High ferritin is associated with liver and bone marrow iron accumulation: Effects of 1-year deferoxamine treatment in hemodialysis-associated iron overload.

BACKGROUND: Iron (Fe) supplementation is a critical component of anemia therapy for patients with chronic kidney disease (CKD). However, serum Fe, ferritin, and transferrin saturation, used to guide Fe replacement, are far from optimal, as they can be influenced by malnutrition and inflammation. Currently, there is a trend of increasing Fe supplementation to target high ferritin levels, although the long-term risk has been overlooked. METHODS: We prospectively enrolled 28 patients with CKD on hemodialysis with high serum ferritin (> 1000 ng/ml) and tested the effects of 1-year deferoxamine treatment, accompanied by withdrawal of Fe administration, on laboratory parameters (Fe status, inflammatory and CKD-MBD markers), heart, liver, and iliac crest Fe deposition (quantitative magnetic resonance imaging [MRI]), and bone biopsy (histomorphometry and counting of the number of Fe positive cells in the bone marrow). RESULTS: MRI parameters showed that none of the patients had heart iron overload, but they all presented iron overload in the liver and bone marrow, which was confirmed by bone histology. After therapy, ferritin levels decreased, although neither hemoglobin levels nor erythropoietin dose was changed. A significant decrease in hepcidin and FGF-23 levels was observed. Fe accumulation was improved in the liver and bone marrow, reaching normal values only in the bone marrow. No significant changes in turnover, mineralization or volume were observed. CONCLUSIONS: Our data suggest that treatment with deferoxamine was safe and could improve Fe accumulation, as measured by MRI and histomorphometry. Whether MRI is considered a standard tool for investigating bone marrow Fe accumulation requires further investigation. Registry and the registration number of clinical trial: ReBEC (Registro Brasileiro de Ensaios Clinicos) under the identification RBR-3rnskcj available at: https://ensaiosclinicos.gov.br/pesquisador.

Astragaloside IV attenuates ferroptosis and protects against iron overload-induced retinal injury.

Retinal injury may be exacerbated by iron overload. Astragaloside IV (AS-IV) has potential applications in the food and healthcare industry to promote eye health. We sought to determine the mechanisms responsible for the protective effects of AS-IV on photoreceptor and retinal pigment epithelium cell death induced by iron overload. We conducted in vitro and in vivo experiments involving AS-IV pretreatment. We tested AS-IV for its ability to protect iron-overload mice from retinal injury. In particular, we analyzed the effects of AS-IV on iron overload-induced ferroptosis in 661W and ARPE-19 cells. AS-IV not only attenuated iron deposition and retinal injury in iron-overload mice but also effectively reduced iron overload-induced ferroptotic cell death in 661W and ARPE-19 cells. AS-IV effectively prevented ferroptosis by inhibiting iron accumulation and lipid peroxidation. In addition, inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) eliminated the protective effect of AS-IV against ferroptosis. The results suggest that ferroptosis might be a significant cause of retinal cell death associated with iron overload. AS-IV provides protection from iron overload-induced ferroptosis, partly by activating the Nrf2 signaling pathway.

Skin complications during iron chelation therapy for beta-thalassemia: overview and treatment approach.

Thalassemia is an inherited genetic disorder of hemoglobin that affects a large population worldwide, and it is estimated that between 50,000 and 60,000 infants with thalassemia are born each year. The most common treatment for thalassemia is blood transfusion, which leads to iron overload. This in itself is a serious clinical condition, and is commonly managed with iron chelation therapy. However, iron chelators can cause various skin complications, including hyperpigmentation, skin rash, itching, and photosensitivity. These skin side effects can impact patients' quality of life. Therefore, this article provides a comprehensive overview of skin complications caused by iron chelators, along with a proposed comprehensive approach to their management in patients with beta-thalassemia. Key strategies include patient education, regular skin assessment, sun protection measures, symptomatic relief with topical corticosteroids and antihistamines, and consideration of treatment modification if severe complications occur. Collaboration between hematologists and dermatologists, along with psychological support and regular follow-up, is an essential component of this multidisciplinary approach. By implementing these strategies, healthcare providers can optimize skin care for patients with beta-thalassemia treated with iron chelators and improve their quality of life.

