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Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance. Chemoresistance limits the success of chemotherapy in patients with cancer. Here, the authors perform 30 genome wide CRISPR knockout screens to identify genes associated to resistance against commonly used chemotherapeutics across multiple cancer types, followed by 26 second round CRISPR screens to identify druggable targets of chemoresistance. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a common neurotrosis disorder of the central nervous system (CNS), which has dramatic consequences on the integrity of damaged tissue. In this study, we investigated the neuroprotective effect and anti-inflammatory actions of osthole, a natural coumarin derivative, in both in vivo and in vitro TBI models. We first prepared a mouse model of cortical stab wound brain injury, investigated the capacity for osthole to prevent secondary brain injury and further examined the underlying mechanism. We revealed that osthole significantly improved the neurological function, increased the number of neurons beside injured site. Additionally, osthole treatment reduced the expression of microglia and glial scar, lowered the level of the proinflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α), and blocked the activation of nuclear factor kappa B (NF-κB). Furthermore, the protective effect of osthole was also examined in SH-SY5Y cells subjected to scratch injury. Treatment of osthole prominently suppressed cell apoptosis and inflammatory factors release by blocking injury-induced IκB-α phosphorylation and NF-κB translocation, and upregulated the IκB-α which functions in the NF-κB signaling pathway of SH-SY5Y cells. However, NF-κB signaling pathway was inhibited by pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, the anti-inflammatory effect of osthole was abolished. In conclusion, our findings demonstrated that osthole attenuated inflammatory response by inhibiting the NF-κB pathway in TBI. [ABSTRACT FROM AUTHOR]

In our previous study, we found that osthole could promote the ability of proliferation and differentiation in normal neural stem cells (NSCs) under normal condition. Then, we used tert-butyl hydroperoxide (t-BHP) to establish the model of senescence NSCs to detect the effects of osthole. Interestingly, the immunofluorescence results showed that osthole (100 μM) could enhance the ability of proliferation and differentiation, and CCK-8 assay results showed that osthole could also enhance the cell viabilities. Then, SA-β-gal assay results showed that osthole could decrease the positive of senescence cells. Flow cytometric analysis results showed that osthole could decrease the mixture of G0 and G1 phase. Reverse transcriptase (RT)-polymerase chain reaction results showed that osthole could downregulate the expression of p16 mRNA, and western blot analysis results showed that the expressions of the target protein decreased in p16-pRb signaling pathway with osthole treatment. In conclusion, these results indicated that osthole could probably delay cells senescence through p16-pRb signaling pathway. [ABSTRACT FROM AUTHOR]

Accumulation of β-amyloid peptide (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). It has been reported that osthole exerts its neuroprotective effect on neuronal synapses, but its exact mechanism is obscure. Recently, microRNAs have been demonstrated to play a crucial role in inducing synaptotoxicity by Aβ, implying that targeting microRNAs could be a therapeutic approach of AD. In the present study, we investigated the neuroprotective effects of osthole on a cell model of AD by transducing APP Swedish mutant (APPswe, APP) into mouse cortical neurons and human SH-SY5Y cells. In this study, the cell counting kit CCK-8, apoptosis assay, immunofluorescence analysis, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction, and Western blot assay were used. We found that osthole could enhance cell viability, prevent cell death, and reverse the reduction of synaptic proteins (synapsin-1, synaptophysin, and postsynaptic density-95) in APP-overexpressed cells, which was attributed to increases in microRNA-9 (miR-9) expression and subsequent decreases in CAMKK2 and p-AMPKα expressions. These results demonstrated that osthole plays a neuroprotective activity role in part through upregulating miR-9 in AD. [ABSTRACT FROM AUTHOR]