Ferrous Fumarate

As an executor of pyroptosis, gasdermin D (GSDMD) plays a critical role in inflammatory diseases and cancer. Thus, GSDMD is currently being widely explored as a drug target. Existing inhibitors targeting GSDMD, such as necrosulfonamide, disulfiram, and fumarate, primarily prevent pyroptosis by modifying human/mouse C191/C192 in the N-terminal fragment of GSDMD. However, cysteine modification can prevent the function of important proteins or enzymes, thereby leading to adverse reactions. Here, we chose an alternative key intervention site for GSDMD activation, which is located at the oligomerization interface I of its pore-forming structure. Through high-throughput virtual and experimental screening and in combination with efficacy and pharmacological validation, we have identified two safe, specific "repurposed drugs" that potently suppress GSDMD-mediated pyroptosis. Moreover, the candidates exhibited synergistic therapeutic effects of "1 + 1>2" in murine sepsis and tumorigenesis models. These recently identified GSDMD inhibitors hold great promise for clinical translation in the development of anti-inflammatory and anti-cancer immunotherapies.

Soybean (Glycine max L.) serves not only as food for humans, animals, and industrial purposes, but is also a plant that can be used to comprehend molecular mechanisms occurring in stress response to various development techniques. To reveal the effect of applying dicarboxylic acids as stress priming agents on a metabolic level in soybean leaf extracts, the chemical profile of methanolic extracts were collected at different time points (1 h, 2 h, 12 h, 24 h, 1 week, 2 weeks and 3 weeks) after spraying were analyzed using ¹H-NMR based metabolomics by way of PCA and OPLS-DA. The OPLS-DA revealed several metabolites, including organic acids (fumarate, citrate and malate) and amino acids (asparagine, alanine and GABA), which accumulated in higher amounts, with fumarate accumulating the highest in Glycine max L. leaf extracts compared to untreated leaves. Denaturing 1DE gels were prepared for MS-based protein analysis and the presence of fatty acids (linolenic, oleic and α-linolenic acid) were confirmed by gas chromatography coupled with mass spectrometry (GC-MS), which served as jasmonic acid precursors. The MS-based profiling of proteins on the denaturing 1DE gels revealed several proteins that were differentiated between the treated and untreated leaf extracts. These proteins included ferritins, CaM, ferredoxin-thioredoxin reductase and chalcone-flavanone isomerase 1A. Following the treatment, fumarate was significantly elevated at 12 h to 3 weeks, compared to other compounds. It is, therefore, proposed that elevated quantities of fumarate could be related to the KEAP1-NRF2 metabolic pathway. This study represents the initial investigation of the effect of dicarboxylic acid application as a stress priming agent on Glycine max L. using ¹H-NMR metabolomic analysis, GC-MS and proteomic analysis.