Design, synthesis, and evaluation of pirfenidone-NSAIDs conjugates for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal, chronic and progressive lung disease that threaten public health like many cancers. In this study, targeting the significant driving factor, inflammatory response, of the IPF, several conjugates of pirfenidone (PFD) with non-steroidal anti-inflammatory drugs (NSAIDs), along with their derivatives, were designed and synthesized to enhance the anti-IPF potency of PFD. Among these compounds, the (S)-ibuprofen-PFD conjugate 5b exhibited the most potent anti-proliferation activity against NIH3T3 cells, demonstrating up to a 343-fold improvement compared to PFD (IC50 = 0.04 mM vs IC50 = 13.72 mM). Notably, 5b exhibited superior activity in inhibiting the migration of macrophages induced by TGF-ß compared to PFD. Additionally, 5b demonstrated significant suppression of TGF-ß-induced migration of NIH3T3 cells and induction of apoptosis in NIH3T3 cells. Mechanistic studies revealed that 5b reduced the expression of collagen I and α-SMA by inhibiting the TGF-ß/SMAD3 pathway. In a bleomycin-induced pulmonary fibrosis model, treatment with 5b (40 mg/kg/day, orally) exhibited a more pronounced effect on reducing the degree of histopathological changes in lung tissue and alleviating collagen deposition compared to PFD (100 mg/kg/day, orally). Moreover, 5b could block the expression of collagen I, α-SMA, fibronectin, and pro-inflammatory factors (IL-6, IFN-γ, and TNF-α) compared to PFD, while demonstrating low toxicity in vivo. These preliminary results indicated that the hybridization of PFD with NSAIDs represented an effective modification approach to improve the anti-IPF potency of PFD. Consequently, 5b emerged as a promising candidate for the further development of new anti-IPF agents.

LncRNA LINC00847 accelerates melanoma progression by regulating miR-133a-3p/TGFBR1 axis.

AIMS: Growing evidence has suggested that lncRNAs play a regulatory role in tumorigenesis. Dysregulation of a newly identified lncRNA (LINC00847) has been involved in several tumors. Nevertheless, the expression and roles of lncRNAs in skin melanoma remain unclear. Therefore, we attempted to investigate the expressions and roles of lncRNAs in this study. MATERIALS AND METHODS: Expression levels of LINC00847 were quantified in tissue samples from the TCGA database and clinically recruited participants. LINC00847 was inhibited in cells by transfecting with si-LINC00847 or si-NC. Expressions of LINC00847 and miR-133a-3p were determined using RT-qPCR, and the TGFBR1 level was determined using Western blotting. Targeting sites of LINC00847 with miR-133a-3p and miR-133a-3p with TGFBR1 were predicted by bioinformatic tools and proved by dual-luciferase reporter system and RNA immunoprecipitation. Cell proliferation, invasion, and migration abilities were assessed using CCK8, cell colony formation, cell wound scratch, and transwell assay, respectively. RESULTS: In both TCGA and clinical cohorts, the expression of LINC00847 was abnormally upregulated in skin melanoma tissues than that of benign nevus. Besides, LINC00847 expression increased more markedly in A375 and SK-MEL-28 cells than in normal epidermal melanocytes (HEMa-LP cells). LINC00847 knockdown remarkably restrained skin melanoma cell proliferation, metastasis, and wound healing rate. Furthermore, miR-133a-3p/TGFBR1 was the downstream target for LINC00847. LINC00847 negatively regulated miR-133a-3p expression in skin melanoma cells. Both miR-133a-3p inhibitors and TGFBR1 vector transfection reversed the effect of LINC00847 silence in skin melanoma cells. CONCLUSION: LINC00847 was highly expressed in skin melanoma, and its overexpression accelerated the malignant tumor behavior of skin melanoma cells. The miR-133a-3p /TGFBR1 axis was involved in the roles of LINC00847 in skin melanoma.

Recent progress of micro/nanomotors to overcome physiological barriers in the gastrointestinal tract.

