Synthesis, Antimicrobial Evaluation, and Interaction of Emodin Alkyl Azoles with DNA and HSA.

OBJECTIVE: This study aimed to overcome the growing antibiotic resistance. Moreover, the new series of emodin alkyl azoles were synthesized. METHOD: The novel emodin alkyl azoles were synthesized using commercial emodin and azoles by alkylation. The NMR and HRMS spectra were employed to confirm the structures of novel prepared compounds. The in vitro antibacterial and antifungal activities of the prepared emodin compounds were studied by the 96-well plate method. The binding behavior between emodin 4-nitro imidazole compound 3c and S. aureus DNA was researched using an ultraviolet-visible spectrophotometer. Furthermore, fluorescence spectrometry was used to explore the interaction with human serum albumin (HSA). RESULTS: The in vitro antimicrobial results displayed that compound 3c gave relatively strong activities with MIC values of 4-16 µg/mL. Notably, this compound exhibited 2-fold more potent activity against S. aureus (MIC = 4 µg/mL) and E. coli (MIC = 8 µg/mL) strains than clinical drug Chloromycin (MIC = 8 and 16 µg/mL). The UV-vis absorption spectroscopy showed that 4-nitro imidazole emodin 3c could form the 3c-DNA complex by intercalating into S. aureus DNA, inhibiting antimicrobial activities. The simulation results displayed that the emodin 3c and DNA complex were formed by hydrogen bonds. The spectral experiment demonstrated that compound 3c could be transported by human serum albumin (HSA) via hydrogen bonds. The molecular simulation found that the hydroxyl group and the nitroimidazole ring of the emodin compound showed an important role in transportation behavior. CONCLUSION: This work may supply useful directions for the exploration of novel antimicrobial agents.

Emodin Alcohols: Design, Synthesis, Biological Evaluation and Multitargeting Studies with DNA, RNA, and HSA.

OBJECTIVE: A series of novel emodin alcohols were designed and prepared in an effort to overcome the increasing microorganism resistance. METHODS: Novel emodin alcohols were prepared from commercial emodin and different nitrogen-containing heterocycles via different synthetic strategies, such as O-alkylation and N-alkylation. The antimicrobial activity of synthesized emodin compounds was evaluated in vitro by a two-fold serial dilution technique. The interaction of emodin compound 3d with biomolecule was researched using UV-vis spectroscopic method and fluorescence spectroscopy. RESULTS: Emodin compound 3d containing 2-methyl-5-nitro imidazole ring showed relatively good antimicrobial activity. Notably, it exhibited equivalent activity against S. aureus in comparison to the reference drug norfloxacin (MIC = 4 g/mL). The combination of strong active compound 3d with reference drugs showed better antimicrobial activity with less dosage and a broader antimicrobial spectrum than their separate use. Further research displayed that emodin compound 3d could intercalate into S. aureus DNA to form the 3d-DNA complex, which might correlate with the inhibitory activity. The hydrogen bonds were found between S. aureus DNA gyrase and strong active compound 3d during the docking research, which were in accordance with the spectral experiment results. The interaction with yeast RNA of compound 3d could also form a complex via hydrogen bonds. The hydrogen bonds were found to play a major role in the transportation of emodin compound 3d by human serum albumin (HSA), as confirmed by molecular simulation. CONCLUSION: This work provides a promising starting point to optimize the structures of emodin derivatives as potent antimicrobial agents.

Effectiveness of six-step complex decongestive therapy for treating upper limb lymphedema after breast cancer surgery.

