Pharmacokinetics and tissue distribution of furanodiene W/O/W multiple emulsions in rats by a fast and sensitive HPLC-APCI-MS/MS method.

A sensitive and specific HPLC-APCI-MS/MS method was developed and validated for the quantification of furanodiene, a natural antitumor compound in rat plasma and tissues. W/O/W multiple emulsions of furanodiene, identified through microscope-observation and eosin staining method, were prepared with a two-step-procedure. Pharmacokinetics and tissue distribution were studied in rats after oral, intraperitoneal and intravenous injection with the dose of 5, 10 and 50 mg/kg, respectively. The assay achieved a good sensitivity and specificity for the determination of furanodiene in biological samples. The results showed that the concentration-time curves of furanodiene in rats after intravenous injection were fitted to a two-compartment model and the linear pharmacokinetic characteristic. The highest concentration in rat tissue was observed in the spleen, followed by heart, liver, lung, kidney, small intestine and brain. Comparing with the low concentration in plasma, furanodiene could be detected in various tissue samples after oral or intraperitoneal injection which indicated furanodiene had good and rapid tissue uptake. The results suggested that the wide tissue distribution of furanodiene could conduce to the therapeutic effects, but the short biological half-life limited its further application as an antitumor agent. The results are helpful for the structure modification of furanodiene as an antitumor candidate.

The Compatibility of Alisma and Atractylodes Affects the Biological Behaviours of VSMCs by Inhibiting the miR-128-5p/p21 Gene.

Objective: The compatibility of Alisma and Atractylodes (AA) has been estimated to exhibit antiatherosclerotic effects, but the mechanism remains unclear. This study aimed to identify the role of AA in oxidized low-density lipoprotein (ox-LDL)-induced vascular smooth muscle cell (VSMC) behaviours and to explore the effects of microRNAs (miRNAs). Methods: A scratch wound-healing assay was used to detect the migration of VSMCs, and immunocytochemistry and western blotting for SM22ɑ were used to evaluate phenotypic transformation. Bromodeoxyuridine (BrdU) immunocytochemistry and flow cytometry were applied to detect the proliferation of VSMCs. miRNA microarray profiling was performed using Lianchuan biological small RNA sequencing analysis. VSMCs were transfected with the miR-128-5p mimic and inhibitor, and the migration, phenotypic modulation, and proliferation of VSMCs were investigated. The 3'UTR-binding sequence site of miR-128-5p on the p21 gene was predicted and assessed by luciferase assays. Result: AA and the extracellular regulated protein kinase 1/2 (ERK1/2) blocker U0126 markedly inhibited migration, elevated smooth muscle 22α (SM22α) expression, repressed VSMC proliferation, elevated miR-466f-3p and miR-425-3p expression, and suppressed miR-27a-5p and miR-128-5p expression in ox-LDL-induced VSMCs. miR-128-5p targets the tissue inhibitor of metalloproteinases (TIMPs), silent information regulator 2 (SIRT2), peroxisome proliferator-activated receptor (PPAR), and p21 genes, which are linked to the behaviours of VSMCs. The miR-128-5p mimic promoted the migration and proliferation of VSMCs and suppressed p21, p27, and SM22ɑ expression. The inhibitor increased p21, p27, and SM22ɑ expression and repressed the migration, phenotypic transformation, and proliferation of VSMCs. miR-128-5p directly targeted the 3'UTR-binding sequences of the p21 gene, negatively regulated p21 expression, and supported the proliferation of VSMCs. Conclusion: Our research showed that the migration, phenotypic transformation, and proliferation of ox-LDL-induced VSMCs were repressed by AA through inhibiting miR-128-5p by targeting the p21 gene, which may provide an effective option for the treatment of atherosclerosis.

Role of Cdk5 in Amyloid-beta Pathology of Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease with irreversible cognitive impairment. So far, successful treatment and prevention for this disease are deficient in spite of delaying the progression of cognitive impairment and dementia. Cyclin dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinase family, is involved in AD pathogenesis and may be a pathophysiological mediator that links the major pathological features of AD. Cdk5 dysregulation interferes with the proteolytic processing of Amyloid-beta Protein Precursor (APP) and modulates amyloidbeta (Aß) by affecting three enzymes called α-, ß- and γ-secretase, which are critical for the hydrolysis of APP. Given that the accumulation and deposition of Aß derived from APP are a common hinge point in the numerous pathogenic hypotheses of AD, figuring out that influence of specific mechanisms of Cdk5 on Aß pathology will deepen our understanding of AD.

Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice.

BACKGROUND: Liver kinase B1 (LKB1)/5'-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer's disease (AD). Amyloid-ß (Aß) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aß pathology. METHODS: The Aß levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKß1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry. RESULTS: BBR inhibited Aß expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKß1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice. CONCLUSION: BBR alleviates Aß pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

Rationally introduce multi-competitive binding interactions in supramolecular gels: a simple and efficient approach to develop multi-analyte sensor array.

Sensor arrays are a powerful tool for multianalyte sensing and the development of an efficient sensor array has become one of the most intriguing problems. However, sensor arrays often employ lots of receptors which need large amounts of work to synthesise. This study describes an efficient method for the fabrication of a simple sensor array based on the competitive binding in supramolecular gels. By rationally introducing various well-designed competitive binding interactions into the supramolecular gel, which is self-assembled from a naphthylhydrazone-based organogelator, a supramolecular gel-based twenty-two-member sensor array has been created. Interestingly, the sensor array has been shown to accurately identify fourteen kinds of important ions (F-, Cl-, I-, CN-, HSO4-, SCN-, S2-, OH-, Al3+, Fe3+, Zn2+, Hg2+, Pb2+ and H+) in water. It's important to note that this sensor array needs only one synthesized receptor. Moreover, using this method, we also obtained a series of ion response fluorescent supramolecular materials, which could act as security display materials. Therefore, it's a novel and facile way for the design of a simple sensor array as well as ion response fluorescent supramolecular materials.

A novel supramolecular metallogel-based high-resolution anion sensor array.

A novel anion sensor array based on supramolecular metallogels has been developed. It could accurately identify CN(-), SCN(-), S(2-) and I(-) in water. Interestingly, this sensor array is based on a novel design approach termed "competitive coordination control AIE mode" to develop anion-responsive gels which need only one synthesized gelator G1.

A "keto-enol tautomerization"-based response mechanism: a novel approach to stimuli-responsive supramolecular gel.

A novel approach to stimuli-responsive gel termed the "keto-enol tautomerization"-based response mechanism was proposed. By tautomerization, vinyl ketone-based gelator G3 can be self-assembled into an organogel (OG3) accompanied by strong AIE. OG3 shows reversible dual-channel response for S(2-). The response process is based on the reversible deprotonation of the enol moiety in the tautomerized gelator G3'.