Search Results (81)

Background: Polycythemia vera (PV) is characterized by mutation JAK2 V617F, elevated blood counts, and risk of thrombosis. Ropeginterferon alfa-2b (ropeg) approved for PV at a low-starting dose and slow-titration schema with efficacy at 12 months with assessment visits every three months. This period might be at thrombotic risk resulting from inadequate control of hematological parameters and JAK2. The study was aimed at assessing its efficacy at less than 12 months with assessment visits every two weeks. Methods: Thirteen patients with Hydroxyurea (HU)/Intolerance (HU/I) high-risk PV and pruritus were treated with ropeg at a low-starting dose and slow-titration schema with assessment visits every two weeks. The primary endpoint was the complete hematological response (CHR) at less than 12 months. The secondary endpoints were the CHR rates, CHR dose, durable CHR, and reduction in JAK2V617F variant allele frequency (VAF). Results: The CHR of patients was 8 weeks in 30.7% (4/13), 16 weeks in 30.7% (4/13), and 24 weeks in 38.4% (5/13), respectively, with a mean time of 4.15 months. Durable CHR was at 20, 28, and 36 weeks, respectively, with a mean time of 6.55 months. JAK2 VAF continuously declined from 43.38% at baseline to 12.96% at durable CHR. Eleven patients (85%) achieved partial molecular response (PMR) and two (15.38%) complete molecular responses (CMRs) and all patients resolved the pruritus. No adverse event (AE) or thrombosis occurred. Conclusions: We report that ropeg is efficacious under the low-starting dose and slow-titration regimen in obtaining CHR and molecular response (MR) at less than 12 months. Full article

Background/Objectives: Hydroxyurea (HU), a cornerstone treatment for sickle cell disease (SCD), exhibits marked interindividual pharmacokinetic/pharmacodynamic (PK/PD) variability that remains poorly understood. This study aimed to establish a population PK model using OPTIMDREP randomized trial data (NCT06464458), quantify parameter variability, and identify covariates influencing HU PK and hematological response. Methods: Plasma sampling data from 22 SCD patients (20 pediatric and 2 adult patients; median age: 11.2 years [range: 2.5–35.7]) on once-daily oral HU underwent a non-compartmental analysis (NCA) followed by nonlinear mixed-effects modeling (MonolixSuite^®). PK variability covariates and PK/PD correlations with the mean corpuscular volume (MCV), reticulocytes, fetal hemoglobin percentage (HbF%) and neutrophils were investigated. Results: NCA identified two absorption phenotypes (rapid/slow), with higher maximum concentration values observed for rapid (36.5 ± 18.8 mg/L) compared to slow (22.3 ± 8.4 mg/L) (p = 0.0013) profiles but not statistically different total exposures, apparent clearances (Cl/F) or volumes of distribution (V_d/F). The population approach identified the one-compartment model (first-order absorption and linear elimination) and confirmed the absorption phenotype as the key absorption rate (k_a) covariate (9.93 vs. 1.36 h⁻¹), explaining half of the k_a interindividual variability (IIV). The median-normalized body weight was retained for both the Cl/F and V_d/F, as it significantly reduced the objective function value. No hematological parameter was correlated to PK parameters. However, rapid absorbers showed a superior response on the MCV (Δ = 9.1 fL, p < 0.0001), reticulocytes (Δ = −42.2 G/L, p < 0.01), and HbF% trend (Δ = 2.8%, p = 0.0835) but not on neutrophil counts (p = 0.8757). Conclusions: The absorption phenotype, a novel covariate explaining half of the k_a IIV, predicts a superior erythropoietic response without toxicity in SCD patients. These findings support absorption phenotype integration into PK-guided dosing algorithms to optimize early-response biomarkers and personalize HU therapy. Full article