BACKGROUND: Complex decongestive therapy (CDT) is currently recommended as the standard treatment for lymphedema. CDT is a four-step detumescence therapy that can effectively treat upper limb lymphedema after breast cancer surgery, and is considered non-invasive, painless and without side effects. AIM: To determine the effectiveness of a six-step CDT involving a foam granule bandage for the treatment of upper extremity lymphedema pressure after breast cancer surgical intervention. METHODS: The study included 100 patients with upper extremity lymphedema after breast cancer surgery. The surgical methods were mastectomy plus axillary lymph node dissection and breast preservation plus sentinel lymph node biopsy. The study population was further divided into the experimental group and control group with 50 cases in each group. The control group was given conventional CDT (four-step method), which included skin care, freehand lymphatic drainage, foam granule pressurized bandage, and functional exercise. In the experimental group, a six-step CDT method was applied that involved a foam particle bandage combined with air wave pressure therapy in addition to the four steps of conventional CDT. Patients in both groups were given one course of treatment daily (20 times), and the changes in body moisture and subjective symptoms were measured before and after treatment, preoperatively and 20 times after treatment. RESULTS: No statistically significant differences in 50-Hz bioelectrical impedance and extracellular moisture ratio were observed between the two groups before treatment, suggesting comparability of the baseline data. After treatment, the 50-Hz bioelectrical impedance of the experimental group was significantly higher than that in the control group, and the extracellular moisture ratio was significantly lower than that in the control group. A comparison of the differences between the two groups before and after treatment indicated that the treatment effect in the experimental group was better than that in the control group. After 20 treatments, according to subjective evaluations, the tightness and swelling of the limbs in the experimental group were significantly reduced as compared with those in the control group. CONCLUSION: The six-step CDT method can effectively reduce lymphedema, promote lymphatic circulation, and alleviate the subjective symptoms of patients, and thereby improve the quality of life and treatment compliance among patients.

TGFß1-transfected tendon stem cells promote tendon fibrosis.

BACKGROUND: In aged people, tendon injuries frequently occur during sporting and daily activities. In clinical practice, typical physiotherapeutic, pharmacotherapeutic, and surgical techniques do not result in the full recovery of injured tendons, which may lead to chronic degenerative disease. METHODS: We first isolated tendon stem cells (TSCs) from rats and transfected them with the TGFß1 gene, resulting in TGFß1-TSCs. The proliferation of TSCs was detected using the Cell Counting Kit 8, and TSCs were identified by immunofluorescence analysis and differentiation capacity analysis. Aggrecan, COL2A1, alpha smooth muscle actin (α-SMA), and p-Smad2 expression levels were detected using western blotting and quantitative reverse transcription polymerase chain reaction. Additionally, a tendon injury model was generated to explore the effect of TGFß1 on the repair of the tendon by TSCs. RESULTS: Compared with fibrinogen treatment, TSC + fibrinogen or TGFß1-TSC + fibrinogen treatment significantly promoted the fibrosis of injured tendons, as evidenced by histological analyses, with TGFß1-TSC + fibrinogen having a greater effect than TSC + fibrinogen. In TGFß1-TSCs, increased expression levels of aggrecan and COL2A1 indicated that TGFß1 signaling induced chondrogenic differentiation. Meanwhile, the increased collagen and α-SMA protein levels indicated that TGFß1 promoted fibrogenesis. Additionally, TGFß1 stimulated the production of phosphorylated Smad2 in TSCs, which suggested that the chondrogenic and fibrogenic differentiation of TSCs, as well as tissue regeneration, may be associated with the TGFß1/Smad2 pathway. CONCLUSION: TGFß1-TSC therapy may be a candidate for effective tendon fibrosis.

Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics.

