Search Results (383)

Chelation therapy is currently successfully applied to reduce the aluminum burden and its neurodegenerative consequences. In view of a possible application to aluminum chelation therapy, here we have studied the complexation of hydroxybenzoic acids, namely, vanillic, syringic and gallic acids, towards aluminum ion at physiologically relevant conditions as regards temperature (37 °C) and ionic strength (i.e., 0.16 M NaCl). The solubility values and the protonation constants of the hydroxybenzoic acids were primarily assessed to estimate the competition of these acids towards aluminum and H⁺ ions. Then, potentiometric titrations were carried out, and the speciation analysis indicated a pH-dependent complexation occurring at a 1:1 hydroxybenzoic acid-to-aluminum ratio for vanillic and syringic, and 1:1, 2:1 and 3:1 ligand-to-Al(III) ratios for gallic. Gallic acid forms more stable complexes with Al(III) ion than vanillic and syringic acids and could therefore represent a good candidate for being used as sequestering agents for Al(III) ion. Full article

Based on the established neuroprotective properties of indole-based compounds and their significant potential as multi-targeted therapeutic agents, a series of synthetic indole–phenolic compounds was evaluated as multifunctional neuroprotectors. Each compound demonstrated metal-chelating properties, particularly in sequestering copper ions, with quantitative analysis revealing approximately 40% chelating activity across all the compounds. In cellular models, these hybrid compounds exhibited strong antioxidant and cytoprotective effects, countering reactive oxygen species (ROS) generated by the Aβ(25–35) peptide and its oxidative byproduct, hydrogen peroxide, as demonstrated by quantitative analysis showing on average a 25% increase in cell viability and a reduction in ROS levels to basal states. Further analysis using thioflavin T fluorescence assays, circular dichroism, and computational studies indicated that the synthesized derivatives effectively promoted the self-disaggregation of the Aβ(25–35) fragment. Taken together, these findings suggest a unique profile of neuroprotective actions for indole–phenolic derivatives, combining chelating, antioxidant, and anti-aggregation properties, which position them as promising compounds for the development of multifunctional agents in Alzheimer’s disease therapy. The methods used provide reliable in vitro data, although further in vivo validation and assessment of blood–brain barrier penetration are needed to confirm therapeutic efficacy and safety. Full article

Thalassemia is an autosomal recessive hereditary chronic hemolytic anemia characterized by a partial or complete deficiency in the synthesis of alpha- or beta-globin chains, which are essential components of adult hemoglobin. Mutations in the globin genes lead to the production of unstable globin chains that precipitate within cells, causing hemolysis. This shortens the lifespan of mature red blood cells (RBCs) and results in the premature destruction of RBC precursors in the bone marrow. Regular red blood cell transfusions are the standard treatment for thalassemia. However, these transfusions can lead to increased iron overload, which can impair vital systems such as the liver, heart, ovaries, and endocrine system. Focusing on female reproductive endocrinology, recurrent blood transfusions can cause iron accumulation in the pituitary and hypothalamus, leading to hypogonadotropic hypogonadism (HH), the most common endocrinopathy in these patients, affecting 40–91% of women. Recurrent transfusions and the resulting iron overload can also lead to oxidative stress and ovarian damage in patients with beta-thalassemia major (BTM). Despite advancements in iron chelation therapy, hypothalamic–pituitary damage associated with HH contributes to subfertility and sexual dysfunction, often with little to no recovery. In women exposed to gonadotoxic drugs, particularly those with BTM, anti-Mullerian hormone (AMH)—a marker of ovarian reserve—is frequently used to assess ovarian damage. This review aims to explore the pathophysiology of β-thalassemia and its major clinical manifestations, with a focus on endocrine complications and their impact on ovarian reserve. It also investigates how metabolomics can provide insights into the disease’s metabolic alterations and inform current and emerging therapeutic strategies to mitigate complications and optimize patient outcomes, potentially leading to more effective and personalized treatments. Full article

