scholarly journals Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2353 ◽  
Author(s):  
Sophia L Samodelov ◽  
Zhibo Gai ◽  
Gerd A Kullak-Ublick ◽  
Michele Visentin
Keyword(s):  
Intestinal Absorption ◽  
De Novo ◽  
Therapeutic Potential ◽  
Folate Receptor ◽  
Kidney Injury ◽  
Acid Synthesis ◽  
Water Soluble ◽  
Neurological Deficits ◽  
High Dose ◽  
Renal Reabsorption

Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to methionine. Due to their key roles in nucleic acid synthesis and in DNA methylation, inhibiting the folate pathway is still one of the most efficient approaches for the treatment of several tumors. Methotrexate and pemetrexed are the most prescribed antifolates and are mainly used in the treatment of acute myeloid leukemia, osteosarcoma, and lung cancers. Normal levels of folates in the blood are maintained not only by proper dietary intake and intestinal absorption, but also by an efficient renal reabsorption that seems to be primarily mediated by the glycosylphosphatidylinositol- (GPI) anchored protein folate receptor α (FRα), which is highly expressed at the brush-border membrane of proximal tubule cells. Folate deficiency due to malnutrition, impaired intestinal absorption or increased urinary elimination is associated with severe hematological and neurological deficits. This review describes the role of the kidneys in folate homeostasis, the molecular basis of folate handling by the kidneys, and the use of high dose folic acid as a model of acute kidney injury. Finally, we provide an overview on the development of folate-based compounds and their possible therapeutic potential and toxicological ramifications.

Pantothenate biosynthesis in higher plants

2005 ◽  
Vol 33 (4) ◽  
pp. 743-746 ◽  
Author(s):  
K.M. Coxon ◽  
E. Chakauya ◽  
H.H. Ottenhof ◽  
H.M. Whitney ◽  
T.L. Blundell ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
De Novo ◽  
Higher Plants ◽  
Acyl Carrier Protein ◽  
Expression Patterns ◽  
Acid Synthesis ◽  
Water Soluble ◽  
Genes Encoding ◽  
Green Fluorescent ◽  
Micro Organisms

Pantothenate (vitamin B5) is a water-soluble vitamin essential for the synthesis of CoA and ACP (acyl-carrier protein, cofactors in energy yielding reactions including carbohydrate metabolism and fatty acid synthesis. Pantothenate is synthesized de novo by plants and micro-organisms; however, animals obtain the vitamin through their diet. Utilizing our knowledge of the pathway in Escherichia coli, we have discovered and cloned genes encoding the first and last enzymes of the pathway from Arabidopsis, panB1, panB2 and panC. It is unlikely that there is a homologue of the E. coli panD gene, therefore plants must make β-alanine by an alternative route. Possible candidates for the remaining gene, panE, are being investigated. GFP (green fluorescent protein) fusions of the three identified plant enzymes have been generated and the subcellular localization of the enzymes studied. Work is now being performed to elucidate expression patterns of the transcripts and characterize the proteins encoded by these genes.

Hyaluronidase synthase 3 (HAS3) variant and anthracycline-related cardiomyopathy: A report from the Children’s Oncology Group.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10004-10004
Author(s):  
Can-Lan Sun ◽  
Xuexia Wang ◽  
Wei Liu ◽  
Saro Armenian ◽  
Hakon Hankonarson ◽  
...  
Keyword(s):  
Childhood Cancer ◽  
De Novo ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Snp Array ◽  
Heart Association ◽  
Host Susceptibility ◽  
High Dose ◽  
Modifying Effect ◽  
Dose Dependent

10004 Background: The strong dose-dependent association between anthracyclines and cardiomyopathy limits the therapeutic potential of this extremely effective class of agents, demanding identification of those at highest risk, such that anthracycline exposure may be tailored. Methods: In a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy in cancer survivors by using the ITMAT/Broad/CARe cardiovascular SNP-array to profile common SNPs in 2100 genes considered most relevant to de novo cardiovascular disease. All cases of cardiomyopathy fulfilled American Heart Association (AHA) criteria for cardiac compromise and were confirmed echocardiographically. Results: Using a matched case-control design (93 cases, 194 controls, all non-Hispanic white survivors of childhood cancer) we identified a common SNP rs2232228 in hyaluronan synthase (HAS3) gene that exerts a substantial modifying effect on anthracycline dose-dependent risk of cardiomyopathy. Among individuals with GG genotype, cumulative anthracycline exposure was not associated with cardiomypathy risk at any dose. Individuals with AA genotype, exposed to >250mg/m2 anthracyclines, had an 8.5-fold increased cardiomyopathy risk (95%CI, 2.0-35.6, p=0.004). Replication in an independent set of 76 patients (adult-onset and childhood cancer; all races) with anthracycline-related cardiomyopathy revealed the odds of cases with AA genotype in the high-dose anthracycline group to be 4.5-times higher (95%CI, 1.1-18.4, p=0.04). Hyaluronan (HA) – produced by HAS3 – is a ubiquitous component of extracellular matrix (ECM). ECM is involved in tissue remodeling; the extent of cardiac remodeling/repair after anthracycline-induced cardiac injury is possibly modulated by variability in HA production. Conclusions: The significant modifying effect of HAS3 genotype on the dose-dependent association between anthracycline and cardiomyopathy risk suggests that, upon confirmation in prospective studies, genotyping HAS3 may be considered when evaluating risk of anthracycline-related cardiomyopathy.

scholarly journals Salvia miltiorrhizaInjection Ameliorates Renal Damage Induced by Lead Exposure in Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Lei Li ◽  
Yuanyuan Zhang ◽  
Juanjuan Ma ◽  
Weichong Dong ◽  
Qiongtao Song ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Salvia Miltiorrhiza ◽  
Kidney Injury ◽  
Serum Levels ◽  
Organ Injury ◽  
Therapeutic Drug ◽  
High Dose ◽  
Protective Effects ◽  
Pb Accumulation ◽  
And Function