Gefitinib has been available in the market for 20 years, but its pharmacokinetic mechanism of response is little known. In this study, we examined the pharmacokinetic and metabolomic profiles in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A total of 216 advanced NSCLC patients were enrolled, and administered gefitinib at the standard dosage of 250 mg/day, which was established in heterogeneous subjects with non-sensitive mutations. We identified and quantified three main metabolites (named as M1, M2 and M3) in the plasma of patients, the correlations between the concentration of gefitinib/metabolites and efficacy were analyzed. In exploratory and validation set, gefitinib concentration was not correlated with clinical effects. Considering the result that the therapeutic effects of 250 mg/2-day was better than that of 250 mg/day in a multiple center clinical trial, the standard dose might be higher than that for maximal efficacy according to the hypothetical dose-response curve. Among the three metabolites, the IC50 of M2 in HCC827 and PC9 cell lines was significantly lower, and Conc.brain/Conc.plasma of M2 in mice was significantly higher than those of gefitinib, suggesting its higher potential to penetrate blood-brain barrier and might be more effective in the treatment of brain metastatic tumor than gefitinib. Consistently and attractively, higher M2 plasma concentration was found to be correlated with better clinical outcome in patients with brain metastases (the median PFS of CM2 < 12 ng/mL and CM2 ≥ 12 ng/mL were 17.0 and 27.1 months, respectively, P = 0.038). The plasma concentration of M2 ≥ 12 ng/mL was a strong predictor of the PFS of NSCLC patients. In conclusion, for NSCLC patients with EGFR sensitive mutations, the standard dose is suspectable and could be decreased reasonably. M2 plays an important role in efficacy and may be more effective in the treatment of metastatic tumor than gefitinib.

Hepatic Vps33b deficiency aggravates cholic acid-induced cholestatic liver injury in male mice.

Vacuolar protein sorting 33B (VPS33B) is important for intracellular vesicular trafficking process and protein interactions, which is closely associated with the arthrogryposis, renal dysfunction, and cholestasis syndrome. Our previous study has shown a crucial role of Vps33b in regulating metabolisms of bile acids and lipids in hepatic Vps33b deficiency mice with normal chow, but it remains unknown whether VPS33B could contribute to cholestatic liver injury. In this study we investigated the effects of hepatic Vps33b deficiency on bile acid metabolism and liver function in intrahepatic cholestatic mice. Cholestasis was induced in Vps33b hepatic knockout and wild-type male mice by feeding 1% CA chow diet for 5 consecutive days. We showed that compared with the wild-type mice, hepatic Vps33b deficiency greatly exacerbated CA-induced cholestatic liver injury as shown in markedly increased serum ALT, AST, and ALP activities, serum levels of total bilirubin, and total bile acid, as well as severe hepatocytes necrosis and inflammatory infiltration. Target metabolomics analysis revealed that hepatic Vps33b deficiency caused abnormal profiles of bile acids in cholestasis mice, evidenced by the upregulation of conjugated bile acids in serum, liver, and bile. We further demonstrated that the metabolomics alternation was accompanied by gene expression changes in bile acid metabolizing enzymes and transporters including Cyp3a11, Ugt1a1, Ntcp, Oatp1b1, Bsep, and Mrp2. Overall, these results suggest a crucial role of hepatic Vps33b deficiency in exacerbating cholestasis and liver injury, which is associated with the altered metabolism of bile acids.

Design, Synthesis and Antimicrobial Evaluation of Novel Benzimidazoleincorporated Naphthalimide Derivatives as Salmonella typhimurium DNA Intercalators, and Combination Researches.

OBJECTIVE: A series of novel benzimidazole-incorporated naphthalimide derivatives were designed and prepared in an effort to overcome the increasing antibiotic resistance. METHODS: The target novel benzimidazole-incorporated naphthalimide derivatives were synthesized from commercial 4-bromo-1,8-naphthalic anhydride and o-phenylene diamine by aminolysis, Nalkylation and so on. The antimicrobial activity of the synthesized compounds was evaluated in vitro by a two-fold serial dilution technique. The interaction of compound 10g with Salmonella typhimurium DNA was studied using UV-vis spectroscopic methods. RESULTS: Compound 10g bearing a 2,4-dichlorobenzyl moiety exhibited the best antimicrobial activities in this series relatively; especially, it exhibited comparable activity against Salmonella typhimurium in comparison with the reference drug Norfloxacin (MIC = 4 µg/mL). Further research showed that compound 10g could effectively intercalate into the Salmonella typhimurium DNA to form the 10g-DNA complex, which might correlate with the inhibitory activity. Molecular docking results demonstrated that naphthalimide compound 10g could interact with base-pairs of DNA hexamer duplex by π-π stacking. Additionally, the combination of the strong active compound with clinical drugs exhibited better antimicrobial efficiency with less dosage and broader antimicrobial spectrum than the separate use of them alone. Notably, these combined systems were more sensitive to Fluconazole-insensitive M. ruber. CONCLUSION: This work provides a promising starting point to optimize the structures of benzimidazole- incorporated naphthalimide derivatives as potent antimicrobial agents.

