Publications by authors named "Lowther W"

Hyperoxaluria is a condition in which there is a pathologic abundance of oxalate in the urine through either hepatic overproduction (primary hyperoxaluria [PH]) or excessive enteric absorption of dietary oxalate (enteric hyperoxaluria [EH]). Severity can vary with the most severe forms causing kidney failure and extrarenal manifestations. To address the current challenges and innovations in hyperoxaluria, the 14th International Hyperoxaluria Workshop convened in Perugia, Italy, bringing together international experts for focused presentation and discussion.

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Cannabinoid receptor interacting protein 1a (CRIP1a) modulates CB cannabinoid receptor G-protein coupling in part by altering the selectivity for Gα subtype activation, but the molecular basis for this function of CRIP1a is not known. We report herein the first structure of CRIP1a at a resolution of 1.55 Å.

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Article Synopsis
  • Glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) are key targets for treating primary hyperoxaluria (PH) as they contribute to oxalate production.
  • A research team designed novel dual inhibitors targeting both GO and LDHA to potentially enhance treatment effectiveness over individual drugs.
  • Despite the inhibitors showing promise in laboratory assays, they struggled with liver exposure, limiting the potential benefits of using them together compared to single-agent treatments.
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Human peroxiredoxins (Prx) are a family of antioxidant enzymes involved in a myriad of cellular functions and diseases. During the reaction with peroxides (e.g.

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Article Synopsis
  • Tumorigenesis is associated with increased mitochondrial reactive oxygen species (mROS), prompting cancer cells to enhance their antioxidant defenses and redox signaling pathways.
  • *Thiostrepton (TS) targets mitochondrial peroxiredoxin 3 (PRX3), an enzyme that detoxifies hydrogen peroxide, by modifying its key cysteine residues, leading to PRX3 inactivation.
  • *Studies show that PRX3 expression and mROS levels correlate with sensitivity to TS in malignant mesothelioma, indicating that PRX3's structural properties make it a promising target for therapies that increase prooxidants in cancer cells.
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(Ct) is a bacterial intracellular pathogen responsible for a plethora of diseases ranging from blindness to pelvic inflammatory diseases and cervical cancer. Although this disease is effectively treated with antibiotics, concerns for development of resistance prompt the need for new low-cost treatments. Here we report the activity of spilanthol (SPL), a natural compound with demonstrated anti-inflammatory properties, against Ct infections.

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Endocannabinoid signaling depends upon the CB and CB cannabinoid receptors, their endogenous ligands anandamide and 2-arachidonoylglycerol, and intracellular proteins that mediate responses via the C-terminal and other intracellular receptor domains. The CB receptor regulates and is regulated by associated G proteins predominantly of the Gi/o subtypes, β-arrestins 1 and 2, and the cannabinoid receptor-interacting protein 1a (CRIP1a). Evidence for a physiological role for CRIP1a is emerging as data regarding the cellular localization and function of CRIP1a are generated.

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Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association.

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The major clinical manifestation of the Primary Hyperoxalurias (PH) is increased production of oxalate, as a consequence of genetic mutations that lead to aberrant glyoxylate and hydroxyproline metabolism. Hyperoxaluria can lead to the formation of calcium-oxalate kidney stones, nephrocalcinosis and renal failure. Current therapeutic approaches rely on organ transplants and more recently modifying the pathway of oxalate synthesis using siRNA therapy.

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Cannabinoid receptor interacting protein 1a (CRIP1a) is an important CB cannabinoid receptor-associated protein, first identified from a yeast two-hybrid screen to modulate CB-mediated N-type Ca currents. In this paper we review studies of CRIP1a function and structure based upon in vitro experiments and computational chemistry, which elucidate the specific mechanisms for the interaction of CRIP1a with CB receptors. N18TG2 neuronal cells overexpressing or silencing CRIP1a highlighted the ability of CRIP1 to regulate cyclic adenosine 3',5'monophosphate (cAMP) production and extracellular signal-regulated kinase (ERK1/2) phosphorylation.

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Peroxiredoxins (Prx) are enzymes that efficiently reduce hydroperoxides through active participation of cysteine residues (C, C). The first step in catalysis, the reduction of peroxide substrate, is fast, 10 - 10 Ms for human Prx2. In addition, the high intracellular concentration of Prx positions them not only as good antioxidants but also as central players in redox signaling pathways.

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To prevent the accumulation of reactive oxygen species and limit associated damage to biological macromolecules, cells express a variety of oxidant-detoxifying enzymes, including peroxiredoxins. In Saccharomyces cerevisiae, the peroxiredoxin Tsa1 plays a key role in peroxide clearance and maintenance of genome stability. Five homodimers of Tsa1 can assemble into a toroid-shaped decamer, with the active sites in the enzyme being shared between individual dimers in the decamer.

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Peroxiredoxins have a long-established cellular function as regulators of redox metabolism by catalyzing the reduction of peroxides (e.g., H₂O₂, lipid peroxides) with high catalytic efficiency.

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Cysteine sulfinic acid or S-sulfinylation is an oxidative post-translational modification (OxiPTM) that is known to be involved in redox-dependent regulation of protein function but has been historically difficult to analyze biochemically. To facilitate the detection of S-sulfinylated proteins, we demonstrate that a clickable, electrophilic diazene probe (DiaAlk) enables capture and site-centric proteomic analysis of this OxiPTM. Using this workflow, we revealed a striking difference between sulfenic acid modification (S-sulfenylation) and the S-sulfinylation dynamic response to oxidative stress, which is indicative of different roles for these OxiPTMs in redox regulation.

