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Coelenterazine-Dependent Luciferases as a Powerful Analytical Tool for Research and Biomedical Applications.
Krasitskaya, VV, Bashmakova, EE, Frank, LA
International journal of molecular sciences. 2020;(20)
Abstract
: The functioning of bioluminescent systems in most of the known marine organisms is based on the oxidation reaction of the same substrate-coelenterazine (CTZ), catalyzed by luciferase. Despite the diversity in structures and the functioning mechanisms, these enzymes can be united into a common group called CTZ-dependent luciferases. Among these, there are two sharply different types of the system organization-Ca2+-regulated photoproteins and luciferases themselves that function in accordance with the classical enzyme-substrate kinetics. Along with deep and comprehensive fundamental research on these systems, approaches and methods of their practical use as highly sensitive reporters in analytics have been developed. The research aiming at the creation of artificial luciferases and synthetic CTZ analogues with new unique properties has led to the development of new experimental analytical methods based on them. The commercial availability of many ready-to-use assay systems based on CTZ-dependent luciferases is also important when choosing them by first-time-users. The development of analytical methods based on these bioluminescent systems is currently booming. The bioluminescent systems under consideration were successfully applied in various biological research areas, which confirms them to be a powerful analytical tool. In this review, we consider the main directions, results, and achievements in research involving these luciferases.
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Angiotensin Receptor Blockers Versus Angiotensin Converting Enzyme Inhibitors for the Treatment of Arterial Hypertension and the Role of Olmesartan.
Omboni, S, Volpe, M
Advances in therapy. 2019;(2):278-297
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Blood pressure lowering by all classes of antihypertensive drugs is accompanied by significant reductions of stroke and major cardiovascular (CV) events. Drugs acting on the renin-angiotensin-aldosterone system, such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), showed similar benefit on major CV events to other antihypertensive medications. In real-world practice, ARBs reduced by 10% the incidence of CV mortality, non-fatal myocardial infarction, non-fatal stroke and provided superior protection against CV events than ACEIs in high-risk patients. Despite similar antihypertensive properties and a favourable safety profile for both ACEIs and ARBs, evidence indicates that patients treated with ARBs have lower rates of withdrawal for adverse events and greater persistence to therapy than those treated with ACEIs. Among ARBs, olmesartan is one of the latest generation compounds introduced in clinical practice for treating hypertension: head-to-head comparative trials suggest that the efficacy of olmesartan is superior to that of commonly prescribed ACEIs (ramipril and perindopril). The drug, administered as a monotherapy or in combination with a dihydropyridine calcium channel blocker or a thiazide diuretic, has proved to be effective in maintaining blood pressure stability over 24 h, with a favourable safety profile and low discontinuation rates. These properties are pivotal for considering olmesartan as a useful antihypertensive agent especially for high-risk patients (e.g. elderly, diabetics, patients with metabolic syndrome).Funding: Article preparation and open access fee were funded by Menarini International Operations Luxembourg S.A. (M.I.O.L.).
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Effect of antihypertensive treatment on 24-h blood pressure variability: pooled individual data analysis of ambulatory blood pressure monitoring studies based on olmesartan mono or combination treatment.
Omboni, S, Kario, K, Bakris, G, Parati, G
Journal of hypertension. 2018;(4):720-733
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OBJECTIVE To evaluate the impact of olmesartan alone or combined with one to three antihypertensive drugs on 24-h blood pressure variability (BPV) and on distribution of BP reduction in a pooled individual data analysis of 10 double-blind, randomized, ambulatory BP monitoring (ABPM) studies. METHODS ABPMs were performed before and after 6-12 weeks of treatment with placebo (n = 119), active control monotherapy [n = 1195, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), dihydropyridine calcium channel blockers (DCCBs)] olmesartan monotherapy (n = 1410), active control dual combination [n = 79, DCCB + thiazide diuretic (TD)], olmesartan dual combination (n = 637, DCCB or TD), and triple combination therapy (n = 102, DCCB+TD). 24-h BPV was calculated as unweighted or weighted SD of the mean BP, and average real variability. BP control was assessed by smoothness index and treatment-on-variability index. RESULTS The greatest effect on 24-h systolic BPV/diastolic BPV was observed under olmesartan triple [-2.6/-1.9; -1.9/-1.3; -1.4/-1.3 mmHg] and active control dual combination [-1.8/-1.4; -1.9/-1.5; -1.2/-1.1 mmHg]. Smoothness indexes and treatment-on-variability indexes were significantly (P = 0.0001) higher under olmesartan dual (1.53/1.22, 1.67/1.29, 2.05/1.59), olmesartan triple (2.47/1.85, 2.80/2.06, 3.64/2.67), or active control dual combination (1.70/1.26, 1.85/1.33, 2.29/1.65) than under monotherapies (control: 0.86/0.73, 0.80/0.65, 1.01/0.82; olmesartan: 1.02/0.86, 0.95/0.78, 1.23/1.00). They were also greater in patients receiving high-dose olmesartan monotherapy or high-dose olmesartan dual combination than in the corresponding low-dose group. CONCLUSION Olmesartan plus a DCCB and/or a TD produces a larger, more sustained, and smoother BP reduction than placebo and monotherapies, a desirable feature for a more effective prevention of the cardiovascular consequences of uncontrolled hypertension.
