Analysis on internal mechanism of zedoary turmeric in treatment of liver cancer based on pharmacodynamic substances and pharmacodynamic groups

Zedoary tumeric (Curcumae Rhizoma, Ezhu in Chinese) has a long history of application and has great potential in the treatment of liver cancer. The anti liver cancer effect of zedoary tumeric depends on the combined action of multiple pharmacodynamic substances. In order to clarify the specific mechanism of zedoary tumeric against liver cancer, this paper first analyzes the mechanism of its single pharmacodynamic substance against liver cancer, and then verifies the joint anti liver cancer mechanism of its "pharmacodynamic group". By searching the research on the anti hepatoma effect of active components of zedoary tumeric in recent years, we found that pharmacodynamic substances, including curcumol, zedoarondiol, curcumenol, curzerenone, curdione, curcumin, germacrone, β-elemene, can act on multi-target and multi-channel to play an anti hepatoma role. For example, curcumin can regulate miR, GLO1, CD133, VEGF, YAP, LIN28B, GPR81, HCAR-1, P53 and PI3K/Akt/mTOR, HSP70/TLR4 and NF-κB. Wnt/TGF/EMT, Nrf2/Keap1, JAK/STAT and other pathways play an anti hepatoma role. Network pharmacological analysis showed that the core targets of the "pharmacodynamic group" for anti-life cancer are AKT1, EGFR, MAPK8, etc, and the core pathways are neuroactive live receiver interaction, nitrogen metabolism, HIF-1 signaling pathway, etc. At the same time, by comparing and analyzing the relationship between the specific mechanisms of pharmacodynamic substance and "pharmacodynamic group", it is found that they have great reference significance in target, pathway, biological function, determination of core pharmacodynamic components, formation of core target protein interaction, in-depth research of single pharmacodynamic substance, increasing curative effect and so on. By analyzing the internal mechanism of zedoary tumeric pharmacodynamic substance and "pharmacodynamic group" in the treatment of liver cancer, this paper intends to provide some ideas and references for the deeper pharmacological research of zedoary tumeric and the relationship between pharmacodynamic substance and "pharmacodynamic group".     

Simultaneous Determination of Six Compounds in Rat Plasma by Ultra‑Performance Liquid Chromatography with Tandem Mass Spectrometry: Application in the Pharmacokinetic Study of Qing Gan‑Shu Yu‑Fang

A rapid and high selective ultra?performance liquid chromatography (UPLC) with tandem mass spectrometry method for simultaneous determination of six compounds including albiflorin, paeoniflorin, picroside I, picroside II, saikosaponin A, and saikosaponin D in rat plasma was developed and validated using butyl p-hydroxybenzoate as an internal standard. One-step direct protein precipitation with acetonitrile was used to extract the compounds from the rat plasma samples. Chromatographic separation was achieved using an ACQUITY UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm) at a flow rate of 0.4 mL/min, using gradient mode containing 0.1% formic acid in water and acetonitrile were used as the Mobile phase A and B. Electrospray ionization in negative ion mode and multiple reaction monitoring were used to identify and quantify active components. Calibration curves showed good linearity (R2 > 0.9908) over a wide concentration range for all compounds. The intra- and interday precision (relative standard deviation) ranged 2.4%–7.0% and 2.6%–8.0%, respectively. The accuracy (relative error) was from ?13.0% to 13.2% at all quality control levels. The recovery ranged from 81.1% to 92.5%. The validated method was successfully applied to pharmacokinetic study in rats after oral administration of Qing Gan?Shu Yu?Fang. The results show that one can draw a conclusion that these six active ingredients can be quickly absorbed and play a pharmacodynamic role rapidly in vivo.     

