The astrocytic zinc transporter ZIP12 is a synaptic protein that contributes to synaptic zinc levels in mouse auditory cortex.

Synaptically released zinc is a neuronal signaling system that arises from the actions of the presynaptic vesicular zinc transporter protein ZnT3. Mechanisms that regulate the actions of zinc at synapses are of great importance for many aspects of synaptic signaling in the brain. Here, we identify the astrocytic zinc transporter protein ZIP12 as a candidate mechanism that contributes to zinc clearance at cortical synapses.

Poststroke hyperglycemia dysregulates cap-dependent translation in neural cells.

Aims: Post stroke hyperglycemia has been shown to deter functional recovery. Earlier findings have indicated the cap-dependent translation regulator 4E-BP1 is detrimentally upregulated in hyperglycemic conditions. The present study aims to test the hypothesis that hyperglycemic ischemic reperfusion injury (I/R) affects normal protein translation poststroke.

Loss of the mitochondrial protein mitoNEET in mice is associated with cognitive impairments and increased neuroinflammation.

Background: Mitochondrial dysfunction is implicated in several neurodegenerative diseases associated with memory and cognitive deficits, including Alzheimer's disease. Changes in bioenergetic function results in reactive oxygen species, oxidative damage and consequently neuroinflammation, which contributes to neuronal cell loss.

Objective: In this study, we evaluated the impact of the loss of the redox active [2Fe-2S] mitochondrial-associated protein mitoNEET (CISD1) on neuroinflammation and cognition using an age-appropriate preclinical model.

Synthesis and evaluation of enzyme inhibition by novel TT01001 derivatives as monoamine oxidase B inhibitors.

Monoamine oxidase (MAO) B is a promising target for treating stroke reperfusion injury, Parkinson's disease as well as other neurodegenerative diseases. Pharmacological inhibitors of this enzyme have demonstrated the ability to modulate critical neurotransmitter levels, decrease damaging reactive oxygen species and neuroinflammation, and improve mitochondrial dysfunction. We identified TT01001 from a pilot screen which showed good potency for inhibiting MAO-B, with a half-maximal inhibitory concentration below 10 μM.

Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts.

: Breast cancer (BC) is the second most commonly diagnosed cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle.

Preclinical evaluation of ELP-004 in mice.

This study provides a detailed understanding of the preclinical pharmacokinetics and metabolism of ELP-004, an osteoclast inhibitor in development for the treatment of bone erosion. Current treatments for arthritis, including biological disease-modifying antirheumatic drugs, are not well-tolerated in a substantial subset of arthritis patients and are expensive; therefore, new treatments are needed. Pharmacokinetic parameters of ELP-004 were tested with intravenous, oral, and subcutaneous administration and found to be rapidly absorbed and distributed.

Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts.

Unlabelled: Breast cancer (BC) is the most prevalent cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle.

Flash nanoprecipitation assisted self-assembly of ionizable lipid nanoparticles for nucleic acid delivery.

Ionizable lipid nanoparticles (LNPs) have emerged as a powerful tool for the intracellular delivery of nucleic acids. Following the recent success of LNP-based siRNA therapeutics and mRNA vaccines, the use of ionizable lipids for nucleic acid delivery has tremendously increased. Here, we introduce a flash nanoprecipitation (FNP) approach using the confined impingement (CIJ) mixer to stably self-assemble ionizable LNPs.

Targeting myeloperoxidase limits myeloid cell immunosuppression enhancing immune checkpoint therapy for pancreatic cancer.

Pancreatic ductal adenocarcinoma is a devastating disease characterized by an extreme resistance to current therapies, including immune checkpoint therapy. The limited success of immunotherapies can be attributed to a highly immunosuppressive pancreatic cancer microenvironment characterized by an extensive infiltration of immune suppressing myeloid cells. While there are several pathways through which myeloid cells contribute to immunosuppression, one important mechanism is the increased production of reactive oxygen species.