Hydroxyurea (HU) is a ribonucleotide reductase inhibitor widely used for the treatment of sickle cell disease and myeloproliferative disorders, yet a precise nitric oxide (NO) synthase (NOS)-dependent mechanism remains incompletely defined. The role of NOS3 in HU-mediated proliferation, cell cycle, and apoptosis was analyzed in HEL92.1.7 erythroleukemic cells and primary mouse erythroid progenitors upon genetic knockdown/knockout and pharmacological NOS2/NOS3 inhibition. NOS3 expression, phosphorylation, NO and citrulline production, and protein nitrosylation were assessed via immunoblotting and biochemical assays. Computational docking and molecular dynamics simulations were performed to examine the interaction between HU and NOS3. HU enhanced NOS3 expression and phosphorylation, leading to increased NO and citrulline production. Computational analysis predicted HU binding within the NOS3 active site, whereas functional activation was AKT1-dependent. A biotin switch assay revealed cooperative NOS2-/NOS3-mediated protein nitrosylation under HU treatment. NOS3 depletion or inhibition abrogated HU-induced S-phase accumulation and restored cell proliferation. NOS3 protein depletion increased late apoptosis in erythroleukemic cells, while in murine erythroid cells, both Nos3 deficiency and inhibition decreased early and increased late apoptosis. NOS2 and NOS3 act as complementary mediators of proliferation and apoptosis, with NOS3 playing a distinct role in HU-induced proliferation arrest in erythroid cells. These findings highlight the therapeutic potential of NOS targeting to enhance the efficacy of HU and overcome resistance in hematologic malignancies. Full article

Faithful DNA replication is essential for genome stability but is constantly challenged by metabolic and oxidative stresses. Hydroxyurea (HU), a widely used antiproliferative drug, is traditionally known to inhibit ribonucleotide reductase and deplete dNTP pools. Recent studies, especially in Saccharomyces cerevisiae, reveal that HU-induced replication stress also arises from reactive oxygen species (ROS), which oxidize DNA, impair iron–sulfur-dependent replication enzymes, and disrupt replisome function. These combined effects promote helicase–polymerase uncoupling, accumulation of RPA-coated ssDNA, and activation of the Mec1–Rad53 (ATR–CHK1) checkpoint, leading to strand-specific changes such as PCNA unloading and reduced lagging-strand synthesis. When protective pathways are overwhelmed, HU-treated forks collapse, generating chromosome breaks and genome instability. This review summarizes current understanding of how HU remodels replication forks through both ROS-dependent and ROS-independent pathways and highlights emerging insights into how these mechanisms influence genome stability and may be exploited for therapeutic benefit. Full article

Background/Objectives: The rhizome of Gastrodia elata Blume (Tianma) is a functional food with medicinal value in China, used to improve the health of the central nervous system and reported to exhibit anti-cellular senescent activity. P-hydroxybenzaldehyde (P-HBA) is a key aromatic compound isolated from Tianma; however, its potential to mitigate cellular senescence remains unclear. Methods: We employed ultra-performance liquid chromatography-mass spectrometry to identify the chemical characterization of Tianma extract. Cell viability assay, senescence-associated-β-galactosidase (SA-β-Gal) assay, and immunofluorescence staining and autophagy analysis were used to evaluate the anti-senescent activity of P-HBA and other Tianma components. Results: Our findings demonstrate that Tianma methanol extract (TME) and P-HBA significantly reduce cellular senescent inducer hydroxyurea (HU)-induced DNA damage, SA-β-Gal activity increase, and autophagic dysfunction in human SH-SY5Y cells. Notably, an autophagy inhibitor, chloroquine, can reduce anti-cellular senescent activity of P-HBA. Conclusions: These results suggest that P-HBA exhibits the effect of reducing cellular senescent phenotypes, and its effect is achieved by enhancing autophagy. Full article

Understanding the functions of all genes and their biological mechanisms based on comprehensive genome regulation mechanisms is an important issue in life sciences. YnfL is an uncharacterized LysR family transcription factor in Escherichia coli. Genomic SELEX screening was performed to identify YnfL regulatory targets in the E. coli genome and reveal the function of YnfL. Nine loci on the E. coli genome were identified as regulatory targets of YnfL, and the target genes were involved in supplying DNA substrates and DNA repair. RT-qPCR analysis in vivo revealed that YnfL activates its target genes during the stationary phase. Tests for drug resistance that causes DNA damage revealed that ynfL deficiency increased abnormal cell filamentation and the appearance of anucleate cells in the presence of hydroxyurea. Furthermore, ynfL deficiency reduced cell survival under long-term nitrogen starvation conditions. In summary, we propose renaming ynfL to hydroxyurea sensitivity regulator (husR). These findings contribute to understanding DNA maintenance and long-term survival through transcriptional regulation. Full article