Background/Objectives: In the absence of physiological mechanisms to excrete excessive iron, the administration of iron chelation therapy is necessary. Age and hormones have an impact on the absorption, distribution, metabolism, and excretion of the medications used to treat iron excess, resulting in notable sex- and gender-related variances. Methods: Here, we aimed to review the literature on sex and gender in iron overload assessment and treatment. Results: The development of iron chelators has shown to be a successful therapy for lowering the body’s iron levels and averting the tissue damage and organ failure that follows. Numerous studies have described how individual factors can impact chelation treatment, potentially impact therapeutic response, and/or result in inadequate chelation or elevated toxicity; however, most of these data have not considered male and female patients as different groups, and particularly, the effect of hormonal variations in women have never been considered. Conclusions: An effective iron chelation treatment should take into account sex and gender differences. Full article

Background: Fibroblast activation protein (FAP)-targeted theranostic radiopharmaceuticals have shown desired tumor-to-background organ selectivity due to the ubiquitous presence of FAP within the tumor microenvironment. However, suboptimal tumor retention and fast clearance have hindered their use to deliver effective cancer therapies. With well-documented FAP-targeting moieties and linkers appending them to optimal chelators, the development of copper radiopharmaceuticals has attracted considerable interest, given the fact that an ideal theranostic pair of copper radionuclides (⁶⁴Cu: t_1/2 = 12.7 h; 17.4% β⁺; E_β⁺_max = 653 keV and ⁶⁷Cu: t_1/2 = 2.58 d; 100% β⁻; E_β⁻_max = 562 keV) are available. Herein, we report our design, synthesis, and comparative evaluation of monovalent and divalent FAP-targeted theranostic conjugates constructed from our previously reported bifunctional chelator scaffold (BFS) based on 1,4,8,11-tetraaza-bicyclo [6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A), which forms the most stable complex with Cu(II). Methods: After synthesis and characterization, the monovalent and divalent conjugates were radiolabeled with ⁶⁴Cu for in vitro cell assays, followed by in vivo positron emission tomography (PET) imaging evaluation in relevant mouse models. Results: Both ⁶⁴Cu-labeled conjugates showed high in vitro stability and anticipated FAP-mediated cell binding and internalization. The divalent one showed significantly higher FAP-specific tumor uptake than its monovalent counterpart. Conclusions: Our results demonstrate that the BFS-based multivalent approach can be practically used to generate FAP-targeted radiotheranostic agents for effective cancer diagnosis and treatment. Full article

Cisplatin (DDP), a platinum-chelated compound renowned for its antitumor activity, is often utilized in cancer therapy. However, its real-world clinical efficacy is compromised by poor solubility and low stability, which impedes wider clinical application. Our study aimed to address these limitations of DDP through host–guest supramolecular chemistry approaches. We explored the potential of 18-crown-6 as the host molecule to solubilize and stabilize DDP, the guest molecule. Utilizing techniques such as UV–visible spectroscopy, Fourier-transform infrared spectroscopy, Raman spectroscopy, and molecular docking, we conducted a comprehensive analysis on the physical state and inclusion mode of the DDP@18-crown-6 complex. Phase solubility studies and Job’s plot confirmed that the DDP@18-crown-6 complex significantly enhanced the aqueous solubility of DDP, with an optimal 1:1 binding ratio. Stability analyses revealed that this complex markedly improved the stability of DDP in pure water. Meanwhile, the stabilization effects of DDP@18-crown-6 were remarkably elevated when combined with 0.9% sodium chloride. In vitro antitumor assays in A549 cell lines demonstrated that the DDP@18-crown-6 complex outperformed raw DDP in cytotoxicity, showing a significantly lower IC₅₀ value. This research offered a promising strategy for DDP solubilization and stabilization, facilitating its anticancer therapeutic efficacy. Full article

