Structure-activity relationship investigation of coumarin-chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors.

Chalcones containing tertiary amine side-chains have potent activity as acetylcholinesterase (AChE) inhibitors. However, the effects of the location of the tertiary amine groups as well as of other groups on AChE and butyrylcholinesterase (BChE) activity have not been reported. Here, we report the synthesis and testing of 36 new coumarin-chalcone hybrids (5d-7j, 9d-11f, 12k-13m) against AChE and BChE. The nature and position of the chalcone substituents had major effects on inhibitory activity as well as selectivity for AChE over BChE. Compounds with para-substituted chalcone fragments in which the substituents were choline-like had potent activity against AChE and poor activity against BChE, while ortho-substituted analogs exhibited an opposite effect. Replacement of the terminal amine groups by amide, alkyl or alkenyl groups abrogated activity. Compound 5e showed potent inhibitory activity [Formula: see text]) and good selectivity for AChE over BChE (ratio 27.4), and a kinetic study showed that 5e exhibited mixed-type inhibition against AChE. Computational docking results indicate that 5e binds to Trp 279, Tyr334 and Trp 84 in AChE, but only to Trp 82 in BChE. Overall, the results show that coumarin-chalcone hybrids with choline-like side-chains have promising activity and selectivity against AChE and be promising therapeutic leads for Alzheimer's disease.

Structure-activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors.

A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a-4c and 7a-7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity in vitro. Structure-activity relationship investigation revealed that the substituted position of dimethylamine side chain markedly influenced the inhibitory activity and selectivity against AChE and BChE. In addition, it seemed that the bioactivity of picolinamide amide derivatives was stronger than that of benzamide derivatives. Among them, compound 7a revealed the most potent AChE inhibitory activity (IC50: 2.49 ± 0.19 µM) and the highest selectivity against AChE over BChE (Ratio: 99.40). Enzyme kinetic study indicated that compound 7a show a mixed-type inhibition against AChE. The molecular docking study revealed that this compound can bind with both the catalytic site and the peripheral site of AChE.

HAP1 helps to regulate actin-based transport of insulin-containing granules in pancreatic ß cells.

Huntingtin-associated protein 1 (HAP1) is enriched in neurons and binds to polyglutamine-expanded huntingtin. It consists of two alternatively spliced isoforms, HAP1A and HAP1B, which differ only in their short C-terminal sequences. Both HAP1A and HAP1B have been also detected in pancreatic ß cells, where the loss of HAP1 impairs glucose-stimulated insulin secretion. Here, we use time-lapse laser scanning confocal microscopy to provide direct evidence that HAP1A, but not HAP1B, co-localizes and co-migrates with insulin-containing vesicles and actin-based myosin Va motor protein in the INS-1 pancreatic ß cell line. Knocking down HAP1 expression using small interfering RNA significantly inhibited actin-based transport of insulin vesicles following glucose stimulation. Co-immunoprecipitation experiments demonstrated interaction between HAP1A, myosin Va, and phogrin, a transmembrane protein in insulin-containing vesicles. Stimulating INS-1 cells with glucose increased the association of HAP1A with myosin Va, while silencing HAP1 expression reduced the association of myosin Va with phogrin after glucose stimulation, without affecting levels of myosin Va or actin. Our results provide real-time evidence in living cells that HAP1 may help regulate transport of insulin-containing secretory granules along cortical actin filaments. This also raises the possibility that HAP1 may play an important role in actin-based secretory vesicle trafficking in neurons.

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors.

Solid tumors can be divided into benign solid tumors and solid malignant tumors in the academic community, among which malignant solid tumors are called cancers. Cancer is the second leading cause of death in the world, and the global incidence of cancer is increasing yearly New cancer patients in China are always the first. After the concept of stem cells was introduced in the tumor community, the CSC markers represented by ALDH1 have been widely studied due to their strong CSC cell characteristics and potential to be the driving force of tumor metastasis. In the research results in the past five years, it has been found that ALDH1 is highly expressed in various solid cancers such as breast cancer, lung cancer, colorectal cancer, liver cancer, gastric cancer, cervical cancer, esophageal cancer, ovarian cancer, head,and neck cancer. ALDH1 can activate and transform various pathways (such as the USP28/MYC signaling pathway, ALDH1A1/HIF-1α/VEGF axis, wnt/ß-catenin signaling pathway), as well as change the intracellular pH value to promote formation and maintenance, resulting in drug resistance in tumors. By targeting and inhibiting ALDH1 in tumor stem cells, it can enhance the sensitivity of drugs and inhibit the proliferation, differentiation, and metastasis of solid tumor stem cells to some extent. This review discusses the relationship and pathway of ALDH1 with various solid tumors. It proposes that ALDH1 may serve as a diagnosis and therapeutic target for CSC, providing new insights and new strategies for reliable tumor treatment.

Metformin: A promising drug for human cancers.

Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo, and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.

Simultaneous optimization of ultrasound-assisted extraction for total flavonoid content and antioxidant activity of the tender stem of Triarrhena lutarioriparia using response surface methodology.

The asparagus of Triarrhena lutarioriparia (TL) is a popular vegetable with abundant chemical compounds in China. This study aims to optimize the ultrasound-assisted extraction (UAE) method for its content of total flavonoid and antioxidant activities by response surface methodology (RSM). Box-Behnken design was adopted to evaluate the influences of ethanol concentration, extraction time and solvent-to-sample ratio on the extraction yield of total flavonoid and the antioxidant activity. Considering the maximum content of extracted total flavonoids and antioxidant activity, the optimal extraction conditions were acquired with 70% (v/v) ethanol by UAE for 60 min at a solvent-to-sample ratio of 40 mL/g. The proportion of the extraction of total flavonoid was 15.88 mg/g and antioxidant activity reached 79.53%. The RSM would be recommended as an appropriate model for simultaneous optimization of the UAE conditions for the content of total flavonoid and the antioxidant activity of asparagus of TL.

Development of a Method for Simultaneous Determination of Two Stilbenes and Four Anthraquinones from Polygonum Cuspidatum by RP-HPLC.

Background: Polygonum cuspidatum Sieb. et Zucc. (named Huzhang in China) is a traditional and popular Chinese medicinal herb used in removing jaundice, clearing heat-toxin, improving blood circulation, expelling stasis, dispelling wind and dampness, repelling phlegm, and suppressing cough. It is widely used in drug and functional food fields and distributed throughout the world, including in China, Japan, and North America. Objective: To control the quality of Polygonum cuspidatum, an effective, reliable, and simple method for simultaneous determination of two stilbenes (polydatin, resveratrol) and four anthraquinones (emodin, physcion, rhein, and anthraglycoside B) was developed and validated for the first time in this study by reversed-phase HPLC (RP-HPLC). Methods: Separation was carried out on Agilent C18 column (250 × 4.6 mm I.D., 5 µm) with acetonitrile and 0.10% aqueous phosphoric acid as mobile phase and gradient elution at a flow rate of 0.8 mL/min. Detection was conducted with mobile wavelength at 30°C. Results: Good validation of the method including linearity, precision, repeatability, and recovery was performed. The contents of the studied analytes are significantly different, and resveratrol and rhein in particular existed in greater fluctuation among the samples. Conclusion: A simple, reliable, and sensitive method has been successfully established and applied to the analysis for simultaneous determination of the target compounds in 11 batches of samples. Highlights: Separation and quantitative analysis of two stilbenes and four anthraquinones from P. cuspidatum were developed by RP-HPLC. This method is convenient, sensitive, and accurate and can provide a reliable basis for further applications of P. cuspidatum in drug or food fields.