Evaluation of Inflammation and Oxidative Stress Markers in Patients with Obstructive Sleep Apnea (OSA).

Background: The identification of circulating markers of oxidative stress and systemic inflammation might enhance risk stratification in obstructive sleep apnea (OSA). We investigated the association between specific haematological parameters, as easily measurable markers of oxidative stress and inflammation, and the degree of hypoxia during polysomnography using the apnea hypopnea index (AHI), oxygen desaturation index (ODI), and oxygen saturation (SpO2), in OSA patients. Methods: Associations between polysomnographic parameters and demographic, clinical, and laboratory characteristics were assessed in a consecutive series of patients with OSA attending the Respiratory Disease Unit of the University Hospital of Sassari, north Sardinia (Italy), between 2015 and 2019. Results: In 259 OSA patients (195 males and 64 females), the body mass index (BMI) was significantly and positively associated with the AHI and ODI, and negatively associated with the mean SpO2. No haematological parameter was independently associated with the AHI or ODI. By contrast, albumin, neutrophil, and monocyte counts, and the systemic inflammatory response index (SIRI) were independently associated with a lower SpO2. Conclusions: Our results suggest that albumin and specific haematological parameters are promising markers of reduced oxygen saturation in OSA.

Association between Red Blood Cell Distribution Width and Obstructive Sleep Apnea Syndrome: A Systematic Review and Meta-Analysis.

Although polysomnography is the gold standard method to diagnose obstructive sleep apnea syndrome (OSAS), there is an ongoing quest for simpler and relatively inexpensive biomarkers of disease presence and severity. To address this issue, we conducted a systematic review of the potential diagnostic role of the red blood cell distribution width (RDW), a routine hematological parameter of red blood cell volume variability, in OSAS. A total of 1478 articles were initially identified in the databases PubMed, Web of Science, Scopus, Embase, and Google Scholar, from their inception to February 2023, and 20 were selected for final analysis. The RDW was significantly higher in OSAS than in non-OSAS subjects (SMD = 0.44, 95% CI 0.20 to 0.67, p < 0.001; low certainty of evidence). In univariate meta-regression, the mean oxygen saturation (SpO2) was significantly associated with the effect size. No significant between-group differences were observed in subgroup analyses. Notably, in OSAS subjects, the RDW SMD progressively increased with disease severity. In conclusion, these results suggest that the RDW is a promising biomarker of OSAS (PROSPERO registration number: CRD42023398047).

A systematic review and meta-analysis of homocysteine concentrations in chronic obstructive pulmonary disease.

Patients with chronic obstructive pulmonary disease (COPD) often suffer from other conditions, such as cardiovascular disease, that further increase the risk of adverse outcomes in this group. Serum homocysteine concentrations are positively associated with cardiovascular risk and have also been reported to be increased in COPD. This meta-analysis investigated the association between homocysteine concentrations and COPD. A systematic search of publications in the electronic databases PubMed, Web of Science, Scopus, and Google Scholar, from inception to September 2021, was conducted using the following terms: "Homocysteine" or "Hcy" and "Chronic Obstructive Pulmonary Disease" or "COPD". Weighted mean differences (WMDs) were calculated to evaluate differences in homocysteine concentrations between COPD patients and non-COPD subjects. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. Nine studies in 432 COPD patients (mean age 65 years, 65% males) and 311 controls (mean age 65 years, 56% males) were identified. Pooled results showed that serum homocysteine concentrations were significantly higher in patients with COPD (WMD = 2.91 µmol/L, 95% CI 2.00-3.82 µmol/L; p < 0.001; high certainty of evidence). No publication bias was observed. Our results support the hypothesis that increased homocysteine concentrations are significantly associated with COPD and may account, at least in part, for the increased cardiovascular risk in these patients.

Comparison of Clinical Features, Complete Blood Count Parameters, and Outcomes between Two Distinct Waves of COVID-19: A Monocentric Report from Italy.