Background: Hexokinase (HK) deficiency is a rare autosomal recessively inherited disease manifested by chronic nonspherocytic hemolytic anemia. Most patients present with a mild to severe course of the disease (fetal hydrocephalus, neonatal hyperbilirubinemia, severe anemia). We reviewed 37 cases of patients with hexokinase deficiency described so far, focusing on the severity of the disease, clinical presentation, treatment applied, and genetic test results. Methods: We present a 10-year-old girl who initially presented with symptoms of weakness, excessive fatigue, and yellowing of the skin and sclerae. Genetic testing detected the (TA)7 variant in both alleles of the UGT1A1 gene and diagnosed Gilbert’s disease. In the follow-up, red cell hemolysis was observed. The diagnosis was extended, and tests for red cell enzymopathy were performed and a reduced level of hexokinase—0.65 IU/gHb (normal 0.78–1.57) was found. Next-generation sequencing revealed a new sense-change variant in exon 7 in the hexokinase gene not previously reported in databases. Results: Up to this date, only around 37 cases of hexokinase deficiency associated with hereditary nonspherocytic hemolytic anemia have been documented around the world. Diagnosing hexokinase deficiency involves clinical evaluation, laboratory testing, and genetic analysis. Management focuses on treating symptoms and preventing complications; there is no cure for the underlying enzyme deficiency. In patients with severe anemia, the treatment is multiple blood transfusions followed by iron chelation therapy. Conclusions: Understanding and diagnosing hexokinase deficiency is critical for providing appropriate care and improving the quality of life for affected individuals. Full article

Pythiosis, a rare and formidable infectious disease caused by Pythium insidiosum, is characterized by profound uncertainties in achieving definitive diagnoses, suboptimal outcomes, and an exceptionally high mortality rate. Here, we present a rare case of human spinal pythiosis in southern China. With advanced metagenomic sequencing technology, Pythium insidiosum was pinpointed as the causative pathogen. We discovered that the inoculation of either tissue fragments or homogenate yielded more successful results and enabled a moderate extension of the culture duration to 5–10 days through an exhaustive comparison of diverse inoculation and culture conditions for general clinical specimens. A pronounced genetic affinity of the isolated strain towards the Pythium insidiosum strain MCC 13 was detected after a comprehensive whole-genome sequencing analysis. Antifungal agents exhibited negligible sensitivity towards Pythium insidiosum in an antimicrobial susceptibility test. Conversely, antibacterial agents such as oxazolidinones, tetracyclines, macrolides, and amphenicols demonstrated varying degrees of sensitivity, albeit with most of their minimum inhibitory concentrations (MICs) substantially surpassing the safe concentration ranges for effective clinical treatment. Notably, tigecycline stood out as a promising candidate, exhibiting favorable therapeutic effects at moderate concentrations, making it a potential drug of choice for the control of pythiosis. A combined susceptibility test suggested that combinations of tetracyclines with macrolides, oxazolidinones, and amphenicols exhibited synergistic antibacterial effects, with the combination of doxycycline and trimethoprim–sulfamethoxazole (TMP-SMX) in particular playing a pivotal role. To our surprise, the MICs of iron chelators, specifically deferiprone and deferoxamine, against the strain were exceedingly low, which led to the speculation that exogenous iron chelators may have competitively inhibited the iron-chelating enzymes of the strain. The research derived from this single, rare case has certain limitations, but considering that there are currently no reports of invasive infections of deep organs in humans caused by Pythium insidiosum, the above findings can offer novel insights into the treatment of invasive pythiosis. Combination therapy based on tetracyclines, especially tigecycline, the use of TMP-SMX, and the adjunctive use of iron chelators, represent promising approaches to tackle the clinical challenges in the treatment of invasive pythiosis. However, further studies, including similar cases of spinal pythiosis and in vivo trials, are still needed to validate them. In addition, while paying attention to the therapeutic potentials of the above plans, we should also closely monitor the risks and side effects that may arise from excessive MICs or the expanded use of related drugs during the treatment process. Full article