Oral administration is a convenient administration route for gastrointestinal disease therapy with good patient compliance. But the nonspecific distribution of the oral drugs may cause serious side effects. In recent years, oral drug delivery systems (ODDS) have been applied to deliver the drugs to the gastrointestinal disease sites with decreased side effects. However, the delivery efficiency of ODDS is tremendously limited by physiological barriers in the gastrointestinal sites, such as the long and complex gastrointestinal tract, mucus layer, and epithelial barrier. Micro/nanomotors (MNMs) are micro/nanoscale devices that transfer various energy sources into autonomous motion. The outstanding motion characteristics of MNMs inspired the development of targeted drug delivery, especially the oral drug delivery. However, a comprehensive review of oral MNMs for the gastrointestinal diseases therapy is still lacking. Herein, the physiological barriers of ODDS were comprehensively reviewed. Afterward, the applications of MNMs in ODDS for overcoming the physiological barriers in the past 5 years were highlighted. Finally, future perspectives and challenges of MNMs in ODDS are discussed as well. This review will provide inspiration and direction of MNMs for the therapy of gastrointestinal diseases, pushing forward the clinical application of MNMs in oral drug delivery.

Identification of Two Novel Carbapenemase-Encoding Hybrid Plasmids Harboring blaNDM-5 and blaKPC-2 in a Clinical ST11-KL47 Klebsiella pneumoniae.

Background: Emergence of blaKPC and blaNDM co-harboring Klebsiella pneumoniae has escalated the threat of Carbapenem-resistant Klebsiella pneumoniae (CRKP) to healthcare. It remains unknown the prevalence and molecular characteristics of CRKP co-producing KPC and NDMs carbapenemases in Henan. Methods and Results: Twenty-seven CRKP strains isolated from different times were selected randomly in affiliated cancer hospital of Zhengzhou University from January 2019 to January 2021, among which one KPC-2 and NDM-5 positive CRKP named K9 was isolated from an abdominal pus sample of a 63-year-old male patient with leukemia. Sequencing of K9 determined that K9 belonged to ST11-KL47, which is resistant to antibiotics such as meropenem, ceftazidime-avibactam and tetracycline. K9 carried two different plasmids that contained blaNDM-5 and blaKPC-2. Both plasmids were shown to be novel hybrid plasmids and IS26 played an important role in generation of two plasmids. Gene blaKPC-2 was flanked by the NTEKPC-Ib-like genetic structure (IS26-ΔTn3-ISKpn8-blaKPC-2-ISKpn6-IS26) and was located on a conjugative IncFII/R/N type hybrid plasmid. Conclusion: The resistance gene blaNDM-5 located on a region organized as IS26-blaNDM-5-ble-trpF-dsbD-ISCR1-sul1-aadA2-dfrA12-IntI1-IS26 was carried by a phage-plasmid. We described a clinical CRKP co-producing KPC-2 and NDM-5 and emphasized an urgent need to control their further spread.

Impact of Platelet-Rich Fibrin Combined with Silver Nanoparticle Dressing on Healing Time and Therapeutic Efficacy of Chronic Refractory Wounds.

Introduction: Objective • This study aimed to investigate the clinical value of combining platelet-rich fibrin (PRF) with nano silver (AgNP) dressing in the treatment of chronic refractory wounds. Introduction: Methods • A total of 120 patients with chronic refractory wounds were selected from our hospital between January 2020 and January 2022. The patients were randomly divided into the control group and the study group, with 60 cases in each group. The control group received basic treatment combined with AgNP dressing, while the study group received PRF combined with AgNP dressing. A comparison was made between the two groups in terms of wound healing time, hS-CRP levels, VISUAL analogue scale (VAS) scores, procalcitonin (PCT) levels, clinical efficacy, and complications. Introduction: Results • Before treatment, there were no significant differences in hS-CRP, VAS, and PCT levels between the two groups (P > .05). However, after treatment, the study group showed significantly lower hS-CRP, VAS, and PCT levels compared to the control group (P < .05). The study group also exhibited a shorter wound healing time, a higher rate of excellent and good curative effect (95.00% vs 81.67%) compared to the control group (χ2 = 5.175, P < .05), and a lower incidence of wound complications (6.67% vs 21.67%) compared to the control group (χ2 = 4.386, P < .05). Introduction: Conclusions • The combination of PRF and AgNP dressing can effectively alleviate pain and local inflammation in patients with chronic refractory wounds, improve the wound healing rate, shorten the healing time, and reduce the risk of complications such as infection spread.

