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1.
N Engl J Med ; 390(11): 1060, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38478008
2.
J Korean Med Sci ; 39(8): e81, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38442722

RESUMO

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by uncontrolled terminal complement activation, which leads to intravascular hemolysis (IVH), thromboembolism (TE), renal failure, and premature mortality. METHODS: We performed a secondary analysis of data collected from patients enrolled in the Korean National PNH Registry to assess the relative importance of risk factors, specifically lactate dehydrogenase (LDH) and hemoglobin (Hb), in predicting the incidence of TE, impaired renal function, and death in complement inhibitor-naïve patients with PNH. RESULTS: Multivariate regression modeling indicated that LDH ≥ 1.5 × upper limit of normal (ULN), male sex, and pain were associated with increased risk of TE (P = 0.016, 0.045, and 0.033, respectively), hemoglobinuria and pain were associated with an increased risk of impaired renal function (P = 0.034 and 0.022, respectively), and TE was associated with an increased incidence of death (P < 0.001). Hb < 8 g/dL was not a predictor of TE, impaired renal function, or death in multivariate regression analyses. Standardized mortality ratio analysis indicated that LDH ≥ 1.5 × ULN (P < 0.001), Hb < 8 g/dL (P < 0.001), and Hb ≥ 8 g/dL (P = 0.004) were all risk factors for death; in contrast, patients with LDH < 1.5 × ULN had similar mortality to the general population. CONCLUSION: In complement inhibitor-naïve patients with PNH, LDH ≥ 1.5 × ULN was a significant predictor of TE, and TE was a significant predictor of death. Hb was not a significant predictor of TE, impaired renal function, or death. Therefore, controlling IVH will improve clinical outcomes for patients with PNH.


Assuntos
Hemoglobinúria Paroxística , Tromboembolia , Humanos , Masculino , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/diagnóstico , Inativadores do Complemento , L-Lactato Desidrogenase , Dor , República da Coreia
3.
Clin Transplant ; 38(3): e15277, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38485664

RESUMO

As the number of patients living with kidney failure grows, the need also grows for kidney transplantation, the gold standard kidney replacement therapy that provides a survival advantage. This may result in an increased rate of transplantation from HLA-mismatched donors that increases the rate of antibody-mediated rejection (AMR), which already is the leading cause of allograft failure. Plasmapheresis, intravenous immunoglobulin therapy, anti-CD20 therapies (i.e., rituximab), bortezomib and splenectomy have been used over the years to treat AMR as well as to prevent AMR in high-risk sensitized kidney transplant recipients. Eculizumab and ravulizumab are monoclonal antibodies targeting the C5 protein of the complement pathway and part of the expanding field of anticomplement therapies, which is not limited to kidney transplant recipients, and also includes complement-mediated microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and ANCA-vasculitis. In this narrative review, we summarize the current knowledge concerning the pathophysiological background and use of anti-C5 strategies (eculizumab and ravulizumab) and C1-esterase inhibitor in AMR, either to prevent AMR in high-risk desensitized patients or to treat AMR as first-line or rescue therapy and also to treat de novo thrombotic microangiopathy in kidney transplant recipients.


Assuntos
Proteínas Inativadoras do Complemento , Transplante de Rim , Rim , Humanos , Transplante Homólogo , Transplante de Rim/efeitos adversos , Aloenxertos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle
5.
Toxicon ; 242: 107690, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38508242