Exposure to lead (Pb) can induce kidney injury and our recent studies have found thatSalvia miltiorrhiza(SM) injection, a traditional Chinese medicine, could protect against the organ injury induced by iron overload. This study was designed to investigate the protective effects of SM injection on nephrotoxicity induced by Pb acetate in mice and to elucidate the potential mechanism(s). Healthy male mice were randomly divided into four groups: control, Pb, low-doseSalvia miltiorrhiza(L-SM), and high-doseSalvia miltiorrhiza(H-SM). SM injection dose dependently reduced the Pb accumulation in the kidney, decreased kidney coefficients, and ameliorated renal structure and function from the morphology analysis. Meanwhile, SM administration downregulated serum levels of blood urea nitrogen (BUN) and creatinine (CR), decreased malondialdehyde (MAD) content, and increased activities of super oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the kidney homogenate. Moreover, SM injection reduced the level of renal apoptosis by immunohistochemical staining analysis. Our findings implicate the therapeutic potential of SM injection for Pb-induced nephrotoxicity, which were at least partly due to the decrease of Pb accumulation, inhibition of lipid peroxidation, and suppression of renal apoptosis. These results provided preliminary experimental support for Danshen as a therapeutic drug for Pb poisoning diseases.

Therapeutic Potential of Vitamin C: An Overview of Various Biological Activities

2019 ◽  
Vol 10 (04) ◽  
pp. 605-612
Author(s):  
Lata Rani ◽  
Neelam Sharma ◽  
Sukhbir Singh ◽  
Ajmer Singh Grewal
Keyword(s):  
Vitamin C ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
The Body ◽  
Water Soluble ◽  
Leafy Vegetables ◽  
High Dose ◽  
Black Currant ◽  
Green Leafy Vegetables ◽  
Age Related

Vitamins are vital nutrients that are required for different body functions properly, and they are provided to the body externally through diet. Vitamin C, also known as ascorbic acid, is an essential nutrient that is required for the proper running of different body functions. It is a water-soluble vitamin and lost during the processing of food. The main sources of vitamin C are citrus fruits (kakadu plum, acerola cherries, guavas, kiwi, lemon, lychees, kale, oranges, peaches, tomatoes, black currant, thyme, parsley, rose hips, kale and strawberries), green leafy vegetables (chilli peppers, tomato, sweet yellow peppers, parsley, brussel sprouts, potatoes, mustard spinach and broccoli), fortified cereal and some animals. Vitamin C deficiency leads to scurvy, which mainly affects older, malnourished adults. Vitamin C acts as a strong antioxidant, and this property enriches various biological activities. It is believed that high dose of vitamin C may help in reducing the risk of various diseases like cancer, diabetes, cardiovascular disorders, blood pressure, respiratory syndromes, common cold, reproduction, cognitive diseases, skin problems, age-related muscular degeneration, cataract and may enhance immunity. This mini-review article has been planned to discuss sources, deficiency symptoms, daily requirements, therapeutic potential, and various biological activities of vitamin C. Various therapeutic and pharmacological activities of vitamin C will be discussed in detail with suitable examples.

scholarly journals General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shay Laps ◽  
Fatima Atamleh ◽  
Guy Kamnesky ◽  
Hao Sun ◽  
Ashraf Brik
Keyword(s):  
Drug Discovery ◽  
Disulfide Bonds ◽  
Unsolved Problem ◽  
De Novo ◽  
Therapeutic Potential ◽  
Selective Activation ◽  
One Pot ◽  
Synthetic Strategy ◽  
The One ◽  
Game Changer

AbstractDespite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery.

Acute kidney injury and nephrotic syndrome associated with eltrombopag therapy in chronic idiopathic thrombocytopenic purpura

2021 ◽  
Vol 14 (4) ◽  
pp. e241462
Author(s):  
Suchi Anindita Ghosh ◽  
Jean Patrick ◽  
Kyaw Zin Maw
Keyword(s):  
Acute Kidney Injury ◽  
Renal Failure ◽  
Nephrotic Syndrome ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Kidney Injury ◽  
High Dose ◽  
Chronic Idiopathic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Antibody Screen ◽  
Auto Antibody

A 77-year-old man was admitted with severe acute kidney injury and nephrotic syndrome. He was started on eltrombopag for chronic idiopathic thrombocytopenic purpura 6 weeks earlier. An ultrasound of the kidneys was normal and an auto-antibody screen was negative. The use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient’s development of acute renal failure and eltrombopag therapy. Literature review identified only one other case of nephrotic syndrome and acute kidney injury associated with eltrombopag therapy in which a kidney biopsy revealed focal segmental glomerulosclerosis. Due to the challenges faced during the prevailing SARS-CoV-2 pandemic and persistent low platelet counts a renal biopsy was not undertaken. On stopping eltrombopag, the patients renal function stabilised and he successfully went into remission following treatment with high dose corticosteroids and diuretics. This report of a serious case of reversible renal failure and nephrotic syndrome after treatment with eltrombopag may serve to inform clinicians about the possible severe renal adverse effects of eltrombopag before its commencement for future use.

scholarly journals Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury

2021 ◽  
Vol 22 (10) ◽  
pp. 5386
Author(s):  
Maria Namwanje ◽  
Bijay Bisunke ◽  
Thomas V. Rousselle ◽  
Gene G. Lamanilao ◽  
Venkatadri S. Sunder ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
Graft Loss ◽  
Kidney Injury ◽  
Adaptive Immune ◽  
Consumption Rates ◽  
Regulatory Phenotype

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.

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