The Value of Continuous Closed Negative Pressure Drainage Combined with Antibacterial Biofilm Dressing in Postoperative Wound Healing for Severe Pancreatitis.

Objective: To investigate the application value of continuous vacuum sealing drainage (VSD) combined with antibacterial biofilm hydraulic fiber dressing in wound healing after surgery for severe acute pancreatitis (SAP). Methods: A total of 82 SAP patients who underwent minimally invasive surgery in our hospital from March 2021 to September 2022 were randomly divided into two groups using a random number table method. Each group consisted of 41 cases. Both groups received surgical treatment, with the control group receiving VSD treatment and the observation group receiving VSD treatment combined with antibacterial biofilm hydraulic fiber dressing. The postoperative recovery efficiency, preoperative and postoperative wound area reduction rate, pressure ulcer healing score (PUSH), serum biological indicators (white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT)), and the rate of wound-related adverse reactions were compared between the two groups. Results: There was no statistical difference between the two groups in the time to resume eating (P > .05). However, the wound healing time and hospitalization days in the observation group were significantly shorter than those in the control group (P < .05). After 7 and 14 days of treatment, the wound area reduction rate in the observation group was significantly higher than in the control group, and the PUSH score was significantly lower than in the control group (P < .05). WBC, CRP, and PCT levels in the observation group were lower than in the control group (P < .05). The incidence of wound-related adverse reactions in the observation group (12.20%) was significantly lower than that in the control group (34.15%) (P < .05). Conclusions: The application of VSD combined with antibacterial biofilm hydraulic fiber dressing in the postoperative wound healing of SAP has a significant effect. It improves wound healing efficiency, reduces pressure ulcer scores, decreases inflammation indicators, and lowers the incidence of adverse reactions. While further research is needed to determine its impact on infection and inflammation prevention, this treatment approach shows promise for clinical application.

Design, synthesis and biological evaluation of 3-aryl-7-hydroxy scopoletin derivatives as autophagy activators against tumorigenesis.

A natural product scopoletin, which also contains an ortho-substituted phenolic structure in its skeleton, was found in some medicinal plants. In this study, to develop scopoletin-based autophagy activators, various aryl substitutes were introduced at the 3-positon or 4-position of scopoletin skeleton with the ortho-substituted phenolic structure retained. A total of twenty-three derivatives were synthesized, evaluated for their antiproliferation activity against four cancer cells (MCF-7, HeLa, PC3, and MGC803), and discussed for their structure-activity relationships (SARs). Among these derivatives, 5c was the most potent compound with an excellent improvement of antiproliferation activity against PC3 and MGC803 cells compared to the parental scopoletin. 5c displayed up to 17.9- and 5.7-fold improvement of antiproliferation activities against PC3 and MGC803 cells compared to 5-FU (IC50 = 0.14 µM vs IC50 = 2.50 µM, IC50 = 1.02 µM vs IC50 = 5.81 µM), respectively. Moreover, 5c showed excellent selectivity between cancer cells and one normal cell (GES-1). Further mechanism investigations confirmed that 5c inhibited PC3 and MGC803 cell proliferation via inducing autophagy. Interestingly, 5c also induced mitochondria-mediated apoptosis in PC3 cells but not in MGC803 cells. Moreover, 5c possessed the ability to suppress colony formation and migration of PC3 and MGC803 cells. In addition, 5c arrested the cell cycle at the G2/M phase of PC3 cells.

Expression and Role of CXCL13 and MiR-186-5p in the Trigeminal Ganglion of a Rat Model of Trigeminal Neuralgia.

AIM: This study sought to reveal the roles of CXCL13 and miR-186-5p in a rat model (adult male Sprague-Dawley rats, 7-8 weeks old, 180-200 g) of trigeminal neuralgia (TN) established via chronic constriction injury of the infraorbital nerve (ION-CCI). MATERIAL AND METHODS: The results of behavioural tests and the expression levels of miR-186-5p and CXCL13 in the trigeminal ganglion (TG) were compared between the sham and ION-CCI groups, as well as the consequences of the miR-186-5p mimic and inhibitor. RESULTS: Compared with the sham-operated rats, ION-CCI rats displayed mechanical hypersensitivity in the von Frey hair test. Western blotting revealed the upregulation of CXCL13 and downregulation of miR-186-5p in the TG of ION-CCI rats relative to their expression in sham rats. Furthermore, an miR-186-5p mimic decreased CXCL13 protein levels and increased the mechanical withdrawal thresholds of ION-CCI rats. CXCL13 protein levels also increased after the injection of an miR-186-5p inhibitor. Finally, miR-186-5p was found to be expressed in the TG and was downregulated in ION-CCI rats compared to sham rats. CONCLUSION: miR-186-5p may negatively regulate CXCL13 to influence the occurrence and development of TN. Collectively, our findings shed new light on novel therapies for the treatment of TN.

