The impact of increased serum ferritin levels in late pregnancy on pregnancy outcomes: a multi-center cohort study in China.

How to Differentiate Pediatric Enteroviral Meningoencephalitis from Scrub Typhus Meningitis: A Single-Center Retrospective Study from Yunnan Province, China.

PurposeAction of metformin, the preferred pharmacologic treatment for type 2 diabetes (T2D), remains incompletely understood. Metformin induces an iron starvation response in yeast, suggesting tissue iron might be related to metformin responsiveness. We therefore examined the effects of different levels of tissue iron on metformin action.Subjects and MethodsWe examined glycemic responses to metformin and effects on downstream targets of metformin in mice on diabetogenic diets with different iron contents and performed a retrospective study of metformin effectiveness as a function of serum ferritin, a reliable marker of tissue iron, in human patients after initiation of metformin therapy.ResultsMetformin provided the most glycemic benefit to mice on the normal-iron diet, compared to high or low iron. The low-iron diet itself provided glycemic benefit, and on low iron, metformin provided no additional benefit. These results were parallelled by effects of dietary iron on downstream targets of metformin action, including AMP-dependent kinase and glycerol-3-phosphate dehydrogenase 2. Increased protein modification by O-linked N-acetylglucosamine (O-GlcNAc) mimicked lower iron levels, abrogated the effect of high iron, and resulted in smaller relative metformin responses on glycemia and downstream reporters. Humans with higher or lower levels of the iron biomarker ferritin also exhibited a decreased HbA1c response to metformin.ConclusionDietary iron and serum ferritin predict the glycemic response to metformin in mouse models and humans with T2D. Protein O-GlcNAcylation has effects paralleling low iron and may play a role in mediating these interactions.

Introduction Recent studies have shown a link between iron status and immune response following infection or vaccination. We aimed to investigate whether plasma ferritin and plasma iron concentrations at time of vaccination were associated with the development and temporal decay of immune response to SARS-CoV-2 vaccination over 6 months. Materials and methods We used data from the Zurich SARS-CoV-2 Vaccine Cohort (n=572). Participants were recruited from a random sample stratified by age groups (18–64 years, >65 years) and vaccine types (Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, Johnson & Johnson JNJ-78436735). Iron parameters were measured at baseline (prior to vaccination), whereas different immunity markers were measured at baseline, 4 weeks, 6 weeks, 3 months, and 6 months. We investigated the association between plasma ferritin and plasma iron levels and immunity markers using linear mixed-effect models, and estimated half-life based on linear decay models. Results Plasma ferritin and plasma iron concentrations were within the normal physiological range, and the prevalence of iron deficiency (4.5%) and inflammation (2.3%) was low. For every 50 μg/L increase in plasma ferritin concentration, we observed a 5.2% increase in Anti-S IgG antibodies, and a 13.6-19.9% increase in neutralizing antibodies against the Ancestral, Delta, and Omicron BA1 viral variants. Similarly, the highest plasma ferritin quartile showed a 14.9% increase in Anti-S IgG antibodies, and a 47.1-82.2% increase in Anti-Ancestral, Anti-Delta, and Anti-Omicron neutralizing antibodies compared to the lowest quartile. Despite high concentrations at 6 months, shorter mean half-lives of Anti-S IgG antibodies were observed in the highest quartiles of plasma ferritin concentrations (Q3: 121.4 days; Q4: 109.8 days vs . Q1: 152.1 days). Plasma iron results were less consistent and generally no evidence for associations was found. Conclusion In this predominantly iron-replete cohort, higher plasma ferritin at the time of vaccination was associated with stronger vaccination-induced humoral immune responses to SARS-CoV-2 over 6 months.