Despite a decrease in prevalence and incidence rates, beta thalassemia continues to represent a significant public health challenge worldwide. In high-resource settings, children with thalassemia have an open prognosis, with a high chance of reaching adulthood and old age with a good quality of life. This is achievable if transfusion therapy is properly managed, effectively mitigating ineffective erythropoiesis and its associated complications while also minimizing excessive iron accumulation. Adequate iron chelation is essential to maintain reactive forms of iron within the normal range throughout life, thus preventing organ damage caused by hemosiderosis, which inevitably results from a regular transfusion regimen. New therapies, both curative, such as gene therapy, and non-curative, such as modulators of erythropoiesis, are becoming available for patients with transfusion-dependent beta thalassemia. Two curative approaches based on gene therapy have been investigated in both adults and children with thalassemia. The first approach uses a lentivirus to correct the genetic defect, delivering a functional gene copy to the patient’s cells. The second approach employs CRISPR/Cas9 gene editing to directly modify the defective gene at the molecular level. No non-curative therapies have received approval for pediatric use. Among adults, the only available drug is luspatercept, which is currently undergoing clinical trials in pediatric populations. However, in many countries around the world, the new therapeutic options remain a mirage, and even transfusion therapy itself is not guaranteed for most patients, while the choice of iron chelation therapy depends on drug availability and affordability. Full article

Targeted radionuclide therapy (TRT) for internal pathway-directed treatment is a game changer for precision medicine. TRT improves tumor control while minimizing damage to healthy tissue and extends the survival for patients with cancer. The application of theranostic-paired TRT along with cellular phenotype and genotype correlative analysis has the potential for malignant disease management. Chelation chemistry is essential for the development of theranostic-paired radiopharmaceuticals for TRT. Among image-guided TRT, ⁶⁸Ga and ^99mTc are the current standards for diagnostic radionuclides, while ¹⁷⁷Lu and ²²⁵Ac have shown great promise for β- and α-TRT, respectively. Their long half-lives, potent radiobiology, favorable decay schemes, and ability to form stable chelation conjugates make them ideal for both manufacturing and clinical use. The current challenges include optimizing radionuclide production processes, coordinating chelation chemistry stability of theranostic-paired isotopes to reduce free daughters [this pertains to ²²⁵Ac daughters ²²¹Fr and ²¹³Bi]-induced tissue toxicity, and improving the modeling of micro dosimetry to refine dose–response evaluation. The empirical approach to TRT delivery is based on standard radionuclide administered activity levels, although clinical trials have revealed inconsistent outcomes and normal-tissue toxicities despite equivalent administered activities. This review presents the latest optimization methods for chelation-based theranostic radiopharmaceuticals, advancements in micro-dosimetry, and SPECT/CT technologies for quantifying whole-body uptake and monitoring therapeutic response as well as cytogenetic correlative analyses. Full article

Background: The present study undertakes the purification of a novel polysaccharide from Tunisian prickly pear (Opuntiaficus-indica (L.) Mill.) rackets (PPPRs) and the determination of its physicochemical properties, structure, antibacterial and antioxidant properties, as well as its in vitro and in vivo wound healing potential. Methods: The PPPR was structurally analyzed by Fourier Transform Infrared Spectroscopy (FTIR) and UV/Visible Spectroscopy, revealing characteristic bands of polysaccharides. According to thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and Gas Chromatography–Mass Spectrometry (GC–MS) analyses. Results: The crude PPPR is an heteropolysaccharide composed of glucose (62.4%), galactose (19.37%), mannose (10.24%), and rhamnose (7.98%), with an average molecular weight of 90.94 kDa. This novel polysaccharide exhibited notable antioxidant potential assessed by four different in vitro assays: the 2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay, ferric reducing power, ferrous chelating activity, and scavenging activity against 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS). In addition, the PPPR displayed high antibacterial activities with a MIC of 2.5 mg/mL against Salmonella Typhimurium and Pseudomonas aeruginosa, cytocompatibility properties, and non-cytotoxicity. Subsequently, the effect of the PPPR on skin wound healing was studied in a diabetic rat model induced by alloxan, revealing a significant acceleration in the wound healing process. This acceleration was evidenced by the expedited recovery of the dermis, increased formation of blood vessels, and enhanced tissue granulation. Conclusion: Therefore, the findings offer fresh perspectives on the creation of a potentially efficient and promising racket polysaccharide-based therapy for the treatment of persistent diabetic wounds. Full article

