Ti3C2Tx MXene loaded with indocyanine green for synergistic photothermal and photodynamic therapy for drug-resistant bacterium.

Infections caused by antibiotic-resistant bacteria are a critical threat to human health. Considering the difficulties and time-consuming nature of synthesizing new antibiotics, it is of great significance and importance to develop the antibiotic-independent antibacterial approaches against drug-resistant bacteria. Nanomaterials-based photothermal therapy (PTT) and photodynamic therapy (PDT) have attracted much attention due to their broad-spectrum bactericidal activity, low toxicity, and drug-free feature. In this work, we loaded indocyanine green (ICG) on the Ti3C2Tx MXene nanosheets (454 nm) so as to combine the photothermal effect of MXene with the photodynamic effect of ICG. Without near-infrared (NIR) irradiation, MXene (20 µg/mL), ICG (5 µg/mL) or ICG-loaded MXene (ICG-MXene) showed no significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Under NIR, however, the viability loss of MRSA remarkably increased to 45% for MXene, 66% for ICG and 100% for ICG-MXene. We further found that the great anti-MRSA activity of ICG-MXene under NIR was attributed to the combination of photothermal effect of MXene (high temperature) and photodynamic effect of ICG (high level of reactive oxygen species). Our findings indicate that MXene can be used as both the photothermal agent and the carrier of photosensitizers to achieve the synergistic PTT/PDT therapy for bacterial infections.

Facile and Selective Determination of Total Phthalic Acid Esters Level in Soft Drinks by Molecular Fluorescence Based on Petroleum Ether Microextraction and Selective Derivation by H2SO4.

Determining the level of phthalic acid esters (PAEs) in packaged carbonated beverages is a current need to ensure food safety. High-selectivity and -accuracy identification of individual PAEs can be achieved by chromatographic and mass spectrometric (MS) techniques. However, these methods are slow; involve complicated, expensive instruments in professional laboratories; and consume a large amount of organic solvents. As such, a food analysis method is needed to conveniently and rapidly evaluate multiple contaminants on site. In this study, with the assistance of ultrasound, we quickly determined the total PAEs in soft drinks using 1.5 mL of petroleum ether in one step. Then, we determined the characteristic molecular fluorescence spectrum of all PAEs in samples (excitation (Ex)/emission (Em) at 218/351 nm) using selectively concentrated sulfuric acid derivatization. The relative standard deviations of the fluorescent intensities of mixed solutions with five different PAEs were lower than 7.1% at three concentration levels. The limit of detection of the proposed method is 0.10 µmol L-1, which matches that of some of the chromatographic methods, but the proposed method uses less organic solvent and cheaper instruments. These microextraction devices and the fluorescence spectrometer are portable and provide an instant result, which shows promise for the evaluation of the total level of PAEs in beverages on site. The proposed method successfully detected the total level of PAEs in 38 kinds of soft drink samples from local supermarkets, indicating its potential for applications in the packaged beverage industry.

Alumina nanoparticles-induced heterophil extracellular traps exacerbate liver injury by regulating oxidative stress and inflammation in chickens.

Widely used alumina nanoparticles (Al2O3 NPs) exposed to the environment pose a serious threat to human and animal health. The formation of heterophil extracellular traps (HETs) is a mechanism of innate immune defense against infection, but excessive HETs cause pathological damage. Here, we aim to explore the influence and mechanism of Al2O3 NPs on the formation of HETs in vitro, and further investigate the role of HETs release in histopathological damage after Al2O3 NPs treatment. Immunofluorescence analysis showed that Al2O3 NPs induced the formation of HETs, which was characterized by modified histones and elastase in the DNA backbone. Fluorescence microplate analysis showed that HETs formation was dependent on NADPH oxidase, P38, extracellular regulated protein kinases (ERK1/2) pathways and glycolysis. In vivo investigation showed that Al2O3 NPs significantly caused HETs release and liver damage. Biochemical analysis showed that Al2O3 NPs inhibited the activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). Real-time fluorescence quantification results showed that Al2O3 NPs caused the overexpression of inflammation-related molecules interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), caspase-1 and caspase-11. All these changes were significantly changed by DNase I (Degradation reagent for HETs). Together, these suggest that Al2O3 NPs-induced HETs exacerbate liver injury by regulating oxidative stress and inflammatory responses, which provide a new perspective and potential prophylaxis and treatment targets for Al2O3 NPs toxicological research.

