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Chemistry (Weinheim An Der Bergstrasse,... Sep 2023A series of new conjugates comprised from a small synthetic antimicrobial peptide (AMP) and a siderophore-type vector component was designed and tested for activity on...
A series of new conjugates comprised from a small synthetic antimicrobial peptide (AMP) and a siderophore-type vector component was designed and tested for activity on P. aeruginosa PAO1 and several genetically modified strains. As AMP, the well-established arginine-tryptophane combination K(RW) (P1) was chosen with an added lysine for siderophore attachment. This peptide is easy to prepare, modify, and possesses good anti-bacterial activity. On the vector part, we examined several moieties: (i) the natural siderophore deferoxamine (DFO); (ii) bidentate iron chelators based on the hydroxamate building block (4 a-c) ; (iii) the non-siderophore chelators deferasirox (DFX) and deferiprone-carboxylate (DFP-COOH). All conjugates were prepared by solid phase synthesis techniques and fully characterized by HPLC and mass spectrometry (including HR-MS). Fe uptake assays indicate a receptor-mediated uptake for 4 a-c, DFP-COOH and DFO, which is dependent on the outer membrane transporter FoxA in the case of DFO. All conjugates showed increased antibacterial activity against P. aeruginosa compared to the parent peptide P1 alone when investigated in iron-depleted medium. MIC values were as low as 2 μM (for P1-DFP) on wild type P. aeruginosa. The activity of P1-DFO and P1-DFP was even better on genetically mutated strains unable to produce siderophores (down to 0.5 μM). Although the DFX vector on its own was not able to transport iron inside the bacterial cell as shown by Fe uptake studies, the P1-DFX conjugate had excellent antibacterial activity compared to P1 (2 μM, and as low as 0.25 μM on a receptor-deficient strain unable to produce siderophores), suggesting that the conjugates were indeed recognized and internalized by an (unknown) transporter. Control experiments with an equimolar mixture of P1 and DFX confirm that the observed activity is intrinsic to vectorization. This work thus demonstrates the power of linking small AMPs covalently to siderophores for a new class of Trojan Horse antibiotics, with P1-DFP and P1-DFX being the most potent conjugates.
Topics: Siderophores; Pseudomonas aeruginosa; Iron; Anti-Bacterial Agents; Membrane Transport Proteins; Peptides; Carrier Proteins
PubMed: 37541431
DOI: 10.1002/chem.202300364 -
Human & Experimental Toxicology 2023Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a...
Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a wide range of oxidation - reduction activities. Whenever iron exceeds the cellular metabolic needs, its excess causes changes in the products of cellular respiration, such as superoxide, hydrogen peroxide and hydroxyl. The formation of these compounds causes cellular toxicity. Lack of control over reactive oxygen species causes damages to DNA, proteins, and lipids. Conversely, superoxide, hydrogen peroxide and hydroxyl are reactive oxygen species, using antioxidants, restoring DNA function, and controlling iron stores lead to natural conditions. Iron poisoning causes clinical manifestations in the gastrointestinal tract, liver, heart, kidneys, and hematopoietic system. When serum iron is elevated, serum iron concentrations, total iron-binding capacity (TIBC) and ferritin will also increase. Supportive care is provided by whole bowel irrigation (WBI), esophagogastroduodenoscopy is required to evaluate mucosal injury and remove undissolved iron tablets. The use of chelator agents such as deferoxamine mesylate, deferasirox, deferiprone, deferitrin are very effective in removing excess iron. Of course, the combined treatment of these chelators plays an important role in increasing iron excretion, and reducing side effects.
Topics: Humans; Iron; Iron Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Reactive Oxygen Species; Superoxides; Hydrogen Peroxide; Pyridones; Benzoates; Triazoles; DNA
PubMed: 37526177
DOI: 10.1177/09603271231192361 -
Caspian Journal of Internal Medicine 2023Growth retardation is a long-term complication in pediatric transfusion-dependent thalassemias (TDTs), presented as short-stature and upper body segment shortening. The...
