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International Journal of Molecular... Dec 2021Cardiovascular complications due to accelerated arterial stiffening and atherosclerosis are the leading cause of morbimortality in Western society. Both pathologies are... (Review)
Review
Cardiovascular complications due to accelerated arterial stiffening and atherosclerosis are the leading cause of morbimortality in Western society. Both pathologies are frequently associated with vascular calcification. Pathologic calcification of cardiovascular structures, or vascular calcification, is associated with several diseases (for example, genetic diseases, diabetes, and chronic kidney disease) and is a common consequence of aging. Calcium phosphate deposition, mainly in the form of hydroxyapatite, is the hallmark of vascular calcification and can occur in the medial layer of arteries (medial calcification), in the atheroma plaque (intimal calcification), and cardiac valves (heart valve calcification). Although various mechanisms have been proposed for the pathogenesis of vascular calcification, our understanding of the pathogenesis of calcification is far from complete. However, in recent years, some risk factors have been identified, including high serum phosphorus concentration (hyperphosphatemia) and defective synthesis of pyrophosphate (pyrophosphate deficiency). The balance between phosphate and pyrophosphate, strictly controlled by several genes, plays a key role in vascular calcification. This review summarizes the current knowledge concerning phosphate and pyrophosphate homeostasis, focusing on the role of extracellular pyrophosphate metabolism in aortic smooth muscle cells and macrophages.
Topics: Diphosphates; Humans; Phosphates; Vascular Calcification
PubMed: 34948333
DOI: 10.3390/ijms222413536 -
Best Practice & Research. Clinical... Dec 2021In contrast to gout, no disease-modifying therapies currently exist that reduce articular crystal deposition of calcium pyrophosphate crystals (CPPs). Treatment is aimed... (Review)
Review
In contrast to gout, no disease-modifying therapies currently exist that reduce articular crystal deposition of calcium pyrophosphate crystals (CPPs). Treatment is aimed at ameliorating the inflammatory response and reducing the frequency and severity of clinical symptoms due to CPP deposition (CPPD). Despite being one of the most common forms of inflammatory arthritis, CPPD remains under-studied and evidence-based treatment guidelines remain lacking. Commonly used treatments for clinical manifestations of CPPD (non-steroidal anti-inflammatory drugs [NSAIDs], colchicine and corticosteroids [CSs]) are extrapolated from use in gout. Anakinra and tocilizumab can be used in refractory cases. Though no current crystal-targeted treatments exist, studies suggest that nucleoside analogues and phosphocitrate can attenuate calcification of human cartilage ex-vivo. Hindering research, is the lack of a well-defined description of CPPD. However, international working groups have convened to establish classification criteria and validated outcome domains for CPPD. This should help facilitate the setting up of large multicentre studies, with well-defined cohorts, which can evaluate suitable therapies, providing high levels of evidence to guide clinicians. Here, we summarise and discuss the currently available anti-inflammatory treatment options for CPPD and discuss potential future crystal-targeted approaches.
Topics: Calcium Pyrophosphate; Chondrocalcinosis; Colchicine; Gout; Humans; Joints
PubMed: 34756508
DOI: 10.1016/j.berh.2021.101720 -
Cell Sep 2023Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria....
Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (CPP, lipid II, and lipid III). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.
