Biomechanopharmacology of Chinese Medicine Based on Mechano-ion Channel Piezo1： A Review / 中国实验方剂学杂志

Ischemic stroke is one of the leading causes of death and disability worldwide. In Han dynasty， HUA Tuo proposed the original preventive medicine idea that "with good blood circulation， the disease cannot be born"， which opened a broad space for the cross-research of blood-related mechanical factors and pharmacology. In the pathogenesis of ischemic stroke， mechanical factors comprehensively affect the function and crosstalk of platelets and endothelial cells. In recent years， as the well-known effects on thrombosis and stroke， more attention has been paid to hemodynamic factors as the participants involved in pathological mechanisms and potential therapeutic targets of ischemic stroke. The mechanical force ion channel Piezo1 widely exists on the surface of many types of cells. Besides being regulated by chemical and endogenous substances， Piezo1 responds to different mechanical conditions， regulates the opening and closing of channels， and activates different downstream signaling pathways. Piezo1 is now regarded as an important connection between mechanical and biochemical signals. A variety of Chinese medicine can affect the activity of Piezo1 protein， which may prevent and treat thrombotic diseases such as ischemic stroke through Piezo1 protein. In this paper， the effects of Piezo1 protein on the physiological and pathological functions of endothelial cells and platelet under different mechanical conditions and the role of Piezo1 in the process of thrombosis were reviewed， as well as the effects of Chinese medicine， chemical medicine， and endogenous substances targeting Piezo1 channel. These could provide new ideas for further exploring the mechanisms of Chinese medicines in activating blood circulation， developing new drugs， and deepening biomechanical-pharmacology research.

Artemisinin-Ginkgo biloba extract combination therapy for Plasmodium yoelii.

Malaria remains a widespread life-threatening infectious disease, leading to an estimated 219 million cases and around 435,000 deaths. After an unprecedented success, the antimalarial progress is at a standstill. Therefore, new methods are urgently needed to decrease drug resistant and enhance antimalarial efficacy. According to the alteration of erythrocyte biomechanical properties and the immune evasion mechanism of parasites, drugs, which can improve blood circulation, can be chosen to combine with antimalarial drugs for malaria treatment. Ginkgo biloba extract (GBE), one of drug for vascular disease, was used to combine with artemisinin for Plasmodium yoelii therapy. Artemisinin-GBE combination therapy (AGCT) demonstrated remarkable antimalarial efficacy by decreasing infection rate, improving blood microcirculation and modulating immune system. Besides, the expression of invasion related genes, such as AMA1, MSP1 and Py01365, can be suppressed by AGCT, hindering invasion process of merozoites. This new antimalarial strategy, combining antimalarial drugs with drugs that improve blood circulation, may enhance the antimalarial efficacy and ameliorate restoration ability, proving a potential method for finding ideal compatible drugs to improve malaria therapy.

Micro-/Nano-Scale Biointerfaces, Mechanical Coupling and Cancer Therapy.

The interaction between cancer cells and their microenvironment is an indispensable link in cancer progression that occurs on the interfaces between them and presents typical biointerfacial behavior. Recently, the cancer cell/microenvironment interface has begun to attract more attention because of its fundamental roles in cancer growth and metastasis, which is promising for the efficacy of anti-cancer drugs and other important effects. In this review, we focused on mechanical coupling of the biointerfaces and their application in cancer early diagnosis, the pharmacology of anticancer agents and the design of the anticancer drug carriers. Newly developed strategies for cancer therapy based on mechanical coupling, such as correcting cell mechanics defects, tunable rigidity for drug delivery and topography-coupled-mechanical drug design, and drug screening, provide a proof of concept that cell mechanics offer a rich drug target space, allowing for the possible corrective modulation of tumor cell behavior. Biomechanopharmacology is therefore important to recognize the biomechanical factors and to control them not only for improvement in our knowledge of cancer but also for the development of new drugs and new uses of old drugs.

Porous Matrix Stiffness Modulates Response to Targeted Therapy in Breast Carcinoma.

Porous matrix stiffness modulates response to targeted therapy. Poroelastic behavior within porous matrix may modulate the molecule events in cell-matrix and cell-cell interaction like the complex formation of human epidermal growth factor receptor-2 (HER2)-Src-α6ß4 integrin, influencing the targeted therapy with lapatinib.

Anti-inflammatory effect of acetylharpagide demonstrated by its influence on leukocyte adhesion and transmigration in endothelial cells under controlled shear stress.

This research was aimed to investigate the anti-inflammatory mechanism of acetylharpagide extracted from Ajuga decumbens Thunb. Human umbilical vein endothelial cells (HUVECs) and human monocytic leukemia cell line THP-1 were employed as experimental materials. The MTT assay (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) was used to determine the safe dose range of acetylharpagide. TNF-α (20 ng/ml) was used to model THP-HUVECs adhesion/transmigration and trypsin was used to model wounding of HUVECs under controlled shear stress of 0.1 Pa and 0.2 Pa (5 h) by Bioflux1000 assays accordingly. Effects of acetylharpagide were dynamically monitored by microscopic time-lapse photography. Acetylharpagide within the concentration of 0-200 µM showed no sign of toxicity to HUVECs and THP-1. Acetylharpagide dose-dependently inhibited THP-1 adhesion to TNF-α activated HUVECs monolayer with an IC50 of 171 µM under static conditions. Acetylharpagide at 200 µM inhibited leukocyte adhesion and transmigration to HUVECs monolayer activated by TNF-α under 0.1 Pa shear stress (P < 0.05). The compound at 200 µM also inhibited HUVECs migration under 0.2 Pa in the wound healing model compared with the control group (P < 0.05). In conclusion, the anti-inflammatory effects of acetylharpagide are possibly related to inhibiting leukocytes adhesion and transmigration. Moreover, acetylharpagide also inhibits the endothelial cells migration notably, which might be the additional action responsible for its effect in reliving-chronic inflammatory progress.

Influence of fluid shear stress on anti-platelet aggregation of salvianolic acid B / 医用生物力学

Objective To study effects of flow shear stress combined with salvianolic acid B (Sla B) on anti-platelet aggregation and its possible mechanism under the theoretical framework of biomechanopharmacology. Methods 2×4 factor experimental design was employed. By using Bioflux 1000 microfluidic system, shear stresses of 0.02 Pa and 1.5 Pa were applied together with four levels of Sla B concentration treatment on human vascular endothelial cells (HUVECs) for 20 hours. Then the cell supernatant was collected to detect concentration of 6-keto-PGF1α and vWF by ELISA and their effects on ADP-induced platelet aggregation were tested. Immunofluorescence method was used to detect vWF in endothelial cell cytoplasm. Results Physical shear stress of 1.5 Pa combined with Sla B of 100 μg/mL could significantly promote the endothelial secretion of 6-keto-PGF1α as compared to low shear stress condition (P<0.05). The endothelial cell supernatant under shear stress of 1.5 Pa showed an obvious anti-platelet aggregation effect. As the single factor, shear stresses significantly influenced vWF secretion (P<0.01), but Sla B had no obvious effects on vWF secretion. Conclusions Sla B inhibited ADP-induced platelet aggregation by increasing endothelial secretion of PGI2 under physical shear stresses. From the view of biomechaopharmacology (interaction between blood flow, blood vessel and blood), the physical flow shear stress is beneficial for the anti-thrombosis effect of Sla B.