Relationship between chronic kidney disease and sarcopenia.

Few studies have investigated the relationship between sarcopenia and mild to moderate renal decline. This study aimed to investigate the relationship between chronic kidney disease (CKD) and sarcopenia. In total, 123 patients hospitalized with CKD and 57 healthy volunteers who underwent physical examination during the same period (control group) were analyzed. Body compositions were measured by dual-energy X-ray absorptiometry, and the relative appendicular skeletal muscle index (RASMI) was calculated. Muscular strength was evaluated using hydraulic hand dynamometer. Walking speed within 6 m was measured for muscular function assessment. Single-photon emission computed tomography was performed to measure the glomerular filtration rate of CKD patients, who were then divided into CKD1 (55 patients in CKD stages 1 and 2) and CKD2 (68 patients in CKD stages 3-5). RASMI showed a downward trend with CKD progression (P = 0.001). Multivariate logistic regression analysis showed that age and CKD progression were independent risk factors for sarcopenia. The morbidity of sarcopenia was significantly greater in CKD patients than in healthy volunteers, and the degree of muscle loss was closely related to CKD progression.

Mutational Analysis of a Familial Adenomatous Polyposis Pedigree with Bile Duct Polyp Phenotype.

A large number of colorectal cancers have a genetic background in China. However, due to insufficient awareness, the diagnostic rate remains low and merely 5-6% of colorectal cancer patients are diagnosed with hereditary colorectal cancer. Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disease caused by mutations in the adenomatous polyposis coli (APC) gene. Different mutation sites in APC are associated with the severity of FAP, risks of carcinogenesis, and extraintestinal manifestations. We used next-generation sequencing (NGS) and capture techniques to screen suspected mutation points in the proband in this pedigree. Using modified Sanger sequencing, we identified members of the family who were carriers of this variant and whether this segregated well with disease occurrence. FAP family members had multiple adenomatous polyps in their gastrointestinal tracts, some of which developed into cancer with age. Two subjects presented a rare common bile duct polyp phenotype. No extraintestinal manifestations were observed. A heterozygous frameshift mutation in APC exon 16 (NM_000038.6) was observed in the proband and in other patients: c.3260_3261del (p.Leu1087GlnQfs ∗ 31) (rs587782305); the variant call format was CCT/C. Due to the deletion of two bases, a stop codon appeared after 31 amino acids, and the protein was truncated prematurely, which affected the conformation of the protein. Pedigree genetic linkage analysis showed that the clinical phenotype cosegregated with the APC mutation p.L1087fs. This mutation may be the pathogenic in this FAP family and responsible for this rare common bile duct polyp.

Interleukin 6 regulates the expression of programmed cell death ligand 1 in thyroid cancer.

