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Lancet (London, England) Apr 2023
Topics: Humans; Hemophilia A; Hemophilia B; Acetylgalactosamine; RNA, Small Interfering; Factor VIII
PubMed: 37003290
DOI: 10.1016/S0140-6736(23)00514-7 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Sep 2022To analyze the salivary metabolic profile of patients with periodontitis through metabolomic techniques and to explore the metabolic patterns associated with periodontal...
OBJECTIVE
To analyze the salivary metabolic profile of patients with periodontitis through metabolomic techniques and to explore the metabolic patterns associated with periodontal diseases.
METHODS
Liquid chromatography/mass spectrometry (LC/MS) technique in conjunction with principal component analysis (PCA) analysis and orthogonal partial least squares identification (OPLS-DA) method was used to study the metabolomics of saliva samples from gingivitis patients, periodontitis patients, and healthy controls, with 10 samples for each group. We examined the correlation between migration in metabolic profile and the progression of periodontal diseases.
RESULTS
Saliva metabolite profiles of gingivitis and periodontitis patients was significantly different from those of the healthy controls. Significant differences were identified between the different groups for eight salivary metabolites, including arachidonic acid, tyramine, L-arginine, thymine, N-acetylgalactosamine sulfate, prostaglandin E2, L-phenylalanine, and 5-aminoimidazole-4-carboxamide-riboside (AICAR). In comparison with those of the health controls, the concentration of AICAR in patients with gingivitis and periodontitis was lower and the metabolic trend was down-regulated, while the other metabolites were up-regulated.
CONCLUSION
Salivary metabolic profile changes along with the progression of periodontal diseases. Abnormal metabolism of the periodontal tissue and of pathogenic microorganisms related to periodontal diseases is one of the mechanisms involved in the pathogenesis, development and prognosis of periodontal diseases.
Topics: Acetylgalactosamine; Arachidonic Acid; Arginine; Biomarkers; Dinoprostone; Gingivitis; Humans; Metabolomics; Periodontal Diseases; Periodontitis; Phenylalanine; Sulfates; Thymine; Tyramine
PubMed: 36224687
DOI: 10.12182/20220960207 -
Drug Metabolism and Disposition: the... Jul 2021Givosiran is an -acetylgalactosamine-conjugated RNA interference therapeutic that targets 5'-aminolevulinate synthase 1 mRNA in the liver and is currently marketed for...
Nonclinical Pharmacokinetics and Absorption, Distribution, Metabolism, and Excretion of Givosiran, the First Approved -Acetylgalactosamine-Conjugated RNA Interference Therapeutic.
Givosiran is an -acetylgalactosamine-conjugated RNA interference therapeutic that targets 5'-aminolevulinate synthase 1 mRNA in the liver and is currently marketed for the treatment of acute hepatic porphyria. Herein, nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of givosiran were characterized. Givosiran was completely absorbed after subcutaneous administration with relatively short plasma elimination half-life (t; less than 4 hours). Plasma exposure increased approximately dose proportionally with no accumulation after repeat doses. Plasma protein binding was concentration dependent across all species tested and was around 90% at clinically relevant concentration in human. Givosiran predominantly distributed to the liver by asialoglycoprotein receptor-mediated uptake, and the t in the liver was significantly longer (∼1 week). Givosiran was metabolized by nucleases, not cytochrome P450 (P450) isozymes, across species with no human unique metabolites. Givosiran metabolized to form one primary active metabolite with the loss of one nucleotide from the 3' end of antisense strand, AS(N-1)3' givosiran, which was equipotent to givosiran. Renal and fecal excretion were minor routes of elimination of givosiran as approximately 10% and 16% of the dose was recovered intact in excreta of rats and monkeys, respectively. Givosiran is not a substrate, inhibitor, or inducer of P450 isozymes, and it is not a substrate or inhibitor of uptake and most efflux transporters. Thus, givosiran has a low potential of mediating drug-drug interactions involving P450 isozymes and drug transporters. SIGNIFICANCE STATEMENT: Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion (ADME) properties of givosiran were characterized. Givosiran shows similar pharmacokinetics and ADME properties across rats and monkeys in vivo and across human and animal matrices in vitro. Subcutaneous administration results in adequate exposure of givosiran to the target organ (liver). These studies support the interpretation of toxicology studies, help characterize the disposition of givosiran in humans, and support the clinical use of givosiran for the treatment of acute hepatic porphyria.
