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Oxidative Medicine and Cellular... 2017Glycine is most important and simple, nonessential amino acid in humans, animals, and many mammals. Generally, glycine is synthesized from choline, serine,... (Review)
Review
Glycine is most important and simple, nonessential amino acid in humans, animals, and many mammals. Generally, glycine is synthesized from choline, serine, hydroxyproline, and threonine through interorgan metabolism in which kidneys and liver are the primarily involved. Generally in common feeding conditions, glycine is not sufficiently synthesized in humans, animals, and birds. Glycine acts as precursor for several key metabolites of low molecular weight such as creatine, glutathione, haem, purines, and porphyrins. Glycine is very effective in improving the health and supports the growth and well-being of humans and animals. There are overwhelming reports supporting the role of supplementary glycine in prevention of many diseases and disorders including cancer. Dietary supplementation of proper dose of glycine is effectual in treating metabolic disorders in patients with cardiovascular diseases, several inflammatory diseases, obesity, cancers, and diabetes. Glycine also has the property to enhance the quality of sleep and neurological functions. In this review we will focus on the metabolism of glycine in humans and animals and the recent findings and advances about the beneficial effects and protection of glycine in different disease states.
Topics: Animals; Cardiovascular Diseases; Choline; Dietary Supplements; Glycine; Humans; Kidney; Liver; Metabolic Diseases
PubMed: 28337245
DOI: 10.1155/2017/1716701 -
International Journal of Molecular... Apr 2022Glyphosate, a non-selective systemic biocide with broad-spectrum activity, is the most widely used herbicide in the world. It can persist in the environment for days or... (Review)
Review
Glyphosate, a non-selective systemic biocide with broad-spectrum activity, is the most widely used herbicide in the world. It can persist in the environment for days or months, and its intensive and large-scale use can constitute a major environmental and health problem. In this systematic review, we investigate the current state of our knowledge related to the effects of this pesticide on the nervous system of various animal species and humans. The information provided indicates that exposure to glyphosate or its commercial formulations induces several neurotoxic effects. It has been shown that exposure to this pesticide during the early stages of life can seriously affect normal cell development by deregulating some of the signaling pathways involved in this process, leading to alterations in differentiation, neuronal growth, and myelination. Glyphosate also seems to exert a significant toxic effect on neurotransmission and to induce oxidative stress, neuroinflammation and mitochondrial dysfunction, processes that lead to neuronal death due to autophagy, necrosis, or apoptosis, as well as the appearance of behavioral and motor disorders. The doses of glyphosate that produce these neurotoxic effects vary widely but are lower than the limits set by regulatory agencies. Although there are important discrepancies between the analyzed findings, it is unequivocal that exposure to glyphosate produces important alterations in the structure and function of the nervous system of humans, rodents, fish, and invertebrates.
Topics: Animals; Central Nervous System Depressants; Glycine; Herbicides; Neurotoxicity Syndromes; Glyphosate
PubMed: 35562999
DOI: 10.3390/ijms23094605 -
Clinical Lymphoma, Myeloma & Leukemia Sep 2021Glyphosate-based formulations (GBFs), such as Roundup, are the most heavily used herbicides in the world. In 2015, the International Agency for Research on Cancer (IARC)... (Review)
Review
Glyphosate-based formulations (GBFs), such as Roundup, are the most heavily used herbicides in the world. In 2015, the International Agency for Research on Cancer (IARC) concluded that glyphosate and GBFs are probably carcinogenic to humans (group 2A), mainly for non-Hodgkin lymphoma (NHL). However, this finding has been controversial, and most pesticide regulatory agencies have not followed their lead. The purpose of this review was to examine the scientific literature linking exposure to glyphosate and GBFs to the development of NHL, with emphasis on new findings since publication of the IARC report. The epidemiologic studies provide ample evidence for an association between exposure to GBFs and an increased risk of NHL. Animal studies have shown that glyphosate is carcinogenic in rodents and causes NHL in mice. Mechanistic studies have demonstrated that glyphosate and GBFs are genotoxic to human lymphocytes, the normal cell of origin of NHL, both in vitro and in vivo. Genotoxic and other biological effects have also been shown in various animal and cell models with these agents even at low doses. A novel mechanism underlying the specificity of glyphosate for NHL, that is upregulation of the B-cell genome mutator enzyme activation-induced cytidine deaminase, has recently been demonstrated. These findings were evaluated holistically using the guidelines for evaluation of general causation set forth by Bradford Hill. This evaluation provides coherent and compelling evidence that glyphosate and GBFs are a cause of NHL in humans exposed to these agents. These findings should prompt new reviews by pesticide regulatory agencies around the world.
