Organ-on-a-chip academic research is in its blossom. Drug toxicity evaluation is a promising area in which organ-on-a-chip technology can apply. A unique advantage of organ-on-a-chip is the ability to integrate drug metabolism and drug toxic processes in a single device, which facilitates evaluation of toxicity of drug metabolites. Human organ-on-a-chip has been fabricated and used to assess drug toxicity with data correlation with the clinical trial. In this review, we introduced the microfluidic chip models of liver, kidney, heart, nerve, and other organs and multiple organs, highlighting the application of these models in drug toxicity detection. Some biomarkers of toxic injury that have been used in organ chip platforms or have potential for use on organ chip platforms are summarized. Finally, we discussed the goals and future directions for drug toxicity evaluation based on organ-on-a-chip technology.

Chaihu Shugan San (CSS) is a well-known herbal formula used to nourish liver and blood, promote blood circulation and Qi flow in Traditional Chinese Medicine. Modern pharmacological studies and clinical uses showed that CSS could ameliorate cognitive dysfunction of Alzheimer's disease (AD). The present study aimed to elucidate the multi-target mechanisms of CSS on AD using network pharmacology analysis and verify its effect by biological experiments. Firstly, a total of 152 active compounds in CSS, 520 predicted biological targets and 160 AD-related targets were identified. Subsequently, the networks including herb-compound-target network, AD-target network, and CSS potential target-AD target network were constructed. 60 key targets highly responsible for the beneficial effect of CSS on AD were identified by central network topological analysis. They were significantly characterized as nuclear or cytoplasmic proteins with molecular function of protein binding. They were also enriched in various biological processes through PI3K-Akt signaling pathway, MAPK signaling pathway and HIF signaling pathway by GO function and KEGG pathway enrichment analysis. Pretreatment with CSS ameliorated Aβ-induced neural cell death and reduced the number of apoptotic cells in differentiated PC12 cells. Moreover, increased phosphorylation of Akt accompanied with decreased Bax expression was found after CSS pretreatment, suggesting that Akt signaling pathway was involved in the protective effect of CSS against neural cells death. The present study systematically revealed the multi-target mechanisms of CSS on AD using network pharmacology approach, as well as validated the protective effect of CSS against Aβ-induced neural cells death through Akt signaling pathway. It provided indications for further mechanistic studies and also for the development of CSS as a potential treatment for AD patients.

Evodiamine (EVO), an indole alkaloid derived from Rutaceae plants Evodia rutaecarpa (Juss.) Benth.、Evodia rutaecarpa (Juss.) Benth. Var. bodinieri (Dode) Huang or Evodia rutaecarpa (Juss.) Benth. Var. officinalis (Dode) Huang, has anti-inflammatory and anti-tumor activities. Our previous study found that EVO attenuates colitis by regulating gut microbiota and metabolites. However, little is known about its effect on colitis-associated cancer (CAC). In this study, the protective effects of EVO on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and tumor mice were observed, and the underlying potential mechanism was clarified. The results suggested that EVO ameliorated AOM/DSS-induced colitis by inhibiting the intestinal inflammation and improving mucosal barrier function. And EVO significantly reduced the number and size of AOM/DSS-induced colorectal tumors along with promoted apoptosis and inhibited proliferation of epithelial cell. Moreover, EVO promoted the enrichment of SCFAs-producing bacteria and reduced the levels of the pro-inflammatory bacteria, which contributes to the changes of microbiota metabolism, especially tryptophan metabolism. Furthermore, inflammatory response (like Wnt signaling pathway、Hippo signaling pathway and IL-17 signaling pathway) were effectively alleviated by EVO. Our study demonstrated that the protective therapeutic action of EVO on CAC is to inhibit the development of intestinal inflammation-cancer by regulating gut microbiota metabolites and signaling pathways of colon intestinal epithelial, which may represent a novel agent for colon cancer prevention via manipulation of gut microbiota.

(±)-Hypandrone A (1), a pair of highly modified PPAP enantiomers, with an unprecedented caged 2,8,17-trioxapentacyclo-[11.4.2.0 ^1,9 .0 ^4,9 .0 ^10,15 ]-nonadecane core, were isolated from the fruits of Hypericum androsaemum .

Phosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting PI3Kα have attracted considerable interest in recent years. Molecular hybridization, with the advantage of simplified pharmacokinetics and drug-drug interactions, emerged as one of the important avenues for discovering potential drugs. This study aimed to construct PI3Kα inhibitors by hybridization and investigate their antitumor activity and mechanism. 26 quinazoline-2-indolinone derivatives were obtained by molecular hybridization, and their structure-activity relationship was analyzed by MTT, in vitro kinase activity and molecular docking. The biological evaluation of compound 8 was performed by transwell, flow cytometry, laser scanning confocal microscopy, Western blot, CTESA and immunohistochemistry. Here, we employed molecular hybridization methods to construct a series of quinazoline-2-indolinone derivatives as PI3Kα selective inhibitors. Encouragingly, representative compound 8 exhibited a PI3Kα enzymatic IC₅₀ value of 9.11 nM and 10.41/16.99/37.53-fold relative to the biochemical selectivity for PI3Kβ/γ/δ, respectively. Moreover, compound 8 effectively suppressed the viability of B16, HCT116, MCF-7, H22, PC-3, and A549 cells (IC₅₀ values: 0.2 μM ∼ 0.98 μM), and dramatically inhibited the proliferation and migration of NSCLC cells, as well as induced mitochondrial apoptosis through the PI3K/Akt/mTOR pathway. Importantly, compound 8 demonstrated potent in vivo anti-tumor activity in non-small cell lung cancer mouse models without visible toxicity. This study presented a new avenue for the development of PI3Kα inhibitors and provided a solid foundation for novel QHIDs as potential future therapies for the treatment of NSCLC.