Coordination polymers (CPs) are garnering attention in the field of medicine day by day. The goal is to develop a CP with biosafe and environment-friendly characteristics. Herein, we report two such novel 3D coordination polymers of zinc-inosine-5′-monophosphate (Zn-IMP) and bpe/azpy (as linkers) which were engineered as metal–organic frameworks that can be used as drug carriers for hydroxyurea (HU). We employed SCXRD, PXRD, solid-state CD, FTIR and TGA for crystal structure characterizations; the results achieved 3D coordination polymers which contain a P2₁ space group with chiral distorted tetrahedral geometry. Solution phase studies like UV–vis and CD were carried out to understand mechanistic pathways for interaction and chirality, respectively. We have also performed computational studies to evaluate the drug delivery capacity of both 3D CPs. Molecular docking and multi-pH molecular dynamics (MD) quantify that HU binds more strongly with CP−1 (ΔG =−10.87 ± 0.12) as compared to CP−2 (ΔG = −7.59 ± 0.26 kcal·mol⁻¹), at normal and basic pH. MD simulation analysis indicated that a more compact and rigid cavity is observed by CP−1 as compared to CP−2 at physiological pH. Across acidic pH, for CP−1 the ligand RMSD increases markedly and U becomes slightly less negative, which indicated partial loss of contacts, thus releasing drugs in a tumor-like environment more easily. These result showed that CP−1 offers stronger binding, higher structural stability and a more pronounced pH-responsive release profile than CP−2, making CP-1 more promising candidate for targeted HU drug delivery, while CP−2 may serve as a weaker-binding, faster-release complement. Full article

Hydroxyurea (HU) is a cytostatic drug used in oncotherapy. The drug has inhibitory effects on bone marrow and epithelial cells and causes minor side effects in the skin, including nail deformity, alopecia, and hyperpigmentation, and severe side effects, including skin tumors and nonhealing ulcers. Herein, we report the case of a patient who received HU therapy for polycythemia vera. The patient had type 2 diabetes and atherosclerosis. Onychodystrophy and a non-healing ulcer developed. Severe deep tissue infection and osteomyelitis, rare complications of a HU-related ulcer, were also diagnosed later. Diabetes and atherosclerosis made the condition more severe. Complex systemic and local therapy led to complete healing of the ulcer and osteomyelitis. Based on the literature and our own experience, a care protocol was proposed for the dermatological follow-up of patients under HU treatment. This recommendation may be particularly useful in the treatment of patients treated with hydroxyurea who suffer from atherosclerosis, diabetes, or leg ulcers and are therefore at increased risk of severe skin and deep tissue infections. Full article

We describe a patient with post-essential thrombocythaemia myelofibrosis treated with intermittent hydroxyurea (Hu) therapy (20 mg/Kg, given as a single dose, thrice weekly), achieving sustained disease control and regression of bone marrow fibrosis. Additionally, we discuss the efficacy of and rationale for use of intermittent Hu therapy in patients with myeloproliferative neoplasms, including those deemed to be Hu-resistant or intolerant to the commonly used continuous therapy. Full article

