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Frontiers in Endocrinology 2021The ubiquitous exposure of humans to microplastics (MPs) through inhalation of particles in air and ingestion in dust, water, and diet is well established. Humans are... (Review)
Review
The ubiquitous exposure of humans to microplastics (MPs) through inhalation of particles in air and ingestion in dust, water, and diet is well established. Humans are estimated to ingest tens of thousands to millions of MP particles annually, or on the order of several milligrams daily. Available information suggests that inhalation of indoor air and ingestion of drinking water bottled in plastic are the major sources of MP exposure. Little is known on the occurrence of MPs in human diet. Evidence is accumulating that feeding bottles and medical devices can contribute to MP exposure in newborns and infants. Biomonitoring studies of human stool, fetus, and placenta provide direct evidence of MP exposure in infants and children. MPs <20 µm were reported to cross biological membranes. Although plastics were once perceived as inert materials, MP exposure in laboratory animals is linked to various forms of inflammation, immunological response, endocrine disruption, alteration of lipid and energy metabolism, and other disorders. Whereas exposure to MPs itself is a concern, MPs can also be sources of exposure to plastic additives and other toxicants. Exposure of human cell lines to MP additives such as phthalates, bisphenols, and organotins causes adverse effects through the activation of nuclear receptors, peroxisome proliferator-activated receptors (PPARs) α, β, and γ, and retinoid X receptor (RXR), leading to oxidative stress, cytotoxicity, immunotoxicity, thyroid hormone disruption, and altered adipogenesis and energy production. The size, shape, chemical composition, surface charge, and hydrophobicity of MPs influence their toxicity. Maternal transfer of MPs to the developing fetus has been demonstrated in exposed laboratory animals and through the analysis of human placenta. In laboratory animal studies, maternal exposure to MPs altered energy and lipid metabolism in offspring and subsequent generations. Moreover, concomitant with the global increase in plastics production, the prevalence of overweight and obesity in human populations has increased over the past five decades, and there is evidence to support the hypothesis that MPs and their additives are potential obesogens. Even though MP exposures are ubiquitous and toxic effects from such exposures are a concern, systematic studies on this topic remain urgently needed.
Topics: Animals; Humans; Microplastics; Obesity; Overweight
PubMed: 34484127
DOI: 10.3389/fendo.2021.724989 -
Nature Apr 2020Present estimates suggest that of the 359 million tons of plastics produced annually worldwide, 150-200 million tons accumulate in landfill or in the natural...
Present estimates suggest that of the 359 million tons of plastics produced annually worldwide, 150-200 million tons accumulate in landfill or in the natural environment. Poly(ethylene terephthalate) (PET) is the most abundant polyester plastic, with almost 70 million tons manufactured annually worldwide for use in textiles and packaging. The main recycling process for PET, via thermomechanical means, results in a loss of mechanical properties. Consequently, de novo synthesis is preferred and PET waste continues to accumulate. With a high ratio of aromatic terephthalate units-which reduce chain mobility-PET is a polyester that is extremely difficult to hydrolyse. Several PET hydrolase enzymes have been reported, but show limited productivity. Here we describe an improved PET hydrolase that ultimately achieves, over 10 hours, a minimum of 90 per cent PET depolymerization into monomers, with a productivity of 16.7 grams of terephthalate per litre per hour (200 grams per kilogram of PET suspension, with an enzyme concentration of 3 milligrams per gram of PET). This highly efficient, optimized enzyme outperforms all PET hydrolases reported so far, including an enzyme from the bacterium Ideonella sakaiensis strain 201-F6 (even assisted by a secondary enzyme) and related improved variants that have attracted recent interest. We also show that biologically recycled PET exhibiting the same properties as petrochemical PET can be produced from enzymatically depolymerized PET waste, before being processed into bottles, thereby contributing towards the concept of a circular PET economy.