Clinical efficacy of thalidomide for various genotypes of beta thalassemia.

OBJECTIVE: The objective of this study was to investigate the therapeutic efficacy of thalidomide across various genotype presentations of ß-thalassemia so as to facilitate the early screening of thalidomide-sensitive thalassemia cases and to understand the impact of iron overload on thalidomide. METHODS: From our initial sample of 52 patients, we observed 48 patients with ß-thalassemia for two years after administration of thalidomide. This cohort included 34 patients with transfusion-dependent thalassemia (TDT) and 14 patients with non-transfusion-dependent thalassemia (NTDT). We recorded the values of hemoglobin (Hb), fetal hemoglobin (HbF), and serum ferritin (SF) in the baseline period and at 1, 3, 6, 12, 18, and 24 months after enrollment, as well as the pre- and post-treatment blood transfusion volume in all 48 cases. According to the increase in Hb levels from baseline during the 6-month observation period, the response to thalidomide was divided into four levels: main response (MaR), minor response (MiR), slow response (SLR), and no response (NR). A decrease in serum ferritin levels compared to baseline was considered alleviation of iron overload. We calculated the overall response rate (ORR) as follows: ORR = MaR + MiR + SLR/number of observed cases. RESULTS: The ORR was 91.7% (44/48 cases), and 72.9% showed MaR (35/48 cases). Among the 34 patients with TDT, 21 patients (61.8%) were free of blood transfusion, and the remaining 13 patients still required blood transfusion, but their total blood transfusion volume reduced by 31.3% when compared to the baseline. We found a total of 33 cases with 10 combinations of advantageous genes, which included 5 cases with ßCD41-42/ßCD17 and 6 cases with ßCD41-42/ß-28. Based on the treatment outcomes among the 48 cases in the observation group, there were 33 cases in the MaR group and 15 cases in the SLR/NR group. There was a difference in HbF between the two groups at baseline (P = 0.041). There were significant differences between the two groups in Hb and HbF at the time points of 6 and 12 months, respectively (P < 0.001). Compared to the baseline measurement, there was a significant decrease in the level of SF at months 12 and 24 (P < 0.001). CONCLUSION: In this study, we identified 10 ß-thalassemia gene combinations that were sensitive to thalidomide. These gene combinations can be used for initial screening and to predict the therapeutic effect of thalidomide in clinical practice. We examined the therapeutic response to thalidomide and found that the administration of thalidomide in combination with standardized iron removal was more beneficial in reducing iron overload.

Analysis of mechanism, therapeutic strategies, and potential natural compounds against atherosclerosis by targeting iron overload-induced oxidative stress.

Ferroptosis is a novel form of cell demise characterized primarily by the reduction of trivalent iron to divalent iron, leading to the release of reactive oxygen species (ROS) and consequent induction of intense oxidative stress. In atherosclerosis (AS), highly accumulated lipids are modified by ROS to promote the formation of lipid peroxides, further amplifying cellular oxidative stress damage to influence all stages of atherosclerotic development. Macrophages are regarded as pivotal executors in the progression of AS and the handling of iron, thus targeting macrophage iron metabolism holds significant guiding implications for exploring potential therapeutic strategies against AS. In this comprehensive review, we elucidate the potential interplay among iron overload, inflammation, and lipid dysregulation, summarizing the potential mechanisms underlying the suppression of AS by alleviating iron overload. Furthermore, the application of Traditional Chinese Medicine (TCM) is increasingly widespread. Based on extant research and the pharmacological foundations of active compounds of TCM, we propose alternative therapeutic agents for AS in the context of iron overload, aiming to diversify the therapeutic avenues.

Iron Chelators and Alzheimer's Disease Clinical Trials.