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Pharmacological interventions for the prevention of insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults.
van den Blink, QU, Garcez, K, Henson, CC, Davidson, SE, Higham, CE
The Cochrane database of systematic reviews. 2018;(4):CD010604
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BACKGROUND Pelvic radiotherapy is a treatment delivered to an estimated 150,000 to 300,000 people annually across high-income countries. Fractures due to normal stresses on weakened bone due to radiotherapy are termed insufficiency fractures. Pelvic radiotherapy-related interruption of the blood supply to the hip is termed avascular necrosis and is another recognised complication. The reported incidences of insufficiency fractures are 2.7% to 89% and risk of developing avascular necrosis is 0.5%. These complications lead to significant morbidity in terms of pain, immobility and consequently risk of infections, pressure sores and mortality. OBJECTIVES To assess the effects of pharmacological interventions for preventing insufficiency fractures and avascular necrosis in adults over 18 years of age undergoing pelvic radiotherapy. SEARCH METHODS We performed electronic literature searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and DARE to 19 April 2017. We also searched trial registries. Further relevant studies were identified through handsearching of citation lists of included studies. SELECTION CRITERIA Randomised controlled trials (RCTs) or non RCTs with concurrent comparison groups including quasi-RCTs, cluster RCTs, prospective cohort studies and case series of 30 or more participants were screened. We included studies assessing the effect of pharmacological interventions in adults over 18 years of age undergoing radical pelvic radiotherapy as part of anticancer treatment for a primary pelvic malignancy. We excluded studies involving radiotherapy for bone metastases. We assessed use of pharmacological interventions at any stage before or during pelvic radiotherapy. Interventions included calcium or vitamin D (or both) supplementation, bisphosphonates, selective oestrogen receptor modulators, hormone replacement therapy (oestrogen or testosterone), denosumab and calcitonin. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trial quality and extracted data. We contacted study authors to obtain missing data. Data were to be pooled using the random-effects model if study comparisons were similar, otherwise results were to be reported narratively. MAIN RESULTS We included two RCTs (1167 participants). The first RCT compared zoledronic acid with placebo in 96 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.The second RCT had four treatment arms, two of which evaluated zoledronic acid plus adjuvant androgen suppression compared with androgen suppression only in 1071 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.Both studies were at a moderate to high risk of bias and all evidence was judged to be of very low certainty.The studies provided no evidence on the primary outcomes of the review and provided limited data in relation to secondary outcomes, such that meta-analyses were not possible. Both studies focused on interventions to improve bone health in relation to androgen deprivation rather than radiation-related insufficiency fractures and avascular necrosis. Few fractures were described in each study and those described were not specific to insufficiency fractures secondary to radiotherapy. Both studies reported that zoledronic acid in addition to androgen deprivation and pelvic radiotherapy led to improvements in BMD; however, the changes in BMD were measured and reported differently. There was no available evidence regarding adverse effects. AUTHORS' CONCLUSIONS The evidence relating to interventions to prevent insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults is of very low certainty. This review highlights the need for prospective clinical trials using interventions prior to and during radiotherapy to prevent radiation-related bone morbidity, insufficiency fractures and avascular necrosis. Future trials could involve prospective assessment of bone health including BMD and bone turnover markers prior to pelvic radiotherapy. The interventions for investigation could begin as radiotherapy commences and remain ongoing for 12 to 24 months. Bone turnover markers and BMD could be used as surrogate markers for bone health in addition to radiographic imaging to report on presence of insufficiency fractures and development of avascular necrosis. Clinical assessments and patient reported outcomes would help to identify any associated adverse effects of treatment and quality of life outcomes.
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Methanobactins: from genome to function.