Topics: Actinobacteria; Burkholderiales; Carboxylic Ester Hydrolases; Disulfides; Enzyme Assays; Enzyme Stability; Fusarium; Hydrolases; Models, Molecular; Phthalic Acids; Plastics; Polyethylene Terephthalates; Polymerization; Protein Engineering; Recycling; Thermobifida
PubMed: 32269349
DOI: 10.1038/s41586-020-2149-4 -
The Journal of Allergy and Clinical... Mar 2023An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case... (Meta-Analysis)
Meta-Analysis
BACKGROUND
An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case series and cohort studies; however, evidence to support its routine clinical use is lacking.
OBJECTIVE
The aim of this systematic review and meta-analysis was to evaluate the clinical effectiveness and safety of omalizumab in patients with ABPA.
METHODS
We conducted a systematic search across standard databases using specific key words until May 13, 2021. We performed a meta-analysis to compare the effectiveness (exacerbations, oral corticosteroid [OCS] use, lung function, and patient-reported asthma control) and safety of pre- and post-omalizumab treatment. Subgroup analyses were performed for treatment duration and underlying disease.
RESULTS
In total, 49 studies (n = 267) were included in the qualitative synthesis and 14 case series (n = 186) in the quantitative meta-analysis. Omalizumab treatment significantly reduced the annualized exacerbation rate compared with pretreatment (mean difference, -2.09 [95% CI, -3.07 to -1.11]; P < .01). There was a reduction in OCS use (risk difference, 0.65 [95% CI, 0.46-0.84]; P < .01), an increase in termination of OCS use (risk difference, 0.53 [95% CI, 0.24-0.82]; P < .01), and a reduction in OCS dose (milligrams per day) (mean difference, -14.62 [95% CI, -19.86 to -9.39]; P < .01) in ABPA patients receiving omalizumab. Omalizumab improved FEV % predicted by 11.9% (95% CI, 8.2-15.6; P < .01) and asthma control, and was well-tolerated.
CONCLUSIONS
Omalizumab treatment reduced exacerbations and OCS use, improved lung function and asthma control in patients with ABPA, and was well-tolerated. The results highlight the potential role of omalizumab in the treatment of ABPA.
Topics: Humans; Omalizumab; Aspergillosis, Allergic Bronchopulmonary; Cystic Fibrosis; Asthma; Adrenal Cortex Hormones
PubMed: 36581073
DOI: 10.1016/j.jaip.2022.12.012 -
Drug Metabolism and Disposition: the... Mar 2020The 20 uridine diphosphate glycosyl-transferases (UGTs) encoded in the human genome form an essential homeostatic network of overlapping catalytic functions that surveil...
The 20 uridine diphosphate glycosyl-transferases (UGTs) encoded in the human genome form an essential homeostatic network of overlapping catalytic functions that surveil and regulate the activity and clearance of scores of small molecule metabolites. Biochemical and biophysical UGT studies have been hampered by the inability to purify these membrane-bound proteins. Here, using cell-free expression and nanodisc technology, we assemble and purify to homogeneity the first UGT nanodisc-the human UGT2B7•nanodisc. The complex is readily isolated in milligram quantities. It is stable and its initial-rate parameters are identical within error to those associated with UGT2B7 in microsomal preparations (i.e., Supersomes). The high purity of the nanodisc preparation simplifies UGT assays, which allows complexities traditionally associated with microsomal assays (latency and the albumin effect) to be circumvented. Each nanodisc is shown to harbor a single UGT2B7 monomer. The methods described herein should be widely applicable to UGTs, and these findings are expected to set the stage for experimentalists to more freely explore the structure, function, and biology of this important area of phase II metabolism. SIGNIFICANCE STATEMENT: Lack of access to pure, catalytically competent human uridine diphosphate glucuronosyl-transferases (UGTs) has long been an impediment to biochemical and biophysical studies of this disease-relevant enzyme family. Here, we demonstrate this barrier can be removed using nanodisc technology-a human UGT2B7•nanodisc is assembled, purified to homogeneity, and shown to have activity comparable to microsomal UGT2B7.