Alzheimer's disease (AD) is a major neurodegenerative disorder impacting millions of people with cognitive impairment and affecting activities of daily living. The deposition of neurofibrillary tangles of hyperphosphorylated tau proteins and accumulation of amyloid-ß (Aß) are the main pathological characteristics of AD. However, the actual causal process of AD is not yet identified. Oxidative stress occurs prior to amyloid Aß plaque formation and tau phosphorylation in AD. The role of master antioxidant, glutathione, and metal ions (e.g., iron) in AD are the frontline area of AD research. Iron overload in specific brain regions in AD is associated with the rate of cognitive decline. We have presented the outcome from various interventional trials involving iron chelators intended to minimize the iron overload in AD. To date, however, no significant positive outcomes have been reported using iron chelators in AD and warrant further research.

The impact of sickle cell disease and its treatment on ovarian reserve in reproductive-aged Black women.

We compared serum anti-Mullerian hormone (AMH) levels in women with sickle cell disease (SCD) (n = 152) to those of Black comparison women (n = 128) between the ages of 20 and 45 years and evaluated the impact of hydroxyurea (HU) and iron overload on ovarian reserve in those with SCD. SCD treatment was abstracted from medical records. Linear regression models were fit to examine the relationship between log(AMH) and SCD, adjusting for age. The analysis was repeated to account for HU use (current, previous, never) and iron overload (ferritin ≥1000 ng/mL vs. <1000 ng/mL). AMH estimates among women with SCD were lower than those among comparison women (2.23, 95% confidence interval [CI] 1.80-2.76 vs. 4.12, 95% CI 3.11-5.45, respectively). Women with SCD who were currently using HU had 63% lower (95% CI 43-76) AMH values than comparison women; those with SCD with prior or no HU use also had lower AMH estimates than comparison women, but the difference was less pronounced. There were no differences in predicted AMH values among women with SCD for those with and without iron overload. Women with SCD and low AMH may have a shorter reproductive window and may benefit from referral to a reproductive specialist.

Comparison of Yearly Cost Related to Complications Between Deferasirox and Deferiprone Monotherapy in Thalassemia.

BACKGROUND: Hemoglobin disorders such as thalassemia major have created an economic burden on the health care system. Iron chelation therapy (ICT) is the most expensive cost component in patients with thalassemia. ICT was administered to reduce the toxic effects of iron overload. This study aims to compare the costs of iron chelators as monotherapy in patients with thalassemia major in Indonesia, specifically in Cipto Faculty of Medicine, Universit. METHODS: This is a retrospective analytical observational study. Data were collected from the thalassemia registry from 2016 to 2019. Patients' age, gender, type of thalassemia, and type of iron chelation were recorded. Complications and total annual costs were evaluated. All thalassemia patients aged ≥2 years who were only receiving monotherapy ICT and had no history of therapy switching were eligible. We excluded subjects who moved out to other facilities or lost to follow-up. RESULTS: From a total of 256 subjects, 249 subjects were included. The median age is 28 years old. Both sexes were represented equally. As many as 96.8% of subjects have thalassemia beta. Deferiprone was the most common iron chelator used (86.7%). Complications were observed in the subjects based on 4-year data collection; most of them were cardiomyopathy, diabetes mellitus, delayed puberty, and malnutrition ( P =0.422; P =0.867; P =0.004; and P =0.125, respectively). Deferiprone had a lower mean annual cost of USD 3581 than deferasirox, which had a cost of USD 6004. CONCLUSIONS: Cardiomyopathy, diabetes mellitus, delayed puberty, and malnutrition were the most common complications found in the study. This study showed that deferiprone should be taken as consideration as a drug of choice to treat iron overload in thalassemia provided by Indonesian national health insurance which is less costly despite the probability of complications found after the treatment was given. Further investigations are required to evaluate contributing factors of complications in thalassemia.

COMPARATIVE STUDY OF OXIDATIVE STRESS IN PATIENTS WITH Β -THALASSEMIA MAJOR ON DEFERASIROX VERSUS DEFEROXAMINE THERAPY.