Programmed cell death ligand 1 (PD-L1), inducing T cell exhaustion to facilitate immune escape of tumor cells, is upregulated by interleukin 6 (IL-6) in T cell lymphoma and ovarian cancer. The purpose of this study is to investigate the expression of IL-6 and PD-L1 in thyroid cancer, and whether IL-6 regulates PD-L1 expression. As a result, IL-6 and PD-L1 were highly expressed in thyroid cancer tissues. Multivariate logistic analysis showed that tumor size, distant metastasis, and risk stratification were significantly associated with IL-6 expression (P < .05), and multifocality, lymph node metastasis, distant metastasis, risk stratification, and IL-6 expression were identified as the independent predictors of PD-L1 expression (P < .05). The invasiveness of thyroid cancer was significantly enhanced after IL-6 treatment or PD-L1 overexpression. PD-L1 positive rate correlated with IL-6 expression in cancer tissues (P < .001), and after IL-6 treatment, the PD-L1 expression in TPC-1 and BCPAP significantly increased. The mitogen-activated protein kinase pathway (MAPK) and the Janus-activated kinase (JAK)-signal transducers and activators of transcription 3 (STAT3) signaling pathways were activated by IL-6, and the IL-6-induced PD-L1 expression decreased after treatment with these two signaling pathway inhibitors. Knockdown of transcription factors c-Jun and stat3 suppressed the expression of PD-L1 induced by IL-6, and these two factors could bind to PD-L1 gene promoter directly and promote its transcription. It is concluded that IL-6 and PD-L1 are overexpressed in thyroid cancer and are related to tumor invasiveness. IL-6 upregulates PD-L1 expression through the MAPK and JAK-STAT3 signaling pathways, which function via transcription factors c-Jun and stat3.

Targeted bile acids and gut microbiome profiles reveal the hepato-protective effect of WZ tablet (Schisandra sphenanthera extract) against LCA-induced cholestasis.

Cholestasis is caused by the obstacle of bile formation or secretion and can develop into severe liver diseases. We previously reported the ethanol extract of Schisandra sphenanthera (Wuzhi tablet, WZ) can significantly protect against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice, partially due to the activation of PXR pathway and promotion of liver regeneration. However, the effect of WZ on the bile acids profile and gut microbiome in cholestastic mice remain unknown. In this study, the effect of WZ against LCA-induced liver injury was evaluated and its effect on the bile acids metabolome and gut microbiome profiles in cholestastic mice was further investigated. Targeted metabolomics analysis was performed to examine the change of bile acids in the serum, liver, intestine and feces. The change of intestinal flora were detected by the genomics method. Targeted metabolomics analysis revealed that WZ enhanced the excretion of bile acids from serum and liver to intestine and feces. Genomics analysis of gut microbiome showed that WZ can reverse LCA-induced gut microbiome disorder to the normal level. In conclusion, WZ protects against LCA-induced cholestastic liver injury by reversing abnormal bile acids profiles and alteration of gut microbiome.

[Electroacupuncture improved learning-memory ability by reducing hippocampal apoptosis and suppressing JNK signaling in rats with vascular dementia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation on the expression of c-Jun terminal kinase(JNK)signaling pathway-related proteins in the hippocampus of vascular dementia (VD) rats, so as to explore its mechanisms underlying improvement of VD. METHODS: Male Sprague-Dawley rats were randomly divided into sham operation, model and EA groups (n＝10 rats per group). The VD model was prepared by repeated occlusion of the bilateral common carotid arteries for 10 min and reperfusion for 10 min (3 times in total). The rats in the EA group received EA (2 Hz, 2 mA) at "Dazhui"(GV14)，"Baihui"(GV20), and bilateral "Housanli"(ST36) ，"Geshu"(BL17) for 10 min, once daily for 14 days. The learning-memory abi-lity was detected by Morris water maze tests, the distribution of hippocampal neurons detected by Nissl staining, and the apoptosis of hippocampal neurons detected by using TdT-mediated dUTP nick-end labeling (TUNEL) method. The expressions of JNK, phosphorylated JNK (p-JNK), cysteine-containing aspartate-specific proteases-8 (Caspase-8) and Caspase-3 proteins were detected by Western blot. RESULTS: After modeling and compared with the sham operation group, the escape latency was significantly prolonged (P<0.01) and the number of safe-platform quadrant crossing obviously decreased (P<0.01), suggesting a reduction of learning-memory ability. The number of hippocampal neurons was considerably reduced (P<0.01), and that of hippocampal apoptotic neurons remarkably increased in the model group (P<0.01). Whereas, the expression levels of hippocampal apoptosis-related proteins as JNK, p-JNK, Caspase-8 and Caspase-3, as well as the apoptotic index were significantly up-regulated (P<0.01). Following EA intervention, the learning-memory ability was apparently improved (P<0.01), and the number of hippocampal neurons was considerably increased (P<0.01), the hippocampal apoptotic cell number, apoptosis index and the expression levels of JNK, p-JNK, Caspase-8 and Caspase-3 were significantly down-regulated (P<0.01). CONCLUSION: EA intervention can improve the learning-memory ability of VD rats, which may be associated with its effects in reducing hippocampal apoptosis by suppressing JNK signaling pathway.