Background/Objectives: Fever can develop from several causes, including infectious diseases, noninfectious inflammatory diseases (NIID), malignancies, and other medical conditions. Although serum ferritin (SF) level can help differentiate infectious from non-infectious diseases, its discriminative ability (specificity) is far from satisfactory. The aim of this study was to develop a diagnostic prediction model to distinguish infectious diseases from other febrile illnesses using only common blood tests available on admission, in addition to SF level, in patients with undiagnosed fever. Methods: This single-center retrospective observational study included patients with fever of unidentified origin aged ≥18 years admitted to a Japanese acute care hospital between 1 January 2013, and 31 December 2022. They were divided into infectious and non-infectious disease groups based on their final diagnosis. Machine learning and multivariable logistic regression analysis were used to develop a model to differentiate infectious diseases from non-infectious diseases. Model performance was evaluated using area under the curve (AUC), shrinkage coefficient, and stratified likelihood ratio. Results: Among the 143 patients included, 73 had infectious diseases. A prediction model consisting of five factors—serum white blood cell count, neutrophil percentage, platelet count, lactate dehydrogenase level, and log-transformed SF level—was developed. The AUC of the model was 0.794 (95% confidence interval: 0.721–0.867) with a sensitivity of 77.1%, specificity of 68.5%, shrinkage coefficient of 0.876, and stratified likelihood ratio of 0.13–5.04. Conclusions: We developed a prediction model consisting of only five high-performing indicators, which would help differentiate infectious diseases from other fever causes early after admission.

Outcomes following CD22 CAR T-cells in B-ALL: a tale of two manufacturing strategies.

Anemia in general and iron deficiency constitute a public health problem, particularly about blood donation. Blood donation can lead to anemia, particularly deficiency anemia under certain conditions. This study therefore aims to determine the prevalence of anemia and iron deficiency anemia in blood donors and identify associated factors. We conducted an analytical cross-sectional study over 4 months. Blood donors were recruited at the blood bank of the Bafoussam Regional Hospital. Blood samples were collected in EDTA and dry tubes for biological tests, among which full blood counts, serum ferritin level, and serum iron following standard assay protocols (flow cytometry, sandwich Elisa, and spectrophotometric). The results obtained were analyzed using R software version 4.3.2. The significance threshold for analyses was set at p value < 0.05. In total, 210 blood donors were included in the study. The sex ratio was 5.3 in favor of men. The mean age was 29.69 ± 7.98 years. The most common type of donation was paid donation (38.6%); 70% of the donations were sporadic. Out of the 210 donors, 63 (30%) had anemia, and 45 (21.4%) had iron deficiency. The mean hemoglobin level was 10.81 ± 0.89 g/dL in anemic donors (AD), and 12.84 ± 1.18 g/dL in non-anemic donors (NAD) (p < 0.001). The mean red blood cell count was 4.67 ± 0.55 T/L in AD and 5.21 ± 0.62 T/L in NAD (p < 0.001). The mean hemoglobin levels were 10.8 ± 0.87 g/dL in AD, and 12.9 ± 1.17 g/dL in NAD (p < 0.001). Serum iron level differed in AD compared to NAD with respective means of 305 ± 128 µg/dL in AD and 386.00 ± 207 µg/dL in NAD (p < 0.001). Macroplateletosis was identified as a predictive factor of iron deficiency anemia during blood donation (OR = 2.93; 95% CI = [1.00; 8.59]; p = 0.054). This study reports a high frequency of iron deficiency anemia in blood donors. This suggests a systematic exploration of anemia and iron deficiency anemia in blood donors is useful to preserve donor safety and ensure the efficacy of blood transfusion.

Matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) is a viable curative option for children with transfusion-dependent thalassemia major lacking a matched sibling donor. This study aimed to evaluate outcomes of MUD-HSCT in pediatric patients (≤ 12 years) because data on such a cohort are sparse. A retrospective analysis was conducted on 25 patients with thalassemia (≤12 years) who underwent MUD-HSCT. Data on patient demographics, transplant characteristics, post-transplant complications, and survival outcomes were collected. Kaplan-Meier survival analysis was used to estimate overall survival (OS), thalassemia-free survival (TFS), graft-versus-host and relapse-free survival (GRFS), and graft-versus-host and thalassemia-free survival (GTFS). Cox regression analysis was performed to identify predictors of GRFS. Median age at transplantation was 9 years; 60.9% were male. Most patients (68%) were Nanfang Class III. Median ANC and platelet engraftment occurred at 16 and 15 days, respectively. Acute and chronic GVHD were observed in 52% and 16% of patients, respectively. CMV reactivation occurred in 24%. Estimated 5-year OS, TFS, GRFS, and GTFS were 95.8%, 92%, 75.8%, and 92%, respectively. Elevated ferritin levels > 2500 ng/mL were independently associated with inferior GRFS (HR: 0.040; p-value = 0.031). In conclusion, MUD-HSCT yields excellent outcomes for OS and TFS in pediatric patients with thalassemia aged ≤ 12 years. High pre-transplant ferritin adversely impacted GRFS, underscoring the importance of iron control. These findings support MUD-HSCT as a viable option with appropriate pre-transplant optimization and GVHD management.