Flash nanoprecipitation allows easy fabrication of pH-responsive acetalated dextran nanoparticles for intracellular release of payloads.

Acetalated dextran (Ac-Dex) nanoparticles are currently of immense interest due to their sharp pH-responsive nature and high biodegradability. Ac-Dex nanoparticles are often formulated through single- or double-emulsion methods utilizing polyvinyl alcohol as the stabilizer. The emulsion methods utilize toxic organic solvents such as dichloromethane or chloroform and require multi-step processing to form stable Ac-Dex nanoparticles.

SOX71, A Biocompatible Succinyl Derivative of the Triarylmethyl Radical OX071 for In Vivo Quantitative Oxygen Mapping Using Electron Paramagnetic Resonance.

Purpose: This study aimed to develop a biocompatible oximetric electron paramagnetic resonance (EPR) spin probe with reduced self-relaxation, and sensitivity to oxygen for a higher signal-to-noise ratio and longer relaxation times at high oxygen concentration, compared to the reference spin probe OX071.

Procedures: SOX71 was synthesized by succinylation of the twelve alcohol groups of OX071 spin probe and characterized by EPR at X-Band (9.5 GHz) and at low field (720 MHz).

Cancer-associated somatic mutations in human phosphofructokinase-1 reveal a critical electrostatic interaction for allosteric regulation of enzyme activity.

Metabolic reprogramming, including increased glucose uptake and lactic acid excretion, is a hallmark of cancer. The glycolytic 'gatekeeper' enzyme phosphofructokinase-1 (PFK1), which catalyzes the step committing glucose to breakdown, is dysregulated in cancers. While altered PFK1 activity and expression in tumors have been demonstrated, little is known about the effects of cancer-associated somatic mutations.

Role of cytochrome P450-epoxygenase and soluble epoxide hydrolase in the regulation of vascular response.

The role of cytochrome P450-epoxygenase has been seen in cardiovascular physiology and pathophysiology. The aberration in CYP450-epoxygenase genes occur due to genetic polymorphisms, aging, or environmental factors, that increase susceptibility to cardiovascular diseases (CVDs). The actual role played by the CYP450-epoxygenases is the metabolism of arachidonic acid (AA) and linoleic acid (LA) into epoxyeicosatrienoic acids (EETs) and epoxyoctadecaenoic acid (EpOMEs) metabolites (oxylipins) and others, which is involved in vasodilation and myocardial-protection.

Development of a fluorescence screening assay for binding partners of the iron-sulfur mitochondrial protein mitoNEET.

MitoNEET belongs to the CDGSH Iron-Sulfur Domain (CISD)-gene family of proteins and is a [2Fe-2S] cluster-containing protein found on the outer membrane of mitochondria. The specific functions of mitoNEET/CISD1 remain to be fully elucidated, but the protein is involved in regulating mitochondrial bioenergetics in several metabolic diseases. Unfortunately, drug discovery efforts targeting mitoNEET to improve metabolic disorders are hampered by the lack of ligand-binding assays for this mitochondrial protein.

Biochemical Control of the Mitochondrial Protein MitoNEET by Biological Thiols and Lipid-derived Electrophiles.

MitoNEET is a mitochondrial [2Fe-2S] protein known for its involvement in cellular metabolism, iron regulation, and oxidative stress. The protein has been associated with diseases ranging from diabetes to Parkinson's disease which has prompted development of compounds designed to selectively target mitoNEET. Unfortunately, drug development is limited due to a lack of understanding on the mechanistic level how mitoNEET integrates into pathophysiological processes.

Release of hepatic xanthine oxidase (XO) to the circulation is protective in intravascular hemolytic crisis.