Thalassemia represents a diverse group of inherited hematological disorders characterized by defective globin chain synthesis, leading to chronic anemia and associated complications. The complicated pathophysiology of beta-thalassemia involves genetic mutations or rarely deletions of the beta-globin gene on chromosome 11 whereas alpha-thalassemia involves deletions in the HBA1 and HBA2 genes or occasionally alterations to the DNA sequence in or around these genes. These mutation and deletion effects disrupt the balance of α/β-globin chain production, resulting in ineffective erythropoiesis, hemolysis, and a cascade of clinical manifestations including anemia, bone deformities, and iron overload. Advances in diagnostic techniques have enhanced our ability to detect and characterize these mutations, facilitating early and accurate diagnoses. Current management strategies encompass regular blood transfusions, the use of hydroxyurea to improve hemoglobin levels, and iron chelation therapy to prevent iron-related organ damage. Moreover, other therapeutics such as thalidomide for those not responding to hydroxyurea, Sirolimus for patients with immunodeficiencies, and use of vitamin E as an antioxidant have proven to be effective. Innovative therapies such as gene therapy and bone marrow transplantation offer promising curative potential, opening a new era in the treatment of thalassemia. This review focuses on pathophysiological mechanisms underlying thalassemia, explores the diagnostic methodologies, and highlights recent advancements in therapeutic approaches. Full article

Copper is a vital trace element in oxidized and reduced forms. It plays crucial roles in numerous biological events such as redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy, and immune modulation. Maintaining the balance of copper in the body is essential because its deficiency and excess can be harmful. Abnormal copper metabolism has a two-fold impact on the development of tumors and cancer treatment. Cuproptosis is a form of cell death that occurs when there is excessive copper in the body, leading to proteotoxic stress and the activation of a specific pathway in the mitochondria. Research has been conducted on the advantageous role of copper ionophores and chelators in cancer management. This review presents recent progress in understanding copper metabolism, cuproptosis, and the molecular mechanisms involved in using copper for targeted therapy in cervical cancer. Integrating trace metals and minerals into nanoparticulate systems is a promising approach for controlling invasive tumors. Therefore, we have also included a concise overview of copper nanoformulations targeting cervical cancer cells. This review offers comprehensive insights into the correlation between cuproptosis-related genes and immune infiltration, as well as the prognosis of cervical cancer. These findings can be valuable for developing advanced clinical tools to enhance the detection and treatment of cervical cancer. Full article

Iron plays a crucial role in various metabolic processes. However, the impact of 5-aminolevulinic acid (ALA) in combination with iron chelators on iron metabolism and the efficacy of ALA-photodynamic therapy (PDT) remain inadequately understood. This study aimed to examine the effect of thiosemicarbazone derivatives during ALA treatment on specific genes related to iron metabolism, with a particular emphasis on mitochondrial iron metabolism genes. In our study, we observed differences depending on the cell line studied. For the HCT116 and MCF-7 cell lines, in most cases, the decrease in the expression of selected targets correlated with the increase in protoporphyrin IX (PPIX) concentration and the observed photodynamic effect, aligning with existing literature data. The Hs683 cell line showed a different gene expression pattern, previously not described in the literature. In this study, we collected an extensive analysis of the gene variation occurring after the application of novel thiosemicarbazone derivatives and presented versatile and effective compounds with great potential for use in ALA-PDT. Full article

Oxidative stress is a key factor in the development of chronic diseases such as type 2 diabetes, cardiovascular diseases, and liver disorders. Antioxidant therapies that target oxidative damage show significant promise in preventing and treating these conditions. Berberine, an alkaloid derived from various plants in the Berberidaceae family, enhances cellular defenses against oxidative stress through several mechanisms. It activates the AMP-activated protein kinase (AMPK) pathway, which reduces mitochondrial reactive oxygen species (ROS) production and improves energy metabolism. Furthermore, it boosts the activity of key antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), thus protecting cells from oxidative damage. These actions make berberine effective in managing diseases like type 2 diabetes, cardiovascular conditions, and neurodegenerative disorders. Silymarin, a flavonolignan complex derived from Silybum marianum, is particularly effective for liver protection. It activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, enhancing antioxidant enzyme expression and stabilizing mitochondrial membranes. Additionally, silymarin reduces the formation of ROS by chelating metal ions, and it also diminishes inflammation. This makes it beneficial for conditions like non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disorders. This review aims to highlight the distinct mechanisms by which berberine and silymarin exert their antioxidant effects. Full article