circ_NOTCH3 Functions as a Protooncogene Competing With miR-205-5p, Modulating KLF12 Expression and Promoting the Development and Progression of Basal-Like Breast Carcinoma.

Breast cancer is the most common type of cancer diagnosed among women, and basal-like breast carcinoma (BLBC) has been associated with a more aggressive histology, poorer prognosis, and non-responsiveness to hormone therapy. In the present study, the role and molecular mechanism of circular (circ)_NOTCH3 in the development and progression for BLBC was identified. circ_RNAs array was used to screen the ectopic expression of hsa_circ_0109177 (circ_NOTCH3) in BLBC. RT-qPCR was conducted to evaluate the circ_NOTCH3 expression in BLBC tissues and paired normal tissues, as well as related cell lines. Cell function changes were analyzed following circ_NOTCH3 or micro (mi)RNA overexpression or co-expression. Bioinformatics analysis and dual-luciferase reporter assay were performed to predict and verify the binding sites between circ_NOTCH3 and miRNAs. Gene expression changes were assessed using western blotting. circ_NOTCH3 had a significantly higher expression in BLBC tissues and cell lines. The upregulation of circ_NOTCH3 promoted the proliferation, migration, invasion and inhibited the apoptosis for BLBC cells. The opposite results were observed following miR-205-5p overexpression. However, the co-expression of circ_NOTCH3 and miR-205-5p resulted in those restoration. circ_NOTCH3 is capable of binding to miR-205-5p, and upregulating its target gene KLF12, which can be downregulated by miR-205-5p overexpression and restored by the co-expression of circ_NOTCH3 and miR205-5p. circ_NOTCH3, being an protooncogene and a powerful biomarker, can function as a sponge, compete with miR-205-5p, modulate KLF12 expression, and promote the development and progression of BLBC.

Design and Synthesis of Novel Sulfonamide-Derived Triazoles and Bioactivity Exploration.

OBJECTIVE: Due to the incidence of resistance, a series of sulfonamide-derived 1,2,4- triazoles were synthesized and evaluated. METHOD: The novel sulfonamide-derived 1,2,4-triazoles were prepared starting from commercial acetaniline and chlorosulfonic acid by sulfonylation, aminolysis, N-alkylation and so on. The antimicrobial activity of the synthesized compounds were evaluated in vitro by two-fold serial dilution technique. RESULTS: In vitro antimicrobial evaluation found that 2-chlorobenzyl sulfonamide 1,2,4-triazole 7c exhibited excellent antibacterial activities against MRSA, B. subtilis, B. typhi and E. coli with MIC values of 0.02-0.16 µmol/mL, which were comparable or even better than Chloromycin. The preliminary mechanism suggested that compound 7c could effectively bind with DNA, and also it could bind with human microsomal heme through hydrogen bonds in molecular docking. Computational chemical studies were performed on compound 7c to understand the structural features that are essential for activity. Additionally, compound 7c could generate a small amount of reactive oxygen species (ROS). CONCLUSION: Compound 7c could serve as a potential clinical antimicrobial candidate.

