Polyunsaturated Fatty Acids in Quinoa Induce Ferroptosis of Colon Cancer by Suppressing Stemness.

Polyunsaturated fatty acids (PUFAs) are essential nutrients for the human body, playing crucial roles in reducing blood lipids, anti-inflammatory responses, and anticancer effect. Quinoa is a nutritionally sound food source, rich in PUFAs. This study investigates the role of quinoa polyunsaturated fatty acids (QPAs) on quelling drug resistance in colorectal cancer. The results reveal that QPA downregulates the expression of drug-resistant proteins P-gp, MRP1, and BCRP, thereby enhancing the sensitivity of colorectal cancer drug-resistant cells to the chemotherapy drug. QPA also inhibits the stemness of drug-resistant colorectal cancer cells by reducing the expression of the stemness marker CD44. Consequently, it suppresses the downstream protein SLC7A11 and leads to ferroptosis. Additionally, QPA makes the expression of ferritin lower and increases the concentration of free iron ions within cells, leading to ferroptosis. Overall, QPA has the dual-function reversing drug resistance in colorectal cancer by simultaneously inhibiting stemness and inducing ferroptosis. This study provides a new option for chemotherapy sensitizers and establishes a theoretical foundation for the development and utilization of quinoa.

Terpenoids from quinoa reverse drug resistance of colon cancer by upregulating miR-495-3p.

BACKGROUND: Quinoa contains far more nutrients than any traditional grain crop. It is known that terpenoids in quinoa have anti-inflammatory and antitumor effects, but their role in reversing drug resistance remains unclear. RESULTS: Our previous studies showed that quinoa-derived terpenoid compounds (QBT) can inhibit the occurrence and development of colon cancer. This study further indicates that QBT markedly reverse drug resistance of colon cancer. The results showed that QBT combined with 5-fluorouracil (5-Fu) treatment significantly enhanced the chemotherapy sensitivity of HCT-8/Fu, compared with 5-Fu treatment alone. Moreover, we found that QBT significantly reduced the expression of drug-resistant proteins (P-gp, MRP1, BCRP), and increased the accumulation of chemotherapy drugs. Taking P-gp as the target for biogenesis prediction analysis, results showed that upregulation of miR-495-3p enhanced the chemosensitivity of drug-resistant HCT-8/Fu cells. Besides, the results showed that miR-495-3p was abnormally methylated in HCT-8/Fu compared with HCT-8 colon cancer cells. The expression of methyltransferases DNMT1, DNMT3a and DNMT3b was abnormal. After QBT treatment, the expression level of methyltransferases returned to normal. In addition, the QBT + 5Fu group showed inhibition of tumors in nude mice. CONCLUSION: QBT treatment downregulated the expression of drug-resistant protein P-gp by inhibiting the methylation of miR-495-3p, and enhanced the accumulation of 5-Fu in vivo, which in turn reversed its chemoresistance. This suggests that QBT has potential ability as a new drug-resistance reversal agent in colorectal cancer. © 2024 Society of Chemical Industry.

High-throughput identification and determination of antifungal triazoles in human plasma using UPLC-QDa.

Triazoles are common agents for invasive fungal infections, while therapeutic drug monitoring is needed to improve antifungal efficacy and reduce toxicity. This study aimed to exploit a simple and reliable liquid chromatography-mass spectrometry method for high-throughput monitoring of antifungal triazoles in human plasma using UPLC-QDa. Triazoles in plasma were separated by chromatography on a Waters BEH C18 column and detected using positive ions electrospray ionization fitted with single ion recording. M+ for fluconazole (m/z 307.11) and voriconazole (m/z 350.12), M2+ for posaconazole (m/z 351.17), itraconazole (m/z 353.13) and ketoconazole (m/z 266.08, IS) were selected as representative ions in single ion recording mode. The standard curves in plasma showed acceptable linearities over 1.25-40 µg/mL for fluconazole, 0.47-15 µg/mL for posaconazole and 0.39-12.5 µg/mL for voriconazole and itraconazole. The selectivity, specificity, accuracy, precision, recovery, matrix effect, and stability met acceptable practice standards under Food and Drug Administration method validation guidelines. This method was successfully applied to the therapeutic monitoring of triazoles in patients with invasive fungal infections, thereby guiding clinical medication.

Tumor-secreted GRP78 induces M2 polarization of macrophages by promoting lipid catabolism.

Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism, which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type. Mechanistically, entered GRP78 located in lipid droplets of macrophages, and elevated protein stabilization of adipose triglyceride lipase ATGL by interacting with it to inhibit its ubiquitination. Increased ATGL promoted the hydrolysis of triglycerides and the production of arachidonic acid (ARA) and docosahexaenoic acid (DHA). Excessive ARA and DHA interacted with PPARγ to encourage its activation, which mediated the M2 polarization of macrophages. In summary, our study showed that secreted GRP78 in the tumor hypoxic microenvironment mediated the domestication of tumor cells to macrophages and maintained tumor immunosuppressive microenvironment by promoting lipolysis, and the lipid catabolism not only provides energy for macrophages but also plays an important role in maintenance of immunosuppressive properties.

Salvianolic acid A attenuates inflammation-mediated atherosclerosis by suppressing GRP78 secretion of endothelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvianolic acid A (SAA) is the main active component of the classic anti-atherosclerotic drug Salvia miltiorrhiza Bunge. Inflammation-induced infiltration of monocyte/macrophages into the vascular wall is the initiating step in atherogenesis, and targeted blocking of this step may provide a promising avenue for the precise treatment of atherosclerosis. However, the effect of salvianolic acid A on macrophages is still unknown. AIM OF THE STUDY: To evaluate the effect of SAA on macrophage infiltration and the underlying mechanism of SAA against atherosclerosis. MATERIALS AND METHODS: Vascular endothelial cells were stimulated with lipopolysaccharide (LPS) to simulate the inflammatory environment, and its effect on monocyte/macrophages was evaluated. Mass spectrometry was used to identify the proteins that play a key role and further validated them. LncRNA sequencing, western blot analysis, RNA immunoprecipitation, and RNA pulldown were used to elucidate the mechanism of SAA against atherosclerosis. Finally, ApoE-/- mice were fed a high-fat diet to creat an in vivo atherosclerosis model. Secretory GRP78 content, lipid levels, plaque area, macrophage infiltration, and degree of inflammation were assessed by standard assays after 16 weeks of intragastric administration of SAA or biweekly tail vein injections of GRP78 antibody. RESULTS: After LPS stimulation, the increased secretion of GRP78 recruits circulating monocyte/macrophages and drives monocyte/macrophage adhesion and invasion into the vascular intima to promote atherosclerosis progression. Interestingly, SAA exerts anti-atherosclerosis effects by inhibiting the secretion of GRP78. Further mechanistic studies indicated that SAA upregulates the expression of lncRNA NR2F2-AS1, which reverses the abnormal localization of the KDEL receptor (KDELR) caused by inflammation. It promotes the homing of GRP78 from the Golgi apparatus to the endoplasmic reticulum rather than secreting outside the cell. CONCLUSION: SAA alleviates atherosclerosis by inhibiting GRP78 secretion via the lncRNA NR2F2-AS1-KDELR axis. The findings not only provide a new direction for the precise therapy of atherosclerosis based on secretory GRP78 but also elucidate the pharmacological mechanism of SAA against atherosclerosis, putting the foundation for further development and clinical application of SAA drugs.

T-2 toxin cytotoxicity mediated by directly perturbing mitochondria in human gastric epithelium GES-1 cells.

T-2 toxin is one of the most toxic trichothecenes and harmful to human health and animal husbandry. The mechanism underlying its growth suppression remains unclear, especially for mitochondrial damage in human gastric epithelial cells. In the present study, we investigated cell death caused by T-2 toxin in a human gastric epithelial cell line (GES-1) and the possible mechanism of T-2-induced cytotoxicity. T-2 strongly reduced the viability of GES-1 cells in a time- and dose-dependent manner within a small range of concentrations. However, when the concentrations of T-2 were >40 nM, there was no concentration dependence, only time dependence. Moreover, T-2 induced apoptosis, with the activation of caspase-3 in GES-1 and mitochondrial membrane potential (MMP) decrease and cytochrome c release. T-2 also resulted in the accumulation of reactive oxygen species (ROS) and DNA damage with a positive signal of p-H2A.X in GES-1 cells. While T-2 caused a MMP decrease, DNA damage and cell death were not blocked by pretreatment with 3 mM glutathione (GSH), a typical scavenger of ROS. The induction of mitochondrial permeability transition pore (mPTP) regulators voltage-dependent anion channel (VDAC1) and cyclophilin D (CypD) were also observed in T-2-treated cells. Interestingly, cyclosporine A (CsA), a CypD inhibitor, significantly reversed the drop in MMP and the DNA damage, as well as ROS accumulation caused by T-2. Additionally, GES-1 cell death could also be protected to some extent by 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS), an inhibitor of VDAC1, especially the combination of CsA and DIDS, and 3 mM GSH could further enhance the effect of CsA + DIDS on cell viability. In conclusion, our present findings indicate that the T-2 induced MMP decrease, DNA damage and cell death, as well as ROS accumulation in GES-1 cells, starts with T-2 directly perturbing the mitochondria triggering ROS generation by acting on CypD and VDAC1. This study presents a new viewpoint for evaluating the toxicity of T-2 toxin.