Dassama, LM, Kenney, GE, Rosenzweig, AC
Metallomics : integrated biometal science. 2017;(1):7-20
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Methanobactins (Mbns) are ribosomally produced, post-translationally modified peptide (RiPP) natural products that bind copper with high affinity using nitrogen-containing heterocycles and thioamide groups. In some methanotrophic bacteria, Mbns are secreted under conditions of copper starvation and then re-internalized as a copper source for the enzyme particulate methane monooxygenase (pMMO). Genome mining studies have led to the identification and classification of operons encoding the Mbn precursor peptide (MbnA) as well as a number of putative transport, regulatory, and biosynthetic proteins. These Mbn operons are present in non-methanotrophic bacteria as well, suggesting a broader role in and perhaps beyond copper acquisition. Genetic and biochemical studies indicate that specific operon-encoded proteins are involved in Mbn transport and provide insight into copper-responsive gene regulation in methanotrophs. Mbn biosynthesis is not yet understood, but combined analysis of Mbn structures, MbnA sequences, and operon content represents a powerful approach to elucidating the roles of specific biosynthetic enzymes. Future work will likely lead to the discovery of unique pathways for natural product biosynthesis and new mechanisms of microbial metal homeostasis.
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Chronic Myeloid Leukemia Associated Hypercalcemia: A Case Report and Literature Review.
Toro-Tobón, D, Agosto, S, Ahmadi, S, Koops, M, Bruder, JM
The American journal of case reports. 2017;:203-207
Abstract
BACKGROUND Hypercalcemia associated with chronic myeloid leukemia (CML) is an ominous sign. Although rare, several cases have been reported and multiple pathophysiologic mechanisms have been independently proposed. We present a patient case and a literature review of the clinical presentation and mechanisms of CML-associated hypercalcemia. CASE REPORT A 58-year-old male with a past medical history of CML diagnosed six years earlier, presented to the emergency department with one week of acute confusion, disorientation, polyuria, and polydipsia. On physical examination, we observed tachycardia, altered mental status, and dehydration. Blood analysis revealed leukocytosis, thrombocytosis, and marked hypercalcemia (18.6 mg/dL). His chest CT scan showed diffuse lytic lesions and bone destruction concerning for diffuse bone marrow involvement. The patient was diagnosed with hypercalcemia in the context of a CML blast phase. Treatment with hydration, calcitonin, and zoledronic acid lead to control of his symptoms and normalization of his serum calcium levels. After discharged, the patient was maintained on palliative treatment and zoledronic acid management without new episodes of hypercalcemia. However, eight months later, the patient died. CONCLUSIONS Evidence from the literature demonstrates a highly variable clinical presentation of CML-associated hypercalcemia, commonly occurring during an accelerated or a blast phase, and associated with poor survival. Multiple mechanisms could be involved and are not exclusive of each other. Better understanding of the pathophysiologic mechanisms involved in CML-associated hypercalcemia could lead to improvement in clinical and laboratory evaluation of these patients and be the foundation for the development of better management strategies and possibly target-directed therapy to positively improve prognosis.
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Adding Water to the Mill: Olmesartan-Induced Collagenous Sprue-A Case Report and Brief Literature Review.
Desruisseaux, C, Bensoussan, M, Désilets, E, Tran, HK, Arcand, R, Poirier, G, Wisniewski, A, Manière, T
Canadian journal of gastroenterology & hepatology. 2016;:4837270
Abstract
Collagenous sprue (CS) is a distinct clinicopathological disorder histologically defined by a thickened subepithelial band (Freeman, 2011). It is a rare condition which has been recently observed in a significant proportion of sprue-like enteropathy associated with olmesartan, a novel entity described by Rubio-Tapia et al. in 2012. CS is historically associated with a poor prognosis (Marthey et al., 2014). However, histological and clinical improvements have been described in most studies with concomitant usage of corticosteroids and/or gluten-free diet (Marthey et al., 2014). We report a unique case of olmesartan-induced collagenous sprue in a 79-year-old man that showed complete histological and clinical remission with the sole withdrawal of the incriminating drug. The literature on this topic is briefly reviewed.
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Toxicities following treatment with bisphosphonates and receptor activator of nuclear factor-κB ligand inhibitors in patients with advanced prostate cancer.
Gartrell, BA, Coleman, RE, Fizazi, K, Miller, K, Saad, F, Sternberg, CN, Galsky, MD
European urology. 2014;(2):278-86
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CONTEXT Advanced prostate cancer (PCa) is associated with skeletal complications, both as a result of bone metastases and because of fractures associated with fragility due to androgen-deprivation therapy (ADT). Osteoclast inhibitors are commonly used to reduce skeletal complications but are associated with a number of potential adverse events. OBJECTIVE To review clinical trials of osteoclast inhibitors in advanced PCa, to discuss the adverse event profile of these agents, and to discuss strategies to address specific adverse events. EVIDENCE ACQUISITION PubMed was searched for reports of clinical trials of osteoclast inhibitors in advanced PCa. As zoledronic acid and denosumab are used most commonly in this disease, these trials were the focus. The literature was reviewed to identify key publications addressing the prevention and management of adverse events associated with these drugs. EVIDENCE SYNTHESIS The major findings of the trials and the adverse events are discussed. Prevention and management of common adverse events are addressed. CONCLUSIONS Zoledronic acid prevents loss of bone mineral density associated with ADT and delays skeletal-related events in metastatic castration-resistant PCa (mCRPC). Denosumab reduces the incidence of fragility fractures associated with ADT, delays the onset of bone metastases in nonmetastatic castration-resistant disease, and is superior to zoledronic acid in the prevention of skeletal complications in mCRPC. Adverse events associated with both agents include osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab. Zoledronic acid requires dose modifications for renal insufficiency, is contraindicated in severe renal insufficiency, and has been associated with deterioration of renal function. Appropriate patient selection with close attention to dental health, supplementation with calcium and vitamin D, and monitoring of laboratory values are effective strategies to minimize the impact of adverse events associated with osteoclast inhibitors in advanced PCa.
