While reactive oxygen species (ROS) is generally considered harmful, a relevant amount of ROS is necessary for a number of cellular functions, including the intracellular signal transduction. In order to deal with an excessive amount of ROS, organisms are equipped with a sufficient amount of antioxidants together with NF‐E2‐related factor‐2 (NRF2), a transcription factor that plays a key role in the protection of organisms against environmental or intracellular stresses. While the NRF2 activity has been generally viewed as beneficial to preserve the integrity of organisms, recent studies have demonstrated that cancer cells hijack the NRF2 activity to survive under the oxidative stress and, therefore, a close check must be kept on the NRF2 activity in cancer. In the present review, we briefly highlight important progresses in understanding the molecular mechanism, structure, and function of KEAP1 and NRF2 interaction. In addition, we provide general perspectives that justify conflicting views on the NRF2 activity in cancer.

Coffee is one of the most popular beverages worldwide. Its effect on health is generally regarded as beneficial in many studies. However, there are growing concerns about the adverse effect of coffee consumption on cardiovascular disease (CVD) due to the potential aggravating impact on the cardiovascular system attributed to various compounds within coffee. This review is focused on deteriorative effects of coffee consumption on CVDs with possible mechanisms. Patients with risk factors of CVDs should prudently consider heavy consumption of coffee as it may exacerbate hypertension, dyslipidemia, and atherosclerosis, and increase the odds of cardiovascular events. J-shaped or U-shaped dose-response graphs of coffee consumption and CVD parameters partially explain the inconsistency of conclusions between coffee studies on CVD, highlighting a moderate intake of coffee. Moreover, there are discrepancies in results from clinical studies elucidating considerable influences of confounding factors including gender and smoking status on outcomes of those conducted to reveal the actual impact of coffee consumption on CVDs. Physical features of subjects including genetic variations and body mass index (BMI) make it difficult to determine moderate intake of coffee for individuals in terms of caffeine metabolism. Further epidemiological studies with consideration about characteristics of the study population are needed to determine the exact effect of coffee consumption on CVD.

The network pharmacology (NP) approach is a valuable novel methodology for understanding the complex pharmacological mechanisms of medicinal herbs. In addition, various in silico analysis techniques combined with the NP can improve the understanding of various issues used in natural product research. This study assessed the therapeutic effects of Arum ternata (AT), Poria cocos (PC), and Zingiber officinale (ZO) on hyperlipidemia after network pharmacologic analysis. A protein–protein interaction (PPI) network of forty-one key targets was analyzed to discover core functional clusters of the herbal compounds. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) term enrichment analysis identified significant categories of hypolipidemic mechanisms. The STITCH database indicated a high connection with several statin drugs, deduced by the similarity in targets. AT, PC, and ZO regulated the genes related to the energy metabolism and lipogenesis in HepG2 cells loaded with free fatty acids (FFAs). Furthermore, the mixture of three herbs had a combinational effect. The herbal combination exerted superior efficacy compared to a single herb, particularly in regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1 (CPT-1). In conclusion, the network pharmacologic approach was used to assess potential targets of the herbal combination for treatment. Experimental data from FFA-induced HepG2 cells suggested that the combination of AT, PC, and ZO might attenuate hyperlipidemia and its associated hepatic steatosis.

Despite its deleterious effects on living cells, oxidative stress plays essential roles in normal physiological processes and provides signaling molecules for cell growth, differentiation, and inflammation. Macrophages are equipped with antioxidant mechanisms to cope with intracellular ROS produced during immune response, and Nrf2 (NF‐E2‐related factor 2)/HO‐1 (heme oxygenase‐1) pathway is an attractive target due to its protective effect against ROS‐induced cell damage in inflamed macrophages. We investigated the effects of ethanol extract of A. villosum (AVEE) on lipopolysaccharide‐ (LPS‐) stimulated inflammatory responses generated via the Nrf2/HO‐1 signaling pathway in murine peritoneal macrophages and RAW 264.7 cells. AVEE was found to suppress the NF‐κB signaling pathway, thus, to reduce proinflammatory cytokine, nitric oxide, and prostaglandin levels in peritoneal macrophages and Raw 264.7 cells treated with LPS, and to enhance HO‐1 expression by activating Nrf2 signaling. Furthermore, these anti‐inflammatory effects of AVEE were diminished when cells were pretreated with SnPP (a HO‐1 inhibitor). HPLC analysis revealed AVEE contained quercetin, a possible activator of the Nrf2/HO‐1 pathway. These results show A. villosum ethanol extract exerts anti‐inflammatory effects by activating the Nrf2/HO‐1 pathway in LPS‐stimulated macrophages.

Targeting Toll‐like receptor 4/myeloid differentiation factor 2 (TLR4/MD2) signaling is regarded as a potential strategy for treating inflammatory diseases. Saponaria officinalis L. is rich in saponin, which include quillaic acid, gypsogenin, saponarin, and hederagenin. We evaluated the pharmacological activity of a Saponaria officinalis extract in THP‐1 derived macrophages and RAW264.7 macrophages. TLR4/MyD88 complex formation and downstream signals were investigated by co‐immunoprecipitation (Co‐IP). In silico docking simulation was conducted to predict binding scores and perform 3D modeling of saponarin‐TLR4/MD2 complex. A hexane fraction of Saponaria officinalis (SH) and fr.1 (a sub‐fraction 1 of SH) inhibited mitogen‐activated protein kinase (MAPK) signaling, nuclear factor kappa b (NF‐κB) activity, cytokine production, and the expressions of marker genes specific for M1 polarization. The inhibitory effects of fr.1 and saponarin on TLR4/MyD88 complex formation were observed by western blotting TLR4 co‐immunoprecipitated proteins. Saponarin and fr.1 markedly attenuated LPS‐induced inflammatory cytokines, thus reducing mortality and morphological abnormality in zebrafish larvae. Finally, docking simulation revealed that saponarin can directly interact with TLR4/MD2 complex to inhibit downstream signalings. Our findings suggest that saponarin reduces downstream inflammatory response by disrupting TLR4/MD2 complex and blocking MyD88‐dependent inflammatory signaling.

Renal cell carcinoma (RCC) represents the most common form of kidney cancer, which accounts for 3–5% newly diagnosed cancer cases. Since limited therapies are available for RCC, a search for new options is required. Therefore, in this study, we evaluated the combination effect of cinnamaldehyde (CNM) and hyperthermia treatment. CNM treatment combined with 43 °C hyperthermia synergistically increased cytotoxicity in RCC cell line ACHN cells. Through Western blot assays, we observed increased apoptosis signaling and decreased proliferation/metastasis signaling, along with a repressed heat shock protein 70 level. In flow cytometry analyses, CNM and hyperthermia combination clearly induced apoptosis and mitochondrial potential of ACHN cells, while arresting the cell cycle. Investigation of reactive oxygen species (ROS) suggested a significant increase of ROS generation by CNM and 43 °C hyperthermia co-treatment. We could verify that ROS is crucial in the apoptotic action of combination treatment with CNM and hyperthermia through further experiments regarding an ROS scavenger. Overall, we suggest CNM and hyperthermia combination treatment as an alternative option of anticancer strategies for RCC.