DTTZ suppresses ferroptosis and reverses mitochondrial dysfunction in normal tissues affected by chemotherapy.

Conventional antineoplastic therapies cause severe normal tissue damage and existing cytoprotectants with acute toxicities or potential tumor protection limit their clinical application. We evaluated the selective cytoprotection of 2,2-dimethylthiazolidine hydrochloride in this study, which could protect normal tissue toxicity without interfering antineoplastic therapies. By using diverse cell lines and A549 xenograft model, we discovered a synthetic aminothiol 2,2-dimethylthiazolidine hydrochloride selectively diminished normal cellular ferroptosis via SystemXc-/Glutathione Peroxidase 4 pathway upon antineoplastic therapies without interfering the anticancer efficacy. We revealed the malignant and non-malignant tissues presenting different energy metabolism patterns. And cisplatin induces disparate replicative stress, contributing to the distinguishable cytoprotection of 2,2-dimethylthiazolidine in normal and tumor cells. The compound pre-application could mitigate cisplatin-induced normal cellular mitochondrial oxidative phosphorylation (OXPHOS) dysfunction. Pharmacologic ablation of mitochondria reversed 2,2-dimethylthiazolidine chemoprotection against cisplatin in the normal cell line. Combined, these results provide a potential therapeutic adjuvant to selectively diminish normal tissue damages retaining antineoplastic efficacy.

Impact of "expanding powers and strengthening counties" reform on basic public education services: Empirical evidence from Sichuan, China.

The quality of a country's education system is both an indicator of its present level of development and a predictor of future economic advancement. This study intended to explore the impact of the "expanding power and strengthening counties" reform on the supply of basic public education resources. A combination of qualitative and quantitative methods was used to analyze the panel data of 114 counties in Sichuan Province from 2005 to 2017, including 78 counties with expanded powers. The study found that the "expanded power strong counties (EPSC)" had a significant positive impact on the supply level of funding resources measured by per capita public education expenditure. The time effect of the EPSC on the supply of teacher resources for county public education was manifested as a sharp increase in the supply level in the three years before the reform. The supply level tended to be stable after four years of reform. The economic resources supply level was relatively stable in the first three years and rose sharply after four years. There was a downward trend after the reform for 8 years. The structural effect has shown a more significant incentive effect on the supply of public education resources to strong and weak counties. But compared with the weak counties with lower economic development levels, the strong counties with higher economic development levels have a more noticeable effect of their decentralization reform on improving the supply level of public education resources.

Design of Monovalent Cerium-Based Metal Organic Frameworks as Bioinspired Superoxide Dismutase Mimics for Ionizing Radiation Protection.

Superoxide dismutase (SOD) is one of the major antioxidants in vivo and is expected to play critical roles on the defense against reactive oxygen species (ROS)-mediated damages, such as ionizing radiation damages. Herein, inspired by the function and structure of natural SODs and cerium oxide nanozymes, two monovalent cerium-based metal organic frameworks (Ce-MOFs), CeIIIBTC and CeIVBTC, were designed for superoxide radical (O2•-) elimination and ionizing radiation protection. These two Ce-MOFs selectively scavenge O2•- and are excellent SOD mimics. Like natural SODs and cerium oxide nanozymes, the SOD-like catalytic mechanism of Ce-MOFs involves a cycle between Ce(IV) and Ce(III). Furthermore, by constructing monovalent Ce-MOFs, we found that high-valent CeIVBTC are more effective SOD-like nanozymes compared to CeIIIBTC. With smaller size, better monodispersity, and more effective SOD-like activity, CeIVBTC nanozymes were further applied for ionizing radiation protection. Both in vitro and in vivo results demonstrated that CeIVBTC nanozymes could efficiently scavenge ROS, prevent cells from γ-ray radiation-induced cell viability decrease and DNA damages, and improve the survival rate of irradiated mice by recovering the bone marrow DNA damage and alleviating oxidative stress of tissues. The protective effect and good biocompatibility of CeIVBTC nanozymes will enable the development of Ce-MOFs-based radioprotectants and facilitate treatment of other ROS-related diseases.

ROS-Responsive and pH-Sensitive Aminothiols Dual-Prodrug for Radiation Enteritis.

Radiation exposure can immediately trigger a burst of reactive oxygen species (ROS), which can induce severe cell death and long-term tissue damage. Therefore, instantaneous release of sufficient radioprotective drugs is vital to neutralize those accumulated ROS in IR-exposed areas. To achieve this goal, we designed, synthesized, and evaluated a novel oral ROS-responsive radioprotective compound (M1) with high biocompatibility and efficient ROS-scavenging ability to act as a promising oral drug for radiation protection. The compound is stably present in acidic environments and is hydrolyzed in the intestine to form active molecules rich in thiols. M1 can significantly remove cellular ROS and reduce DNA damage induced by γ-ray radiation. An in vivo experiment showed that oral administration of M1 effectively alleviates acute radiation-induced intestinal injury. Immunohistochemical staining showed that M1 improved cell proliferation, reduced cell apoptosis, and enhanced the epithelial integrity of intestinal crypts. This study provides a promising oral ROS-sensitive agent for acute intestinal radiation syndrome.

ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway.

Given the relentless renewal ability of intestinal crypt-base stem cells, small intestine in the gastrointestinal (GI) tract is more vulnerable to radiation-induced disruption. Through promoting epithelial integrity and reducing intracellular reactive oxygen species (ROS) levels, hypoxia-inducible factors (HIFs) have been proved to exhibit radioprotective effects in the GI tract. Therefore, enhancing stability or transcriptional activity of HIFs might be a therapeutic strategy for developing radioprotectors. Factor inhibiting HIF (FIH or HIF-1AN) can hamper transcriptional capacity of HIF-1α via interacting with Asn803 in its C-terminal domain. Previously, we discovered promoting HIF-1α transcriptional activity in vitro by FIH inhibitor-N-oxalyl-D-phenylalanine (NOFD) exerts radioprotection on cells. However, the radioprotective effect of FIH inhibitor on the GI tract and its competing endogenous RNA (ceRNA) regulatory network from the FIH/HIF axis has never been addressed. Here we verified radioprotection of NOFD for the GI tract by an animal model and performed whole-transcriptome analysis to fully elucidate the radioprotective mechanism from the FIH/HIF axis against GI syndrome. We identified two novel circular RNAs (circRNAs) (circRNA_2909 and circRNA_0323) and two long non-coding RNAs (lncRNAs) (NONMMUT140549.1 and NONMMUT148249.1) that promote expression of HIF1A and NOS2 in the HIF-1 pathway by sponging microRNAs (miRNAs), especially mmu-miR-92a-1-5p. The de-repression of HIF-1α transcriptional capacity by inhibiting FIH proteomic activity suggests a new therapeutic strategy in alleviating radiation-induced GI syndrome.

Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions.

Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01-TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC50 of 0.21 µM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-RasG12V protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.