Aim and objective: To find out the proportion of transfusion reaction symptoms of beta-thalassemia in paediatric age group patients and to estimate the biochemical parameters of liver functions and correlate them with serum ferritin levels. Material and method: The present cross-sectional study was conducted on 120 children with known beta thalassemia aged between 2-12 years on repeated blood transfusion. A thorough clinical examination with particular importance on the presence of pallor, jaundice, and signs of thalassemic features was done. An abdominal examination was done to rule out hepatosplenomegaly. Blood samples were collected for appropriate investigations including serum ferritin level, transferrin saturation, and liver function test. Results: In this study, 27.5% and 72.5% of children belonged to the 2-5 years and 6-12 years age category respectively. The majority of study subjects were male (65.33%). The incidence of jaundice, ascites, and hepatomegaly was found to be 90.83%, 36.67%, and 100% respectively. The incidence of jaundice, ascites, and hepatomegaly are more common in older age children. A significant positive correlation was found between serum ferritin and total bilirubin, direct bilirubin, and SGPT (P&lt;0.05). Conclusion: In the present study, there was a positive significant correlation between serum ferritin and total bilirubin, direct bilirubin, and SGPT. Thus, as serum ferritin increases there is an increase in liver function parameters and enzymes and there will be more derangement in liver function probably because of an iron overload condition.

To maintain a stable blood supply while protecting donor and recipient health, the World Health Organization (WHO) recommends minimum inter-donation intervals of 12 weeks for men and 16 weeks for women. These recommendations are merely based on observational studies reporting reduced haemoglobin (Hb) and iron levels and increased deferrals in repeat donors. This systematic review aims to examine the best available experimental evidence on how whole-blood donation frequency impacts donor health. PubMed (Medline, PMC and NCBI Bookshelf), Embase and the Cochrane Library were systematically searched by two reviewers independently. Risk of bias and certainty of evidence were evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Four records on three randomized controlled trials (RCTs) were included. The results showed that donating every 12 weeks may reduce Hb and ferritin levels compared to not donating. Similarly, shortening inter-donation intervals (from 12 to 8 or 10 weeks for men and from 16 to 12 or 14 weeks for women) may lead to decreased Hb and ferritin levels, increased low-Hb deferral and increased reporting of tiredness, fainting, dizziness and restless legs. Evidence was of low to very low certainty, and limitations in study design and imprecision prohibit strong recommendations on optimal inter-donation intervals. In the absence of more robust evidence and pending future high-quality RCTs, it is prudent to adhere to the current WHO guidelines on minimum inter-donation intervals for whole-blood donation, that is, 12 weeks for men and 16 weeks for women, as a precautionary measure.