Topics: 5-Aminolevulinate Synthetase; Acetylgalactosamine; Animals; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Half-Life; Injections, Subcutaneous; Intestinal Elimination; Macaca fascicularis; Male; Models, Animal; Porphobilinogen Synthase; Porphyrias, Hepatic; Pyrrolidines; Rats; Renal Elimination; Tissue Distribution
PubMed: 33941543
DOI: 10.1124/dmd.121.000381 -
Journal of Internal Medicine May 2022Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral... (Review)
Review
Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an acute porphyria attack. Until recently, the sole specific treatment for acute porphyria attacks consisted of the intravenous administration of hemin. Although attacks are often sporadic, some patients develop recurrent acute attacks, with devastating effects on quality of life. Liver transplantation has historically been the sole curative treatment option. The clinical manifestations of AHP are attributed to the accumulation of the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway. We reviewed the background and current status of AHP treatment using liver-directed small interfering RNA targeting ALAS1. The therapeutic aim was to normalize the levels of ALAS1, which is highly upregulated during acute porphyria attacks. Givosiran is now an approved drug for use in adults and adolescents aged 12 years and older. The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo. The clinical trials (phases I, II, and III) were all randomized and placebo controlled. Many patients enrolled in the initial clinical trials have continued treatment in open label extension and extended/compassionate-use programs in countries where givosiran is not yet commercially available.
Topics: Acetylgalactosamine; Adolescent; Adult; Heme; Humans; Incidence; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Pyrrolidines; Quality of Life; RNAi Therapeutics
PubMed: 35067977
DOI: 10.1111/joim.13443 -
Hamostaseologie Aug 2020Hemophilia A (HA) and B (HB) are X-linked bleeding disorders caused by mutations in the F8 or F9 gene that result in the absence, or reduced activity, of the... (Review)
Review
Hemophilia A (HA) and B (HB) are X-linked bleeding disorders caused by mutations in the F8 or F9 gene that result in the absence, or reduced activity, of the corresponding clotting factor. The severity of bleeding and related complications is proportional to the amount of residual circulating functional factor. The development of a safe and effective hemophilia treatment lasted several decades and has been mainly based on clotting factor replacement. Advances in the engineering and manufacturing of clotting concentrates have led to the widespread availability of extended half-life products that reduced the number of intravenous infusions needed to achieve adequate trough levels. The recent development of new nonfactor replacement treatments and biotechnology techniques has offered therapeutic alternatives for hemophilia patients with and without inhibitors. These are characterized by an easier route of administration, low immunogenicity, and, regarding gene therapy and cell-based treatments, potential long-term protection from bleeding after a single treatment course. In this review, we analyze recent progresses in the management of hemophilia and discuss opportunities and challenges.
