Biology subjects

Bell, H.

Publications and source records attributed to Bell, H..

4 recordsLinked to original sources

bioRxiv2023

Sulfide oxidation promotes hypoxic angiogenesis and neovascularization

Angiogenic programming in the vascular endothelium is a tightly regulated process to maintain tissue homeostasis and is activated in tissue injury and the tumor microenvironment. The metabolic basis of how gas signaling molecules regulate angiogenesis is elusive. Herein, we report that hypoxic upregulation of NO synthesis in endothelial cells reprograms the transsulfuration pathway and increases H2S biogenesis. Furthermore, H2S oxidation by mitochondrial sulfide quinone oxidoreductase (SQOR) rather than downstream persulfides, synergizes with hypoxia to induce a reductive shift, limiting endothelial cell proliferation that is attenuated by dissipation of the mitochondrial NADH pool. Tumor xenografts in whole-body WBCreSQORfl/fl knockout mice exhibit lower mass and reduced angiogenesis compared to SQORfl/fl controls. WBCreSQORfl/fl mice also exhibit reduced muscle angiogenesis following femoral artery ligation, compared to controls. Collectively, our data reveal the molecular intersections between H2S, O2 and NO metabolism and identify SQOR inhibition as a metabolic vulnerability for endothelial cell proliferation and neovascularization. HighlightsO_LIHypoxic induction of *NO in endothelial cells inhibits CBS and switches CTH reaction specificity C_LIO_LIHypoxic interruption of the canonical transsulfuration pathway promotes H2S synthesis C_LIO_LISynergizing with hypoxia, SQOR deficiency induces a reductive shift in the ETC and restricts proliferation C_LIO_LISQOR KO mice exhibit lower neovascularization in tumor xenograft and hind limb ischemia models C_LI

biochemistry↗

bioRxiv2022

Discovery and molecular basis of chloride as an allosteric activator and catalytic inhibitor for Class-D lactamases.

Oxacillinase (OXA)-48-like carbapenemases are epidemic class D {beta}-lactamases in Enterobacterales, resulting in high mortality. Though the chemical mechanism has been clearly established, for decades, the link between the biphasic kinetic behaviour of these enzymes, which significantly impacts antibiotic efficacy, and the state of carbamylated lysine has been elusive. Here, substituting N-carbamylated lysine73 with a chemically-stable N-acetyl lysine allows us to prove the origin of catalytic inhibition is not decarbamylation and enables us to capture an unprecedented inactive acyl-intermediate wedged in place by a chloride ion against the conserved residue arginine250. We here identify chloride as a "Janus effector" acting by allosteric activation of the burst phase and inhibition of the steady-state for a series of {beta}-lactam substrates in kinetic assays. Chloride ions are necessarily present in both laboratory and clinical OXA activity assays and their inseparable role is now identified. Our finding suggests a new direction for the discovery of next-generation antibiotics specific for {beta}-lactamases of Class D.

biochemistry↗

bioRxiv2022

Microenvironmental Ammonia Enhances T cell Exhaustion in Colorectal Cancer

Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and unbiased multi-omic analyses in this model reveals a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion and decrease proliferation. CRC patients have increased serum ammonia, and our ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. Our findings indicate that ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies. Statement of SignificanceWe demonstrate that ammonia accumulates in the microenvironment of colorectal cancer. Ammonia alters T-cells redox singling leading to a decrease in T cell proliferation and an increase in T cell exhaustion. Enhancing ammonia clearance reduces tumor size, increases survival, and increases the efficacy to immunotherapies.

cancer biology↗

bioRxiv2020

Microbiota metabolic exchange is critical for colorectal cancer redox homeostasis and growth

Intestinal microbiota play a fundamental role in human health and disease. Microbial dysbiosis is a hallmark of colorectal cancer (CRC) as tumor stage-specific shifts potentiate tumor growth, influence the inflammatory microenvironment, and alter response to therapy. Recent work has demonstrated a critical role for microbial metabolite exchange in host response. However, the role of most microbial metabolites in colon cancer growth is unclear. To better understand how metabolic exchange between the microbiota and tumor epithelium alter CRC growth, a screen of the most abundant bacterially derived metabolites was assessed. Several metabolites were found to alter CRC growth, but reuterin most significantly suppressed CRC cell proliferation. Reuterin is a bifunctional metabolite containing both hydroxy and aldehyde functional groups. Reuterin is primarily synthesized from glycerol by Lactobacillus reuteri, a commensal bacterium found throughout the gastrointestinal tract. We found that reuterin suppresses growth via alterations to the redox balance of CRC cells. Mechanistically, reuterin potentiates reactive oxygen species (ROS) which leads to irreversible cysteine oxidation and enhanced cell death. Supplementation of either antioxidants or hydrogen sulfide fully rescued growth, suggesting that reuterin is suppressing CRC growth through protein oxidation. These studies demonstrate the potential of reuterin to act as a potent chemotherapeutic for treating colorectal cancers.

cancer biology↗