Flavonols are a class of flavonoids that play a crucial role in regulating plant growth and promoting stress resistance. They are also important dietary components in horticultural crops due to their benefits for human health. In past decades, research on the transcriptional regulation of flavonol biosynthesis in plants has increased rapidly. This review summarizes recent progress in flavonol-specific transcriptional regulation in plants, encompassing characterization of different categories of transcription factors (TFs) and microRNAs as well as elucidation of different transcriptional mechanisms, including direct and cascade transcriptional regulation. Direct transcriptional regulation involves TFs, such as MYB, AP2/ERF, and WRKY, which can directly target the key flavonol synthase gene or other early genes in flavonoid biosynthesis. In addition, different regulation modules in cascade transcriptional regulation involve microRNAs targeting TFs, regulation between activators, interaction between activators and repressors, and degradation of activators or repressors induced by UV-B light or plant hormones. Such sophisticated regulation of the flavonol biosynthetic pathway in response to UV-B radiation or hormones may allow plants to fine-tune flavonol homeostasis, thereby balancing plant growth and stress responses in a timely manner. Based on orchestrated regulation, molecular design strategies will be applied to breed horticultural crops with excellent health-promoting effects and high resistance.

The phosphatidylinositol 3-kinase (PI3K) signalling pathway regulates cell survival, proliferation, migration, metabolism and other vital cellular life processes. In addition, activation of the PI3K signalling pathway is important for cancer development. As a result, a variety of PI3K inhibitors have been clinically developed to treat malignancies. Although several PI3K inhibitors have received approval from the Food and Drug Administration (FDA) for significant antitumour activity, frequent and severe adverse effects have greatly limited their clinical application. These toxicities are mostly on-target and immune-mediated; nevertheless, the underlying mechanisms are still unclear. Current management usually involves intervention through symptomatic treatment, with discontinuation if toxicity persists. Therefore, it is necessary to comprehensively understand these adverse events and ensure the clinical safety application of PI3K inhibitors by establishing the most effective management guidelines, appropriate intermittent dosing regimens and new combination administration. Here, the focus is on the development of PI3K inhibitors in cancer therapy, with particular emphasis on isoform-specific PI3K inhibitors. The most common adverse effects of PI3K inhibitors are also covered, as well as potential mechanisms and management approaches.

Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardiotoxicity, which is a life-threatening risk, has greatly attracted the attention of researchers. In this review, the SMKIs with cardiotoxicity incidence were described exhaustively. The data were collected from 42 clinical trials, 25 FDA-published documents, seven meta-analysis/systematic reviews, three case reports and more than 50 other types of articles. To date, 73% (38 of 52) of SMKIs have reported treatment-related cardiotoxicity. Among the 38 SMKIs with known cardiotoxicity, the rates of incidence of cardiac adverse events were QT prolongation: 47% (18 of 38), hypertension: 40% (15 of 38), left ventricular dysfunction: 34% (13 of 38), arrhythmia: 34% (13 of 38), heart failure: 26% (10 of 38) and ischemia or myocardial infarction: 29% (11 of 38). In the development process of novel SMKIs, more attention should be paid to balancing the treatment efficacy and the risk of cardiotoxicity. In preclinical drug studies, producing an accurate and reliable cardiotoxicity evaluation model is of key importance. To avoid the clinical potential cardiotoxicity risk and discontinuation of a highly effective drug, patients treated with SMKIs should be proactively monitored on the basis of a global standard. Moreover, the underlying mechanisms of SMKI-induced cardiotoxicity need to be further studied to develop new therapies for SMKI-induced cardiotoxicity.

Currently, chemotherapy is the main treatment for tumors, but there are still problems such as unsatisfactory chemotherapy results, susceptibility to drug resistance, and serious adverse effects. Natural compounds have numerous pharmacological activities which are important sources of drug discovery for tumor treatment. The combination of chemotherapeutic drugs and natural compounds is gradually becoming an important strategy and development direction for tumor treatment. In this paper, we described the role of natural compounds in combination with chemotherapeutic drugs in synergizing, reducing drug resistance, mitigating adverse effects and related mechanisms, and providing new insights for future oncology research.

Tumor-associated macrophages (TAMs) has been regarded as the most prominent component in tumor microenvironment. The correlation between TAM density and poor prognosis in Hepatocellular carcinoma (HCC) patients suggests a supportive role for TAMs in tumor progression. Here we employed a co-culture system to interrogate the molecular link between Yes-Associated Protein (YAP) and TAMs chemotaxis in HCC cells. We found that YAP activation was critical for the recruitment of TAMs towards HCC cells. Furthermore, cytokine array and quantitative RT-PCR analyses showed that IL-6 secreted by YAP-activated HCC cells might induce the TAMs recruitment. Interrupting YAP function by statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could robustly suppress the chemotaxis of TAMs. Together with our findings that the expression levels ofIL-6inhumanHCC tumors were highly correlated with the prognosis of HCC patients, the current study highlight the possibility of improving HCC treatment by targeting YAP-IL-6 mediated TAMs recruitment.

Chemoresistance is one of the leading causes for the failure of tumor treatment. Hence, it is necessary to study further and understand the potential mechanisms of tumor resistance to design and develop novel anti-tumor drugs. Post-translational modifications are critical for proteins’ function under physiological and pathological conditions, among which ubiquitination is the most common one. The protein degradation process mediated by the ubiquitin-proteasome system is the most well-known function of ubiquitination modification. However, ubiquitination also participates in the regulation of many other biological processes, such as protein trafficking and protein-protein interaction. A group of proteins named deubiquitinases can hydrolyze the isopeptide bond and disassemble the ubiquitin-protein conjugates, thus preventing substrate proteins form degradation or other outcomes. Ubiquitin-specific protease 7 (USP7) is one of the most extensively studied deubiquitinases. USP7 exhibits a high expression signature in various malignant tumors, and increased USP7 expression often indicates the poor tumor prognosis, suggesting that USP7 is a marker of tumor prognosis and a potential drug target for anti-tumor therapy. In this review, we first discussed the structure and function of USP7. Further, we summarized the underlying mechanisms by which tumor cells develop resistance to anti-tumor therapies, provided theoretical support for targeting USP7 to overcome drug resistance, and some inspiration for the design and development of USP7 inhibitors.