Accumulation of iron in vital organs is increasingly challenging in clinical settings during the lifespan of thalassemia patients. Iron overload hurdle these organs to redox imbalances. Commonly used iron-chelating agents in (deferasirox and, deferoxamine) could have a positive antioxidant role. Therefore, the aim of this study was designed to compare the effects of deferasirox and, deferoxamine, iron-chelating agents in oxidative stress in patients with ß-thalassemic major. In this case series comparative study, 60 known cases of ß-thalassemic patients receiving chelating agents therapy were divided into two groups of thirty, group one consisted of 30 patients 16 male and14 female, who received oral agent deferasirox tablets at dose 20-40mg/kg. Group two consisted of 30 patients, 16 male and 14 female, on intravenous therapy with Deferoxamine at a dose of 20-50mg/kg, Another thirty healthy individuals matched with age and gender, were kept as a control group. Total antioxidant capacity (TAOC) and Malondialdehyde (MDA) were measured in all studied groups. The three groups were similar in terms of age, and gender, A statistically non-significant difference in age (p>0.05) existed between the control and patient groups (10.9±2.93; 11.2±4.1*;11.6±3.6*) respectively. The number of patients in to control group and male-to-female numbers were matched since the ratios were similar. A statistically non-significant difference in BMI (p>0.05) existed between the control and patient groups (17±2, 17.2±2, 18±2.4*) respectively. TAOC is lower in-patient groups, when compared with the control group (27.8 ± 10.7; 32.5 ± 10.2; and 79.5 ± 7 u/ml) respectively, while the MDA value is higher when compared with the control group (7.2±4.6 and, 6.6±4.42; and 0.57±0.26; nmol/ml) respectively. The TAOC in patients group on Deferoxamine, is higher, while MDA is lower than in patients on Defrasirox. The TAOC in patients was reduced and Oxidative stress was enhanced in patients with thalassemia. Deferoxamine is more effective in modulating redox status.

The Importance and Essentiality of Natural and Synthetic Chelators in Medicine: Increased Prospects for the Effective Treatment of Iron Overload and Iron Deficiency.

The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.

Iron chelation therapy for children with transfusion-dependent ß-thalassemia: How young is too young?

In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent ß-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.

Differential effects of iron chelators on iron burden and long-term morbidity and mortality outcomes in a large cohort of transfusion-dependent ß-thalassemia patients who remained on the same monotherapy over 10 years.

We conducted a retrospective cohort study on 663 transfusion-dependent ß-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.

Combination of a TGF-ß ligand trap (RAP-GRL) and TMPRSS6-ASO is superior for correcting ß-thalassemia.

A recently approved drug that induces erythroid cell maturation (luspatercept) has been shown to improve anemia and reduce the need for blood transfusion in non-transfusion-dependent as well as transfusion-dependent ß-thalassemia (BT) patients. Although these results were predominantly positive, not all the patients showed the expected increase in hemoglobin (Hb) levels or transfusion burden reduction. Additional studies indicated that administration of luspatercept in transfusion-dependent BT was associated with increased erythropoietic markers, decreased hepcidin levels, and increased liver iron content. Altogether, these studies suggest that luspatercept may necessitate additional drugs for improved erythroid and iron management. As luspatercept does not appear to directly affect iron metabolism, we hypothesized that TMPRSS6-ASO could improve iron parameters and iron overload when co-administered with luspatercept. We used an agent analogous to murine luspatercept (RAP-GRL) and another novel therapeutic, IONIS TMPRSS6-LRx (TMPRSS6-ASO), a hepcidin inducer, to treat non-transfusion-dependent BT-intermedia mice. Our study shows that RAP-GRL alone improved red blood cell (RBC) production, with no or limited effect on splenomegaly and iron parameters. In contrast, TMPRSS6-ASO improved RBC measurements, ameliorated splenomegaly, and improved iron overload most effectively. Our results provide pre-clinical support for combining TMPRSS6-ASO and luspatercept in treating BT, as these drugs together show potential for simultaneously improving both erythroid and iron parameters in BT patients.

Jian-Pi-Gu-Shen-Hua-Yu Decoction Alleviated Diabetic Nephropathy in Mice through Reducing Ferroptosis.