This cross-sectional study aimed to compare serum vitamin B12, 25-hydroxyvitamin D (25-OHD), ferritin, and iron levels between adults diagnosed with attention deficit hyperactivity disorder (ADHD) and healthy controls, and to evaluate the relationship between these biochemical markers and the severity of ADHD symptoms. In this cross-sectional study, a total of 35 adults with ADHD and 36 age- and sex-matched healthy controls who presented to a psychiatry outpatient clinic in Sakarya in 2024 were included. Participants' demographic data and clinical characteristics were collected through interviews, while laboratory findings were examined using blood samples taken at the time of inclusion in the study. The severity of ADHD symptoms was assessed using the Adult ADHD Self-Report Scale (ASRS) and the Wender-Utah Rating Scale (WURS). Serum vitamin B12 and 25-hydroxyvitamin D levels were significantly lower in the ADHD group compared with controls (p < 0.001). No significant differences were observed in ferritin and iron levels (p > 0.05). Vitamin B12 and 25-hydroxyvitamin D levels showed moderate-to-strong negative correlations with symptom severity. For example, vitamin B12 levels correlated with ASRS inattention (r = - 0.54, p = 0.00009) and WURS inattention (r = - 0.56, p = 0.000002), while 25-hydroxyvitamin D levels correlated with ASRS hyperactivity/impulsivity (r = - 0.53) and WURS depression (r = - 0.54). These findings indicate that lower serum vitamin B12 and 25-hydroxyvitamin D levels are associated with greater ADHD symptom severity in adults. The results underscore the potential relevance of biochemical factors in adult ADHD and suggest that assessment of vitamin status may be considered in future clinical and research contexts.

Background aim Despite the remarkable efficacy of chimeric antigen receptor T-cell (CAR-T) therapy in relapsed/refractory multiple myeloma (R/R MM), treatment response and toxicity exhibit considerable heterogeneity. This study aimed to evaluate the prognostic significance of baseline peripheral blood inflammatory ratios—namely, the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR)—in patients with R/R MM receiving CAR-T therapy, and to develop an integrated prognostic index based on these parameters. Methods We conducted a retrospective analysis of 197 R/R MM patients who received CAR-T therapy. The optimal cut-off values for NLR, MLR, and PLR were determined using receiver operating characteristic (ROC) curve analysis. Associations between these ratios and treatment efficacy, CAR transgene expansion, cytokine release syndrome (CRS), and progression-free survival (PFS) were evaluated. A composite Cellular Inflammatory Prognostic Index (CIPI) integrating NLR, MLR, and PLR was developed to assess prognostic stratification. Results Optimal cut-offs for NLR, MLR, and PLR were 2.55, 0.35, and 145, respectively. Patients with low baseline inflammatory ratios exhibited significantly higher CAR transgene expansion and were associated with better treatment responses than that of patients with high baseline inflammatory ratios. The low NLR group showed a superior objective response rate (93.8% vs. 81.2%, p = 0.037) and a longer median PFS was observed in the low NLR group compared with the high NLR group (18.6 vs. 10.9 months, p = 0.0012). Elevated inflammatory ratios correlated with high peak levels of IL-6 and ferritin and an increased incidence of severe CRS (≥ grade 3). The CIPI score effectively stratified patients into low-, intermediate-, and high-risk groups with distinct PFS (median PFS: 18.9, 13.8, and 5.1 months, respectively; p &amp;lt; 0.0001). Multivariate analysis confirmed that the CIPI score was an independent prognostic factor for PFS, along with high tumor burden. Conclusion Baseline peripheral blood inflammatory ratios are closely associated with CAR-T cell efficacy and CRS severity in R/R MM patients receiving CAR-T therapy. The CIPI score represents a simple and reproducible prognostic biomarker that may help individualized risk stratification and inform treatment optimization in CAR-T therapy.

Background/Objectives: Iron deficiency affects 2% of infants under six months of age and 4–18% of infants aged 6–12 months and may lead to anemia. Given the consequences of iron deficiency in infancy and the importance of adequate nutrition, this study aimed to assess indicators of iron metabolism in infants whose parents participated in nutritional education. Methods: The study included 104 infants, divided into a study group (SG, n = 52) receiving a nutritional education intervention and a control group (CG, n = 52). Peripheral blood morphology parameters and biochemical markers, e.g., iron status (serum iron, transferrin, ferritin, and hepcidin), were evaluated at 3 and 12 months of age. Additionally, at study end, parents completed a three-day dietary diary to assess their infant’s iron intake. Results: After nearly one year of intervention, no cases of anemia based on hemoglobin concentration were identified in either group. However, infants in the SG were less likely to present iron and ferritin concentrations below reference ranges compared to the CG. In the CG, low ferritin levels occurred more frequently at 12 months than at baseline. This finding may be related to higher dietary iron intake in the SG, as insufficient iron intake was more common among the CG. Heatmap analysis revealed strong positive correlations among erythrocyte indices, confirming their internal consistency. No single parameter emerged as a superior marker of iron deficiency, emphasizing the need for a combined assessment of iron status. Conclusions: Parental nutritional education may improve iron status and reduce the risk of iron metabolism disorders in infants.