BACKGROUND: Since the beginning of the SARS-CoV-2 pandemic, the ability to predict the trajectory of the disease has represented a major challenge for clinicians. There is recent evidence that complete blood cell count (CBC)-derived inflammation indexes have predictive value in COVID-19. We aimed to describe any changes in the clinical features, CBC-derived ratios, and outcomes of patients admitted to our hospital across two temporally distinct waves. METHODS: We retrospectively assessed and compared the clinical characteristics and blood cell count values of patients hospitalized during the second and fourth waves of COVID-19, and explored any outcome differences in terms of the level of respiratory support required and transfer to intensive care. RESULTS: We observed that fourth-wave patients were older, less male-predominant, and carried more comorbidities compared to the second-wave patients but, nevertheless, experienced more favorable outcomes. A strong internal correlation was documented for both waves between outcomes and CBC-derived ratios, with the fourth-wave cases displaying lower admission values of the neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII). No significant differences were found for lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI). CONCLUSIONS: We observed that both admission values of CBC-derived indexes and adverse respiratory outcomes decreased from the second to the fourth wave of COVID-19. These data represent a contribution to the existing knowledge on the role of CBC-derived indexes as a potential tool to help clinicians to quickly differentiate in-hospital patients at increased risk of serious illness and death.

Clinical significance of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in acute exacerbations of COPD: present and future.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a leading cause of hospitalisation and death in COPD patients. In addition to the identification of better strategies to prevent AECOPD, there is an intense focus on discovering novel markers of disease severity that enhance risk stratification on hospital admission for the targeted institution of aggressive versus supportive treatments. In the quest for such biomarkers, an increasing body of evidence suggests that specific indexes derived from routine complete blood counts, i.e. the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), can significantly predict adverse outcomes in AECOPD. This narrative review discusses the current evidence regarding the association between the NLR and the PLR on admission and several clinical end-points (need for invasive ventilation, noninvasive mechanical ventilation failure, admission to an intensive care unit, pulmonary hypertension, length of hospitalisation, and mortality) in AECOPD. Future research directions and potential clinical applications of these haematological indexes in this patient group are also discussed.

Vaccination Status and Number of Vaccine Doses Are Independently Associated with the PaO2/FiO2 Ratio on Admission in Hospitalized COVID-19 Patients.

INTRODUCTION: Coronavirus Disease-19 (COVID-19) vaccines reduce the risk of severe disease and mortality. However, the association between vaccination status and number of doses and the PaO2/FiO2 ratio, a clinical measure of hypoxemia associated with an increased risk of intensive care treatment and mortality, has not been investigated. METHODS: We retrospectively assessed a consecutive series of 116 patients admitted to hospital with a primary diagnosis of COVID-19 between January and April 2022. Demographic, clinical, and laboratory data were collected within 24 h from admission. RESULTS: There was a significant positive relationship between the number of vaccine doses and the PaO2/FiO2 ratio (r = 0.223, p = 0.012). This association remained significant after adjusting for confounders. Vaccinated patients had significantly higher PaO2/FiO2 ratios than the unvaccinated (median: 250; IQR: 195-309 vs. 200; IQR: 156-257, p = 0.013). CONCLUSION: These results highlight the importance of the number of vaccine doses received in reducing the degree of hypoxia on admission in hospitalized COVID-19 patients.

A Comprehensive Systematic Review and Meta-Analysis of the Association between the Neutrophil-to-Lymphocyte Ratio and Adverse Outcomes in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

The neutrophil-to-lymphocyte ratio (NLR) predicts adverse outcomes in stable chronic obstructive pulmonary disease (COPD); however, its prognostic role in acute exacerbations (AECOPD) is less clear. We conducted a systematic review and meta-analysis of the association between the NLR on admission and adverse outcomes (mortality, need for mechanical ventilation, transfer to the intensive care unit, length of stay, pulmonary hypertension, or their combination) in AECOPD by searching PubMed, Web of Science, and Scopus from inception to April 2022. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and the Grades of Recommendation, Assessment, Development, and Evaluation, respectively. In 15 studies (n = 10,038 patients), the NLR was significantly associated with the risk of adverse outcomes (odds ratio = 1.054, 95% CI 1.016 to 1.093, p = 0.005; low certainty of evidence; standard mean difference = 0.82, 95% CI 0.57 to 1.06, p < 0.001; high certainty of evidence). Pooled sensitivity, specificity, and area under the curve were 0.71 (95% CI 0.64 to 0.77), 0.73 (95% CI 0.65 to 0.80), and 0.78 (95% CI 0.74 to 0.81), respectively. In our study, the NLR on admission was significantly associated with adverse outcomes in AECOPD patients, suggesting the potential utility of this biomarker for early risk stratification and management in this group.