Sickle cell disease (SCD) is the most common monogenic disorder worldwide and remains a major cause of morbidity and mortality. Sickle cell anemia (SCA), the homozygous HbSS genotype, represents the most severe and frequent form within the spectrum of SCD. Hydroxyurea (HU), a ribonucleotide reductase inhibitor, represents the first and most widely used disease-modifying therapy for SCA. This review summarizes current evidence on the mechanisms of action, clinical efficacy, systemic effects, and long-term safety of chronic HU therapy in patients with SCA. A comprehensive literature search was conducted in PubMed up to 2025 using the terms “sickle cell disease,” “sickle cell anemia”, “hydroxyurea,” and “children” or “paediatric.” Eligible studies included randomized controlled trials, cohort studies, and systematic reviews evaluating HU therapy in SCA. Literature analysis showed that HU exerts pleiotropic effects by inducing fetal hemoglobin (HbF) synthesis, improving red blood cell deformability, reducing leukocyte and platelet counts, and enhancing nitric oxide bioavailability. These mechanisms lead to decreased vaso-occlusive crises, acute chest syndrome, transfusion requirements, and overall mortality. Beyond hematologic improvement, HU confers neuroprotective benefits, modulates inflammatory and immune pathways, and supports normal growth and endocrine development in children. Adverse events, primarily mild bone marrow suppression, are dose-dependent and reversible with appropriate monitoring. No evidence supports an increased risk of malignancy with long-term use. In conclusion, chronic HU therapy is a safe, effective, and multifaceted treatment that substantially improves survival and quality of life in patients with SCA. Early initiation and individualized dosing maximize its therapeutic benefits and help prevent irreversible organ damage. Full article

The correct course of DNA replication is crucial to maintaining the integrity of the genome. Any abnormality in this process inevitably leads to replication stress (RS). Hydroxyurea (HU) is a replication stressor widely used to inhibit DNA biosynthesis by depleting the deoxyribonucleoside triphosphate (dNTP) pool. The aim of the study was to examine how the 24-, 48-, and 72 h exposures to 0.75 mM HU affect the localization of fibrillarin (FBL; a highly conserved nucleolar protein and the component of Cajal bodies) and the amount of rRNA transcripts (detected using 5-ethynyl uridine; 5-EU), in root meristem cells of Allium cepa. The consequence of prolonged RS was initially (after 24 h of incubation in HU) a 2-fold increase in 5-EU incorporation into the nucleolus, then (after 48- and 72 h incubations) followed by a gradual decrease in rRNA transcription to a level similar to that of the control. In interphase and in early prophase, both in the control material and during successive periods of incubation of root meristems in HU, the immunofluorescence of FBL accumulated in the fibrillar centers (FCs) of the nucleoli, in the dense fibrillar components (DFC), and in the granular components (GC). In some HU-treated metaphase cells, FBL was localized around the telomeres of the chromosomes, while in telophase, it was found in the fragmented chromosomes. In addition, an increase in the number of Cajal bodies (CBs) was observed during subsequent incubation periods with HU. After 48 and 72 h of treatment with HU, the number of CBs was found to be almost twice that observed in the control series. CBs disappeared in prophase and reappeared in interphase. These results suggest that depending on the duration of RS, changes in the level of rRNA transcription and in the abundance of CBs may correlate with the production of RNP and ribosome biogenesis. Full article

Efficient new methods are needed to support initiatives to reduce, refine, and/or replace toxicity testing in vertebrates. 5-fluorouracil (5FU), hydroxyurea (HU), and ribavirin (RV) are mammalian teratogens. Skeletal, endocrine organ, and cardiac effects are often associated with teratogenesis, and a simple nematode like C. elegans lacks these systems. However, many genetic pathways required for mammalian morphogenesis have at least some conserved elements in this small, invertebrate model. The C. elegans lifecycle is 3 days. The effects of 5FU, HU, and RV on the C. elegans morphology were evaluated on day 4 post-initiation of the feeding after hatching for continuous and 24 h (early-only) developmental exposures. Continuous exposures to 5FU and HU induced increases in the incidences of abnormal gonadal structures that were significantly reduced in early-only exposure groups. The incidence of prolapse increased with continuous 5FU and HU exposures and was further increased in early-only exposure groups. Intestinal prolapse through the vulval muscle in C. elegans may be related to reported 5FU and HU effects on skeletal muscle and the gastrointestinal tract in mammals. Continuous RV exposures induced a phenotype lacking a uterus and gonad arms, as well as vulval anomalies that were largely, but not completely, reversed with early-only exposures, which is consistent with reported reversible reproductive tract anomalies after an RV exposure in mammals. These findings suggest that C. elegans can be used to detect the hazard risk from chemicals that adversely affect conserved pathways involved in organismal morphogenesis, but to determine the fit-for-purpose use of this model in chemical safety evaluations, further studies using larger and more diverse chemical test panels are needed. Full article