Adverse Events at Baseline in a Chinese General Hospital: A Pilot Study of the Global Trigger Tool.

OBJECTIVE: To investigate adverse events (AEs) at baseline in a Chinese general hospital using the Institute for Healthcare Improvement (IHI) Global Trigger Tool (GTT) and discuss the feasibility of this tool to detect AEs in China. METHODS: A total of 10 inpatient records from the hospital were sampled randomly half a month in 2014. The records were reviewed to identify AEs according to the second edition of the IHI GTT for measuring AEs. Triggers and AEs were analyzed using Microsoft Excel 2007. Statistical analyses were performed using IBM SPSS software, version 19.0. RESULTS: A review of 240 patient records identified 51.0% (26/51) triggers in the worksheet, and 33.3% (17/51) were associated with AEs. A total of 70 AEs were identified in 54 patients, including 65.7% (46/70) category E AEs, which represent temporary harm requiring intervention, and 34.3% (24/70) category F AEs, which represent temporary harm requiring initial or prolonged hospitalization. The average rate of AEs per 1000 patient-days was 32.1 ± 20.9. The average rate of AEs per 100 admissions was 29.2 ± 16.1. The average rate of admissions with an AE was 22.5% ± 13.9%. The most significant characteristic of patients with AEs was longer hospital stay. CONCLUSIONS: More than one fifth of adult inpatients in the current study experienced at least one AE resulting in temporary harm, most commonly caused by surgical operations and medication. With some modifications, the IHI GTT is a feasible and effective tool for detecting the overall status of AEs in a Chinese hospital.

Effects of Drying Methods on the Content, Structural Isomers, and Composition of Astaxanthin in Antarctic Krill.

Antarctic krill (Euphausia superba) is one of the important bioresources in Antarctic waters, containing many bioactives (e.g., astaxanthin), which have a highly potential value for commercial exploitation. In this study, the effects of processing methods on the content, structural isomers, and composition of astaxanthins (free astaxanthin and astaxanthin esters) were studied. Three drying methods, comprising freeze-drying, microwave drying, and hot-air drying, were used. Free astaxanthin (Ast), astaxanthin monoesters (AM), and astaxanthin diesters (AD) in boiled krill (control) and dried krill were extracted and analyzed using high-resolution mass spectrometry with ultraviolet detection. After the three processes, total astaxanthin loss ranged from 8.6 to 64.9%, and the AM and AD contents ranged from 78.3 to 16.6 and 168.7 to 90.5 µg/g, respectively. Compared to other kinds of astaxanthin esters, astaxanthin esters, which linked to eicosapentaenoic acid and docosahexaenoic acid, as well as the Ast, were more easily degraded, and AM was more susceptible to degradation than AD. All-E-astaxanthin easily transformed to the 13Z-astaxanthin than to the 9Z-astaxanthin during the drying process, but the proportions of optical isomers changed due to drying by no more than 5%. The results suggested that freeze-drying, low-power microwave drying (≤1 kW), and low-temperature hot-air drying (≤60 °C) are optimal drying methods for ensuring the quality of krill products.

Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1.

Osteosarcoma (OS), which is the most common primary malignant bone tumor, has a high incidence of pulmonary metastasis. CCL18 (C-C motif chemokine ligand 18), which is secreted by tumor-associated macrophages (TAMs), has been found to be increased in various tumors and is associated with tumor metastasis. However, the role of CCL18 in OS remains unclear. Here, we evaluated the effect of CCL18 on the OS cell lines MG63 and 143B and explored its potential mechanisms. We found that CCL18 enhanced the proliferation and migration of OS cells and upregulated UCA1 through transcription factor EP300. Subsequently, we further revealed that the downstream Wnt/ß-catenin signaling pathway participated in this process. In addition, the high expression of CCL18 in both tissue and serum from patients was closely related to pulmonary metastasis and poor survival in OS patients. The tumor xenograft models also showed that CCL18 promoted the metastasis of OS cells. Collectively, our study indicated that macrophage-derived CCL18 promotes OS proliferation and metastasis via the EP300/UCA1/Wnt/ß-catenin pathway and that CCL18 may be used as a prognostic marker and therapeutic target of OS. KEY MESSAGES: CCL18 promotes proliferation and migration of osteosarcoma cells by EP300/ UCA1/ Wnt/ß-catenin pathway. CCL18+ TAMs are significantly correlated with pulmonary metastasis and poor survival in osteosarcoma patients. CCL18 may be used as a prognostic marker and therapeutic target for osteosarcoma.

