-
Current Rheumatology Reports Aug 2023This article aims to review the challenges to diagnosis and management of calcium crystal deposition diseases and evaluate the literature published over the past 3 years. (Review)
Review
PURPOSE OF REVIEW
This article aims to review the challenges to diagnosis and management of calcium crystal deposition diseases and evaluate the literature published over the past 3 years.
RECENT FINDINGS
The awaited development of classification criteria is an essential step in the progression of calcium crystal deposition disease clinical research. There have been recent improvements in the accuracy of imaging for the diagnosis of crystal deposition diseases with published definitions of characteristic features. Factors associated with acute flares of disease have been identified and an association with increased cardiovascular risk has been demonstrated. Targeted treatment options for calcium crystal diseases remain elusive. However, there have been advances in understanding the molecular mechanisms of disease revealing potential targets for future drug development. Calcium-crystal deposition diseases are increasing in incidence and prevalence as populations age and continue to associate with a high burden of disability. Despite this, calcium crystal deposition disease remains under-studied with a paucity of evidence-based treatment guidelines.
Topics: Humans; Chondrocalcinosis; Calcium; Calcium Pyrophosphate
PubMed: 37249830
DOI: 10.1007/s11926-023-01106-9 -
Chemical Reviews Oct 2022Glycoconjugates are major constituents of mammalian cells that are formed covalent conjugation of carbohydrates to other biomolecules like proteins and lipids and often... (Review)
Review
Glycoconjugates are major constituents of mammalian cells that are formed covalent conjugation of carbohydrates to other biomolecules like proteins and lipids and often expressed on the cell surfaces. Among the three major classes of glycoconjugates, proteoglycans and glycoproteins contain glycans linked to the protein backbone amino acid residues such as Asn for -linked glycans and Ser/Thr for -linked glycans. In glycolipids, glycans are linked to a lipid component such as glycerol, polyisoprenyl pyrophosphate, fatty acid ester, or sphingolipid. Recently, glycoconjugates have become better structurally defined and biosynthetically understood, especially those associated with human diseases, and are accessible to new drug, diagnostic, and therapeutic developments. This review describes the status and new advances in the biological study and therapeutic applications of natural and synthetic glycoconjugates, including proteoglycans, glycoproteins, and glycolipids. The scope, limitations, and novel methodologies in the synthesis and clinical development of glycoconjugates including vaccines, glyco-remodeled antibodies, glycan-based adjuvants, glycan-specific receptor-mediated drug delivery platforms, ., and their future prospectus are discussed.
Topics: Animals; Humans; Diphosphates; Glycerol; Glycoconjugates; Glycoproteins; Carbohydrates; Polysaccharides; Glycolipids; Vaccines; Proteoglycans; Sphingolipids; Amino Acids; Fatty Acids; Esters; Mammals
PubMed: 36174107
DOI: 10.1021/acs.chemrev.1c01032 -
Cell Reports Dec 2022DNA damage leads to rapid synthesis of poly(ADP-ribose) (pADPr), which is important for damage signaling and repair. pADPr chains are removed by poly(ADP-ribose)...
DNA damage leads to rapid synthesis of poly(ADP-ribose) (pADPr), which is important for damage signaling and repair. pADPr chains are removed by poly(ADP-ribose) glycohydrolase (PARG), releasing free mono(ADP-ribose) (mADPr). Here, we show that the NUDIX hydrolase NUDT5, which can hydrolyze mADPr to ribose-5-phosphate and either AMP or ATP, is recruited to damage sites through interaction with PARG. NUDT5 does not regulate PARP or PARG activity. Instead, loss of NUDT5 reduces basal cellular ATP levels and exacerbates the decrease in cellular ATP that occurs during DNA repair. Further, loss of NUDT5 activity impairs RAD51 recruitment, attenuates the phosphorylation of key DNA-repair proteins, and reduces both H2A.Z exchange at damage sites and repair by homologous recombination. The ability of NUDT5 to hydrolyze mADPr, and/or regulate cellular ATP, may therefore be important for efficient DNA repair. Targeting NUDT5 to disrupt PAR/mADPr and energy metabolism may be an effective anti-cancer strategy.
Topics: Adenosine Diphosphate Ribose; DNA Repair; Poly Adenosine Diphosphate Ribose; Glycoside Hydrolases; DNA Damage; Adenosine Triphosphate
PubMed: 36543120
DOI: 10.1016/j.celrep.2022.111866 -
Cellular Microbiology Jun 2021Inositol polyphosphates (IPs) and inositol pyrophosphates (PP-IPs) regulate diverse cellular processes in eukaryotic cells. IPs and PP-IPs are highly negatively charged... (Review)
Review
Inositol polyphosphates (IPs) and inositol pyrophosphates (PP-IPs) regulate diverse cellular processes in eukaryotic cells. IPs and PP-IPs are highly negatively charged and exert their biological effects by interacting with specific protein targets. Studies performed predominantly in mammalian cells and model yeasts have shown that IPs and PP-IPs modulate target function through allosteric regulation, by promoting intra- and intermolecular stabilization and, in the case of PP-IPs, by donating a phosphate from their pyrophosphate (PP) group to the target protein. Technological advances in genetics have extended studies of IP function to microbial pathogens and demonstrated that disrupting PP-IP biosynthesis and PP-IP-protein interaction has a profound impact on pathogenicity. This review summarises the complexity of IP-mediated regulation in eukaryotes, including microbial pathogens. It also highlights examples of poor conservation of IP-protein interaction outcome despite the presence of conserved IP-binding domains in eukaryotic proteomes.