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A survey and analysis of the role of molecular chaperone proteins and imidazole-containing dipeptide-based compounds as molecular escorts into the skin during stress, injury, water structuring and other types of cutaneous pathophysiology.
Babizhayev, MA, Nikolayev, GM, Nikolayeva, JG, Yegorov, YE
International journal of cosmetic science. 2011;(1):1-16
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Molecular chaperone, heat shock proteins (HSPs), stabilizes intracellular processes of cells under stress. Little is known about the role of molecular chaperone proteins in the skin pathology, rejuvenation and wound healing, or whether their expression is altered by environmental and physiological stress to the skin or systemic disease. The focus of this study was to examine the role of molecular chaperone proteins in the skin's local response to wounding, skin ageing and a range of skin diseases. Free radicals, one form of insult, induce or contribute to adverse effects on the skin, including erythema, oedema, wrinkling, photoaging, inflammation, autoimmune reactions, hypersensitivity, keratinization abnormalities, preneoplastic lesions and skin cancer. A unified view of the molecular and cellular pathogenesis of the skin age-related pathology conditions has led to the search for molecular and chemical chaperones that can slow, arrest or revert disease progression. Specific alpha-crystallin domains and pharmacological imidazole-containing dipeptide chaperone molecules are now emerging that link our biophysical insights with developed skin therapeutic techniques. In this article, we discuss the molecular nature of the stress signals, the mechanisms that underlie activation of the heat shock response, the role of molecular chaperone proteins as skin protective molecules, and strategies for pharmacologically active chaperone molecules and their imidazole-containing dipeptide inducers as regulators of the skin stress response. We discuss how impairment in protein hydration may cause ultrastructural, mechanical and biochemical changes in structural proteins in the aged skin. We have pioneered the molecular chaperone protein activated therapeutic or cosmetic platform to enable simultaneous analysis of water-binding and structuring characteristics for biology of skin ageing and skin disease-related pathways. This cutting-edge technology has improved the way that proteins hydrate in photoaged skin. The mechanisms of skin diseases, ageing, cellular, and signalling pathways mediated by targeting with molecular chaperone protein(s) in patented formulations with imidazole containing dipeptide (N-acetylcarnosine, carcinine, carnosine) are also discussed within this review.
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Bis-histidine-coordinated hemes in four-helix bundles: how the geometry of the bundle controls the axial imidazole plane orientations in transmembrane cytochromes of mitochondrial complexes II and III and related proteins.
Berry, EA, Walker, FA
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 2008;(4):481-98
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Early investigation of the electron paramagnetic resonance spectra of bis-histidine-coordinated membrane-bound ferriheme proteins led to the description of a spectral signal that had only one resolved feature. These became known as "highly anisotropic low-spin" or "large g(max)" ferriheme centers. Extensive work with small-molecule model heme complexes showed that this spectroscopic signature occurs in bis-imidazole ferrihemes in which the planes of the imidazole ligands are nearly perpendicular, deltaphi = 57-90 degrees. In the last decade protein crystallographic studies have revealed the atomic structures of a number of examples of bis-histidine heme proteins. A frequent characteristic of these large g(max) ferrihemes in membrane-bound proteins is the occurrence of the heme within a four-helix bundle with a left-handed twist. The histidine ligands occur at the same level on two diametrically opposed helices of the bundle. These ligands have the same side-chain conformation and ligate heme iron on the bundle axis, resulting in a quasi-twofold symmetric structure. The two non-ligand-bearing helices also obey this symmetry, and have a conserved small residue, usually glycine, where the edge of the heme ring makes contact with the helix backbones. In many cases this small residue is preceded by a threonine or serine residue whose side-chain hydroxyl oxygen acts as a hydrogen-bond acceptor from the N(delta1) atom of the heme-ligating histidine. The deltaphi angle is thus determined by the common histidine side-chain conformation and the crossing angle of the ligand-bearing helices, in some cases constrained by hydrogen bonds to the serine/threonine residues on the non-ligand-bearing helices.