TCM targets ferroptosis: potential treatments for cancer.

Ferroptosis is caused by the accumulation of cellular reactive oxygen species that exceed the antioxidant load that glutathione (GSH) and phospholipid hydroperoxidases with GSH-based substrates can carry When the antioxidant capacity of cells is reduced, lipid reactive oxygen species accumulate, which can cause oxidative death. Ferroptosis, an iron-dependent regulatory necrosis pathway, has emerged as a new modality of cell death that is strongly associated with cancer. Surgery, chemotherapy and radiotherapy are the main methods of cancer treatment. However, resistance to these mainstream anticancer drugs and strong toxic side effects have forced the development of alternative treatments with high efficiency and low toxicity. In recent years, an increasing number of studies have shown that traditional Chinese medicines (TCMs), especially herbs or herbal extracts, can inhibit tumor cell growth and metastasis by inducing ferroptosis, suggesting that they could be promising agents for cancer treatment. This article reviews the current research progress on the antitumor effects of TCMs through the induction of ferroptosis. The aim of these studies was to elucidate the potential mechanisms of targeting ferroptosis in cancer, and the findings could lead to new directions and reference values for developing better cancer treatment strategies.

Dendritic Polymer-Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response.

The dense extracellular matrix (ECM) in solid tumors, contributed by cancer-associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)-based nanomedicines (poly[OEGMA-Dendron(G2)-Gly-Phe-Leu-Gly-DAS] (P-DAS) and poly[OEGMA-Dendron(G2)-hydrazone-Epi] (P-Epi)) are developed for sequential delivery of DAS and Epi, respectively. P-DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P-Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer-bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti-programmed cell death 1 (PD-1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P-DAS and P-Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.

Effects of JUNCAO Ganoderma lucidum polysaccharide peptide on slaughter performance and intestinal health of Minxinan black rabbits.

This experiment was conducted to investigate the effects of JUNCAO Ganoderma lucidum polysaccharide peptide (JCGLPP) on slaughter performance and intestinal health of Minxinan black rabbits, which aimed to provide the basis for the application of JCGLPP in meat rabbits. One hundred male weaned Minxinan black rabbits of (33 ± 2) d [(initial body mass (655.65 ± 25.90) g] were randomly divided into four groups with five replicates per group and five rabbits per replicate. The diets were supplemented with 0 (control group), 50 (group I), 100 (group II) and 150 mg·kg-1 (group III) of JCGLPP, respectively. This experiment lasted for 56 days. The results are shown below: (1) The live weight before slaughter of groups I and III was significantly higher than that of control group (p < 0.05); The full net bore weight of group III was significantly higher than that of control group (p < 0.05). (2) pH value of group I was significantly higher than that of control group (p < 0.05); NH3-N content in experimental groups were significantly higher than that in control group(p < 0.05) while NH3-N content in group I was significantly higher than that in groups III and II (p < 0.05); The content of butyric acid in group II was significantly lower than that in control group (p < 0.05); There were no significant differences in acetic acid, isovaleric acid, isobutyric acid and propionic acid in experimental groups compared with control group (p > 0.05). (3) The Occludin content in duodenum, jejunum and ileum of groups I and II was significantly higher than that of control group (p < 0.05). (4) At the phylum level, Firmicutes and Bacteroidetes were the dominant phylum in each group. At the genus level, norank_f__norank_o__Clostridia_UCG-014 in group II were significantly higher than those in control group (p < 0.05). In conclusion, although dietary JCGLPP supplementation could not improve slaughter performance of Minxinan black rabbits, it could improve cecal fermentation parameters and intestinal flora structure and composition of Minxinan black rabbits to a certain extent. Our results revealed that 100 mg·kg-1 might be the optimal concentration obtained in dietary JCGLPP supplementation, which provided ideas and feasibility for drug combination.

Apelin-mediated deamidation of HMGA1 promotes tumorigenesis by enhancing SREBP1 activity and lipid synthesis.

Enhanced fatty acid synthesis provides proliferation and survival advantages for tumor cells. Apelin is an adipokine, which serves as a ligand of G protein-coupled receptors that promote tumor growth in malignant cancers. Here, we confirmed that apelin increased sterol regulatory element-binding protein 1 (SREBP1) activity and induced the expression of glutamine amidotransferase for deamidating high-mobility group A 1 (HMGA1) to promote fatty acid synthesis and proliferation of lung cancer cells. This post-translational modification stabilized the HMGA1 expression and enhanced the formation of the apelin-HMGA1-SREBP1 complex to facilitate SREBP1 activity for lipid metabolism and lung cancer cell growth. We uncovered the pivotal role of apelin-mediated deamidation of HMGA1 in lipid metabolism and tumorigenesis of lung cancer cells.

Vital and Distinct Roles of H2A.Z Isoforms in Hepatocellular Carcinoma.