Topics: Anti-Bacterial Agents; Bacteria; Biological Assay; Diphosphates; Soil Microbiology
PubMed: 37611581
DOI: 10.1016/j.cell.2023.07.038 -
ESC Heart Failure Feb 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the cardiac deposition of insoluble amyloid fibrils formed by misfolded transthyretin proteins and is... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the cardiac deposition of insoluble amyloid fibrils formed by misfolded transthyretin proteins and is associated with various cardiac symptoms, such as progressive heart failure, conduction disturbance, and arrhythmia. The implementation of technetium ( Tc)-labelled bone radiotracer scintigraphy for diagnosing ATTR-CM has enabled accurate diagnosis of the disease with high sensitivity and specificity and positioned this diagnostic modality as an integral part of disease diagnostic algorithms. In 2020, Tc-pyrophosphate scintigraphy received exceptional approval for Japanese national health insurance reimbursement as a diagnostic method of ATTR-CM. Nevertheless, the utility of Tc-labelled bone radiotracer scintigraphy and the importance of an early diagnosis of suspected ATTR-CM using this technique have yet to be internalized as common practice by general cardiologists, and guidance on daily clinical scenarios to consider this technique for a diagnosis of suspected ATTR-CM is warranted. In this review, we discuss the utility of Tc-labelled bone radiotracer scintigraphy for the early diagnosis of ATTR-CM based on published literature and the outcomes of an advisory board meeting. This review also discusses clinical scenarios that could support early diagnosis of suspected ATTR-CM as well as common pitfalls, correct implementation, and future perspectives of Tc-labelled bone radiotracer scintigraphy in daily clinical practice. The clinical scenarios to consider Tc-labelled bone radiotracer scintigraphy in daily practice may include, but are not limited to, patients with a family history of the hereditary type of disease; elderly patients (aged ≥60 years) with unexplained cardiac findings (e.g. cardiac hypertrophy associated with abnormalities on an electrocardiogram, heart failure with preserved ejection fraction associated with unexplained left ventricular hypertrophy, and heart failure with reduced ejection fraction associated with atrial fibrillation and left ventricular hypertrophy); and patients with cardiac hypertrophy associated with diastolic dysfunction, right ventricular/interatrial septum/valve thickness, left ventricular sparkling, or apical sparing. Cardiac hypertrophy and persistent elevation in cardiac troponin in elderly patients are also suggestive of ATTR-CM. Tc-labelled bone radiotracer scintigraphy is also recommended in patients with characteristic cardiac magnetic resonance findings (e.g. diffuse subendocardial late gadolinium enhancement patterns, native T1 increase, and increase in extracellular volume) or patients with cardiac hypertrophy and bilateral carpal tunnel syndrome.
Topics: Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Contrast Media; Diphosphates; Early Diagnosis; Gadolinium; Humans; Middle Aged; Prealbumin; Radionuclide Imaging; Technetium
PubMed: 34841715
DOI: 10.1002/ehf2.13693 -
Arthritis & Rheumatology (Hoboken, N.J.) Oct 2023Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic...
OBJECTIVE
Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease.
METHODS
Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort.
RESULTS
Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers).
CONCLUSION
The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.
Topics: Humans; Calcinosis; Calcium Pyrophosphate; Chondrocalcinosis; Rheumatology; Syndrome; United States
PubMed: 37494275
DOI: 10.1002/art.42619 -
Nature Jun 2022All known triterpenes are generated by triterpene synthases (TrTSs) from squalene or oxidosqualene. This approach is fundamentally different from the biosynthesis of...
All known triterpenes are generated by triterpene synthases (TrTSs) from squalene or oxidosqualene. This approach is fundamentally different from the biosynthesis of short-chain (C-C) terpenes that are formed from polyisoprenyl diphosphates. In this study, two fungal chimeric class I TrTSs, Talaromyces verruculosus talaropentaene synthase (TvTS) and Macrophomina phaseolina macrophomene synthase (MpMS), were characterized. Both enzymes use dimethylallyl diphosphate and isopentenyl diphosphate or hexaprenyl diphosphate as substrates, representing the first examples, to our knowledge, of non-squalene-dependent triterpene biosynthesis. The cyclization mechanisms of TvTS and MpMS and the absolute configurations of their products were investigated in isotopic labelling experiments. Structural analyses of the terpene cyclase domain of TvTS and full-length MpMS provide detailed insights into their catalytic mechanisms. An AlphaFold2-based screening platform was developed to mine a third TrTS, Colletotrichum gloeosporioides colleterpenol synthase (CgCS). Our findings identify a new enzymatic mechanism for the biosynthesis of triterpenes and enhance understanding of terpene biosynthesis in nature.
Topics: Ascomycota; Colletotrichum; Cyclization; Diphosphates; Squalene; Substrate Specificity; Talaromyces; Triterpenes
PubMed: 35650436
DOI: 10.1038/s41586-022-04773-3 -
Radiologic Clinics of North America Jul 2022Crystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints that lead to joint destruction and soft tissue masses. Clinical... (Review)
Review
Imaging of Crystal Disorders:: Calcium Pyrophosphate Dihydrate Crystal Deposition Disease, Calcium Hydroxyapatite Crystal Deposition Disease and Gout Pathophysiology, Imaging, and Diagnosis.
Crystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints that lead to joint destruction and soft tissue masses. Clinical presentation is variable and diagnosis might be challenging. In this article the pathophysiology is addressed, the preferred deposition of crystal arthropathies and imaging findings. Case studies of calcium pyrophosphate dihydrate crystal deposition disease, hydroxyapatite crystal deposition disease, and gout are shown. Guidelines for the use of dual-energy computed tomography are given to enable the diagnosis and follow-up of gout.
Topics: Calcium Pyrophosphate; Chondrocalcinosis; Crystal Arthropathies; Durapatite; Gout; Humans
PubMed: 35672096
DOI: 10.1016/j.rcl.2022.03.007 -
Dental Materials Journal Oct 2022The relative dentin abrasivity-profilometry equivalent values were compared using non-contact profilometry with three subtypes of regular toothpaste and two subtypes of...
The relative dentin abrasivity-profilometry equivalent values were compared using non-contact profilometry with three subtypes of regular toothpaste and two subtypes of whitening toothpaste containing sodium bicarbonate and 35% hydrogen peroxide. Bovine dentin specimens were assigned to six groups: regular toothpaste (R): R1 (BAMBOO SALT GUM OINTMENT); R2 (MEDIAN TARTAR ORIGINAL); R3 (PERIOE Alpha), Reference slurry: RS (calcium pyrophosphate), whitening toothpaste (W): W1 (NET. WT); W2 (Vussen 28 WHITENING). Relative dentin abrasion-profilometry equivalent (RDA-PE) was determined by brushing 10,000 times (n=8). The pH of the toothpaste was measured (n=5) and the abrasive constituents of the toothpaste was analyzed by FE-SEM and EDS. The RDA-PE values ranged from 26 to 166, and the pH level ranges were 4.928-9.153. The RDA-PE value of the whitening toothpaste containing hydrogen peroxide was not high compared with that of the regular toothpaste. The RDA-PE values of whitening toothpaste could vary depending on the mechanism and ingredients of the whitening agents.
Topics: Animals; Bleaching Agents; Calcium Pyrophosphate; Cattle; Dentin; Hydrogen; Materials Testing; Ointments; Sodium Bicarbonate; Tooth Abrasion; Toothbrushing; Toothpastes
PubMed: 35793939
DOI: 10.4012/dmj.2021-303 -
Cell Feb 2023Although many prokaryotes have glycolysis alternatives, it's considered as the only energy-generating glucose catabolic pathway in eukaryotes. Here, we managed to create...
Although many prokaryotes have glycolysis alternatives, it's considered as the only energy-generating glucose catabolic pathway in eukaryotes. Here, we managed to create a hybrid-glycolysis yeast. Subsequently, we identified an inositol pyrophosphatase encoded by OCA5 that could regulate glycolysis and respiration by adjusting 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP) levels. 5-InsP levels could regulate the expression of genes involved in glycolysis and respiration, representing a global mechanism that could sense ATP levels and regulate central carbon metabolism. The hybrid-glycolysis yeast did not produce ethanol during growth under excess glucose and could produce 2.68 g/L free fatty acids, which is the highest reported production in shake flask of Saccharomyces cerevisiae. This study demonstrated the significance of hybrid-glycolysis yeast and determined Oca5 as an inositol pyrophosphatase controlling the balance between glycolysis and respiration, which may shed light on the role of inositol pyrophosphates in regulating eukaryotic metabolism.
Topics: Saccharomyces cerevisiae; Diphosphates; Saccharomyces cerevisiae Proteins; Inositol Phosphates; Glycolysis; Respiration; Pyrophosphatases; Glucose
PubMed: 36758548
DOI: 10.1016/j.cell.2023.01.014 -
Annals of the Rheumatic Diseases Oct 2023Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic...
OBJECTIVE
Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease.
METHODS
Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort.
RESULTS
Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers).
CONCLUSION
The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.
Topics: Humans; United States; Chondrocalcinosis; Rheumatology; Calcium Pyrophosphate; Calcinosis; Syndrome
PubMed: 37495237
DOI: 10.1136/ard-2023-224575