BACKGROUND
Growth retardation is a long-term complication in pediatric transfusion-dependent thalassemias (TDTs), presented as short-stature and upper body segment shortening. The cause of this condition was chronic hypoxia, iron overload, endocrinopathy, inadequate transfusion, and iron chelation. We analyze the relationship between ferritin level and growth status of pediatric TDTs.
METHODS
This was a cross-sectional study on pediatric TDTs aged 2-18 years old at Dr. Soetomo General Academic Hospital Surabaya, Indonesia conducted in 2020. They required blood transfusion every 2-4 weeks. We evaluated the ratio of upper/lower body segments, weight for age Z-score (WAZ), height for age Z-score (HAZ), and body mass index (BMI) Z-score, based on CDC growth chart as growth status parameters. Serum ferritin was checked every three months to determine iron overload and iron chelation (deferiprone, deferasirox and deferoxamine). We used Spearman correlation and Mann-Whitney U test to analyze between variables (α=0.05).
RESULTS
We enrolled 15/29 males with median age 10.5 years. Serum Ferritin had negative correlation with the ratio of upper/lower body segments (rho=-0.552; P=0.002), but not for HAZ (rho=-0.078; P=0.694), WAZ (rho=-0.186; P=0.342), BMI Z-score (rho=-0.089; P=0.653) especially if serum ferritin was above 2500 µ/L. In deferiprone group (n=8), the WAZ (P=0.034) and BMI Z-score (P=0.031) were lower; but the ratio of upper/lower body segments was greater (P=0.039) than the deferasirox group.
CONCLUSION
Growth retardation was more visible in pediatric TDTs with high ferritin and in deferiprone group. The height and the ratio of upper/lower body segments of the body were more affected.
PubMed: 37520873
DOI: 10.22088/cjim.14.3.425 -
La Revue de Medecine Interne Dec 2023Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including... (Review)
Review
Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including transferrin saturation. The classification between hyperferritinemia without iron overload (inflammation, excessive alcohol intake, cytolysis, L-ferritin mutation) or with iron overload is then relatively easy. Dysmetabolic iron overload syndrome is the most common iron overload disease and is defined by an unexplained serum ferritin level elevation associated with various metabolic syndrome criteria and mild hepatic iron content increase assessed by magnetic resonance imaging. Bloodlettings are often poorly tolerated without clear benefit. Type 1 genetic hemochromatosis (homozygous C282Y mutation on the HFE gene) leads to iron accumulation through an increase of dietary iron absorption due to hypohepcidinemia. More than 95% of hemochromatosis are type 1 hemochromatosis but the phenotypic expression is highly variable. Elastography is recommended to identify advanced hepatic fibrosis when serum ferritin exceeds 1000μg/L. Life expectancy is normal when bloodlettings are started early. Ferroportin gene mutation is an autosomal dominant disease with generally moderate iron overload. Chelators are used in iron overload associated with anaemia (myelodysplastic syndromes or transfusion-dependent thalassemia). Chelation is initiated when hepatic iron content exceeds 120μmol/g. Deferasirox is often used as first-line therapy, but deferiprone may be of interest despite haematological toxicity (neutropenia). Deferoxamine (parenteral route) is the treatment of choice for severe iron overload or emergency conditions.
Topics: Humans; Hemochromatosis; Hyperferritinemia; Iron Overload; Iron; Ferritins
PubMed: 37507250
DOI: 10.1016/j.revmed.2023.07.002 -
Gastroenterologia Y Hepatologia Apr 2024
Topics: Humans; Crohn Disease; Deferasirox; Colitis; Ileitis
PubMed: 37468041
DOI: 10.1016/j.gastrohep.2023.07.002 -
European Review For Medical and... Jul 2023β-thalassemia major is an inherited hematological disorder with significant oxidative stress and iron overload. Oxidative stress results in several pathological... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparative effectiveness of adding omega-3 and Manuka honey combination to conventional therapy in preventing and treating oxidative stress in pediatric β-thalassemia major - a randomized clinical trial.