Emergence of a novel hybrid mcr-1-bearing plasmid in an NDM-7-producing ST167 Escherichia coli strain of clinical origin.

Colistin is considered as an antibiotic of 'last resort' for the treatment of lethal infections caused by carbapenem-resistant Enterobacterales (CRE), dissemination of plasmid-borne colistin resistance gene mcr-1, particularly into CRE, resulting in the emergence of strains that approach pan-resistance. A wide variety of plasmid types have been reported for carrying mcr-1. Among which, large IncHI2-type plasmids were multidrug-resistant (MDR) plasmids harbored multiple resistance determinants in addition to mcr-1. Herein, we characterized a novel hybrid IncHI2-like mcr-1-bearing plasmid in an NDM-7-producing ST167 Escherichia coli strain EC15-50 of clinical origin. Antimicrobial susceptibility testing showed E. coli EC15-50 exhibited an extensively drug-resistant (XDR) profile that only susceptible to amikacin and tigecycline. S1-PFGE, Southern hybridization and Whole-genome Sequencing (WGS) analysis identified a 46,161 bp bla NDM-7-harboring IncX3 plasmid pEC50-NDM7 and a 350,179 bp mcr-1-bearing IncHI2/HI2A/N/FII/FIA plasmid pEC15-MCR-50 in E. coli EC15-50. Sequence detail analysis revealed the type IV coupling protein (T4CP) gene was absent on pEC15-MCR-50, explaining that pEC15-MCR-50 was a non-conjugative plasmid. Comparative genetic analysis indicated the hybrid plasmid pEC15-MCR-50 was probably originated from pXGE1mcr-like IncHI2/HI2A/N plasmid and pSJ_94-like IncFII/FIA plasmid, and generated as a result of a replicative transposition process mediated by IS26. Currently, the prevalent mcr-1-carrying IncHI2 plasmids were rarely reported to be fused with other plasmids. The identification of the novel hybrid plasmid pEC15-MCR-50 in this study highlighted the importance of close surveillance for the emergence and dissemination of such fusion MDR plasmids, particularly in NDM-producing Enterobacterales.

SAC3D1 activates Wnt/ß­catenin signalling in hepatocellular carcinoma.

ß­catenin accumulates in hepatocellular carcinoma (HCC); therefore, understanding the mechanism of Wnt/ß­catenin pathway activation is important for HCC therapy. SAC3 domain containing 1 (SAC3D1) is involved in numerous types of cancer, such as gastric cancer. To the best of our knowledge, however, the role of SAC3D1 in HCC has not yet been elucidated. Here, the expression of SAC3D in HCC was examined by quantitative PCR, western blotting and immunohistochemistry. The function of SAC3D1 in HCC were examined using Cell Counting Kit­8 and anchorage­independent growth assay. It was found that the levels of SAC3D1 mRNA and protein were upregulated in HCC. When SAC3D1 was overexpressed, the proliferation of HCC cells was promoted; when the expression of SAC3D1 was disrupted, HCC cell growth was inhibited. When the molecular mechanism was investigated using immunoprecipitation, it was found that SAC3D1 interacted with axin, inhibiting ubiquitination of ß­catenin and elevating protein levels of ß­catenin. In summary, the present study revealed the promoting function of SAC3D1 in the progression of HCC. SAC3D1 may be a promising target for HCC therapy.

Synthesis and structure-activity relationships of pirfenidone derivatives as anti-fibrosis agents in vitro.