Background: Diabetic nephropathy (DN), one of the most frequent complications of diabetes mellitus, is a leading cause of end-stage renal disease. However, the current treatment methods still cannot effectively halt the progression of DN. Jian-Pi-Gu-Shen-Hua-Yu (JPGS) decoction can be used for the treatment of chronic kidney diseases such as DN, but the specific mechanism of action has not been fully elucidated yet. Purpose: The aim of this study is to clarify whether JPGS alleviates the progression of diabetic nephropathy by inhibiting ferroptosis. Materials and Methods: We established a DN mouse model to investigate the therapeutic effect of JPGS in a DN mouse model. Subsequently, we examined the effects of JPGS on ferroptosis- and glutathione peroxidase 4 (GPX4) pathway-related indices. Finally, we validated whether JPGS inhibited ferroptosis in DN mice via the GPX4 pathway using GPX4 inhibitor and ferroptosis inhibitors. Results: The results indicate that JPGS has a therapeutic effect on DN mice by improving kidney function and reducing inflammation. Additionally, JPGS treatment decreased iron overload and oxidative stress levels while upregulating the expression of GPX4 pathway-related proteins. Moreover, JPGS demonstrated a similar therapeutic effect as Fer-1 in the context of DN treatment, and RSL3 was able to counteract the therapeutic effect of JPGS and antiferroptotic effect. Conclusion: JPGS has significant therapeutic and anti-inflammatory effects on DN mice, and its mechanism is mainly achieved by upregulating the expression of GPX4 pathway-related proteins, thereby alleviating iron overload and ultimately reducing ferroptosis.

Effects of HCV Clearance with Direct-Acting Antivirals (DAAs) on Liver Stiffness, Liver Fibrosis Stage and Metabolic/Cellular Parameters.

INTRODUCTION: Chronic hepatitis C (CHC) is a clinical and pathological syndrome with various causes and is characterized by varying degrees of hepatocellular necrosis and inflammation. It is a significant cause of liver transplantation and liver-related death worldwide. The hepatic manifestations of CHC are typically characterized by slowly progressing liver fibrosis, which is a non-specific and often disproportionate response to tissue damage. A large majority of HCV patients have extrahepatic manifestations with varying degrees of severity. HCV infection is a risk factor for cardiovascular disease and diabetes mellitus, which increases insulin resistance, oxidative stress, and iron overload and causes chronic systemic inflammation. HCV infection is treated using direct-acting antivirals (DAAs) with cure rates of over 95 percent, minimal side effects, and shorter therapeutic courses. Despite the effective elimination of the virus, it seemed pertinent to understand to what extent HCV clearance eliminates or attenuates all the systemic alterations already induced by the virus during infection and chronicity. OBJECTIVES: Our study aimed to determine whether eliminating HCV with DAAs alters the severity of liver disease (liver stiffness and liver fibrosis stage by TE) and the metabolic/cellular profile of patients with CHC. MATERIALS AND METHODS: A group of 329 CHC patients from a Gastroenterology and Hepatology outpatient department were prospectively studied. Of these, 134 were also studied with DAAs. The liver fibrosis stage was evaluated by transient elastography (TE) using a FibroScan® device, and two groups were established for the analysis of liver stiffness (LS): mild and moderate stiffness (fibrosis F1 and F2; F1/2) and severe stiffness (fibrosis and cirrhosis F3 and F4; F3/4). Metabolic/cellular parameters were evaluated before and after antiviral treatment using standard methods: alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl-transpeptidase (γ-GT), haptoglobin (Hp), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), free iron (Fe), transferrin saturation (TS), total iron binding capacity (TIBC), ferritin (Ft), glycemia, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and platelets count. The results were statistically analyzed using SPSS 24.0 for Windows. RESULTS: Comparing the fibrosis stage before and after DAAs treatment, we verify a reduction in LS in 85.7% of patients and an improvement in liver fibrosis stage in 22.2% of them after DAAs treatment. Before DAAs treatment, patients showed a 2.410 risk for higher fibrosis stages (F3/4). Comparing metabolic/cellular parameters before and after DAAs treatment, patients showed lower ALP, AST, ALT, γGT, TG, Fe, TIBC, and Ft values and higher TC, LDL, and Hp values after treatment. As such, HCV elimination reduces iron overload and insulin resistance. On the other hand, it caused dyslipidemia, raising total cholesterol and LDL to levels outside the reference values. The improvement in the liver fibrosis stage by TE was mainly associated with higher baseline platelet count and HDL values and lower insulin resistance. CONCLUSIONS: With this study, we were able to contribute to the knowledge of the effects of HCV elimination with DAAs on liver disease and metabolic profile to improve the quality of treatment and follow-up of these patients after HCV elimination.