Effects of green coffee bean extract on C-reactive protein levels: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND & OBJECTIVE: The effects of green coffee bean extract (GCBE) supplementation on inflammatory biomarkers have been widely spread. The purpose of this article was to assess the impact of GCBE supplementation on C-reactive protein (CRP) levels. METHODS: The literature search was performed in four databases (Scopus, PubMed, the Cochrane Library, and Google Scholar) to identify studies that examined the influence of GCBE supplementation on CRP levels up to August 2019. Mean and standard deviation (SD) of the outcomes were used to estimate the weight mean difference (WMD) between intervention and control groups for the follow-up period. RESULTS: Five (5) studies, with 6 arms, reported CRP as an outcome. Statistically, the use of GCBE supplements resulted in a significant change in CRP levels (WMD: -0.017 mg/dL, 95 % CI: -0.032, -0.003, p = 0.018), whose overall findings were obtained from random-effects model. In addition, a significantly greater reduction in CRP was noted for studies with doses of GCBE supplements ≥ 1000 mg/d (WMD: -0.015 mg/dL, 95 % CI: -0.020, -0.010, p < 0.000), length of intervention < 4 weeks (WMD: -0.015 mg/dL, 95 % CI: -0.020, -0.010, p < 0.001), and for non-healthy subjects (WMD: -0.019 mg/dL, 95 % CI: -0.027, -0.011, p < 0.001). Dyslipidemia, hypertension and non-alcoholic fatty liver disease were the ailments of the studies that encompassed non-healthy patients. CONCLUSIONS: This meta-analysis shows that the use of GCBE supplements resulted in a statistical decrease in CRP levels, mainly for non-healthy subjects. However, due to the limited number of studies, further randomized clinical trials are crucial in this regard.

Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents.

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t1/2 = 5.93 h). The results indicate that I-14 could serve as a possible candidate to treat diabetes.

MiR-141-3p Suppresses Tumor Growth and Metastasis in Papillary Thyroid Cancer via Targeting Yin Yang 1.

MicroR-141-3p has been found to be downregulated in papillary thyroid carcinoma (PTC), while little is known about the cellular functions and precise signals elicited by miR-141-3p in PTC. The results of this study indicated that the expression of miR-141-3p was aberrantly down-regulated in PTC tissues and cell lines, compared with the adjacent normal tissues and normal thyroid epithelial cells. Furthermore, the miR-141-3p expression level was negatively associated with TNM stage and lymph node metastasis in PTC. Expression of miR-141-3p effectively inhibited cell growth, promoted apoptosis, and suppressed invasion in PTC cells. Meanwhile, miR-141-3p knockdown with miR-141-3p inhibitor reversed these effects. Consistent with the in vitro study, miR-141-3p also exhibited anti-neoplastic activity in vivo. Moreover, the results revealed that miR-141-3p directly recognized the 3' untranslated region (3'UTR) of Yin Yang 1 (YY1) and negatively regulated the expression of YY1 at both protein and mRNA levels. Ectopic expression of YY1 could effectively abrogate the anti-metastatic and proapoptotic effects of miR-141-3p. In summary, the findings suggested that miR-141-3p can act as a tumor suppressor in PTC and may be a potential therapeutic target for PTC treatment. Anat Rec, 302:258-268, 2019. © 2018 Wiley Periodicals, Inc.

Design, synthesis, and biological evaluation of novel nitric oxide releasing dehydroandrographolide derivatives.

A series of new hybrids of dehydroandrographolide (TAD), a biologically active natural product, bearing nitric oxide (NO)-releasing moieties were synthesized and designated as NO-donor dehydroandrographolide. The biological activities of target compounds were studied in human erythroleukemia K562 cells and breast cancer MCF-7 cells. Biological evaluation indicated that the most active compound I-5 produced high levels of NO and inhibited the proliferation of K562 (IC50 1.55 µmol·L-1) and MCF-7 (IC50 2.91 µmol·L-1) cells, which were more potent than the lead compound TAD and attenuated by an NO scavenger. In conclusion, I-5 is a novel hybrid with potent antitumor activity and may become a promising candidate for future intensive study.