Pirfenidone (PFD) was the first approved drug by FDA for the treatment of idiopathic pulmonary fibrosis (IPF). However, the rapid metabolism of 5-methyl of PFD increases the risk of side effects in clinics. Thus, in this paper, a common practice that a stable amide bond linking various groups used to replace 5-methyl of PFD in medicinal chemistry was applied, and total 18 PFD derivatives were synthesized. All compounds were investigated for their antiproliferation activities against NIH3T3 cells and the structure-activity relationships of the target compounds were also discussed. Among them, YZQ17 possessed potent antiproliferation activity compared to PFD and better potency in inhibiting TGF-ß-induced migration of NIH3T3 cells at a much lower concentration than that of PFD. In addition, YZQ17 dramatically inhibited the expression levels of fibrotic markers α-SMA, collagen I, and fibronectin. Moreover, further mechanistic studies confirmed that YZQ17 exhibited this considerable anti-fibrosis activity via the TGF-ß/Smad2/3 dependent pathway. Finally, the results of human and rat liver microsomes assay in vitro and pharmacokinetic assay in rats confirmed that YZQ17 showed better pharmacokinetics than that of PFD. Collectively, the preliminary study of PFD derivatives modified by the amide group indicated that YZQ17 could be regarded as a lead compound for further investigation and optimization.

Design, synthesis and activity against drug-resistant bacteria evaluation of C-20, C-23 modified 5-O-mycaminosyltylonolide derivatives.

With the increasing incidence of antibiotic resistance, there is an urgent need to develop new antibiotics with excellent activity against drug-resistant bacteria. Three novel series of tylosin semisynthetic derivatives were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. Among these derivatives, compound C-2 demonstrated potent antibacterial activity against both gram-positive and gram negative bacteria, and non mutagenic. More importantly, compound C-2 displayed high antimicrobial potency against Gram-positive bacteria in a murine model, and was found to be more efficient than tildipirosin. Thus, compound C-2 had great potential as a promising lead compound for the treatment of bacterial infection.

Synthesis and Performance of Double-Chain Quaternary Ammonium Salt Glucosamide Surfactants.

A series of double-chain quaternary ammonium salt surfactants N-[N'[3-(gluconamide)] propyl-N'-alkyl]propyl-N,N-dimethyl-N-alkyl ammonium bromide (CnDDGPB, where n represents a hydrocarbon chain length of 8, 10, 12, 14 and 16) were successfully synthesized from D (+)-glucose δ-lactone, N,N-dimethyldipropylenetriamine, and bromoalkane using a two-step method consisting of a proamine-ester reaction and postquaternization. Their surface activity, adsorption, and aggregation behavior in aqueous solution were investigated via measurements of dynamic/static surface tension, contact angle, dynamic light scattering, and transmission electron microscopy. An analysis of their application performance in terms of wettability, emulsifying properties, toxicity, and antibacterial properties was conducted. The results show that with increasing the carbon chain length of the CnDDGPB surfactants, their critical micelle concentration (CMC) increased and the pC20 and efficiency in the interface adsorption of the target product gradually decreased. Moreover, the influence of the hydrophobic carbon chain length on the surface of polytetrafluoroethylene (PTFE) was even greater for the wetting effect, reducing the contact angle to 32° within the length range of C8-C14. The results of the contact angle change and the wettability experiments proved that C10DDGPB exhibited the best wettability. The liquid paraffin and soybean oil emulsification ability of CnDDGPB showed an upward trend followed by a downward trend with the growth of the carbon chain, with C12DDGPB exhibiting the best emulsification performance. The Dlong/Dshort ratio was far lower than 1, which indicates mixed-kinetic adsorption. The surfactants formed spherical micelles and showed a unique aggregation behavior in aqueous solution, which showed an increase-decrease-increase trend with the change in concentration. A cell toxicity and acute oral toxicity experiment showed that the CnDDGPB surfactants were less toxic than the commonly used surfactant dodecyldimethylbenzyl ammonium chloride (1227). In addition, at a concentration of 150 ppm, CnDDGPB exhibited the same bacteriostatic effect as 1227 at a concentration of 100 ppm. The results demonstrate that sugar-based amide cationic surfactants are promising as environmentally friendly disinfection products.

Study on the Mechanism of miR-34a Affecting the Proliferation, Migration, and Invasion of Human Keloid Fibroblasts by Regulating the Expression of SATB1.