Topics: Acetylgalactosamine; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Blood Coagulation Factors; Clinical Trials as Topic; Coagulants; Factor IX; Factor VIII; Genetic Therapy; Hemophilia A; Hemophilia B; Hemorrhage; History, 20th Century; Humans; Infusions, Intravenous; Injections, Subcutaneous; Laboratories; Life Expectancy; Lipoproteins; RNA, Small Interfering; Severity of Illness Index
PubMed: 32726826
DOI: 10.1055/a-1175-6530 -
Neuromolecular Medicine Jun 2020Alzheimer's disease (AD) is the most common cause of dementia and the number of elderly patients suffering from AD has been steadily increasing. Despite worldwide... (Review)
Review
Alzheimer's disease (AD) is the most common cause of dementia and the number of elderly patients suffering from AD has been steadily increasing. Despite worldwide efforts to cope with this disease, little progress has been achieved with regard to identification of effective therapeutics. Thus, active research focusing on identification of new therapeutic targets of AD is ongoing. Among the new targets, post-translational modifications which modify the properties of mature proteins have gained attention. O-GlcNAcylation, a type of PTM that attaches O-linked β-N-acetylglucosamine (O-GlcNAc) to a protein, is being sought as a new target to treat AD pathologies. O-GlcNAcylation has been known to modify the two important components of AD pathological hallmarks, amyloid precursor protein, and tau protein. In addition, elevating O-GlcNAcylation levels in AD animal models has been shown to be effective in alleviating AD-associated pathology. Although studies investigating the precise mechanism of reversal of AD pathologies by targeting O-GlcNAcylation are not yet complete, it is clearly important to examine O-GlcNAcylation regulation as a target of AD therapeutics. This review highlights the mechanisms of O-GlcNAcylation and its role as a potential therapeutic target under physiological and pathological AD conditions.
Topics: Acetylglucosamine; Aged; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antigens, Neoplasm; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Glycosylation; Hexosamines; Histone Acetyltransferases; Humans; Hyaluronoglucosaminidase; Insulin Resistance; Molecular Structure; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroprotective Agents; Phosphorylation; Protein Isoforms; Protein Processing, Post-Translational; Stroke; Uridine Diphosphate; Uridine Diphosphate N-Acetylgalactosamine; tau Proteins
PubMed: 31894464
DOI: 10.1007/s12017-019-08584-0 -
Methods in Molecular Biology (Clifton,... 2021Small interfering RNA (siRNA)-based therapeutics holds the promise to treat a wide range of human diseases that are currently incurable using conventional therapies.... (Review)
Review
Small interfering RNA (siRNA)-based therapeutics holds the promise to treat a wide range of human diseases that are currently incurable using conventional therapies. Most siRNA therapeutic efforts to date have focused on the treatment of liver diseases due to major breakthroughs in the development of efficient strategies for delivering siRNA drugs to the liver. Indeed, the development of lipid nanoparticle-formulated and GalNAc-conjugated siRNA therapeutics has resulted in recent FDA approvals of the first siRNA-based drugs, patisiran for the treatment of hereditary transthyretin amyloidosis and givosiran for the treatment of acute hepatic porphyria, respectively. Here, we describe the current strategies for delivering siRNA drugs to the liver and summarize recent advances in clinical development of siRNA therapeutics for the treatment of liver diseases.
Topics: Acetylgalactosamine; Amyloid Neuropathies, Familial; Animals; Gene Transfer Techniques; Humans; Liver Diseases; Porphyrias, Hepatic; Pyrrolidines; RNA Interference; RNA, Small Interfering; RNAi Therapeutics
PubMed: 33928570
DOI: 10.1007/978-1-0716-1298-9_5 -
Journal of Bioscience and Bioengineering Oct 2016The chicken β-galactoside α2,3-sialyltransferase 1, 2, and 5 (ST3Gal1, 2, and 5) genes were cloned, and their enzymes were expressed in 293FT cells. ST3Gal1 and 2...
The chicken β-galactoside α2,3-sialyltransferase 1, 2, and 5 (ST3Gal1, 2, and 5) genes were cloned, and their enzymes were expressed in 293FT cells. ST3Gal1 and 2 exhibited enzymatic activities toward galactose-β1,3-N-acetylgalactosamine and galactose-β1,3-N-acetylglucosamine. ST3Gal5 only exhibited activity toward lactosylceramide. ST3Gal1 and 2 and previously cloned ST3Gal3 and 6 transferred CMP-sialic acid to asialofetuin. Reverse-transcription-quantitative PCR indicated that ST3Gal1 was expressed at higher levels in the trachea, lung, spleen, and magnum, and the strong expression of ST3Gal5 was observed in the spleen, magnum, and small and large intestines. ST3Gal1, 5, and 6 were also expressed in the tubular gland cells of the magnum, which secretes egg-white proteins. ST3Gal1, 5, and 6 were expressed in the egg chorioallantoic membrane, in which influenza viruses are propagated for the production of vaccines.
