Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling.

Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues.

Gold(III)-P-chirogenic complex induces mitochondrial dysfunction in triple-negative breast cancer.

Chemical agents that specifically exploit metabolic vulnerabilities of cancer cells will be beneficial but are rare. The role of oxidative phosphorylation (OXPHOS) in promoting and maintaining triple-negative breast cancer (TNBC) growth provides new treatment opportunity. In this work, we describe AuPhos-19, a small-molecule gold(III)-based agent bearing a chiral phosphine ligand that selectively disrupts mitochondrial metabolism in murine and human TNBC cells but not normal epithelial cells. AuPhos-19 induces potent cytotoxic effect with half maximal inhibitory concentration (IC50) in the nanomolar range (220-650 nM) across different TNBC cell lines. The lipophilic cationic character of AuPhos-19 facilitates interaction with mitochondrial OXPHOS. AuPhos-19 inhibits mitochondria respiration and induces significant AMPK activation. Depolarization of the mitochondria membrane, mitochondria ROS accumulation, and mitochondria DNA depletion provided further indication that AuPhos-19 perturbs mitochondria function. AuPhos-19 inhibits tumor growth in tumor-bearing mice. This study highlights the development of gold-based compounds targeting mitochondrial pathways for efficacious cancer treatment.

Cancer cell-selective modulation of mitochondrial respiration and metabolism by potent organogold(iii) dithiocarbamates.

Metabolic reprogramming is a key cancer hallmark that has led to the therapeutic targeting of glycolysis. However, agents that target dysfunctional mitochondrial respiration for targeted therapy remains underexplored. We report the synthesis and characterization of ten (10) novel, highly potent organometallic gold(iii) complexes supported by dithiocarbamate ligands as selective inhibitors of mitochondrial respiration. The structure of dithiocarbamates employed dictates the biological stability and cellular cytotoxicity. Most of the compounds exhibit 50% inhibitory concentration (IC50) in the low-micromolar (0.50-2.9 µM) range when tested in a panel of aggressive cancer types with significant selectivity for cancer cells over normal cells. Consequently, there is great interest in the mechanism of action of gold chemotherapeutics, particularly, considering that DNA is not the major target of most gold complexes. We investigate the mechanism of action of representative complexes, 1a and 2a in the recalcitrant triple negative breast cancer (TNBC) cell line, MDA-MB-231. Whole-cell transcriptomics sequencing revealed genes related to three major pathways, namely: cell cycle, organelle fission, and oxidative phosphorylation. 2a irreversibly and rapidly inhibits maximal respiration in TNBC with no effect on normal epithelial cells, implicating mitochondrial OXPHOS as a potential target. Furthermore, the modulation of cyclin dependent kinases and G1 cell cycle arrest induced by these compounds is promising for the treatment of cancer. This work contributes to the need for mitochondrial respiration modulators in biomedical research and outlines a systematic approach to study the mechanism of action of metal-based agents.

Exploring six-coordinate germanium(IV)-diketonate complexes as anticancer agents.

Cancer remains one of the leading causes of death worldwide and despite several attempts using chemotherapy to combat the deadly disease, toxic side effects and drug resistance temper efficacy [1]. Thus, drugs with potentially new mechanisms and lower toxicity to normal cells are needed. Metalloids such as arsenic compounds have been clinically beneficial in fighting cancer, but germanium is yet to gain such prominence [2,3]. We report the synthesis of four octahedral germanium(IV) complexes bearing acetylacetonato ligand, [GeIV(acac)3)]+, with different anions (3 - 6) using a streamlined synthetic approach. The compounds were structurally and electrochemically characterized using NMR, MS, X-ray crystallography, and cyclic voltammetry. The cyclic voltammogram of 3-5 revealed distinct irreversible peaks in the range of -0.9 to -1.9 V, corresponding to Ge(IV)/ Ge(II) or Ge(II)/Ge(0) couple in DMSO. We explored the anticancer activity of the complexes against a panel of cancer cell lines with IC50 values in the sub-micromolar range (9-15 µM). The compounds display ~3-fold selectivity in cancer cells over normal epithelial cells. In addition to the promising anticancer activity, the compounds display high complex stability in biological media, induces G1 arrest, reactive oxygen stress (ROS) accumulation, and mitochondria membrane depolarization in cancer cells. Furthermore, the compounds induce significant apoptosis.