Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer.

BACKGROUND: The intriguing connection between selenium and cancer resembles a captivating puzzle that keeps researchers engaged and curious. While selenium has shown promise in reducing cancer risks through supplementation, its interaction with epigenetics in cervical cancer remains a fascinating yet largely unexplored realm. Unraveling the intricacies of selenium's role and its interaction with epigenetic factors could unlock valuable insights in the battle against this complex disease. RESULT: Selenium has shown remarkable inhibitory effects on cervical cancer cells in various ways. In in vitro studies, it effectively inhibits the proliferation, migration, and invasion of cervical cancer cells, while promoting apoptosis. Selenium also demonstrates significant inhibitory effects on human cervical cancer-derived organoids. Furthermore, in an in vivo study, the administration of selenium dioxide solution effectively suppresses the growth of cervical cancer tumors in mice. One of the mechanisms behind selenium's inhibitory effects is its ability to inhibit histone demethylases, specifically JMJD3 and UTX. This inhibition is observed both in vitro and in vivo. Notably, when JMJD3 and UTX are inhibited with GSK-J4, similar biological effects are observed in both in vitro and in vivo models, effectively inhibiting organoid models derived from cervical cancer patients. Inhibiting JMJD3 and UTX also induces G2/M phase arrest, promotes cellular apoptosis, and reverses epithelial-mesenchymal transition (EMT). ChIP-qPCR analysis confirms that JMJD3 and UTX inhibition increases the recruitment of a specific histone modification, H3K27me3, to the transcription start sites (TSS) of target genes in cervical cancer cells (HeLa and SiHa cells). Furthermore, the expressions of JMJD3 and UTX are found to be significantly higher in cervical cancer tissues compared to adjacent normal cervical tissues, suggesting their potential as therapeutic targets. CONCLUSIONS: Our study highlights the significant inhibitory effects of selenium on the growth, migration, and invasion of cervical cancer cells, promoting apoptosis and displaying promising potential as a therapeutic agent. We identified the histone demethylases JMJD3 and UTX as specific targets of selenium, and their inhibition replicates the observed effects on cancer cell behavior. These findings suggest that JMJD3 and UTX could be valuable targets for selenium-based treatments of cervical cancer.

Polysaccharide from Echinacea purpurea plant ameliorates oxidative stress-induced liver injury by promoting Parkin-dependent autophagy.

BACKGROUND: Acetaminophen (APAP) overdose represents one of the most common drug-induced liver injuries (DILI) worldwide. Oxidative damage to the hepatocytes and their resultant autophagy are the key components in the APAP-induced DILI. Echinacea purpurea polysaccharide (EPPS), the component extracted from the root of Echinacea purpurea (L.) Moench, shows various biological functions including immunoregulation and antioxidant activity. PURPOSE: This study aimed to elucidate the protective effect of EPPS against APAP-induced DILI and the underlying mechanisms. RESULTS: EPPS attenuates APAP overdose induced DILI in mice and ameliorates inflammation and oxidative stress in mice with APAP overdose-induced DILI. Furthermore, EPPS protected the hepatocytes against APAP-induced liver injury by suppressing apoptosis. EPPS ameliorates APAP-induced DILI via an autophagy-dependent mechanism in vivo and increases autophagy with a reduction in oxidative stress and inflammation in vitro. Parkin knockdown prevents the autophagic-dependent manner of EPPS effects in APAP-treated hepatocytes. CONCLUSIONS: EPPS exhibited a strong hepatoprotective effect against APAP-induced DILI and was correlated with reduction of autophagy-dependent oxidant response, inflammation, and apoptosis. Moreover, the findings indicated that EPPS exerts its hepatoprotective effect against APAP mainly via Parkin-dependent autophagy, and the use of EPPS can serve as a promising novel therapeutic strategy for APAP-induced DILI.

One New Conjugate of a Secoiridoid Glucoside with a Sesquiterpene Glucoside from the Flower Buds of Lonicera japonica.

Secosesquside (1), a new secoiridoid glucoside-sesquiterpene conjugate, together with three known secoiridoid derivatives, were isolated from flower buds of Lonicerajaponica. The isolated compounds were elucidated by extensive spectroscopic analyses, especially 2D NMR experiments. The anti-inflammatory activities of the new compound were also evaluated by enzyme-linked immunosorbent assay.