Topics: Acetylgalactosamine; Acetylglucosamine; Animals; Antigens, CD; Asialoglycoproteins; Cell Line; Chickens; Chorioallantoic Membrane; Egg Proteins; Fetuins; Galactose; Glycosylation; Lactosylceramides; Organ Specificity; Recombinant Proteins; Sialyltransferases; Substrate Specificity; beta-Galactoside alpha-2,3-Sialyltransferase
PubMed: 27150510
DOI: 10.1016/j.jbiosc.2016.03.017 -
Signal Transduction and Targeted Therapy Feb 2024Immunostaining in lungs of patients who died with COVID-19 infection showed increased intensity and distribution of chondroitin sulfate and decline in...
Immunostaining in lungs of patients who died with COVID-19 infection showed increased intensity and distribution of chondroitin sulfate and decline in N-acetylgalactostamine-4-sulfatase (Arylsulfatase B; ARSB). To explain these findings, human small airway epithelial cells were exposed to the SARS-CoV-2 spike protein receptor binding domain (SPRBD) and transcriptional mechanisms were investigated. Phospho-p38 MAPK and phospho-SMAD3 increased following exposure to the SPRBD, and their inhibition suppressed the promoter activation of the carbohydrate sulfotransferases CHST15 and CHST11, which contributed to chondroitin sulfate biosynthesis. Decline in ARSB was mediated by phospho-38 MAPK-induced N-terminal Rb phosphorylation and an associated increase in Rb-E2F1 binding and decline in E2F1 binding to the ARSB promoter. The increases in chondroitin sulfotransferases were inhibited when treated with phospho-p38-MAPK inhibitors, SMAD3 (SIS3) inhibitors, as well as antihistamine desloratadine and antibiotic monensin. In the mouse model of carrageenan-induced systemic inflammation, increases in phospho-p38 MAPK and expression of CHST15 and CHST11 and declines in DNA-E2F binding and ARSB expression occurred in the lung, similar to the observed effects in this SPRBD model of COVID-19 infection. Since accumulation of chondroitin sulfates is associated with fibrotic lung conditions and diffuse alveolar damage, increased attention to p38-MAPK inhibition may be beneficial in ameliorating Covid-19 infections.
Topics: Mice; Animals; Humans; N-Acetylgalactosamine-4-Sulfatase; Chondroitin Sulfates; Spike Glycoprotein, Coronavirus; Carbohydrate Sulfotransferases; Angiotensin-Converting Enzyme 2; p38 Mitogen-Activated Protein Kinases; COVID-19; SARS-CoV-2
PubMed: 38355690
DOI: 10.1038/s41392-024-01741-3 -
International Journal of Molecular... Oct 2022The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS... (Review)
Review
The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome). The newly directed attention to the impact of ARSB in human pathobiology indicates a broader, more pervasive effect, encompassing roles as a tumor suppressor, transcriptional mediator, redox switch, and regulator of intracellular and extracellular-cell signaling. By controlling the degradation of chondroitin 4-sulfate and dermatan sulfate by removal or failure to remove the 4-sulfate residue at the non-reducing end of the sulfated glycosaminoglycan chain, ARSB modifies the binding or release of critical molecules into the cell milieu. These molecules, such as galectin-3 and SHP-2, in turn, influence crucial cellular processes and events which determine cell fate. Identification of ARSB at the cell membrane and in the nucleus expands perception of the potential impact of decline in ARSB activity. The regulation of availability of sulfate from chondroitin 4-sulfate and dermatan sulfate may also affect sulfate assimilation and production of vital molecules, including glutathione and cysteine. Increased attention to ARSB in mammalian cells may help to integrate and deepen our understanding of diverse biological phenomenon and to approach human diseases with new insights.
Topics: Humans; Chondroitin Sulfates; Dermatan Sulfate; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase; Sulfates
PubMed: 36361933
DOI: 10.3390/ijms232113146