Background: Sickle cell disease (SCD) is associated with high physical and psychosocial burden among patients and their families. Hydroxyurea (HU) improves health-related quality of life by preventing SCD complications. Despite its availability, HU is underutilised in Tanzania. Perceived self-efficacy for appropriate medication use influences medication usage among individuals with chronic illnesses. We studied factors associated with caregivers’ perceived self-efficacy for appropriate use of HU and its association with HU usage among children with SCD in Dar-es-Salaam. Methods: We conducted a cross-sectional study from May to August 2023. We enrolled 374 caregivers of children with SCD from two regional and two national hospitals. We adapted the self-efficacy for appropriate medication use scale, a multidimensional perceived social support scale, and a patient health questionnaire for assessment of self-efficacy, social support, and depressive symptoms, respectively. Results: Three-quarters of caregivers had high perceived self-efficacy scores for medication use. Attending national hospitals, high social support, and absence of depressive symptoms were positively associated with perceived self-efficacy (adjusted beta coefficient aβ 2.3, 95% CI 0.5–4.2; aβ 9, 95% CI 7.1–10.9; and aβ 5.3, 95% CI 2.8–7.8, respectively). Caregivers with high self-efficacy were 5.3 times more likely to give HU to their children compared with those with low self-efficacy (incidence rate ratio 5.3, 95% CI 3.3–8.3). Conclusions: Hospital levels and psychosocial factors influence caregivers’ perceived self-efficacy for appropriate HU use. We recommend targeted interventions to enhance psychosocial support among caregivers to increase caregivers’ perceived self-efficacy and HU utilization among children with SCD in Tanzania. Full article

Kidney disorders significantly contribute to morbidity and mortality in sickle cell disease (SCD). Acute kidney injury (AKI), a major risk factor for chronic kidney disease (CKD), often arises from intravascular hemolysis, where plasma cell-free heme drives AKI through inflammatory and oxidative stress mechanisms. Hydroxyurea (HU), a well-established SCD-modifying therapy, improves clinical outcomes, but its effects on systemic heme and inflammatory mediators of kidney injury remain underexplored. This study evaluated HU’s impact on plasma heme, pro-inflammatory mediators, kidney injury, and renal histopathology in a sickle cell mouse model. Townes humanized sickle cell mice (HbSS) and non-sickle (HbAA) controls were treated with HU or vehicle for two weeks. HU significantly reduced total plasma heme, lactate dehydrogenase, and pro-inflammatory cytokines (CXCL10, VEGF-A, IFN-γ) in HbSS mice. HU reduced renal injury biomarkers (cystatin C, NGAL) and improved renal histopathology, evidenced by reduced vascular congestion, glomerulosclerosis, and tubular damage. Interestingly, HU did not alter the levels of kidney repair biomarkers (clusterin and EGF). These findings suggest that HU mitigates kidney injury by reducing the deleterious effects of circulating heme and inflammation, supporting its potential to slow or prevent progressive kidney injury in SCD. Full article

Hydroxyurea (HU), a cornerstone treatment for myeloproliferative disorders, is associated with a wide range of cutaneous side effects, from xerosis and hyperpigmentation to more severe conditions like dermatomyositis-like eruptions (DM-LE) and nonmelanoma skin cancers (NMSC), particularly squamous cell carcinoma (SCC). In this review, we present a unique case of HU-induced DM-LE with histological evidence of keratinocyte dysplasia and p53 overexpression, followed by a systematic analysis of similar cases. Our findings reveal that the clinical presentation of DM-LE, while typically considered benign, shares clinical and histological features with hydroxyurea-associated squamous dysplasia (HUSD), a precancerous condition that may progress to SCC in chronically exposed patients. Key insights include the characteristic histopathological findings of DM-LE, the role of chronic HU therapy and UV-induced damage in promoting p53 overexpression, and the overlap between DM-LE and HUSD. Regular dermatologic monitoring, patient education on photoprotection, and the careful assessment of skin lesions in long-term HU users are essential for the early detection and prevention of malignancies. This review underscores the importance of distinguishing between DM-LE, HUSD, and SCC to optimize management and minimize risks associated with HU therapy. Full article