Paraoxonase-1 Concentrations in Obstructive Sleep Apnoea: A Systematic Review and Meta-Analysis.

Obstructive sleep apnoea (OSA) is characterized by overproduction of reactive oxygen species and oxidative stress. The antioxidant enzyme paraoxonase-1 (PON-1) may be useful for monitoring the antioxidant defence systems and the effect of treatments in OSA patients. We investigated, by means of systematic review and meta-analysis, the serum concentrations of PON-1 in OSA patients and non-OSA controls. A literature search was conducted in PubMed, Web of Science, Scopus and Google Scholar databases, from the outset to November 2021, utilizing the terms: "paraoxonase" or "PON" or "paraoxonase-1" or "PON-1" and "obstructive sleep apnoea syndrome" or "OSAS" or "OSA". Eleven studies in 429 OSA patients and 258 non-OSA controls were involved in the meta-analysis. The pooled serum PON-1 concentrations were significantly lower in OSA (standardized mean difference (SMD) = -0.70, 95% CI -1.13 to -0.28; p = 0.001). Despite the extreme between-study heterogeneity, the SMD values were not substantially affected by the sequential omission of individual studies. There was no publication bias. Our systematic review and meta-analysis supports the presence of an impaired antioxidant defence system in OSA, possibly the consequence of intermittent hypoxia. Further studies are required to determine the clinical use of PON-1 measurements for risk stratification and monitoring in OSA patients.

Glutathione Peroxidase in Stable Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis.

Chronic obstructive pulmonary disease (COPD) is a progressive disease that is characterized by a state of persistent inflammation and oxidative stress. The presence of oxidative stress in COPD is the result of an imbalance between pro-oxidant and antioxidant mechanisms. The aim of this review was to investigate a possible association between glutathione peroxidase (GPx), a key component of antioxidant defense mechanisms, and COPD. A systematic search for relevant studies was conducted in the electronic databases PubMed, Web of Science, Scopus, and Google Scholar, from inception to June 2021. Standardized mean differences (SMDs) were used to express the differences in GPx concentrations between COPD patients and non-COPD subjects. Twenty-four studies were identified. In 15 studies assessing whole blood/erythrocytes (GPx isoform 1), the pooled results showed that GPx concentrations were significantly lower in patients with COPD (SMD = -1.91, 95% CI -2.55 to -1.28, p < 0.001; moderate certainty of evidence). By contrast, in 10 studies assessing serum/plasma (GPx isoform 3), the pooled results showed that GPx concentrations were not significantly different between the two groups (very low certainty of evidence). The concentration of GPx-1, but not GPx-3, is significantly lower in COPD patients, suggesting an impairment of antioxidant defense mechanisms in this group.

Circulating Superoxide Dismutase Concentrations in Obstructive Sleep Apnoea (OSA): A Systematic Review and Meta-Analysis.

Obstructive Sleep Apnoea (OSA) is characterized by a pro-oxidant state that results from the recurrent hypoxia-reoxygenation cycles. Superoxide dismutase (SOD), a key antioxidant enzyme involved in the detoxification of superoxide radicals, could represent a reliable marker to monitor the antioxidant defences in OSA. In order to capture and critically appraise the available evidence, we performed a systematic review and meta-analysis of studies reporting SOD concentrations in OSA patients and non-OSA controls in the electronic databases Pubmed, Web of Science, Scopus and Google Scholar. In total, 13 studies in 847 OSA patients and 438 non-OSA controls were included in the meta-analysis. Blood SOD concentrations were significantly lower in OSA patients (SMD = 0.87, p < 0.001). By contrast, serum/plasma SOD concentrations were not significantly different between the two groups. Although extreme between-study heterogeneity was observed, the SMD was not substantially modified when individual studies were sequentially removed. In conclusion, we observed that whole blood, but not serum/plasma, SOD concentrations were significantly lower in OSA patients compared with controls. Our meta-analysis suggests an impaired antioxidant defence in OSA that is more robustly assessed in the corpuscular biological matrix and provides useful background information for further studies investigating the association between SOD changes and clinical status in OSA.

Circulating Malondialdehyde Concentrations in Obstructive Sleep Apnea (OSA): A Systematic Review and Meta-Analysis with Meta-Regression.