SWOT analysis and revelation in traditional Chinese medicine internationalization.

Traditional Chinese medicine (TCM) is currently the best-preserved and most influential traditional medical system with the largest number of users worldwide. In recent years, the trend of TCM adoption has increased greatly, but the process of TCM internationalization has suffered from a series of setbacks for both internal and external reasons. Thus, the process of TCM internationalization faces formidable challenges, although it also has favourable opportunities. Using SWOT analysis, this paper investigates the strengths, weaknesses, opportunities and threats for TCM. These findings can serve as references for TCM enterprises with global ambitions.

Phenylquinoline transient receptor potential vanilloid 1 antagonists for the treatment of pain: Discovery of 1-(2-phenylquinoline-4-carbonyl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide.

Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a phenylquinoline platform that evolved from Cinchophen lead. This design composes three sections: a phenylquinoline headgroup attached to an aliphatic carboxamides, which is tethered at a phenyl tail group. Optimization of this design led to the identification of 37, comprising a pyrrolidine linker and a trifluoromethyl-phenyl tail. In the TRPV1 functional assay, using cells expressed hTRPV1, 37 antagonized capsaicin-induced Ca2+ influx, with an IC50 value of 10.2 nM. In the complete mice analgesic model, 37 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that 37 could be considered as a lead candidate for the further development of antinociceptive drugs.

Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists.

The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg.

Biological activity studies of the novel glucagon-like peptide-1 derivative HJ07.

AIM: To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07. METHOD: A receptor activation experiment was performed in HEK 293 cells and the glucose lowering ability was evaluated with hypoglycemic duration and glucose stabilizing tests. Chronic treatment was performed by daily injection of exendin-4, saline, and HJ07. Body weight and HbA1c were measured every week, and an intraperitoneal glucose tolerance test was performed before treatment and after treatment. RESULTS: HJ07 showed well-preserved receptor activation efficacy. The hypoglycemic duration test showed that HJ07 possessed a long-acting, glucose-lowering effect and the glucose stabilizing test showed that the antihyperglycemic activity of HJ07 was still evident at a predetermined time (12 h) prior to the glucose challenge (0 h). The long time glucose-lowering effect of HJ07 was better than native GLP-1 and exendin-4. Furthermore, once daily injection of HJ07 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. CONCLUSION: The biological activity results of HJ07 suggest that HJ07 is a potential long-acting agent for the treatment of type 2 diabetes.

Improved outcome after spinal cord compression injury in mice treated with docosahexaenoic acid.

In this study we have characterised the locomotor recovery, and temporal profile of cell loss, in a novel thoracic compression spinal cord injury (SCI) in the mouse. We have also shown that treatment with docosahexaenoic acid (DHA) is neuroprotective in this model of SCI, strengthening the growing literature demonstrating that omega-3 polyunsaturated fatty acids are neuroprotective after SCI. Compression SCI in C57BL/6 mice was produced by placing a 10 g weight for 5 min onto a 2 mm × 1.5 mm platform applied to the dura at vertebral level T12. Mice partly recovered from complete hindlimb paralysis and by 28 days post-surgery had plateaued at an average BMS locomotor score of 4.2, equivalent to weight support with plantar stepping. During the same period, neuronal loss at the epicentre increased from 26% of ventral horn neurons by day 1, to 68% by day 28. Delayed loss of oligodendrocytes was also seen (e.g. 84% by day 28 in the dorsal columns) and microglia/macrophage activation was maximal at 7 days. In contrast, axonal damage, judged by a decrease in the non-phosphorylated form of 200 kD neurofilament, was an early event, as the loss was seen by day 1 and did not change markedly over time. Mice that received an intravenous (i.v.) injection of 500 nmol/kg DHA 30 min after SCI, showed improved locomotor recovery and, at 28 day survival, reduced neuronal, oligodendrocyte and neurofilament loss, and reduced microglia/macrophage activation. For some of these indices of SCI, enrichment of the diet with 400 mg/kg/day DHA led to further improvement. However, dietary DHA supplementation, without the initial i.v. injection, was ineffective.