Topics: Bacteria; Diphosphates; Eukaryotic Cells; Humans; Inositol; Polyphosphates; Protein Interaction Maps; Proteome; Virulence
PubMed: 33721399
DOI: 10.1111/cmi.13325 -
Best Practice & Research. Clinical... Dec 2021This review highlights outcomes for patients with calcium pyrophosphate deposition (CPPD) reported in prior studies and underscores challenges to assessing outcomes of... (Review)
Review
This review highlights outcomes for patients with calcium pyrophosphate deposition (CPPD) reported in prior studies and underscores challenges to assessing outcomes of this condition. Prior clinical studies of interventions for CPPD focused on joint damage and calcification on imaging tests, joint pain, swelling, and inflammatory biomarkers. Qualitative interviews with patients with CPPD and healthcare providers additionally identified flares, overall function, and use of analgesic medications as important outcomes. Imaging evidence of joint damage and calcification is likely to be outcomes in future clinical studies of CPPD, though reliability and sensitivity to change in CPPD require further testing for several imaging modalities. Challenges to outcome measurement in CPPD include questions of attribution of signs and symptoms to CPPD versus co-existing forms of arthritis, lack of therapies to prevent or dissolve calcium pyrophosphate crystal deposition, absence of validated patient- or physician-reported CPPD outcome measures, and scarcity of large cohorts in which to study outcomes of different clinical presentations of CPPD.
Topics: Calcium Pyrophosphate; Chondrocalcinosis; Humans; Outcome Assessment, Health Care; Reproducibility of Results
PubMed: 34799278
DOI: 10.1016/j.berh.2021.101724 -
Accounts of Chemical Research Oct 2021The magnificent chemodiversity of more than 95 000 terpenoid natural products identified to date largely originates from catalysis by two types of terpene synthases,... (Review)
Review
The magnificent chemodiversity of more than 95 000 terpenoid natural products identified to date largely originates from catalysis by two types of terpene synthases, prenyltransferases and cyclases. Prenyltransferases utilize 5-carbon building blocks in processive chain elongation reactions to generate linear C isoprenoid diphosphates ( ≥ 2), which in turn serve as substrates for terpene cyclases that convert these linear precursors into structurally complex hydrocarbon products containing multiple rings and stereocenters. Terpene cyclization reactions are the most complex organic transformations found in nature in that more than half of the substrate carbon atoms undergo changes in chemical bonding during a multistep reaction sequence proceeding through several carbocation intermediates. Two general classes of cyclases are established on the basis of the chemistry of initial carbocation formation, and structural studies from our laboratory and others show that three fundamental protein folds designated α, β, and γ govern this chemistry. Catalysis by a class I cyclase occurs in an α domain, where a trinuclear metal cluster activates the substrate diphosphate leaving group to generate an allylic cation. Catalysis by a class II cyclase occurs in a β domain or at the interface of β and γ domains, where an aspartic acid protonates the terminal π bond of the substrate to yield a tertiary carbocation. Crystal structures reveal domain architectures of α, αβ, αβγ, βγ, and β.In some terpene synthases, these domains are combined to yield bifunctional enzymes that catalyze successive biosynthetic steps in assembly line fashion. Structurally characterized examples include bacterial geosmin synthase, an αα domain enzyme that catalyzes a class I cyclization reaction of C farnesyl diphosphate in one active site and a transannulation-fragmentation reaction in the other to yield C geosmin and C acetone products. In comparison, plant abietadiene synthase is an αβγ domain enzyme in which C geranylgeranyl diphosphate undergoes tandem class II-class I cyclization reactions to yield the tricyclic product. Recent structural studies from our laboratory show that bifunctional fungal cyclases form oligomeric complexes for assembly line catalysis. Bifunctional (+)-copalyl diphosphate synthase adopts (αβγ) architecture in which the α domain generates geranylgeranyl diphosphate, which then undergoes class II cyclization in the βγ domains to yield the bicyclic product. Bifunctional fusicoccadiene synthase adopts (αα) or (αα) architecture in which one α domain generates geranylgeranyl diphosphate, which then undergoes class I cyclization in the other α domain to yield the tricyclic product. The prenyltransferase α domain mediates oligomerization in these systems. Attached by flexible polypeptide linkers, cyclase domains splay out from oligomeric prenyltransferase cores.In this Account, we review structure-function relationships for these bifunctional terpene synthases, with a focus on the oligomeric systems studied in our laboratory. The observation of substrate channeling for fusicoccadiene synthase suggests a model for dynamic cluster channeling in catalysis by oligomeric assembly line terpenoid synthases. Resulting efficiencies in carbon management suggest that such systems could be particularly attractive for use in synthetic biology approaches to generate high-value terpenoid natural products.