Xanthine oxidase (XO) catalyzes the catabolism of hypoxanthine to xanthine and xanthine to uric acid, generating oxidants as a byproduct. Importantly, XO activity is elevated in numerous hemolytic conditions including sickle cell disease (SCD); however, the role of XO in this context has not been elucidated. Whereas long-standing dogma suggests elevated levels of XO in the vascular compartment contribute to vascular pathology via increased oxidant production, herein, we demonstrate, for the first time, that XO has an unexpected protective role during hemolysis.

Chemotherapeutic Activity of Pitavastatin in Vincristine Resistant B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells.

Chloroquine reduces neutrophil extracellular trap (NET) formation through inhibition of peptidyl arginine deiminase 4 (PAD4).

Neutrophil extracellular traps (NETs) occur when chromatin is decondensed and extruded from the cell, generating a web-like structure. NETs have been implicated in the pathogenesis of several sterile disease states and thus are a potential therapeutic target. Various pathways have been shown to induce NETs, including autophagy, with several key enzymes being activated like peptidyl arginine deiminase 4 (PAD4), an enzyme responsible for citrullination of histones, allowing for DNA unwinding and subsequent release from the cell.

Structure and biological evaluation of CISD-1/mitoNEET, a KLP-17 tail domain homologue, supports attenuation of paraquat-induced oxidative stress through a p38 MAPK-mediated antioxidant defense response.

CISD-1/mitoNEET is an evolutionarily conserved outer mitochondrial membrane [2Fe-2S] protein that regulates mitochondrial function and morphology. The [2Fe-2S] clusters are redox reactive and shown to mediate oxidative stress and . However, there is limited research studying CISD-1/mitoNEET mediation of oxidative stress in response to environmental stressors.

The Mitochondrial Protein MitoNEET as a Probe for the Allostery of Glutamate Dehydrogenase.

The proteins glutamate dehydrogenase (GDH) and mitoNEET are both targets of drug development efforts to treat metabolic disorders, cancer, and neurodegenerative diseases. However, these two proteins differ starkly in the current knowledge about ligand binding sites. MitoNEET is a [2Fe-2S]-containing protein with no obvious binding site for small ligands observed in its crystal structures.

Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.

Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations.

MitoNEET's Reactivity of Lys55 toward Pyridoxal Phosphate Demonstrates its Activity as a Transaminase Enzyme.

MitoNEET is a [2Fe-2S] redox active mitochondrial protein belonging to the CDGSH iron-sulfur domain (CISD) family of proteins. MitoNEET has been implicated as a potential target for drug development to treat various disorders, including type-2 diabetes, cancer, and Parkinson's disease. However, the specific cellular function(s) for mitoNEET still remains to be fully elucidated, and this presents a significant roadblock in rational drug development.

Interphotoreceptor matrix proteoglycans IMPG1 and IMPG2 proteolyze in the SEA domain and reveal localization mutual dependency.

The interphotoreceptor matrix (IPM) is a specialized extracellular mesh of molecules surrounding the inner and outer segments of photoreceptor neurons. Interphotoreceptor matrix proteoglycan 1 and 2 (IMPG1 and IMPG2) are major components of the IPM. Both proteoglycans possess SEA (sperm protein, enterokinase and agrin) domains, which may support proteolysis.

Targeting Oxidative Stress Involved in Endometriosis and Its Pain.

Endometriosis is a common gynecological disorder seen in women and is characterized by chronic pelvic pain and infertility. This disorder is becoming more prevalent with increased morbidity. The etiology of endometriosis remains to be fully elucidated, which will lead to improved therapeutic options.

Identification of Natural Product Sulfuretin Derivatives as Inhibitors for the Endoplasmic Reticulum Redox Protein ERO1α.

The flavin adenine dinucleotide containing Endoplasmic Reticulum Oxidoreductase-1 α (ERO1α) catalyzes the formation of disulfide bond formation of secretory and transmembrane proteins and contributes towards proper protein folding. Recently, increased ERO1α expression has been shown to contribute to increased tumor growth and metastasis in multiple cancer types. In this report we sought to define novel chemical space for targeting ERO1α function.