Active Components of Pueraria lobata through the MAPK/ERK Signaling Pathway Alleviate Iron Overload in Alcoholic Liver Disease.

OBJECTIVE: To delve into the primary active ingredients and mechanism of Pueraria lobata for alleviating iron overload in alcoholic liver disease. METHODS: Pueraria lobata's potential targets and signaling pathways in treating alcohol-induced iron overloads were predicted using network pharmacology analysis. Then, animal experiments were used to validate the predictions of network pharmacology. The impact of puerarin or genistein on alcohol-induced iron accumulation, liver injury, oxidative stress, and apoptosis was assessed using morphological examination, biochemical index test, and immunofluorescence. Key proteins implicated in linked pathways were identified using RT-qPCR, western blot analysis, and immunohistochemistry. RESULTS: Network pharmacological predictions combined with animal experiments suggest that the model group compared to the control group, exhibited activation of the MAPK/ERK signaling pathway, suppression of hepcidin expression, and aggravated iron overload, liver damage, oxidative stress, and hepatocyte death. Puerarin and genistein, the active compounds in Pueraria lobata, effectively mitigated the aforementioned alcohol-induced effects. No statistically significant disparities were seen in the effects above between the two groups receiving drug therapy. CONCLUSION: This study preliminarily demonstrated that puerarin and genistein in Pueraria lobata may increase hepcidin production to alleviate alcohol-induced iron overload by inhibiting the MAPK/ERK signaling pathway.

Bajitianwan formula extract ameliorates bone loss induced by iron overload via activating RAGE/PI3K/AKT pathway based on network pharmacology and transcriptomic analysis.

Osteoporosis (OP) is closely related to iron overload. Bajitianwan (BJTW) is a traditional Chinese medicine formulation used for treating senile diseases such as dementia and osteoporosis. Modern pharmacological researches have found that BJTW has beneficial effect on bone loss and memory impairment in aging rats. This paper aimed to explore the role and mechanism of BJTW in ameliorating iron overload-induced bone loss. Furthermore, BJTW effectively improved the bone micro-structure of the femur in mice, and altered bone metabolism biomarkers alkaline phosphatase (ALP) and osteocalcin (OCN) in serum, as well as oxidative indexes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) glutathione (GSH) and malondialdehyde (MDA) in liver. As for network pharmacology, 73 components collected from BJTW regulated 99 common targets merged in the BJTW and OP. The results of RNA-seq indicated that there were 418 potential targets in BJTW low dose group (BJTW-L) and 347 potential targets in BJTW high dose group (BJTW-H). Intriguingly, both PI3K-AKT signaling pathway and the AGEs-RAGE signaling pathway were contained in the KEGG pathways enrichment results of network pharmacology and transcriptomics, which were considered as the potential mechanism. Additionally, we verified that BJTW regulated the expression of related proteins in RAGE/PI3K-AKT pathways in MC3T3-E1 cells. In summary, BJTW has potent effect on protecting against iron overload-induced OP, and its mechanism may be related to the activation of the RAGE/PI3K-AKT signaling pathways.

Polypharmacy and medication regimen complexity in transfusion-dependent thalassaemia patients: a cross- sectional study.

BACKGROUND: Medication burden and complexity have been longstanding problems in chronically ill patients. However, more data are needed on the extent and impact of medication burden and complexity in the transfusion-dependent thalassaemia population. AIM: The aim of this study was to determine the characteristics of medication complexity and polypharmacy and determine their relationship with drug-related problems (DRP) and control of iron overload in transfusion-dependent thalassaemia patients. METHOD: Data were derived from a cross-sectional observational study on characteristics of DRPs conducted at a Malaysian tertiary hospital. The medication regimen complexity index (MRCI) was determined using a validated tool, and polypharmacy was defined as the chronic use of five or more medications. The receiver operating characteristic curve analysis was used to determine the optimal cut-off value for MRCI, and logistic regression analysis was conducted. RESULTS: The study enrolled 200 adult patients. The MRCI cut-off point was proposed to be 17.5 (Area Under Curve = 0.722; sensitivity of 73.3% and specificity of 62.0%). Approximately 73% and 64.5% of the patients had polypharmacy and high MRCI, respectively. Findings indicated that DRP was a full mediator in the association between MRCI and iron overload. CONCLUSION: Transfusion-dependent thalassaemia patients have high MRCI and suboptimal control of iron overload conditions in the presence of DRPs. Thus, future interventions should consider MRCI and DRP as factors in serum iron control.