Purpose: Restless Legs Syndrome (RLS) pathophysiology involves central iron deficiency and dopaminergic dysfunction, but the role of peripheral nerves and patient-specific factors like age remains unclear. This study investigated the relationships between serum ferritin, age, and peripheral electrophysiological findings in drug-naïve RLS patients. Methods: A retrospective cohort study was conducted with 95 drug-naïve RLS patients. Comprehensive analysis included serum ferritin levels, detailed nerve conduction studies, and clinical assessments. Statistical evaluations involved subgroup comparisons (based on ferritin and EMG status), correlation analyses, and binary logistic regression to identify independent predictors of abnormal electromyography (EMG). Results: The cohort had a mean age of 53.8 years, with 14.7% having low ferritin. A striking dissociation was observed: all patients (100%) with low ferritin had normal EMG, whereas 41.2% of those with normal ferritin had abnormal EMG (p=0.002). Elderly patients were significantly more likely to exhibit abnormal EMG recordings (62.7 vs. 48.9 years, P&lt;0.001) and had longer symptom duration. Multivariate analysis confirmed advancing age as the sole independent predictor of abnormal EMG (aOR-1:14 per year, P=0.001). Conclusion: This study demonstrates a strong association between peripheral nerve abnormalities and advanced age, particularly in patients with accompanying comorbidities, in drug-naïve RLS patients, while such abnormalities were absent in younger patients with low ferritin. These findings point to potential subgroups with differing pathophysiology. Future research should incorporate advanced electrophysiological methods to better define these subgroups and their clinical relevance.

Surface complexation of cell iron following particle exposure can be relevant to coal mine dust lung disease. We tested the postulate that 1) coal dust and humic substances (HS), a specific component of coal, complex intracellular iron from cultured cells to initiate a functional metal deficiency, 2) the functional cell iron deficiency which results after exposure to coal dust and HS impacts an increased release of both superoxide-related products and pro-inflammatory mediators, and 3) the disruption in iron homeostasis after coal dust exposure is associated with pneumoconiosis in miners. Cell exposures to coal dust and HS initiated a functional iron deficiency, reflected by elevated expression of an importer (divalent metal transporter-1), which increased metal uptake measured as cell non-heme concentrations. Cell exposure to coal dust and HS increased 1) generation of superoxide, measured using Nitroblue Tetrazolium reduction and an Amplex Red assay, and 2) release of interleukin (IL)-6 and IL-8. These measures of oxidative stress and inflammatory mediator release were diminished with co-exposure to iron supporting a relationship of both with a functional cell deficiency of the metal. Using a cohort of retired miners, blood ferritin levels were elevated in those diagnosed with a positive B read for coal workers' pneumoconiosis. Elevated blood ferritin concentrations correlated with progression of disease on B reads obtained one year later in the miners. It is concluded that coal dust and HS can initiate a disruption of iron homeostasis associated with superoxide generation, release of pro-inflammatory cytokines, and pneumoconiosis.