Two novel aromatic hydrocarbons: facile synthesis, photophysical properties and applications in deep-blue electroluminescence.

Two efficient novel fluorescent naphthalene and fluorene-based aromatic hydrocarbon isomers (1 and 2) are prepared and investigated for organic electroluminescence. These compounds show bright violet to deep-blue emission, narrow full width at half maximum (52 nm), and high photoluminescence efficiency (e.g. 0.61 in CH2Cl2, 0.67 in film). Alternation of substituent position on the naphthalene moiety can give rise to remarkable emission variation. The relatively large torsion angle between naphthalene and fluorene suppresses the π-π interactions by weakening the intermolecular interactions in the solid state, which can result in highly efficient fluorescence. Moreover, the 1931 Commission Internationale de L'Eclairage coordinates and maximum emission peak for deep-blue electroluminescence based on 1 are (0.16, 0.08) and 410 nm, respectively.

A novel ent-kaurane diterpenoid analog, DN3, selectively kills human gastric cancer cells via acting directly on mitochondria.

Targeting mitochondria using proper pharmacological agents is considered an attractive strategy for cancer control and management. Herein, we report a newly synthetic triazole analog of Jaridonin, DN3, which exhibits more potent antitumor activity via acting directly on mitochondria. DN3 potently reduced viabilities of gastric cancer cell lines HGC-27 and MGC-803 through inducing apoptosis and cell cycle arrest. But, normal human gastric epithelial cell line GES-1 is more resistant to the growth inhibition by DN3 compared with gastric cancer cells. DN3 induced mitochondrial membrane potential (MMP) decrease and cytochrome c release in intact gastric cancer cell lines. Meanwhile, the DN3 treatment also caused the release of cytochrome c from mitochondria isolated from cancer cell lines in a mitochondrial permeability transition pore complex (PTPC) mediated manner, but not from mitochondria isolated from normal gastric epithelial cell. The induction of mitochondrial PTPC proteins voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) were also observed in DN3-treated cells. More interestingly, DN3 mediated MMP decrease, release of cytochrome c, the expression of VDAC and CypD and apoptosis were blocked by the pretreatment of VDAC1 inhibitor (4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid, DIDS) and CypD inhibitor (cyclosporine A, CsA). In a mouse xenograft model of human gastric cancer, the treatment of 5 mg/kg DN3 led to significant tumor regression without affecting body weight. In conclusion, our findings indicate that DN3 is a potential agent for the treatment of gastric cancer through acting directly on mitochondria, and would be useful for us to design more and better anti-cancer compounds.

Induction of the mitochondria-mediated apoptosis in human esophageal cancer cells by DS2, a newly synthetic diterpenoid analog, is regulated by Bax and caused by generation of reactive oxygen species.

Ent-kaurane diterpene compounds have attracted considerable attention in recent years due to its antitumor, antibacterial, and antiviral activities. However, the clinical development of natural kaurane diterpenes, for example, oridonin for cancer therapy has been hampered by its relatively moderate potency, limited bioavailability. Herein, we report a newly synthetic analog of natural ent-kaurane diterpene, DS2, which exhibits significantly improved activity of antiproliferation against various cancer cell lines relative to oridonin. DS2 treatment triggers the mitochondria-mediated apoptosis and cell cycle arrest in human esophageal cancer cell lines (EC9706, EC109). Interestingly, normal human esophageal epithelial cells (HEECs) and normal human liver cells (HL-7702) are both significantly more resistant to the growth inhibition by DS2 compared with esophageal cancer cells. The DS2-induced apoptosis in EC9706 cells correlated with the drop of mitochondrial membrane potential (MMP), release of cytochrome c into the cytosol and activation of caspase-9 and -3. The induction of proapoptotic proteins p21 and Bax were also observed in DS2-treated cells. The DS2-induced apoptosis was significantly attenuated by knockdown of Bax proteins. Meanwhile, the DS2 treatment caused generation of reactive oxygen species (ROS) in human esophageal cancer cells, but not in HEECs, which was attenuated by pretreatment with ROS scavenger N-acetylcysteine (NAC). More interestingly, the antioxidants pretreatment completely attenuated DS2 mediated loss of the MMP and apoptosis, as well as Bax expression and growth inhibition. In conclusion, the present study reveals that the mitochondria-mediated cell death by DS2 is associated with Bax regulation and ROS generation, and understanding the function and mechanism of DS2 will help us to design better anti-cancer drugs.