Improved outcome after peripheral nerve injury in mice with increased levels of endogenous ω-3 polyunsaturated fatty acids.

Functional recovery after a peripheral nerve injury (PNI) is often poor. There is a need for therapies that protect neurons against injury and enhance regeneration. ω-3 polyunsaturated fatty acids (PUFAs) have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury. The objective of this study was to assess the neuroprotective and pro-regenerative potential of ω-3 PUFAs in PNI. We investigated this in mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs. Dorsal root ganglion (DRG) neurons from wild-type or fat-1 mice were subjected to a mechanical strain or hypoxic injury, and cell death was assessed using ethidium homodimer-1 labeling. The fat-1 background appears to confer robust neuroprotection against both injuries. We then examined the early functional and morphological changes in wild-type and fat-1 mice after a sciatic nerve crush. An accelerated functional recovery 7 d after injury was seen in fat-1 mice when assessed using von Frey filaments and the sciatic nerve functional index. These observations were also mapped to changes in injury-related markers. The injury-induced expression of ATF-3 was decreased in the DRG of fat-1 mice, whereas the axons detected 6 mm distal to the crush were increased. Fat-1 animals also had some protection against muscle atrophy after injury. In conclusion, both in vitro and in vivo experiments support the idea that a higher endogenous ω-3 PUFA could lead to beneficial effects after a PNI.

Stability and bioactivity studies on dipeptidyl peptidase IV resistant glucogan-like peptide-1 analogues.

Glucagon-like peptide-1 (GLP-1) was once considered as an ideal anti-diabetic candidate for its important role in maintaining glucose homeostasis through the regulation of islet hormone secretion, as well as hepatic and gastric function. However, the major therapeutic obstacle for using native GLP-1 as a therapeutic agent is its very short half-life primarily due to their degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). In this study, GLP-1 analogues with modifications in amino acid site 8, 22 and 23 were synthesized using solid phase peptide synthesis. Resistance of these analogues to DPP-IV cleavage was investigated in vitro by incubation of the peptides with DPP-IV or human plasma. Glucoregulating efficacy of the analogues was evaluated in normal Kunming mice using intraperitoneal glucose tolerance model. Glucose lowering effect of combination therapy (analogue plus Vildagliptin) has also been studied. In vitro studies showed that the modified analogues were much more stable than native GLP-1 (nearly 100% of the peptide keep intact after 4 h incubation). In vivo biological activity evaluation revealed that His8-EEE (the most potent GLP-1 analogues in this study) exhibited significantly improved glycemic control potency (approximately 4.1-fold over saline and 2.5-fold over GLP-1) and longer time of active duration (at least 5 h). Combination therapy also showed the trend of its superiority over mono-therapy. Modified analogues showed increased potency and biological half-time compared with the native GLP-1, which may help to understand the structure-activity relationship of GLP-1 analogues.

Synthesis and evaluation of furoxan-based nitric oxide-releasing derivatives of tetrahydroisoquinoline as anticancer and multidrug resistance reversal agents.

Multidrug resistance in tumor cells poses a major obstacle to efficient chemotherapy. Several types of agents have been recognized as multidrug resistance inhibitors, among which the tetrahydroisoquinolines is the most studied. In current study 16 furoxan-based nitric oxide-releasing derivatives of tetrahydroisoquinoline were synthesized. Their cytotoxic activities and effects in reversing multidrug resistance have been evaluated. The results revealed that these compounds had moderate cytotoxic effects. Compounds 7a-f, 7h, and 7l showed higher cytotoxicities than the rest, but lower than adriamycin on K562 cell line. Compounds 7d, 7f, and 7l exhibited potent MDR reversal activities on K562/A02 cell line. The accumulation assay indicated that compounds 7d, 7f, and 7l significantly increased the intracellular accumulation of rhodamine123 in K562/A02 cells. Furthermore, these three compounds produced high concentrations of NO in K562/A02 cells. Potentially, the high concentrations of NO produced by NO donor moieties will lead to an increased cytotoxicity to K562/A02 cells. Our results suggested that compounds 7d, 7f, and 7l had anticancer effects, as well as multidrug resistance reversal effects.