Sustained release of exosomes loaded into polydopamine-modified chitin conduits promotes peripheral nerve regeneration in rats

Exosomes derived from mesenchymal stem cells are of therapeutic interest because of their important role in intracellular communication and biological regulation.On the basis of previously studied nerve conduits,we designed a polydopamine-modified chitin conduit loaded with mesenchymal stem cell-derived exosomes that release the exosomes in a sustained and stable manner.In vitro experiments revealed that rat mesenchymal stem cell-derived exosomes enhanced Schwann cell proliferation and secretion of neurotrophic and growth factors,increased the expression of Jun and Sox2 genes,decreased the expression of Mbp and Krox20 genes in Schwann cells,and reprogrammed Schwann cells to a repair phenotype.Furthermore,mesenchymal stem cell-derived exosomes promoted neurite growth of dorsal root ganglia.The polydopamine-modified chitin conduits loaded with mesenchymal stem cell-derived exosomes were used to bridge 2 mm rat sciatic nerve defects.Sustained release of exosomes greatly accelerated nerve healing and improved nerve function.These findings confirm that sustained release of mesenchymal stem cell-derived exosomes loaded into polydopamine-modified chitin conduits promotes the functional recovery of injured peripheral nerves.     

Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells

Objective:Pancreatic ductal adenocarcinoma(PDAC)is a deadly malignancy,due in large part to its resistance to conventional therapies,including radiotherapy(RT).Despite RT exerting a modest antitumor response,it has also been shown to promote an immunosuppressive tumor microenvironment.Previous studies demonstrated that focal adhesion kinase inhibitors(FAKi)in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory(T regs)cells,and subsequently enhance effector T cell infiltration.FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies.Thus,we investigated the impact of FAK inhibition on RT,its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.Methods:We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.Results:In this study we showed that IN10018,a small molecular FAKi,enhanced antitumor response to RT.Antitumor activity of the combination of FAKi and RT is T cell dependent.FAKi in combination with RT enhanced CD8+T cell infiltration significantly in comparison to the radiation or FAKi treatment alone(P<0.05).FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone(P<0.01).Conclusions:These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.     

Biomechanical behavior of brain injury caused by sticks using finite element model and Hybrid-III testing

Objective: To study the biomechanical mechanism of head injuries beaten with sticks, which is common in the battery or assaultive cases. Methods: In this study, the Hybrid-III anthropomorphic test device and finite element model (FEM) of the total human model for safety (THUMS) head were used to determine the biomechanical response of head while being beaten with different sticks. Total eight Hybrid-III tests and four finite element simulations were conducted. The contact force, resultant acceleration of head center of gravity, intracranial pressure and von Mises stress were calculated to determine the different biomechanical behavior of head with beaten by different sticks. Results: In Hybrid-III tests, the stick in each group demonstrated the similar kinematic behavior under the same loading condition. The peak values of the resultant acceleration for thick iron stick group, thin iron stick group, thick wooden stick group and thin wooden stick group were 203.4 g, 221.1 g, 170.5 g and 122.2 g respectively. In finite element simulations, positive intracranial pressure was initially observed in the frontal comparing with negative intracranial pressure in the contra-coup site. Subsequently the intracranial pressure in the coup site was decreasing toward negative value while the contra-coup intracranial pressure increasing toward positive values. Conclusions: The results illustrated that the stiffer and larger the stick was, the higher the von Mises stress, contact force and intracranial pressure were. We believed that the results in the Hybrid-III tests and THUMS head simulations for brain injury beaten with sticks could be reliable and useful for better understanding the injury mechanism.     

LIM kinases in synaptic plasticity and their potential as therapeutic targets

LIM domain kinases(LIMKs),which modulate cytoskeletal dynamics,are found throughout the central nervous system.The synaptic junctions between neurons show structural alteration or plasticity during neurodevelopment,learning and memory formation,or after injury and disease;in some cases completely new connections form,while others are lost.This remodeling is under the control of the actin cytoskeleton and therefore is influenced by the activity of LIMKs(Scott and Olson,2007).Recent reports discussed in this perspective shed light on the potential role of LIMK in hippocampal dendritic spines and photoreceptor presynaptic terminals and illustrate the importance of LIMK in nerve cell function.