Oxidative stress induced by nocturnal intermittent hypoxia plays a significant pathophysiological role in obstructive sleep apnea (OSA). Malondialdehyde (MDA), one of the most commonly investigated markers of lipid peroxidation, might assist with the monitoring of oxidative balance in OSA. We conducted a systematic review and meta-analysis to evaluate the differences in circulating MDA concentrations between patients with OSA and non-OSA controls. A systematic search was conducted in the electronic databases Pubmed, Web of Science, Scopus and Google Scholar from inception to December 2020 by using the following terms: "malondialdehyde" or "MDA"; and "Obstructive Sleep Apnea Syndrome", "OSAS" or "OSA". We identified 26 studies in 1223 OSA patients and 716 controls. The pooled MDA concentrations were significantly higher in patients with OSA (standardized mean difference (SMD) 1.43 µmol/L, 95% confidence interval (CI) 1.03 to 1.83 µmol/L, p < 0.001). There was extreme heterogeneity between the studies (I2 = 92.3%, p < 0.001). In meta-regression analysis, the SMD was significantly associated with age, the assay type used and publication year. In our meta-analysis, MDA concentrations were significantly higher in OSA patients than in controls. This finding suggests that MDA, which is a marker of lipid peroxidation, is involved in the pathogenesis of OSA and provides insights for future studies investigating its potential clinical use.

Oxidative Stress Biomarkers in Chronic Obstructive Pulmonary Disease Exacerbations: A Systematic Review.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease characterized by a not fully reversible airflow limitation associated with an abnormal inflammatory response. Exacerbations of COPD are of major importance in the acceleration of disease progression, in healthcare costs, and negatively affect the patient's quality of life. Exacerbations are characterized by a further increase in the airway inflammation likely driven by oxidative stress. In order to deepen the knowledge about this topic, several studies have focused on oxidative stress biomarkers levels. This review summarizes the literature findings about oxidative stress biomarkers in exacerbated COPD patients compared to ones in the stable state. METHODS: a systematic search in electronic databases Pubmed, Web of Science, Scopus and Google Scholar from inception to January 2021, was conducted using the terms: "oxidative stress", "chronic obstructive pulmonary disease" or "COPD", "exacerbation". RESULTS: 23 studies were selected for the systematic review. They showed the presence of an imbalance between oxidant and antioxidant molecules in favor of the former in exacerbation of COPD. CONCLUSIONS: future studies using standardized methods in better characterized population are needed. However, this review suggests that targeting oxidative stress could be useful in monitoring the disease progression in COPD patients and especially in those more susceptible to exacerbations.

Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria.

Resistance to antimalarial drugs has spread rapidly over the past few decades. The WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated malaria, but unfortunately these approaches are losing their efficacy in large areas of Southeast Asia. In 2016, artemisinin resistance was confirmed in 5 countries of the Greater Mekong subregion. We focused our study on Syk inhibitors as antimalarial drugs. The Syk protein is present in human erythrocytes, and the membrane of protein band 3 is its major target following activation by oxidant stress. Tyr phosphorylation of band 3 occurs during P. falciparum growth, leading to the release of microparticles containing hemicromes and structural weakening of the host cell membrane, simplifying merozoite reinfection. Syk inhibitors block these events by interacting with the Syk protein's catalytic site. We performed in vitro proteomics and in silico studies and compared the results. In vitro studies were based on treatment of the parasite's cellular cultures with different concentrations of Syk inhibitors, while proteomics studies were focused on the Tyr phosphorylation of band 3 by Syk protein with the same concentrations of drugs. In silico studies were based on different molecular modeling approaches in order to analyze and optimize the ligand-protein interactions and obtain the highest efficacy in vitro. In the presence of Syk inhibitors, we observed a marked decrease of band 3 Tyr phosphorylation according to the increase of the drug's concentration. Our studies could be useful for the structural optimization of these compounds and for the design of novel Syk inhibitors in the future.

Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes.