Total synthesis and antihypertensive activity of (+/-)7,8-dihydroxy-3-methyl-isochromanone-4.

This letter describes the total synthesis, preliminary biological evaluation and mechanism studies of a novel and structurally unique isochromanone, (+/-)7,8-dihydroxy-3-methyl-isochromanone-4 (1), a nature product contained in banana (Musa sapientum L.) peel. The bioassay showed that compound 1 displays potent antihypertensive activity in renal hypertensive rats and further mechanism studies revealed that it is an ACE inhibitor.

Omega-3 fatty acids improve recovery, whereas omega-6 fatty acids worsen outcome, after spinal cord injury in the adult rat.

Spinal cord injury (SCI) is a cause of major neurological disability, and no satisfactory treatment is currently available. Evidence suggests that polyunsaturated fatty acids (PUFAs) could target some of the pathological mechanisms that underlie damage after SCI. We examined the effects of treatment with PUFAs after lateral spinal cord hemisection in the rat. The omega-3 PUFAs alpha-linolenic acid and docosahexaenoic acid (DHA) injected 30 min after injury induced significantly improved locomotor performance and neuroprotection, including decreased lesion size and apoptosis and increased neuronal and oligodendrocyte survival. Evidence showing a decrease in RNA/DNA oxidation suggests that the neuroprotective effect of omega-3 PUFAs involved a significant antioxidant function. In contrast, animals treated with arachidonic acid, an omega-6 PUFA, had a significantly worse outcome than controls. We confirmed the neuroprotective effect of omega-3 PUFAs by examining the effects of DHA treatment after spinal cord compression injury. Results indicated that DHA administered 30 min after spinal cord compression not only greatly increased survival of neurons but also resulted in significantly better locomotor performance for up to 6 weeks after injury. This report shows a striking difference in efficacy between the effects of treatment with omega-3 and omega-6 PUFAs on the outcome of SCI, with omega-3 PUFAs being neuroprotective and omega-6 PUFAs having a damaging effect. Given the proven clinical safety of omega-3 PUFAs, our observations show that these PUFAs have significant therapeutic potential in SCI. In contrast, the use of preparations enriched in omega-6 PUFAs after injury could worsen outcome after SCI.

[Study on the timeliness of the notifiable communicable diseases surveillance system in Fujian province, China, 2004].

OBJECTIVE: To understand the timeliness of the notifiable communicable diseases surveillance system in Fujian province. METHODS: Database from the internet based communicable diseases reporting system was used. RESULTS: The 50th percentile of time between the disease diagnosed and report recorded in medical faculties was 1 day in 2004 which was 6 days less than that in 2001 - 2003. The timeliness rate of 0 day was 46.46%, a 2.7 times over that in 2001 - 2003. The timeliness of notifiable communicable diseases surveillance system in different administrative areas, reporting units and on different diseases was significantly different. Time between the disease diagnosed and report recorded was the shortest in those cases reported by hospitals and traditional Chinese medicine(TCM) hospitals at the county level and above, with 50th percentile as 0 day, but the timeliness rate of 0 day was 50.76% with 70.04% of the cases were reported from hospitals and TCM hospitals of county level and above. Length between the disease diagnosed and reported was the longest in those cases recorded by Centers for Disease Control and Prevention(CDCs) with the 50th percentile as 3 days. The source of cases recorded by CDCs came from hospitals at the township level, where there was no connection to internet but the reporting cards had to be sent to local CDCs. Time between the disease being diagnosed and reported was 2 days in those cases reported by hospitals at the township level. 21.21% of cases were recorded by hospitals of township level and CDCs. The 50th percentile of time shown between the reported records and confirmed by CDCs was 4 hours The 24 hour timeliness rate was 63.65%. CONCLUSION: The timeliness of the notifiable communicable diseases surveillance system had been improved significantly after the medical personnel recording the cases directly through internet. Timeliness could be further improved through access to internet at the hospitals of township level, training of staff and better hospital management systems.