Insight into the molecular mechanism of a herbal injection by integrating network pharmacology and in vitro.

Chinese medical herbs could treat complex diseases through the synergistic effect of multi-components, multi-targets and multi-channels. However, it was difficult to systematically investigate the pharmacological mechanisms of action due to the complex chemical composition and the lack of an effective research approach. Fortunately, network pharmacology as an integrated approach was proposed to systematically investigate and explain the underlying molecular mechanisms of Chinese medical herbs. Reduning injection (RDN) is one of the herbal injections for treatment of upper respiratory tract infections (URTIs). Previous studies revealed the molecular mechanism of RDN on URTIs through network pharmacology. In this work, the mechanism of RDN was verified by enzyme linked immunosorbent assay (ELISA), Western Blot, immunofluorescence assay and electrophoretic mobility shift assay (EMSA) in lipopolysaccharide (LPS)-induced RAW264.7 cells and enzyme assay. RDN dose-dependently suppressed the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß), and reduced the protein expression of inducible NO synthetase (iNOS) and cyclooxygenase-2 (COX-2), which could be related to its suppression on the phosphorylations of mitogen-activated protein (MAP) kinases, including extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase(JNK) and p38, as well as the activation and translocation of nuclear factor-κB (NF-κB). In addition, the activity of RDN on PGE2 was also partly attributed to the inhibition of COX-2 enzyme. Therefore, it can be concluded that RDN inhibited the production of inflammatory mediators and the macrophage activation to treat URTIs via down-regulating the activation of MAPK and NF-κB signaling pathways, which might pave a way to illustrate the molecular mechanism of herbs.

System-level study on synergism and antagonism of active ingredients in traditional Chinese medicine by using molecular imprinting technology.

In this work, synergism and antagonism among active ingredients of traditional Chinese medicine (TCM) were studied at system-level by using molecular imprinting technology. Reduning Injection (RDNI), a TCM injection, was widely used to relieve fever caused by viral infection diseases in China. Molecularly imprinted polymers (MIPs) synthesized by sol-gel method were used to separate caffeic acid (CA) and analogues from RDNI without affecting other compounds. It can realize the preparative scale separation. The inhibitory effects of separated samples of RDNI and sample combinations in prostaglandin E2 biosynthesis in lipopolysaccharide-induced RAW264.7 cells were studied. The combination index was calculated to evaluate the synergism and antagonism. We found that components which had different scaffolds can produce synergistic anti-inflammatory effect inside and outside the RDNI. Components which had similar scaffolds exhibited the antagonistic effect, and the antagonistic effects among components could be reduced to some extent in RDNI system. The results indicated MIPs with the characteristics of specific adsorption ability and large scale preparation can be an effective approach to study the interaction mechanism among active ingredients of complex system such as TCM at system-level. And this work would provide a new idea to study the interactions among active ingredients of TCM.

Insights into the inhibition and mechanism of compounds against LPS-induced PGE2 production: a pathway network-based approach and molecular dynamics simulations.

In comparison to the current target-based screening approach, it is increasingly evident that active lead compounds based on disease-related phenotypes are more likely to be translated to clinical trials during drug development. That is, because human diseases are in essence the outcome of the abnormal function of multiple genes, especially in complex diseases. Therefore, as a conventional technology in the early phase of active lead compound discovery, computational methods that can connect molecular interactions and disease-related phenotypes to evaluate the efficacy of compounds are in urgently required. In this work, a computational approach that integrates molecular docking and pathway network analysis (network efficiency and network flux) was developed to evaluate the efficacy of a compound against LPS-induced Prostaglandin E2(PGE2) production. The predicted results were then validated in vitro, and a correlation with the experimental results was analyzed using linear regression. In addition, molecular dynamics (MD) simulations were performed to explore the molecular mechanism of the most potent compounds. There were 12 hits out of 28 predicted ingredients separated from Reduning injection (RDN). The predicted results have a good agreement with the experimental inhibitory potency (IC50) (correlation coefficient = 0.80). The most potent compounds could target several proteins to regulate the pathway network. This might partly interpret the molecular mechanism of RDN on fever. Meanwhile, the good correlation of the computational model with the wet experimental results might bridge the gap between molecule-target interactions and phenotypic response, especially for multi-target compounds. Therefore, it would be helpful for active lead compound discovery, the understanding of the multiple targets and synergic essence of traditional Chinese medicine (TCM).