Inflammation-driven mechanisms play a central role in adverse outcomes after non-ST-elevation myocardial infarction (NSTEMI), yet simple, widely available biomarkers for early risk stratification remain insufficiently defined. Hemogram-derived indices and iron-related inflammatory markers may provide complementary prognostic information. To evaluate the prognostic significance of the mean platelet volume-to-monocyte ratio (MMR) and serum ferritin in predicting major adverse cardiovascular events (MACE) in patients with NSTEMI, and to assess the association of angiotensin-converting enzyme (ACE) inhibitor therapy with clinical outcomes. This prospective cohort study included 170 consecutive NSTEMI patients admitted to the University Clinical Center Tuzla between February 2022 and January 2023. All patients received dual antiplatelet therapy and high-intensity statins. The baseline evaluation included a complete blood count, serum ferritin, and C-reactive protein. MMR was calculated as the ratio of mean platelet volume to absolute monocyte count. Patients were followed for 12 months for the occurrence of MACE, defined as cardiovascular death, non-fatal myocardial infarction, urgent revascularization, stroke, or hospitalization for heart failure. During follow-up, 103 patients (60.6%) experienced MACE. Admission MMR (18.1 ± 11.7 vs 13.2 ± 5.5; P = 0.003) and ferritin levels (284 ± 396 vs 152 ± 109 µg/L; P = 0.001) were significantly higher in patients with events. In multivariable analysis, both MMR (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.02-1.11; P = 0.008) and ferritin (OR 1.28 per 100 µg/L, 95% CI 1.10-1.55; P = 0.003) independently predicted MACE, while ACE inhibitor therapy was associated with a lower risk (OR 0.24, 95% CI 0.08-0.70; P = 0.01). The combined model demonstrated good discriminative performance (AUC 0.72; 95% CI 0.64-0.80). Elevated admission MMR and ferritin were independently associated with a higher 1-year risk of MACE in patients with NSTEMI. ACE inhibitor therapy was associated with improved outcomes, although causality cannot be inferred. These findings suggest that readily available inflammatory biomarkers may complement established clinical parameters for early risk stratification and support continued guideline-directed pharmacotherapy in NSTEMI.

Pica is an eating disorder characterized by the persistent craving and consumption of non-food substances such as ice, chalk, starch, or raw pasta. Pica symptoms are more common in people with iron deficiency and resolve upon treatment. Without iron supplementation, volunteer blood donors can become iron deficient after repeated donations, making them an ideal population to study pica. A genome-wide association study (GWAS) was conducted with 12,157 volunteer blood donors within the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) RBC-omics study. Three pica outcomes of interest were evaluated, including ice-only consumption, non-ice consumption, or either type of pica (combined). Candidate single nucleotide polymorphisms (SNPs) were tested for replication using all of us (AoU). Within REDS-III, 2.4% of donors reported pica symptoms, and nine genome-wide significant SNPs were identified as associated with pica. Within a stratified European population of 7493 REDS-III donors, seven genome-wide significant SNPs were identified. Both overall and in the European stratum, ferritin levels were lower in pica cases than controls (36.0 ± 43.2 ng/mL vs. 53.3 ± 69.2 ng/mL overall and 33.8 ± 41.0 ng/mL vs. 43.8 ± 55.3 ng/mL). Of these, one SNP, rs73277282, near the gene encoding the neuropeptide VF (NPVF) replicated in the AoU dataset (REDS-III p = 1.53 x 10-8; AoU p = .02). Neuropeptide VF has been previously shown to regulate food intake and energy balance, suggesting that polymorphisms associated with its expression may synergize with iron deficiency to produce pica behaviors.

This study aimed to assess the association between lipid accumulation product (LAP) index, a novel index combining waist circumference (WC) and triglyceride levels, and anthropometric indices, metabolic factors and hepatic function markers in obese subjects with non-alcoholic fatty liver disease (NAFLD). Cross-sectional study. Specialised and subspecialised outpatient clinics of Tabriz University of Medical Sciences. Overall, 232 adult patients with obesity and ultrasound-proven NAFLD were included in the present study. Anthropometric measurements (body weight, height and waist and hip circumferences) were measured, and serum levels of glucose, lipid profile, ferritin and liver enzymes were assessed subsequent to an overnight fasting. Mild and Moderate NAFLD were found in 43.5% and 48.2% of the participants, respectively. LAP index markedly increased with higher grades of steatosis, showing values of 63.72±22.26, 84.57±44.96 and 112.14±56.97 for healthy, grade I and grade II groups, respectively (p<0.001). There were significant differences in body weight (p=0.003), WC (p<0.001), fasting blood sugar (FBS) (p=0.004) and lipid profile (p<0.001) among LAP index quartiles. Moreover, the LAP index was positively correlated with body weight, liver function and, as expected, with lipid profile in all of the subjects with NAFLD. Sex differences showed an additional marked association of LAP with FBS (r=0.363 and p<0.001, respectively) and glycosylated haemoglobin (r=0.321 and p=0.002, respectively) in males and serum aspartate aminotransferase levels in females (r=0.223 and p=0.009, respectively). In conclusion, the LAP index was not only associated with anthropometric indices, metabolic parameters and hepatic function markers, but also increased in line with higher grades of liver steatosis in NAFLD.