Real-world evidence: Long-term safety of deferiprone in a large cohort of patients with sickle cell disease enrolled in a registry for up to 10 years.

Patients with sickle cell disease (SCD) and other anemias who receive blood transfusions are at risk of organ damage due to transfusional iron overload. Deferiprone is an iron chelator with a well-established safety and efficacy profile that is indicated for the treatment of transfusional iron overload. Here, we report safety data from the large-scale, retrospective Ferriprox® Total Care Registry, which involved all patients with SCD taking deferiprone following the 2011 approval of deferiprone in the United States through August 2020. A total of 634 patients who had initiated deferiprone treatment were included. The mean (SD) duration of deferiprone exposure in the registry was 1.6 (1.6) years (range 0 to 9.7 years). In the overall patient population (N = 634), 64.7% (n = 410) of patients reported a total of 1885 adverse events (AEs). In subgroup analyses, 54.6% (n = 71) of pediatric patients and 67.3% (n = 339) of adult patients reported AEs. The most common AEs reported in patients receiving deferiprone were sickle cell crisis (22.7%), nausea (12.1%), vomiting (8.7%), abdominal discomfort (5.4%), and fatigue (5.4%). Neutropenia was reported in four (0.6%) patients and severe neutropenia/agranulocytosis (defined as absolute neutrophil count <0.5 × 109/L) was reported in two (0.3%) patients. Of patients with evaluable data, all cases of neutropenia and severe neutropenia/agranulocytosis resolved with deferiprone discontinuation. Results from the nearly 10 years of real-world data collected in the Ferriprox® Total Care Registry demonstrate that deferiprone is safe and well tolerated in patients with SCD or other anemias who have transfusional iron overload.

Targeting SIRT1, NLRP3 inflammasome, and Nrf2 signaling with chrysin alleviates the iron-triggered hepatotoxicity in rats.

Blood transfusion-requiring diseases such as sickle cell anemia and thalassemia are characterized by an imbalance between iron intake and excretion, resulting in an iron overload (IOL) disorder. Hepatotoxicity is prevalent under the IOL disorder because of the associated hepatocellular redox and inflammatory perturbation. The current work was devoted to investigate the potential protection against the IOL-associated hepatotoxicity using chrysin, a naturally-occurring flavone. IOL model was created in male Wistar rats by intraperitoneal injection of 100 mg/kg elemental iron subdivided on five equal injections; one injection was applied every other day over ten days. Chrysin was administered in a daily dose of 50 mg/kg over the ten-day iron treatment period. On day eleven, blood and liver samples were collected and subjected to histopathological, biochemical, and molecular investigations. Chrysin suppressed the IOL-induced hepatocellular damage as revealed by decreased serum activity of the intracellular liver enzymes and improved liver histological picture. Oxidative damage biomarkers, and pro-inflammatory cytokines were significantly suppressed. Mechanistically, the levels of the redox and inflammation-controlling proteins SIRT1 and PPARγ were efficiently up-regulated. The liver iron load, NLRP3 inflammasome activation, and NF-κB acetylation and nuclear shift were significantly suppressed in the iron-intoxicated rats. Equally important, the level of the antioxidant protein Nrf2 and its target HO-1 were up-regulated. In addition, chrysin significantly ameliorated the IOL-induced apoptosis as indicated by reduction in caspase-3 activity and modulation of BAX and Bcl2 protein abundance. Together, these findings highlight the alleviating activity of chrysin against the IOL-associated hepatotoxicity and shed light on the role of SIRT1, NLRP3 inflammasome, and Nrf2 signaling as potential contributing molecular mechanisms.