OBJECTIVES: To explore the effect and mechanism of miR-34a on the proliferation, migration, and invasion of keloid fibroblasts (KFB). METHODS: Isolate and culture KFB and normal skin fibroblast (NFB), detect the mRNA expression levels of miR-34a and integrin ß5 (SATB1) in KFB and NFB by RT-qPCR, and detect SATB1 by western blot. The level of protein expression, MTT method, Transwell method, RT-qPCR, and western blot were used to detect the effects of overexpression of miR-34a or inhibition of SATB1 expression on the proliferation, migration, and invasion of KFB cells and the expression of related proteins. The dual luciferase reporter gene test verifies the targeting relationship between miR-34a and SATB1. RESULTS: Compared with NFB, the expression of miR-34a was downregulated in KFB and the mRNA and protein expression levels of SATB1 were upregulated. Overexpression of miR-34a or inhibition of SATB1 expression inhibited the proliferation, migration, and invasion of KFB. miR-34a can negatively regulate the expression of SATB1, and overexpression of SATB1 reverses the effects of overexpression of miR-34a on the proliferation, migration, and invasion of KFB. CONCLUSIONS: miR-34a inhibits the proliferation, migration, and invasion of keloid fibroblasts by downregulating the expression of SATB1.

Circular RNA 100146 Promotes Colorectal Cancer Progression by the MicroRNA 149/HMGA2 Axis.

Colorectal cancer (CRC) has developed into the third leading cause of cancer-associated death worldwide. Studies have confirmed that circular RNAs (circRNAs) absorb microRNAs (miRNAs) to regulate the function of downstream genes. This study aimed to explore the underlying mechanism of circRNA 100146 in CRC. The expression of circRNA 100146, miRNA 149 (miR-149), and high mobility group AT-Hook 2 (HMGA2) was detected by quantitative real-time PCR (RT-qPCR). A series of biofunctional effects (cell viability, apoptosis, migration/invasion) were evaluated by the use of methyl thiazolyl tetrazolium (MTT), flow cytometry, and transwell assays. Protein levels were measured by Western blot assay. A xenograft model was established for in vivo experiments. The interactions among circRNA 100146, miR-149, and HMGA2 were evaluated by dual-luciferase reporter assay, RNA immunoprecipitation assays, or RNA pulldown assay. circRNA 100146 was upregulated in CRC tissues and cells. circRNA 100146 knockdown inhibited cell proliferation, promoted apoptosis, and suppressed migration and invasion in vitro and impeded tumor growth in vivo Also, miR-149 was negatively regulated by circRNA 100146 and was targeted to HMGA2 and mediated its expression. Moreover, miR-149 interference abrogated the activities of silenced circRNA 100146 in proliferation, apoptosis, migration, and invasion. Furthermore, HMGA2 overexpression abated the effects described above caused by circRNA 100146 silencing, while the mutations on miR-149 binding sites in the 3' untranslated region (3'-UTR) of HMGA2 led to its loss of this ability. circRNA 100146 knockdown repressed proliferation, enhanced apoptosis, and hindered migration and invasion in SW620 and SW480 cells through targeting the miR-149/HMGA2 axis.

Multiple Attacks Detection in Cyber-Physical Systems Using Random Finite Set Theory.

To invade a cyber-physical system (CPS) successfully, hackers are prone to simultaneously launching multiple cyber attacks on different sensors in a CPS. However, little attention has been paid to the problem of detecting multiple cyber attacks up to now. Therefore, in this paper, we deal with the problem on how to efficiently detect multiple cyber attacks aiming at different sensors in CPSs. To achieve the goal of simultaneously detecting both the number of attacks and the attacked sensors, we formulate this problem via a random finite set (RFS) theory, and then apply an iterative RFS-based Bayesian filter and its approximation to solve the problem. Four numerical experiments with different attacks are provided, and the results have demonstrated the effectiveness of the RFS-based approach for the problem of multiple attacks detection in CPSs.

The relationship between resting electroencephalogram oscillatory abnormalities and schizotypal personality traits in the first-degree relatives of schizophrenia patients.