Gastrointestinal toxicity induced by microcystins.

Microcystins (MCs) are produced by certain bloom-forming cyanobacteria that can induce toxicity in various organs, including renal toxicity, reproductive toxicity, cardiotoxicity, and immunosuppressive effects. It has been a significant global environmental issue due to its harm to the aquatic environment and human health. Numerous investigators have demonstrated that MC exposure can induce a widespread epidemic of enterogastritis with symptoms similar to food poisoning in areas close to lakes. Both in vivo and in vitro studies have provided evidence of positive associations between MC exposure and gastrointestinal toxicity. The toxicity of MCs on the gastrointestinal tract is multidimensional. MCs can affect gastrointestinal barrier function and shift the structure of gut microbiota in different gut regions. Furthermore, MCs can inhibit the secretion of gastrointestinal digestive enzymes and the release of inflammatory cytokines, which affects the expression of immune-related genes in the intestine. The damage of the intestine is closely correlated to MC exposure because the intestine is the main site for the digestion and absorption of nutrients. The damage to the gastrointestinal tract due to MCs was summarized from different aspects, which can be used as a foundation for further exploration of molecular damage mechanisms.

Recent advance in oxazole-based medicinal chemistry.

Oxazole compounds containing nitrogen and oxygen atoms in the five-membered aromatic ring are readily able to bind with a variety of enzymes and receptors in biological systems via diverse non-covalent interactions, and thus display versatile biological activities. The related researches in oxazole-based derivatives including oxazoles, isoxazoles, oxazolines, oxadiazoles, oxazolidones, benzoxazoles and so on, as medicinal drugs have been an extremely active topic, and numerous excellent achievements have been acquired. Noticeably, a large number of oxazole compounds as clinical drugs or candidates have been frequently employed for the treatment of various types of diseases, which have shown their large development value and wide potential as medicinal agents. This work systematically reviewed the recent researches and developments of the whole range of oxazole compounds as medicinal drugs, including antibacterial, antifungal, antiviral, antitubercular, anticancer, anti-inflammatory and analgesic, antidiabetic, antiparasitic, anti-obesitic, anti-neuropathic, antioxidative as well as other biological activities. The perspectives of the foreseeable future in the research and development of oxazole-based compounds as medicinal drugs are also presented. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic oxazole medicinal drugs.

Design, synthesis and antimicrobial evaluation of novel benzimidazole-incorporated sulfonamide analogues.

A novel series of benzimidazole-incorporated sulfonamide analogues were designed and synthesized with an effort to overcome the increasing antibiotic resistance. Compound 5c gave potent activities against Gram-positive bacteria and fungi, and 2,4-dichlorobenzyl derivative 5g showed good activities against Gram-negative bacteria. Both of these two active molecules 5c and 5g could effectively intercalate into calf thymus DNA to form compound-DNA complex respectively, which might block DNA replication to exert their powerful antimicrobial activity. Molecular docking experiments suggested that compounds 5c and 5g could insert into base-pairs of DNA hexamer duplex by the formation of hydrogen bonds with guanine of DNA. The transportation behavior of these highly active compounds by human serum albumin (HSA) demonstrated that the electrostatic interactions played major roles in the strong association of active compounds with HSA, and which was also confirmed by the full geometry calculation optimizations.