Although artemisinin-based combination therapies (ACTs) treat Plasmodium falciparum malaria effectively throughout most of the world, the recent expansion of ACT-resistant strains in some countries of the Greater Mekong Subregion (GMS) further increased the interest in improving the effectiveness of treatment and counteracting resistance. Recognizing that (1) partially denatured hemoglobin containing reactive iron (hemichromes) is generated in parasitized red blood cells (pRBC) by oxidative stress, (2) redox-active hemichromes have the potential to enhance oxidative stress triggered by the parasite and the activation of artemisinin to its pharmaceutically active form, and (3) Syk kinase inhibitors block the release of membrane microparticles containing hemichromes, we hypothesized that increasing hemichrome content in parasitized erythrocytes through the inhibition of Syk kinase might trigger a virtuous cycle involving the activation of artemisinin, the enhancement of oxidative stress elicited by activated artemisinin, and a further increase in hemichrome production. We demonstrate here that artemisinin indeed augments oxidative stress within parasitized RBCs and that Syk kinase inhibitors further increase iron-dependent oxidative stress, synergizing with artemisinin in killing the parasite. We then demonstrate that Syk kinase inhibitors achieve this oxidative enhancement by preventing parasite-induced release of erythrocyte-derived microparticles containing redox-active hemichromes. We also observe that Syk kinase inhibitors do not promote oxidative toxicity to healthy RBCs as they do not produce appreciable amounts of hemichromes. Since some Syk kinase inhibitors can be taken daily with minimal side effects, we propose that Syk kinase inhibitors could evidently contribute to the potentiation of ACTs.

Clinical impact of the two ART resistance markers, K13 gene mutations and DPC3 in Vietnam.

BACKGROUND: In Vietnam, a rapid decline of P. falciparum malaria cases has been documented in the past years, the number of Plasmodium falciparum malaria cases has rapidly decreased passing from 19.638 in 2012 to 4.073 cases in 2016. Concomitantly, the spread of artemisinin resistance markers is raising concern on the future efficacy of the ACTs. An evaluation of the clinical impact of the artemisinin resistance markers is therefore of interest. METHODS: The clinical effectiveness of dihydroartemisinin-piperaquine therapy (DHA-PPQ) has been evaluated in three districts characterized by different rates of ART resistance markers: K13(C580Y) mutation and delayed parasite clearance on day 3 (DPC3). Patients were stratified in 3 groups a) no markers, b) one marker (suspected resistance), c) co-presence of both markers (confirmed resistance). In the studied areas, the clinical effectiveness of DHA-PPQ has been estimated as malaria recrudescence within 60 days. RESULTS: The rate of K13(C580Y) ranged from 75.8% in Krong Pa to 1.2% in Huong Hoa district. DPC3 prevalence was higher in Krong Pa than in Huong Hoa (86.2% vs 39.3%). In the two districts, the prevalence of confirmed resistance was found in 69.0% and 1.2% of patients, respectively. In Thuan Bac district, we found intermediate prevalence of confirmed resistance. Treatment failure was not evidenced in any district. PPQ resistance was not evidenced. Confirmed resistance was associated to the persistence of parasites on day 28 and to 3.4-fold higher parasite density at diagnosis. The effectiveness of malaria control strategies was very high in the studied districts. CONCLUSION: No treatment failure has been observed in presence of high prevalence of ART resistance and in absence of PPQ resistance. K13(C580Y) was strongly associated to higher parasitemia at admission, on days 3 and 28. Slower parasite clearance was also observed in younger patients.

Induction of high tolerance to artemisinin by sub-lethal administration: A new in vitro model of P. falciparum.

Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs) and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1), by treating P. falciparum Palo Alto (PA) cultures with sub-lethal concentrations of dihydroartemisinin (DHA). The resistance phenotype was maintained for over 1 year through monthly maintenance treatments with low doses of 2.5 nM DHA. There was a moderate increase in the DHA IC50 in ARS1 when compared with parental strain PA after 72 h of drug exposure (from 0.68 nM to 2 nM DHA). In addition, ARS1 survived treatment physiologically relevant DHA concentrations (700 nM) observed in patients. Furthermore, we confirmed a lack of cross-resistance against a panel of antimalarials commonly used as partner drugs in ACTs. Finally, ARS1 did not contain Pfk13 propeller domain mutations associated with ART resistance in the Greater Mekong Region. With a stable growth rate, ARS1 represents a valuable tool for the development of new antimalarial compounds and studies to further elucidate the mechanisms of ART resistance.

Total antioxidant capacity in Mediterranean ß-thalassemic patients.