RESUMO

Two field cases of reddish-black pigmenturia occurred where cattle grazed on an established Cenchrus ciliaris (blue buffalo grass) pasture in South Africa. The pasture was noticeably invaded by Indigofera cryptantha, which was heavily grazed. Apart from the discolored urine, no other clinical abnormalities were detected. Urinalysis revealed hemoglobinuria, proteinuria and an alkaline pH. When the animals were immediately removed from the infested pasture, they made an uneventful recovery. However, a bull died when one of the herds could not be removed from the I. cryptantha-infested pasture. Macroscopically, the kidneys were dark red in color and the urinary bladder contained the dark pigmented urine. Microscopically, the renal tubules contained eosinophilic, granular pigment casts in the lumen. In addition, many renal tubular epithelial cells were attenuated with granular cytoplasm and were detached from the basement membranes. Chemical analysis was performed on dried, milled plant material and two urine samples collected during the field investigations. Qualitative UPLC-UV-qTOF/MS analysis revealed the presence of indican (indoxyl-ß-glucoside) in the stems, leaves and pods of I. cryptantha and indoxyl sulfate was identified, and confirmed with an analytical standard, in the urine samples. It is proposed that following ingestion of I. cryptantha, indican will be hydrolysed in the liver to indoxyl and conjugated with sulfate. Indoxyl sulfate will then be excreted in relatively high concentrations in the urine. In the alkaline urine, two indoxyl molecules might dimerize to form leucoindigo with subsequent oxidation to indigo, thus, contributing to the dark pigmentation of the urine. It is also possible that indoxyl sulfate contributed to the renal failure and death of the bull. Although I. suffruticosa-induced hemoglobinuria has been described in Brazil, this is the first report of I. cryptantha-induced pigmenturia in cattle in South Africa.

6.
Blood ; 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38513233

RESUMO

Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anti-complement treatment has revolutionized the natural history of PNH with control of the hemolytic process and abolition of thrombotic events (TE). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anti-coagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anti-coagulants (DOACs). Herein, we accrued a large real-world cohort of PNH patients from four US centers to explore features, predictors of TE and anti-coagulation strategies. Among 267 patients followed-up for a total of 2043 patient/years, 56 (21%) developed TE. This occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TE was halved in patients receiving complement inhibitors (21 vs 40 TE per 1000 patient/years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3% respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (>2 mutations or less) and variant allelic frequency of PIGA mutations. Anti-coagulation with warfarin (39%), DOACs (37%), and low-molecular-weight heparin (16%) was administered for a median of 29 months (9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (8.9-45) while 14 cases discontinued anti-coagulation without TE recurrence at a median time of 51.4 months (29.9-86.8).

7.
Parasites Hosts Dis ; 62(1): 151-156, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38443779

RESUMO

Bovine borreliosis, caused by Borrelia theileri which is transmitted via hard tick bites, is associated with mild clinical symptoms, such as fever, lethargy, hemoglobinuria, anorexia, and anemia. Borrelia theileri infects various animals, such as cattle, deer, horses, goats, sheep, and wild ruminants, in Africa, Australia, and South America. Notably, no case of B. theileri infection has been reported in Korean cattle to date. In this study, 101 blood samples were collected from a Korean indigenous cattle breed, among which 1.98% tested positive for B. theileri via nested PCR. The obtained sequences exhibited high homology with B. theileri strains identified in other regions. Phylogenetic analysis of 16S rRNA confirmed the B. theileri group affiliation; however, flagellin B sequences exhibited divergence, potentially due to regional evolutionary differences. This study provides the first molecular confirmation of B. theileri infection in Korean livestock. Further isolation and nucleotide sequence analyses are necessary to better understand the presence of B. theileri strains in cows in Korea.


Assuntos
Borrelia , Cervos , Feminino , Bovinos , Animais , Cavalos , Ovinos , Filogenia , RNA Ribossômico 16S/genética , Cabras , República da Coreia/epidemiologia
8.
Ann Hematol ; 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38453703