Topics: Glucuronosyltransferase; Humans; Liver; Microsomes, Liver
PubMed: 31892527
DOI: 10.1124/dmd.119.089946 -
Science Advances Oct 2022Homogeneous catalysts have rapid kinetics and keen reaction selectivity. However, their widespread use for industrial catalysis has remained limited because of...
Homogeneous catalysts have rapid kinetics and keen reaction selectivity. However, their widespread use for industrial catalysis has remained limited because of challenges in reusability. Here, we propose a redox-mediated electrochemical approach for catalyst recycling using metallopolymer-functionalized electrodes for binding and release. The redox platform was investigated for the separation of key platinum and palladium homogeneous catalysts used in organic synthesis and industrial chemical manufacturing. Noble metal catalysts for hydrosilylation, silane etherification, Suzuki cross-coupling, and Wacker oxidation were recycled electrochemically. The redox electrodes demonstrated high sorption uptake for platinum-based catalysts ( up to 200 milligrams of platinum per gram of adsorbent) from product mixtures, with up to 99.5% recovery, while retaining full catalytic activity over multiple cycles. The combination of mechanistic studies and electronic structure calculations indicate that selective interactions with anionic intermediates during the catalytic cycle played a key role in the separations. Last, continuous flow cell studies support the scalability and favorable technoeconomics of electrochemical recycling.
PubMed: 36260663
DOI: 10.1126/sciadv.ade3094 -
Cornea Apr 2022The purpose of this study was to characterize rates of opioid prescription for different ulcerative keratitis types.
PURPOSE
The purpose of this study was to characterize rates of opioid prescription for different ulcerative keratitis types.
METHODS
This cohort study included patients diagnosed with ulcerative keratitis according to the University of Michigan electronic health record data between September 1, 2014 and December 22, 2020. Ulcerative keratitis was categorized by etiologic type (bacterial, fungal, viral, acanthamoeba, inflammatory, polymicrobial, or unspecified) using rule-based data classification that accounted for billing diagnosis code, antimicrobial or antiinflammatory medications prescribed, laboratory results, and manual chart review. Opioid prescriptions were converted to morphine milligram equivalent and summed over 90 days from diagnosis. Opioid prescription rate and amount were compared between ulcerative keratitis types.
RESULTS
Of 3322 patients with ulcerative keratitis, 173 (5.2%) were prescribed at least 1 opioid for pain management within 90 days of diagnosis. More patients with acanthamoeba (32.4%), fungal (21.1%), and polymicrobial (25.0%) keratitis were treated with opioids compared with bacterial (6.7%), unspecified (2.9%), or viral (1.8%) keratitis (all Bonferroni adjusted P < 0.05). For the 173 patients who were prescribed opioids, a total of 353 prescriptions were given within 90 days of diagnosis, with half given within the first week after diagnosis. The quantity of opioid prescribed within 90 days from diagnosis was not significantly different between ulcerative keratitis types (P = 0.6559). Morphine milligram equivalent units prescribed ranged from 97.5 for acanthamoeba keratitis to 112.5 for fungal keratitis.
CONCLUSIONS
The type of ulcerative keratitis may influence the opioid prescription rate. Providers can better serve patients needing opioids for pain management through improved characterization of pain and development of more tailored pain management regimens.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Child; Child, Preschool; Corneal Ulcer; Drug Prescriptions; Eye Pain; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pain Management; Practice Patterns, Physicians'; Retrospective Studies
PubMed: 34620771
DOI: 10.1097/ICO.0000000000002893 -
Methods in Enzymology 2023In mammals there are two 3-oxo-4-ene steroid reductases that generate either A/B-trans or A/B cis-ring junctions in the steroid nucleus known as steroid 5α- and 5β-...
