Placental transfer of a hydroxylated polychlorinated biphenyl and effects on fetal and maternal thyroid hormone homeostasis in the rat

Earlier studies at our laboratory indicated that several hydroxylated polychlorinated biphenyls (OH-PCBs) detected in human blood could specifically inhibit thyroxine (T4) transport by competitive binding to the thyroid hormone transport protein transthyretin (TTR) in vitro. In the present study we investigated the effects of prenatal exposure to 5 mg/kg body weight of [14C]-labeled or unlabeled 4-OH-2,3,3',4',5-pentachlorobiphenyl (4-OH-CB107), one of the major metabolites of PCBs detected in human blood, from gestation days (GD) 10 to 16 on thyroid hormone status and metabolism in pregnant rats and their fetuses at GD 17 and GD 20. 4-OH-CB107 is a metabolite of both 2,3,3',4,4'-pentachlorobiphenyl (CB-105) and 2,3',4,4',5-pentachlorobiphenyl (CB-118). We were able to show the accumulation of 4-OH-CB107 in the fetal compartment. The fetal/maternal ratios at GD 20 in liver, cerebellum, and plasma were 11.0, 2.6, and 1.2, respectively. The 14C-4-OH-CB107-derived radioactivity in plasma was bound to TTR in both dams and fetuses. Fetal plasma TT4 and FT4 levels were significantly decreased at GD 17 and GD 20 (89 and 41␛espectively at GD 20). Fetal thyroid stimulating hormone levels were increased by 124 at GD 20. The T4 concentrations in fetal forebrain homogenates at GD20 were reduced by 35°but no effects could be detected on brain T3 concentrations. The deiodination of T4 to T3 was significantly increased in fetal forebrain homogenates at GD 17, and unaltered at GD 20. In addition, no alterations were observed in maternal and fetal hepatic T4-UDP-glucuronosyltransferase activity, type I deiodinase activity, and EROD activity. In conclusion, exposure of pregnant rats to 4-OH-CB107 results in the distribution of the compound in the maternal and fetal compartment, which is probably caused by the binding of the PCB metabolite to TTR. Consequently, TT4 levels in fetal plasma and brain samples were reduced. Despite reductions in fetal brain T4 levels, the active hormone (T3) in fetal brains remained unaffected

Structure of human transthyretin complexed with bromophenols: a new mode of binding

The binding of two organohalogen substances, pentabromophenol (PBP) and 2,4,6-tribromophenol (TBP), to human transthyretin (TTR), a thyroid hormone transport protein, has been studied by in vitro competitive binding assays and by X-ray crystallography. Both compounds bind to TTR with high affinity, in competition with the natural ligand thyroxine (

Edoxaban: an update on the new oral direct factor Xa inhibitor.

Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. Both edoxaban regimens also provided significant reductions in the risk of hemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to-high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.

Stress-Regulated Translational Attenuation Adapts Mitochondrial Protein Import through Tim17A Degradation

SummaryStress-regulated signaling pathways protect mitochondrial proteostasis and function from pathologic insults. Despite the importance of stress-regulated signaling pathways in mitochondrial proteome maintenance, the molecular mechanisms by which these pathways maintain mitochondrial proteostasis remain largely unknown. We identify Tim17A as a stress-regulated subunit of the translocase of the inner membrane 23 (TIM23) mitochondrial protein import complex. We show that Tim17A protein levels are decreased downstream of stress-regulated translational attenuation induced by eukaryotic initiation factor 2α (eIF2α) phosphorylation through a mechanism dependent on the mitochondrial protease YME1L. Furthermore, we demonstrate that decreasing Tim17A attenuates TIM23-dependent protein import, promotes the induction of mitochondrial unfolded protein response (UPR)-associated proteostasis genes, and confers stress resistance in C. elegans and mammalian cells. Thus, our results indicate that Tim17A degradation is a stress-responsive mechanism by which cells adapt mitochondrial protein import efficiency and promote mitochondrial proteostasis in response to the numerous pathologic insults that induce stress-regulated translation attenuation

Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms 'inotersen,' 'AG10,' 'antisense oligonucleotide,' 'hereditary transthyretin amyloidosis,' 'familial amyloid polyneuropathy,' and 'familial amyloid cardiomyopathy' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia

Effects of electron transfer on the stability of hydrogen bonds.

The measurement of the dimerization constants of hydrogen-bonded ruthenium complexes (12, 22, 32) linked by a self-complementary pair of 4-pyridylcarboxylic acid ligands in different redox states is reported. Using a combination of FTIR and UV/vis/NIR spectroscopies, the dimerization constants (KD) of the isovalent, neutral states, 12, 22, 32, were found to range from 75 to 130 M-1 (ΔG0 = -2.56 to -2.88 kcal mol-1), while the dimerization constants (K2-) of the isovalent, doubly-reduced states, (12)2-, (22)2-, (32)2-, were found to range from 2000 to 2500 M-1 (ΔG0 = -4.5 to -4.63 kcal mol-1). From the aforementioned values and the comproportionation constant for the mixed-valent dimers, the dimerization constants (KMV) of the mixed-valent, hydrogen-bonded dimers, (12)-, (22)-, (32)-, were found to range from 0.5 × 106 to 1.2 × 106 M-1 (ΔG0 = -7.78 to -8.31 kcal mol-1). On average, the hydrogen-bonded, mixed-valent states are stabilized by -5.27 (0.04) kcal mol-1 relative to the isovalent, neutral, hydrogen-bonded dimers and -3.47 (0.06) kcal mol-1 relative to the isovalent, dianionic hydrogen bonded dimers. Electron exchange in the mixed valence states imparts significant stability to hydrogen bonding. This is the first quantitative measurement of the strength of hydrogen bonds in the presence and absence of electronic exchange

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Transthyretin amyloidosis (ATTR) is a rare, yet underdiagnosed disease characterized by progressive impairment of neurologic and cardiac function due to deposition of misfolded transthyretin. Despite great efforts, such as the introduction of orthotopic liver transplant, the devastating prognosis for both variant and wild-type ATTR patients remained unchanged over the last decades, mainly due to a lack of specific therapies. Fortunately, recent years saw the introduction of promising targeted therapies, which aim to interfere with the deposition of misfolded transthyretin (TTR) at various stages of the cascade underlying ATTR progression. These include TTR tetramer stabilizers (tafamidis, diflunisal, epigallocatechin-3-gallate), TTR silencers (inotersen, patisiran) and fibril disruptors (monoclonal antibodies, doxycycline and tauroursodeoxycholic acid). In the context of this review we explain their mechanisms of action, analyse their efficacy on neurologic and cardiac function based on all clinical trials conducted to date and discuss their clinical applicability. Eventually suggestions for future clinical research into the field are provided

Advances in the treatment of hereditary transthyretin amyloidosis: A review

Introduction: Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild-type ATTR) throughout the body. Two new therapies-inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy-received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR. Methods: A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR. Results: Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early- and late-stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early-stage disease, and tafamidis, indicated for the treatment of early-stage disease in Europe, or diflunisal, a nonsteroidal anti-inflammatory drug that is used off-label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities. Conclusions: Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.info:eu-repo/semantics/publishedVersio