RESUMO

Pegcetacoplan (Aspaveli®/Empaveli™) is a factor C3 inhibitor that is approved for the treatment of paroxysmal nocturnal hemoglobinuria. An individualized dosing strategy might be useful to improve patient-friendliness and cost-effectiveness of this very expensive drug. Therefore, the aim of this study was to develop an individualized treatment regimen for pegcetacoplan based on the pharmacokinetic-pharmacodynamic data of the manufacturer. We conducted a clinical trial simulation with the approved dosing regimen of 1080 mg twice-weekly and a target concentration intervention-based dosing regimen in patients with and without prior eculizumab use. For eculizumab-naïve patients, the target concentration intervention-based dosing regimen resulted in a comparable fraction of patients with LDH normalization (LDH < 226 U/L) and hemoglobulin normalization (> 12 g/dL) compared to the approved regimen (LDH 50.2% and 50.0% respectively and hemoglobulin 45.6% and 44.4%). A modest dose reduction of ~ 5% was possible with target concentration intervention-based dosing. An intensified dosing interval was necessary in 2.3% of the patients however an interval prolongation was possible in 28.2% of the patients. Similar results were obtained for patients prior treated with eculizumab. In this study we show the potential of an individualized dosing regimen of pegcetacoplan with can improve patient friendliness in approximately 30% of the patients and improve therapy in approximately 2% of the patients at slightly reduced costs.

9.
BMJ Case Rep ; 17(3)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453232

RESUMO

A male patient in his 30s presented with complaints of acute abdominal pain, black stools and red-coloured urine. CT revealed thrombi in the splenic and left renal veins, leading to infarctions. An endoscopy displayed scalloping of the duodenal folds, indicative of intestinal malabsorption syndrome (IMS). Histopathological examination confirmed IMS. Due to the presence of intravascular haemolysis, haemoglobinuria and thrombotic complications, paroxysmal nocturnal haemoglobinuria (PNH) was suspected and subsequently confirmed by flow cytometry. Thus, a diagnosis of classic PNH with IMS and thrombotic complications was established. This unique case highlights the coexistence of PNH and IMS, resembling the complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy disease, suggesting potential shared pathophysiology.


Assuntos
Abdome Agudo , Injúria Renal Aguda , Hemoglobinúria Paroxística , Síndromes de Malabsorção , Trombose , Humanos , Masculino , Abdome Agudo/etiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/complicações , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/diagnóstico , Síndromes de Malabsorção/complicações , Síndromes de Malabsorção/diagnóstico , Trombose/complicações , Adulto
10.
N Engl J Med ; 390(11): 994-1008, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38477987

RESUMO

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).


Assuntos
Anemia Hemolítica , Fator B do Complemento , Inativadores do Complemento , Hemoglobinas , Hemoglobinúria Paroxística , Humanos , Administração Oral , Anemia Hemolítica/complicações , Complemento C5/antagonistas & inibidores , Fator B do Complemento/antagonistas & inibidores , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/efeitos adversos , Inativadores do Complemento/uso terapêutico , Transfusão de Eritrócitos , Cefaleia/induzido quimicamente , Hemoglobinas/análise , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/etiologia , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Hamostaseologie ; 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38335997

RESUMO

CASE: Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare bone marrow disorder caused by acquired mutations in the phosphatidylinositol glycan class A gene, which lead to a partial or total loss of the cellular complement regulators CD55 and CD59.1 In addition to complement-mediated hemolysis and cytopenia, venous and arterial thromboses at multiple and/or unusual sites are a common complication and occur in up to 44% of patients in historic PNH cohorts.1 2.

12.
Biomed Rep ; 20(4): 57, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38414627

RESUMO

Glycosylphosphatidylinositol-glycan (GPI) is an anchor to specific cell surface proteins known as GPI-anchored proteins (APs) that are localized in lipid rafts and may act as cell co-receptors, enzymes and adhesion molecules. The present review investigated the significance of GPI biosynthesis class phosphatidylinositol-glycan (PIG)M and PIGX in GPI synthesis and their implications in human health conditions. PIGM encodes GPI-mannosyltransferase I (MT-I) enzyme that adds the first mannose to the GPI core structure. PIGX encodes the regulatory subunit of GPI-MT-I. The present review summarizes characteristics of the coding sequences of PIGM and PIGX, and their expression in humans, as well as the relevance of GPI-MT-I and the regulatory subunit in maintaining the presence of GPI-APs on the cell surface and their secretion. In addition, the association of PIGM mutations with paroxysmal nocturnal hemoglobinuria and certain types of GPI-deficiency disease and the altered expression of PIGM and PIGX in cancer were also reviewed. In addition, their interaction with other proteins was described, suggesting a complex role in cell biology. PIGM and PIGX are critical genes for GPI synthesis. Understanding gene and protein regulation may provide valuable insights into the role of GPI-APs in cellular processes.