In mammals there are two 3-oxo-4-ene steroid reductases that generate either A/B-trans or A/B cis-ring junctions in the steroid nucleus known as steroid 5α- and 5β- reductases, respectively. There is only one steroid 5β- reductase in each species and these are members of the aldo-keto-reductase (AKR) protein superfamily. The corresponding human enzyme is AKR1D1, and it plays an essential role in bile-acid biosynthesis. Germline mutations in AKR1D1 give rise to bile-acid deficiency. Because of its central role in steroid metabolism and need for detailed structure-function studies there is a need to purify the enzyme to homogeneity and in high yield. We report the purification of milligram amounts of crystallographic quality homogeneous recombinant protein for structure-function studies and its characterization.
Topics: Animals; Humans; Oxidoreductases; Steroids; Bile Acids and Salts; Mammals
PubMed: 37802574
DOI: 10.1016/bs.mie.2023.04.012 -
Chemistry (Weinheim An Der Bergstrasse,... Jul 2021The syntheses, properties and application of the air-stable electron acceptors, diindenopyrazines 4 a-g are reported demonstrating the introduction of functional aryl...
The syntheses, properties and application of the air-stable electron acceptors, diindenopyrazines 4 a-g are reported demonstrating the introduction of functional aryl groups in the 6- and 12-positions. The targets are accessible on the hundred milligram to gram scale. The structure of the aryl groups in 4 a-g modulates their solubility, redox potentials and optical properties. The introduction of electron-poor aryl groups to the electron-poor diindenopyrazine backbone reduces the electron affinity to -4 eV, making the compounds attractive as n-semiconductors. A simple organic field-effect transistor of 4 e -without optimization- shows electron transport with a mobility of up to 0.037 cm V s .
PubMed: 33830516
DOI: 10.1002/chem.202100372 -
Molecules (Basel, Switzerland) Apr 2022A diastereoselective synthesis of the β-anomer of glycinamide ribonucleotide (β-GAR) has been developed. The synthesis was accomplished in nine steps from D-ribose and...
A diastereoselective synthesis of the β-anomer of glycinamide ribonucleotide (β-GAR) has been developed. The synthesis was accomplished in nine steps from D-ribose and occurred in 5% overall yield. The route provided material on the multi-milligram scale. The synthetic β-GAR formed was remarkably resistant to anomerization both in solution and as a solid.
Topics: Glycine; Hydroxymethyl and Formyl Transferases; Phosphoribosylglycinamide Formyltransferase; Ribonucleotides
PubMed: 35458726
DOI: 10.3390/molecules27082528 -
Chemical Science May 2022The synthesis of secondary and tertiary amines through the reductive amination of carbonyl compounds is one of the most significant reactions in synthetic chemistry.... (Review)
Review
The synthesis of secondary and tertiary amines through the reductive amination of carbonyl compounds is one of the most significant reactions in synthetic chemistry. Asymmetric reductive amination for the formation of chiral amines, which are required for the synthesis of pharmaceuticals and other bioactive molecules, is often achieved through transition metal catalysis, but biocatalytic methods of chiral amine production have also been a focus of interest owing to their selectivity and sustainability. The discovery of asymmetric reductive amination by imine reductase (IRED) and reductive aminase (RedAm) enzymes has served as the starting point for a new industrial approach to the production of chiral amines, leading from laboratory-scale milligram transformations to ton-scale reactions that are now described in the public domain. In this perspective we trace the development of the IRED-catalyzed reductive amination reaction from its discovery to its industrial application on kg to ton scale. In addition to surveying examples of the synthetic chemistry that has been achieved with the enzymes, the contribution of structure and protein engineering to the understanding of IRED-catalyzed reductive amination is described, and the consequent benefits for activity, selectivity and stability in the design of process suitable catalysts.
PubMed: 35655886
DOI: 10.1039/d2sc00124a