Although a large amount of studies have manifested resting state electroencephalogram oscillatory abnormalities in schizophrenia and their first-degree relatives and in schizotype, the results are far from consistent and no research found any relationship between electroencephalograph (EEG) abnormalities and schizotypal personality in first-degree relatives. The present study is to verify the modifications of EEG power spectra in eyes-open resting state of schizophrenia and first-degree relatives, and to investigate associations between EEG band power and schizotypal personality traits in first-degree relatives of schizophrenia patients. Participant samples in this study consisted of 33 healthy normal controls, 35 unaffected first-degree relatives of schizophrenia patients and 35 schizophrenia patients. Group differences in resting EEG band power were examined via repeated-measures analysis of variance, and correlation between EEG power and schizotypal personality traits via Pearson Correlation analysis. The results showed that patients with schizophrenia exhibited increased delta, theta and alpha activity over anterior and central regions in eyes-open resting state compared with that of normal control. Gamma band power was found for the first time to be negatively correlated to schizotypal personality traits in first-degree relatives of schizophrenia patients. To conclusion, these findings suggested that low-frequency EEG activity might be neural manifestations of pathophysiological changes in the brain of schizophrenia, and gamma band activity might be an approach to measure the genetic liability of the disorder.

Discovery of chalcone-modified estradiol analogs as antitumour agents that Inhibit tumour angiogenesis and epithelial to mesenchymal transition.

Angiogenesis plays an essential role in tumourigenesis and tumour progression, and anti-angiogenesis therapies have shown promising antitumour effects in solid tumours. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, has been regarded as a potential antitumour agent mainly targeting angiogenesis. Here we synthesized a novel series of chalcones based on 2-methoxyestradiol and evaluated their potential activities against tumours. Compound 11e was demonstrated to have potent antiangiogenic activity. Further studies showed that 11e suppressed tumour growth in human breast cancer (MCF-7) xenograft models without obvious side effects. Evaluation of the mechanism revealed that 11e targeted the epithelial to mesenchymal transition (EMT) process in MCF-7 cells and inhibited HUVEC migration and then contributed to hindrance of angiogenesis. Thus, 11e may be a promising antitumour agent with excellent efficacy and low toxicity.

H2depda: An acyclic adjuvant potentiates meropenem activity in vitro against metallo-ß-lactamase-producing enterobacterales.

Metallo-ß-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) pose an emerging threat to public health worldwide. An effective inhibitor of MBLs is therefore urgently needed for clinical use. In this study, two acyclic pyridine-containing ligands, H2dedpa and compound 8, were discovered with excellent activities when combined with meropenem (MEM) against MBL (blaNDM and blaIMP)-producing clinical isolates, including Escherichia coli, Citrobacter freundii, Proteus mirabilis, Enterobacter cloacae and Klebsiella pneumoniae. In particular, these two compounds improved the activity of MEM against E. coli harboring the blaNDM-4 gene by nearly 40,960 times. H2dedpa (IC50 = 0.17 ±â€¯0.04 µM) and compound 8 (IC50 = 0.04 ±â€¯0.02 µM) showed higher inhibitory activity against blaNDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC50 = 28.84 ±â€¯0.70 µM). A sterilization kinetics experiment showed that H2dedpain combined with MEM could kill 99.9% of bacteria within 24 h H2dedpa and compound 8 are therefore promising MBL inhibitors.

Design, synthesis and antiproliferative effect of 17ß-amide derivatives of 2-methoxyestradiol and their studies on pharmacokinetics.

A series of 17ß-amide-2-methoxyestradiol compounds were synthesized with an aim to enhance the antiproliferative effect of 2-methoxyestradiol. The antiproliferative activity of 2-methoxyestradiol analogs against human cancer cells was investigated. 2-methoxy-3-benzyloxy-17ß-chloroacetamide-1,3,5(10)-triene (5e) and 2-methoxy-3-hydroxy-17ß-butyramide-1,3,5(10)-triene (6c) had comparable or better antitumor activity than 2-methoxyestradiol. The elimination half-life of 6c (t1/2ß=240.93min) is ten times longer than 2-ME and the area under the curve was seven times (AUC0-tmin=2068.20±315.74µgmL-1min) higher than 2-ME, respectively. Whereas 5e had similar pharmacokinetic behavior with 2-ME (t1/2ß=22.28min) with a t1/2ß of 29.5 min. 6c had higher blood concentration, longer actuation duration and better suppression rate against S180 mouse ascites tumor than 2-methoxyestradiol.