Paraquat (PQ) is a herbicide which is used indiscriminately specially in developing countries. The objective of our study is to evaluate the toxicity of PQ on cerebral and pulmonary tissues and the efficacy of Tiron in attenuating such toxicity through focusing in the involvement of Nrf2/HO-1 and TLR4/NF-κB signaling pathways. Rats were divided into 5 groups of 6 rats each: control, Tiron control (200mg/kg), PQ (10mg/kg), Tiron (100mg/kg) + PQ, and Tiron (200mg/kg) + PQ groups. Behavioural tests were performed before euthanasia. Subsequently, serum, brain, and lung samples were collected. Bronchoalveolar lavage (BAL) fluid and cell counting, serum iron and ferritin, oxidative stress biomarkers, histopathological examination along with immunohistochemical assessment of nuclear factor kappa B p65 subunit (NF-κB p65), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme-oxygenase1(HO-1) were performed. Toll-like receptor 4 (TLR4), and interleukin 1beta (IL-1β) were also assessed. Tiron reversed PQ induced cerebral and pulmonary injury by enhancing motor activity confirmed by wire hanging and open field test (OFT), additionally, it decreased serum iron, total leucocytes count (TLC), monocytes and neutrophils count, 4-Hydroxynonenal (4-HNE), malondialdehyde (MDA), along with increased levels of serum ferritin, reduced glutathione (GSH), glutathione peroxidase 4 (GPX4), Nrf2, and total antioxidant capacity (TAC) in cerebral and pulmonary tissues beside improved histopathological alterations compared to PQ- administered group. Also, HO-1 was significantly increased along with a downregulation of TLR4, NF-κB p65, and IL-1β upon Tiron administration. Tiron mitigated PQ induced cerebral and pulmonary toxicity via restoration of ferroptosis balance, decreasing oxidative stress, and downregulation of inflammatory TLR4/ NF-κB pathway in a dose dependent manner.

COVID-19 severity is strongly associated with hyperinflammation. Cyclosporine A (CSA), an interleukin-2 inhibitor with immunomodulatory and antiviral activity, has been proposed as a potential adjunctive therapy. This study evaluated the safety and efficacy of CSA in patients with moderate to severe COVID-19. We conducted A randomized, open-label phase III trial was conducted involving 66 patients with COVID-19. Participants were assigned to one of two groups: the CSA group (n = 23), receiving 6mg/kg/day for 7-14days, and a standard treatment group (n = 43). Clinical improvement (WHO ordinal scale) was the main goal, with C-reactive protein (CRP), ferritin, interleukin-6 ( IL-6), and D-dimer, and safety monitoring for 28days as secondary outcomes significant differences in enrolment. The time to clinical improvement was significantly shorter in the CSA group (4.3 ± 1.0 vs. 5.1 ± 2.3days; p = 0.025). Oxygen supplementation was used in 7 patients (30.43%) versus 12 patients (27.91%) in the standard group, with a p-value of 0.828. No significant differences occurred in the WHO ordinal scale, advanced respiratory support, or mortality. No secondary infections occurred. CSA improved oxygen saturation and reduced CRP and IL-6; differences in saturation at day 14 were not significant. D-dimer and ferritin levels were lower at day 14, with no differences observed at day 7. Cyclosporine did not significantly improve ordinal scale outcomes. However, it was associated with a shorter time to clinical improvement and favorable modulation of inflammatory markers in patients with COVID-19 and cytokine storm, without major safety concerns.