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2-Cys peroxiredoxins (Prxs) modulate hydrogen peroxide (HO)-mediated cell signaling. At high HO levels, eukaryotic Prxs can be inactivated by hyperoxidation and are classified as sensitive Prxs. In contrast, prokaryotic Prxs are categorized as being resistant to hyperoxidation and lack the GGLG and C-terminal YF motifs present in the sensitive Prxs.

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Article Synopsis
  • Endogenous oxalate synthesis is a key factor in calcium oxalate stone disease, particularly in inherited conditions like primary hyperoxaluria (PH), but its mechanisms are not fully understood.
  • A study involving 28 participants measured how hydroxyproline (Hyp) metabolism contributes to the formation of oxalate and glycolate through intravenous infusions, revealing significant differences between healthy individuals and those with various types of PH.
  • Results showed that Hyp metabolism is a significant source of urinary oxalate in individuals with PH, especially PH2 and PH3; however, the main sources of oxalate in PH1 patients remain unidentified.
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The selective reaction of chemical reagents with reduced protein thiols is critical to biological research. This reaction is utilized to prevent cross-linking of cysteine-containing peptides in common proteomics workflows and is applied widely in discovery and targeted redox investigations of the mechanisms underlying physiological and pathological processes. However, known and commonly used thiol blocking reagents like iodoacetamide, N-ethylmaleimide, and others were found to cross-react with oxidized protein sulfenic acids (-SOH) introducing significant errors in studies employing these reagents.

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Article Synopsis
  • CRIP1a interacts with cannabinoid receptors (CBRs) and influences how these receptors interact with G-proteins and β-arrestin proteins.
  • Coimmunoprecipitation studies show that CRIP1a and β-arrestin cannot bind simultaneously to the CBR, indicating they compete for the same binding sites.
  • Overexpressing CRIP1a reduces the redistribution of β-arrestin during receptor internalization, while knocking it down increases β-arrestin activity, suggesting that CRIP1a plays a key role in regulating CBR internalization through its interaction with β-arrestin.
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Fatty acid synthase (FASN), the enzyme that catalyzes de novo synthesis of fatty acids, is expressed in many cancer types. Its potential as a therapeutic target is well recognized, but inhibitors of FASN have not yet been approved for cancer therapy. Orlistat (ORL), an FDA-approved lipase inhibitor, is also an effective inhibitor of FASN.

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Article Synopsis
  • FASN is crucial for synthesizing palmitate, with its expression elevated in cancer, and its activity modulated by various mechanisms.
  • The type II thioesterase TE2 influences fatty acid chain length and has links to breast cancer, but competing interactions with the type I thioesterase TE1 are not well understood.
  • Recent findings reveal the structural differences between TE1 and TE2, with TE2 having a unique capping domain that impacts its catalytic functionality, leading to the release of shorter fatty acids during synthesis.
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Mammalian 2-cysteine peroxiredoxins (Prxs) are susceptible to hyperoxidation by excess H2O2. The cytoplasmic family member Prx2 hyperoxidizes more readily than mitochondrial Prx3 due to slower dimerization of the sulfenic acid (SpOH) intermediate. Four variant amino acids near the C-terminus have been shown to contribute to this difference.

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Dysregulation of signaling pathways and energy metabolism in cancer cells enhances production of mitochondrial hydrogen peroxide that supports tumorigenesis through multiple mechanisms. To counteract the adverse effects of mitochondrial peroxide many solid tumor types up-regulate the mitochondrial thioredoxin reductase 2--thioredoxin 2 (TRX2)--peroxiredoxin 3 (PRX3) antioxidant network. Using malignant mesothelioma cells as a model, we show that thiostrepton (TS) irreversibly disables PRX3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase TRX2 with the triphenylmethane gentian violet (GV) potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers.

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The primary hyperoxalurias (PH), types 1-3, are disorders of glyoxylate metabolism that result in increased oxalate production and calcium oxalate stone formation. The breakdown of trans-4-hydroxy-L-proline (Hyp) from endogenous and dietary sources of collagen makes a significant contribution to the cellular glyoxylate pool. Proline dehydrogenase 2 (PRODH2), historically known as hydroxyproline oxidase, is the first step in the hydroxyproline catabolic pathway and represents a drug target to reduce the glyoxylate and oxalate burden of PH patients.

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Peroxiredoxins (Prxs) detoxify peroxides and modulate H2O2-mediated cell signaling in normal and numerous pathophysiological contexts. The typical 2-Cys subclass of Prxs (human Prx1-4) utilizes a Cys sulfenic acid (Cys-SOH) intermediate and disulfide bond formation across two subunits during catalysis. During oxidative stress, however, the Cys-SOH moiety can react with H2O2 to form Cys sulfinic acid (Cys-SO2H), resulting in inactivation.

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Fatty acid desaturase enzymes perform dehydrogenation reactions leading to the insertion of double bonds in fatty acids, and are divided into soluble and integral membrane classes. Crystal structures of soluble desaturases are available; however, membrane desaturases have defied decades of efforts due largely to the difficulty of generating recombinant desaturase proteins for crystallographic analysis. Mortierella alpina is an oleaginous fungus which possesses eight membrane desaturases involved in the synthesis of saturated, monounsaturated and polyunsaturated fatty acids.

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