PURPOSE: H2A.Z is an oncogenic histone variant that is overexpressed in cancers. Two isoforms of H2A.Z, H2AFZ and H2AFV, are identical except for a three-amino acid difference. However, their isoform-specific functions remain unclear in cancer development. Thereby, this study aimed to investigate whether the two isoforms play distinct functions in hepatocarcinogenesis. MATERIALS AND METHODS: Expressions of H2A.Z isoforms in 116 paired hepatocellular cancerous and para-cancerous tissues were detected by employing qPCR. GEO and TCGA databases were used to probe expressions and prognostic value of the two H2A.Z isoforms. A comprehensive meta-analysis was conducted. Furthermore, co-expressed analysis of H2AFZ and H2AFV was performed by using cBioPortal database. H2A.Z binding genes from Chip-seq were intersected with H2A.Z isoforms co-expressed genes to perform functional annotations. Cell proliferation experiments from H2AFZ knockout HepG2 and BEL-7402 cells were implemented. Finally, RNA-seq was applied to analyse alternative splicing in H2AFZ knockout and wild-type cells. RESULTS: H2AFZ and H2AFV were both significantly upregulated (P < 0.01) in hepatocellular carcinoma and related to poor prognosis (P < 0.01). The two H2A.Z isoforms played vital roles in cell proliferation. It is also predicted that unique functions of H2AFV contain spindle midzone and microtubule, while H2AFZ is especially associated with RNA export and spliceosome. Further, devoid H2AFZ may restrain liver cancer cell proliferation and cause many alternative splicing events. CONCLUSION: Both H2A.Z isoforms play vital and distinct roles in the occurrence and progression of liver cancer, which may pave a way for novel therapeutic applications for cancers in the future.

The composition of microbial aerosols, PM2.5, and PM10 in a duck house in Shandong province, China.

Poultry-emitted air pollutants, including microbial aerosols and particulate matter, have raised concerns due to their potential negative effects on human health and the environment. High concentrations of microbial aerosols can also significantly affect duck production performance, leading to immunosuppression and increased disease susceptibility. We determined the concentrations, distributions, and biological components of the microbial aerosols and particulate matter in a duck house environment. The concentration ranges of the bacteria, fungi, Gram-negative bacteria, Escherichia coli, and endotoxin in the duck houses were 3.3 to 5.2 × 104 CFU/m3, 3.8 to 11.9 × 103 CFU/m3, 2.1 to 3.6 × 103 CFU/m3, 1.3 to 2.7 × 102 CFU/m3, and 0.65 to 2.2 × 103 EU/m3, respectively. We also found the endotoxin levels were higher than the standard that can cause pneumonia (2,000 EU/m3). The concentration ranges of the PM2.5 and PM10 samples were 1.1 to 1.6 × 102 µg/m3 and 1.2 to 1.9 × 102 µg/m3, respectively. At the phylum level, the top 5 bacteria identified in the PM2.5 fraction were Actinobacteria, Firmicutes, Proteobacteria, Bacteroidetes, and Fusobacteria, with Actinobacteria (50.55%) as the most abundant. At the genus level, 293 bacterial groups were identified. Actinobacteria (39.01%) was the most abundant phylum, followed by Firmicutes (5.44%) and Proteobacteria (4.56%). The bacterial distributions that differed between the PM2.5 and PM10 samples were Lactobacillales, Bacilli, Firmicutes, and Bacteroidetes; the fungi that differed were Microbotryomycetes, Sporidiobolales, Agaricomycetes, and Polyporates. Microbial allergens and pathogens were also identified. Corynebacterium had a relative abundance of more than 30% in the PM2.5 and PM10 distributions. Aspergillus was the main fungal allergen and opportunistic pathogen, with a relative abundance of 10%. In conclusion, our research supports that the microbial composition in the duck house environment poses a potential threat to the health of both the ducks and the duck house workers.

Design and optimization of novel hydroxamate-based histone deacetylase inhibitors of Bis-substituted aromatic amides bearing potent activities against tumor growth and metastasis.

Histone deacetylases (HDACs) are one of the most promising drug targets for cancer therapy, and since more than 90% of all cancer-related deaths are associated with tumor metastasis, developing strategies to inhibit tumor metastasis while retaining anti-tumor growth activity are of great interest. Herein we demonstrated the design and identification of a series of novel hydroxamate-based HDAC inhibitors bearing potent activities against tumor growth and metastasis. Optimization of the initial hit resulted in the discovery of new HDAC inhibitors through studying the structure-activity relationship. Among them, compound 11b, one of the most potent leads, exhibited nanomolar IC50 values toward inhibition of class I and IIb HDACs as well as sub-micromolar activity against proliferation and migration of breast cancer cells in vitro. More importantly, it also significantly suppressed tumor growth in a breast tumor xenograft mouse model and dose-dependently blocked in vivo tumor metastasis in a mouse pulmonary metastasis model.

Optimization of 2-(3-(arylalkyl amino carbonyl) phenyl)-3-(2-methoxyphenyl)-4-thiazolidinone derivatives as potent antitumor growth and metastasis agents.

A series of 2,3-diaryl-4-thiazolidinone derivatives were synthesized and evaluated for their antiproliferative properties against two well-known cancer cell lines (A549 as human lung cancer and MDA-MB-231 as human breast cancer). Structure activity relationship (SAR) analysis resulted in the discovery of 2-(3-(arylalkyl amino carbonyl)phenyl)-3-(2-methoxy-phenyl)-4-thiazolidinone derivatives with high potent inhibitory effects on the proliferation of both cancer cell lines. Furthermore, several compounds with potent antiproliferative activities displayed excellent inhibitory activities on migration with an IC50 of about 0.05 µM on MDA-MB-231 cells in two different migration assays. In particular, compound 39 was indicated to suppress tumor growth and metastasis as well as promote survival rate. Intriguingly, this series of analogs have been indicated to inhibit tumor cell proliferation through inducing cell cycle arrest. These results suggested that the new series of 2-(3-(arylalkyl amino carbonyl)phenyl)-3-(2-methoxyphenyl)-4-thiazolidinone derivatives could be regarded and developed as novel highly potential anticancer agents in the future.