Topics: Glycine; Herbicides; Humans; Lymphoma, Non-Hodgkin; Glyphosate
PubMed: 34052177
DOI: 10.1016/j.clml.2021.04.009 -
American Journal of Hematology Feb 2022Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase... (Randomized Controlled Trial)
Randomized Controlled Trial
Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase.
Topics: Aged; Anemia; Double-Blind Method; Female; Glycine; Humans; Isoquinolines; Male; Middle Aged; Myelodysplastic Syndromes; Placebo Effect; Treatment Outcome
PubMed: 34724251
DOI: 10.1002/ajh.26397 -
Clinical Pharmacokinetics Mar 2022The pharmacokinetics of roxadustat are well characterized, with an apparent volume of distribution after oral administration of 22-57 L, apparent clearance of... (Review)
Review
The pharmacokinetics of roxadustat are well characterized, with an apparent volume of distribution after oral administration of 22-57 L, apparent clearance of 1.2-2.65 L/h, and renal clearance of 0.030-0.026 L/h in healthy volunteers; the elimination half-life is 9.6-16 h. Plasma binding is 99% and the fraction eliminated by hemodialysis is 2.34%. As an interpretation of the pharmacodynamics of roxadustat, we proposed a concept with a hypothetical cascade of two subsequent effects, first on erythropoetin (EPO) and second on hemoglobin (delta Hb). The primary effect on EPO is observed within a few hours after roxadustat administration and can be modeled using the sigmoidal Hill equation. The concentration at half-maximum effect can be inferred at 10-36 µg/mL, the Hill coefficient at 3.3, and the effect bisection time at 10-17 h, corresponding to EPO half-life. The subsequent effect on hemoglobin (delta Hb) is observed after several weeks and can be interpreted as an irreversible, dose proportional, unsaturable effect, continuing in agreement with the lifespan of red blood cells of 63-112 days.
Topics: Glycine; Hemoglobins; Humans; Isoquinolines
PubMed: 34905154
DOI: 10.1007/s40262-021-01095-x -
Journal of Clinical Oncology : Official... May 2020Surgery is the primary therapy for localized chondrosarcoma; for locally advanced and/or metastatic disease, no known effective systemic therapy exists. Mutations in the...
PURPOSE
Surgery is the primary therapy for localized chondrosarcoma; for locally advanced and/or metastatic disease, no known effective systemic therapy exists. Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a selective inhibitor of mutant IDH1 approved in the United States for specific cases of acute myeloid leukemia. We report outcomes of patients with advanced chondrosarcoma in an ongoing study exploring ivosidenib treatment.
PATIENTS AND METHODS
This phase I multicenter open-label dose-escalation and expansion study of ivosidenib monotherapy enrolled patients with mutant advanced solid tumors, including chondrosarcoma. Ivosidenib was administered orally (100 mg twice daily to 1,200 mg once daily) in continuous 28-day cycles. Responses were assessed every other cycle using RECIST (version 1.1).
RESULTS
Twenty-one patients (escalation, n = 12; expansion, n = 9) with advanced chondrosarcoma received ivosidenib (women, n = 8; median age, 55 years; range, 30-88 years; 11 had received prior systemic therapy). Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. Twelve patients experienced grade ≥ 3 AEs; only one event was judged treatment related (hypophosphatemia, n = 1). Plasma 2-HG levels decreased substantially in all patients (range, 14%-94.2%), to levels seen in healthy individuals. Median progression-free survival (PFS) was 5.6 months (95% CI, 1.9 to 7.4 months); the PFS rate at 6 months was 39.5%. Eleven (52%) of 21 patients experienced stable disease.
CONCLUSION
In patients with chondrosarcoma, ivosidenib showed minimal toxicity, substantial 2-HG reduction, and durable disease control. Future studies of ivosidenib monotherapy or rational combination approaches should be considered in patients with advanced mutant chondrosarcoma.
