesis.
The study was designed to evaluate the effect of available phosphorus on growth performance, antioxidant capacity and non-specific immunity in hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ E. lanceolatus) fed with high-lipid diets. Juvenile fish (8.06 ± 0.02 g) were subjected to six different dietary treatments over a period of eight weeks. These treatments consisted of diets (16% lipid level and 45% protein level) containing 0.3%, 0.58%, 0.67%, 0.76%, 0.85% and 0.94% available phosphorus (MCP), designated P1 (control), P2, P3, P4, P5 and P6, respectively. The results showed that (1) P1 group had suppressed final weight, weight gain and specific growth rate, while the other phosphorus experimental groups had significantly higher growth performance than the P1 group (P < 0.05). (2) With increasing phosphorus level, serum total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) enzyme activities increased significantly (P < 0.05). (3) With the increase in dietary phosphorus level, the reactive oxygen species (ROS) content in the liver was significantly decreased (P < 0.05). And the malondialdehyde (MDA) content was significantly decreased, while SOD, CAT, lysozyme (LYS), alkaline phosphatase (AKP), aspartate transaminase (AST) enzyme activities, T-AOC and IgM contents were significantly increased (P < 0.05) (4 The expression of antioxidant genes, such as hsp70, hsp90, sod, cat, gpx, were significantly higher in the appropriate phosphorus level groups than P1 group (P < 0.05), meanwhile the expression of proinflammatory factors, such as il6, il8, tnfα, was significantly reduced (P < 0.05). (6) In the attack experiment, the survival rate of P4 group was the highest, and the survival rate of P2 and P1 groups were the lowest. In conclusion, the appropriate addition of phosphorus can improve growth, antioxidant capacity of fish and disease resistance, and we recommend its addition at 0.67% to 0.77% in diet.
The current study investigated the electrophysiological characteristics and radiofrequency ablation in patients with localized reentry within the left atrial appendage during repeated ablation for recurrent atrial fibrillation (AF). A total of 76 patients (21 paroxysmal, 55 persistent) undergoing repeated catheter ablation for recurrent AF were enrolled in this study. Local reentry tachycardia within the left atrial appendage (LAA) was identified through combining activation and entrainment mapping. Left atriography was performed prior to radiofrequency ablation to identify the focus in the LAA. Three patients (1 paroxysmal, 2 persistent) with sustained atrial tachycardias (ATs) were identified during repeated ablation in this cohort. Combined activation and entrainment mapping were applied to localize the reentry. Postpacing interval-tachycardia cycle length differences were <30 msec at the possible site of reentry in varying segments with macro-reentry. This difference was only determined at the base of LAA for local reentry within the LAA. All 3 patients were free of atrial arrhythmias without any complications at the 6-month follow-up following the ablation in the LAA. Combining activation and entrainment mapping were necessary in approaching ATs within the LAA. Performing entrainments in opposite segments of possible loops were valuable in precluding macro-reentry. Focal ablation was safe and effective in this cohort. Therefore localized reentry within the LAA was not uncommon during repeat AF ablation. The present study may thus provide valuable information for clinicians to manage this type of arrhythmia.
The hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ E. lanceolatus) is a new species of grouper crossed from giant grouper (E. lanceolatus) as the male parent and brown-marbled grouper (E. fuscoguttatus) as the female parent. We hypothesized that optimal levels of dietary protein may benefit liver function. High-lipid diets are energetic feeds that conserve protein and reduce costs, and are a hot topic in aquaculture today. Therefore, the objective of the research is to investigated the effects of dietary protein level in high-lipid diets on serum and liver biochemistry, liver histology, and liver immune and antioxidant indexes and gene mRNA expression of the juvenile hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ E. lanceolatus). Six iso-lipidic (161 g/kg) diets were formulated containing graded levels of protein (510 as control, 480,450, 420, 390 and 360 g/kg). Each treatment consisted of three replicates and 30 fish (6.70 ± 0.02 g) in one replicate. After an 8-week feeding experiment, the results indicated the following: (1) With the decreasing of dietary protein level, the specific growth rate (SGR) of groupers increased gradually and then decreased; SGRs of the 390 and 360 g/kg groups were significantly lower than other groups (p < 0.05). (2) In terms of serum and liver, the activity of antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD), and the total antioxidant capacity (T-AOC) content, and the activity of immune enzymes such as lysozyme (LYS) and immunoglobulin (IgM) was significantly increased under the appropriate protein level. (3) Based on liver histology, we know that high or low dietary protein levels cause liver damage. (4) Dietary protein levels can significantly affect the mRNA expression levels of an anti-inflammatory factor gene (tgfβ), pro-inflammatory factor genes (il6, il8), heat shock proteins, and antioxidant and immune genes (hsp70 and hsp90, gpx, nrf2, keap1). It is concluded that the appropriate protein level can promote the growth performance of groupers, improve antioxidant activity and immune enzyme activity in serum and liver, and enhance the expression of immune genes.
Mucinous appendiceal adenocarcinoma (MAA) is a rare, heterogeneous disease. Patients with unrespectable mucinous appendiceal adenocarcinoma presenting with peritoneal spread are treated by intraperitoneal chemotherapy, hyperthermic intraperitoneal chemotherapy, systemic chemotherapy, or targeted therapy. However, there are no guidelines for efficacious drugs against mucinous appendiceal adenocarcinoma. Therefore, relevant high-fidelity models should be investigated to identify effective drugs for individual therapy.Surgical tumor specimens were obtained from a mucinous appendiceal adenocarcinoma patient. The tissue was digested and organoid culture was established. H&E and immunohistochemistry staining as well as DNA sequencing was performed on tissue and organoid. The pathological characteristics and gene mutations of the organoid were compared to those of the original tumor. Drug sensitivity tests were performed on organoid and the patient clinical responds to chemotherapy and targeted therapy was compared.Organoids were successfully established and stably passaged. Pathological characteristics of organoids including H&E staining and expression of protein markers (CK20, CDX-2, STAB2, CD7, PAX8) were consistent to those of the original tumor. Moreover, the organoids carried the same gene mutations as the primary tumor. Sensitivity of the organoids to chemotherapeutic drugs and tyrosine kinase inhibitors included: 5-FU (IC50 43.95 μM), Oxaliplatin (IC50 23.49 μM), SN38 (IC50 1.02 μM), Apatinib (IC50 0.10 μM), Dasatinib (IC50 2.27 μM), Docetaxel (IC50 5.26 μM), Regorafenib (IC50 18.90 μM), and Everolimus (IC50 9.20 μM). The sensitivities of organoid to these drugs were comparable to those of the patient's clinical responses.The mucinous appendiceal adenocarcinoma organoid model which retained the characteristics of the primary tumor was successfully established. Combined organoid-based drug screening and high throughput sequencing provided a promising way for mucinous appendiceal adenocarcinoma treatment.
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