OBJECTIVE
β-thalassemia major is an inherited hematological disorder with significant oxidative stress and iron overload. Oxidative stress results in several pathological complications, including cell death, tissue injury, organ dysfunction, and thyroid dysfunction. The present study examined the effectiveness of omega-3 and Manuka honey combination or Manuka honey alone to the conventional therapy (deferasirox, blood transfusion, and L-carnitine) used for preventing and managing oxidative stress or iron overload-induced oxidative stress conditions in pediatric β-thalassemic patients (type major).
PATIENTS AND METHODS
165 patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design multisite trial. The patients were randomly allocated into three groups, receiving either 1,000 mg omega-3 fish oil [350 mg eicosapentaenoic acid (EPA) and 250 mg docosahexaenoic acid (DHA)] combined with Manuka honey lozenge (344 mg) daily or Manuka honey alone plus the conventional therapy for ten months. Plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), Lactate dehydrogenase (LDH), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), CRP (C-reactive protein), ferritin level, and serum iron were determined at baseline and month 10.
RESULTS
Omega-3 and Manuka honey combination were a significant add-on to conventional therapy of β-thalassemia in reducing the oxidative stress condition. The combination of Omega-3 and Manuka honey reduced the level of F2-isoprostane(8-iso-PGF2α) significantly compared to the Manuka alone and the control groups. Additionally, they showed an antihemolytic action measured by reduced LDH level. The combination restored the patient's lipid profile (LDL-C and HDL-C) significantly compared to the control group. Manuka honey enhanced the action of omega-3 in reducing oxidative stress by reducing serum iron significantly compared to the control group.
CONCLUSIONS
Results showed that omega-3 + Manuka honey was more effective than Manuka alone or the conventional treatment alone in managing oxidative stress of β-thalassemic patients.
Topics: Humans; beta-Thalassemia; Cholesterol, LDL; Honey; Fatty Acids, Omega-3; Oxidative Stress; Iron Overload; Iron
PubMed: 37458648
DOI: 10.26355/eurrev_202307_32960 -
Chemical Research in Toxicology Aug 2023Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver...
Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS and to help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5'-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or -acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.
Topics: Rats; Animals; Activation, Metabolic; Deferasirox; Liver; Hepatocytes; Microsomes, Liver; Acetylcysteine; Glutathione
PubMed: 37435843
DOI: 10.1021/acs.chemrestox.2c00416 -
Medical Molecular Morphology Sep 2023Hereditary hemochromatosis type 4 is an autosomal-dominant inherited disease characterized by a mutation in the SLC40A1 gene encoding ferroportin. This condition can be...
Hereditary hemochromatosis type 4 is an autosomal-dominant inherited disease characterized by a mutation in the SLC40A1 gene encoding ferroportin. This condition can be further subdivided into types 4A (loss-of-function mutations) and 4B (gain-of-function mutations). To date, only a few cases of type 4B cases have been reported, and the treatment has not been clearly mentioned. Here, we report a genotype of hereditary hemochromatosis type 4B involving the heterozygous mutation c.997 T > C (p. Tyr333His) in SLC40A1. The patient was treated with red blood cell apheresis every month for 1 year, followed by oral deferasirox, and the combined therapy was found to be effective.
Topics: Humans; Genotype; Hemochromatosis; Iron Overload; Mutation
PubMed: 37382698
DOI: 10.1007/s00795-023-00359-8 -
BMC Cancer Jun 2023
PubMed: 37353751
DOI: 10.1186/s12885-023-11091-y -
Journal of Biochemical and Molecular... Sep 2023During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and... (Review)
Review
During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B (1) and isavuconazole (2) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole (3) and deferasirox (4) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 (5) and APX001A (6), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.
Topics: Humans; Antifungal Agents; Mucormycosis; COVID-19; Amphotericin B; Mucorales
PubMed: 37345721
DOI: 10.1002/jbt.23417