Topics: Alkyl and Aryl Transferases; Biocatalysis; Humans; Models, Molecular
PubMed: 34254507
DOI: 10.1021/acs.accounts.1c00296 -
Journal of Plant Physiology Jan 2023Free magnesium (Mg) represents a powerful signal arising from interconversions of adenylates (ATP, ADP and AMP). This is a consequence of the involvement of adenylate... (Review)
Review
Free magnesium (Mg) represents a powerful signal arising from interconversions of adenylates (ATP, ADP and AMP). This is a consequence of the involvement of adenylate kinase (AK) which equilibrates adenylates and uses defined species of Mg-complexed and Mg-free adenylates in both directions of its reaction. However, cells contain also other reversible Mg-dependent enzymes that equilibrate non-adenylate nucleotides (uridylates, cytidylates and guanylates), i.e. nucleoside monophosphate kinases (NMPKs) and nucleoside diphosphate kinase (NDPK). Here, we propose that AK activity is tightly coupled to activities of NMPK and NDPK, linking adenylate equilibrium to equilibria of other nucleotides, and with [Mg] controlling the ratios of Mg-chelated and Mg-free nucleotides. This coupling establishes main hubs for adenylate-driven equilibration of non-adenylate nucleotides, with [Mg] acting as signal arising from all nucleotides rather than adenylates only. Further consequences involve an overall adenylate control of UTP-, GTP- and CTP-dependent pathways and the availability of substrates for RNA and DNA synthesis.
Topics: Nucleotides; Magnesium; Adenosine Monophosphate; Adenylate Kinase; Nucleoside-Diphosphate Kinase; Adenosine Triphosphate; Adenosine Diphosphate
PubMed: 36549033
DOI: 10.1016/j.jplph.2022.153901 -
JAMA Oncology Sep 2022Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer...
IMPORTANCE
Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC.
OBJECTIVE
To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC.
DESIGN, SETTINGS, AND PARTICIPANTS
This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies.
INTERVENTIONS
Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects.
MAIN OUTCOMES AND MEASURES
Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity.
RESULTS
Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit.
CONCLUSIONS AND RELEVANCE
The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02912572.
Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; B7-H1 Antigen; DNA Mismatch Repair; Diphosphates; Endometrial Neoplasms; Female; Humans; Immune Checkpoint Inhibitors; Ligands; Neoplasm Recurrence, Local; Phthalazines; Ribose
PubMed: 35900726
DOI: 10.1001/jamaoncol.2022.2181 -
Neuropharmacology Nov 2023Uridine 5'-diphosphoglucose (UDP-G) as a preferential agonist, but also other UDP-sugars, such as UDP galactose, function as extracellular signaling molecules under... (Review)
Review
Uridine 5'-diphosphoglucose (UDP-G) as a preferential agonist, but also other UDP-sugars, such as UDP galactose, function as extracellular signaling molecules under conditions of cell injury and apoptosis. Consequently, UDP-G is regarded to function as a damage-associated molecular pattern (DAMP), regulating immune responses. UDP-G promotes neutrophil recruitment, leading to the release of pro-inflammatory chemokines. As a potent endogenous agonist with the highest affinity for the P2Y receptor (R), it accomplishes an exclusive relationship between P2YRs in regulating inflammation via cyclic adenosine monophosphate (cAMP), nod-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinases (MAPKs), and signal transducer and activator of transcription 1 (STAT1) pathways. In this review, we initially present a brief introduction into the expression and function of P2YRs in combination with UDP-G. Subsequently, we summarize emerging roles of UDP-G/P2YR signaling pathways that modulate inflammatory responses in diverse systems, and discuss the underlying mechanisms of P2YR activation in inflammation-related diseases. Moreover, we also refer to the applications as well as effects of novel agonists/antagonists of P2YRs in inflammatory conditions. In conclusion, due to the role of the P2YR in the immune system and inflammatory pathways, it may represent a novel target for anti-inflammatory therapy.
Topics: Humans; Receptors, Purinergic P2; Uridine Diphosphate Glucose; Uridine Diphosphate Sugars; Inflammation; Glucose
PubMed: 37423482
DOI: 10.1016/j.neuropharm.2023.109655 -
Microbiology (Reading, England) Dec 2020Nudix proteins catalyse hydrolysis of pyrophosphate bonds in a variety of substrates and are ubiquitous in all domains of life. Their widespread presence and broad... (Review)
Review
Nudix proteins catalyse hydrolysis of pyrophosphate bonds in a variety of substrates and are ubiquitous in all domains of life. Their widespread presence and broad substrate specificity suggest that they have important cellular functions. In this review, we summarize the state of knowledge on microbial Nudix proteins involved in pathogenesis.
Topics: Amino Acid Sequence; Bacterial Proteins; Diphosphates; Pyrophosphatases; Sequence Alignment; Viral Proteins; Virulence; Virulence Factors; Nudix Hydrolases
PubMed: 33253082
DOI: 10.1099/mic.0.000993