Topics: Adult; Aged; Aged, 80 and over; Chondrosarcoma; Enzyme Inhibitors; Female; Glycine; Humans; Male; Middle Aged; Pyridines
PubMed: 32208957
DOI: 10.1200/JCO.19.02492 -
International Journal of Environmental... Oct 2020Glyphosate is a non-specific organophosphate pesticide, which finds widespread application in shielding crops against the weeds. Its high solubility in hydrophilic... (Review)
Review
Glyphosate is a non-specific organophosphate pesticide, which finds widespread application in shielding crops against the weeds. Its high solubility in hydrophilic solvents, especially water and high mobility allows the rapid leaching of the glyphosate into the soil leading to contamination of groundwater and accumulation into the plant tissues, therefore intricating the elimination of the herbicides. Despite the widespread application, only a few percentages of the total applied glyphosate serve the actual purpose, dispensing the rest in the environment, thus resulting in reduced crop yields, low quality agricultural products, deteriorating soil fertility, contributing to water pollution, and consequently threatening human and animal life. This review gives an insight into the toxicological effects of the herbicide glyphosate and current approaches to track and identify trace amounts of this agrochemical along with its biodegradability and possible remediating strategies. Efforts have also been made to summarize the biodegradation mechanisms and catabolic enzymes involved in glyphosate metabolism.
Topics: Biodegradation, Environmental; Glycine; Herbicides; Humans; Plant Weeds; Glyphosate
PubMed: 33076575
DOI: 10.3390/ijerph17207519 -
Drugs Sep 2018Ivosidenib (Tibsovo) is a small molecule, orally available inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1) that is being developed by Agios... (Review)
Review
Ivosidenib (Tibsovo) is a small molecule, orally available inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1) that is being developed by Agios Pharmaceuticals for the treatment of cancer in patients with IDH1 mutations. The mutated form of the IDH1 enzyme produces a metabolite, 2-hydroxyglutarate (2-HG), which is thought to play a role in the formation and progression of acute myeloid leukaemia (AML), gliomas and other cancers. Elevated 2-HG levels interfere with cellular metabolism and epigenetic regulation, thereby contributing to oncogenesis. Ivosidenib targets the IDH1 metabolic pathway to prevent a build-up of the oncometabolite 2-HG. This article summarizes the milestones in the development of ivosidenib leading to this first approval in the USA for the treatment of patients with relapsed or refractory AML with a susceptible IDH1 mutation. Clinical development for AML, cholangiocarcinoma, glioma, myelodysplastic syndromes and solid tumours is ongoing worldwide.
Topics: Antineoplastic Agents; Cytochrome P-450 CYP3A; Drug Approval; Enzyme Inhibitors; Epigenesis, Genetic; Glycine; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Pyridines
PubMed: 30209701
DOI: 10.1007/s40265-018-0978-3 -
Nature Dec 2021The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development,...
The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity. Aberrant ALK signalling causes numerous cancers. In particular, full-length ALK is an important driver in paediatric neuroblastoma, in which it is either mutated or activated by ligand. Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides. Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a sensor for the complex by interacting with a ligand-bound second receptor. ALK activation can be abolished through PXL mutation or with PXL-targeting antibodies. Together, these results explain how ALK uses its atypical architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers such as paediatric neuroblastoma.
Topics: Anaplastic Lymphoma Kinase; Animals; Binding Sites; Crystallography, X-Ray; Glycine; Humans; Infant; Ligands; Male; Mice; Models, Molecular; Mutation; NIH 3T3 Cells; Neuroblastoma; Protein Domains; Protein Multimerization
PubMed: 34819665
DOI: 10.1038/s41586-021-04141-7 -
Translational Research : the Journal of... Aug 2018Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple... (Review)
Review
Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple myeloma (MM) and have sales in excess of 3 billion US dollars annually. More importantly, the availability of proteasome inhibitors has greatly improved the survival and quality of life for patients with MM. Despite the remarkable success of proteasome inhibitor therapies to date, the potential for improvement remains, and the development and optimal use of proteasome inhibitors as anticancer agents continues to be an active area of research. In this review, we briefly discuss the features and limitations of the 3 proteasome inhibitor drugs currently used in the clinic and provide an update on current efforts to develop next-generation proteasome inhibitors with the potential to overcome the limitations of existing proteasome inhibitor drugs.
Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Drug Resistance, Neoplasm; Glycine; Humans; Neoplasms; Oligopeptides; Proteasome Inhibitors
PubMed: 29654740
DOI: 10.1016/j.trsl.2018.03.002