BACKGROUND: Beta thalassemia major (BT) is an inherited blood disorder caused by reduced or absent synthesis of the hemoglobin beta chains, associated with profound anemia, jaundice, splenomegaly, expanded bone marrow volume, siderosis and cardiomegaly. Because of repeated blood transfusions, BT patients are subjected to peroxidative tissue injury due to secondary iron overload. OBJECTIVES: The aim of the study was to analyze: 1) the total antioxidant capacity (TAC) value in BT patients (study group) and their healthy controls (control group) from Greece (Central Macedonia) and Italy (Sardinia); correlations between 2) the TAC and ferritin levels of BT patients, and 3) the TAC and ferritin values in BT patients with different chelation therapies. MATERIAL AND METHODS: The studied group consisted of 60 subjects diagnosed with BT (41 female, mean age: 41.5 ± 9.5 years) and 40 healthy controls matched with age and sex (31 female, mean age: 38.5 ± 3.7 years). Desferrioxamine (DFO) was the basic previous chelation regimen for all BT patients. Antioxidant activity was assayed spectrophotometrically, using a TAC Kit (Total Antioxidant Capacity Colorimetric assay kit, produced by Cayman Chemical Co.), and ferritin was assayed by immunoturbidimetry. RESULTS: Lower levels of TAC were observed in BT patients of both countries when compared with controls (1.83 mmol/L vs 2.7 mmol/L in the Italian study group and controls and 2.42 mmol/L vs 3.2 mmol/L in the Greek study group and controls). There were no significant correlations between plasmatic TAC and ferritin. Furthermore, deferasirox was the only chelation treatment in which TAC showed a correlation in both regions. CONCLUSIONS: Our results potentially suggest that the reduced levels of TAC detectable in BT patients could demonstrate their reduced antioxidant defensive mechanisms.

Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress.

Band 3 (also known as the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intraerythrocytic stage of Plasmodium falciparum's lifecycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream, we decided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization. We demonstrate here that multiple Syk kinase inhibitors both prevent parasite-induced band 3 tyrosine phosphorylation and inhibit parasite-promoted membrane destabilization. We also show that the same Syk kinase inhibitors suppress merozoite egress near the end of the parasite's intraerythrocytic lifecycle. Because the entrapped merozoites die when prevented from escaping their host erythrocytes and because some Syk inhibitors have displayed long-term safety in human clinical trials, we suggest Syk kinase inhibitors constitute a promising class of antimalarial drugs that can suppress parasitemia by inhibiting a host target that cannot be mutated by the parasite to evolve drug resistance.

Band 3 Erythrocyte Membrane Protein Acts as Redox Stress Sensor Leading to Its Phosphorylation by p (72) Syk.

In erythrocytes, the regulation of the redox sensitive Tyr phosphorylation of band 3 and its functions are still partially defined. A role of band 3 oxidation in regulating its own phosphorylation has been previously suggested. The current study provides evidences to support this hypothesis: (i) in intact erythrocytes, at 2 mM concentration of GSH, band 3 oxidation, and phosphorylation, Syk translocation to the membrane and Syk phosphorylation responded to the same micromolar concentrations of oxidants showing identical temporal variations; (ii) the Cys residues located in the band 3 cytoplasmic domain are 20-fold more reactive than GSH; (iii) disulfide linked band 3 cytoplasmic domain docks Syk kinase; (iv) protein Tyr phosphatases are poorly inhibited at oxidant concentrations leading to massive band 3 oxidation and phosphorylation. We also observed that hemichromes binding to band 3 determined its irreversible oxidation and phosphorylation, progressive hemolysis, and serine hyperphosphorylation of different cytoskeleton proteins. Syk inhibitor suppressed the phosphorylation of band 3 also preventing serine phosphorylation changes and hemolysis. Our data suggest that band 3 acts as redox sensor regulating its own phosphorylation and that hemichromes leading to the protracted phosphorylation of band 3 may trigger a cascade of events finally leading to hemolysis.

Artemisinin resistance, some facts and opinions.

Resistance to artemisinin derivatives (ARTs) in malaria disease is currently defined as a delayed parasite clearance following artemisinin combined therapy (ACT). Although ACT is still widely effective, the first evidence of artemisinin resistance was described in 2009 in Southeast Asia. Since then, resistance to ARTs / ACT has been monitored showing an increasing trend. The demonstrated resistance to all drugs that are currently associated to ART, the ambiguous finding that ART resistance is observed only in presence of resistance to the partner drug, the lack of a mechanistic rationale to choose the partner drugs and the lack of markers with known specificity and sensitivity to monitor ART resistance, represent the most worrisome issues.