13.
Artigo em Inglês | MEDLINE | ID: mdl-38310489

RESUMO

BACKGROUND: High-voltage pulses can cause hemolysis. OBJECTIVES: The authors evaluated the occurrence of hemoglobinuria after pulsed-field ablation (PFA) and its impact on renal function in patients with atrial fibrillation (AF). METHODS: A consecutive series of patients with AF undergoing PFA were included in this analysis. The initial patients who did not receive postablation hydration immediately after the procedure were classified as group 1 (n = 28), and the rest of the study patients who received planned fluid infusion (0.9% sodium chloride ≥2 L) after the procedure were categorized as group 2 (n = 75). RESULTS: Of the 28 patients in group 1, 21 (75%) experienced hemoglobinuria during the 24 hours after catheter ablation. The mean postablation serum creatinine (S-Cr) was significantly higher than the baseline value in those 21 patients (1.46 ± 0.28 mg/dL vs 0.86 ± 0.24 mg/dL, P < 0.001). Of those 21 patients, 4 (19%) had S-Cr. >2.5 mg/dL (mean: 2.95 ± 0.21 mg/dL). The mean number of PF applications was significantly higher in those 4 patients than in the other 17 patients experiencing hemoglobinuria (94.63 ± 3.20 vs 46.75 ± 9.10, P < 0.001). In group 2 patients, no significant changes in S-Cr were noted. The group 2 patients received significantly higher amounts of fluid infusion after catheter ablation than did those in group 1 (2,082.50 ± 258.08 mL vs 494.01 ± 71.65 mL, P < 0.001). In multivariable analysis, both hydration (R2 = 0.63, P < 0.01) and number of PFA applications (R2 = 0.33, P < 0.01) were independent predictors of postprocedure acute kidney injury. CONCLUSIONS: On the basis of our findings, both the number of PFA applications and postablation hydration were independent predictors of renal insult that could be prevented using planned fluid infusion immediately after the procedure.

15.
J Leukoc Biol ; 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38315716

RESUMO

The mechanism underlying autophagy in paroxysmal nocturnal hemoglobinuria (PNH) remains largely unknown. We previously sequenced the entire genome exon of the CD59- cells from 13 patients with PNH and found genes such as CUX1 encoding Cut-like homeobox 1. Peripheral blood samples from nine patients with PNH and seven healthy controls were obtained to measure CUX1 expression. The correlation between CUX1 mRNA expression and PNH clinical indicators was analyzed. To simulate CUX1 expression in patients with PNH, we generated a panel of PNH cell lines by knocking out PIGA in K562 cell lines and transfected lentivirus with CUX1. CCK-8 and EDU assay assessed cell proliferation. Western blotting was used to detect Beclin1, LC3A, LC3B, ULK1, PI3K, AKT, p-AKT, mTOR, and p-mTOR protein levels. Autophagosomes were observed with transmission electron microscopy. Chloroquine was used to observe CUX1 expression in PNH after autophagy inhibition. Leukocytes from patients with PNH had lower levels of CUX1 mRNA expression and protein content than healthy controls. The lactose dehydrogenase level and the percentage of PNH clones were negatively correlated with CUX1 relative expression. We reduced CUX1 expression in a PIGA-knockout K562 cell line, leading to increased cell proliferation. Levels of autophagy markers Beclin1, LC3B, LC3A and ULK1 increased, and autophagosomes increased. Furthermore, PI3K/AKT/mTOR protein phosphorylation levels were lower. CUX1 expression did not change and cell proliferation decreased in CUX1 knocked down PNH cells after inhibition of autophagy by chloroquine. In brief, CUX1 loss-of-function mutation resulted in stronger autophagy in PNH.

16.
Blood Adv ; 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38315872

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Breakthrough hemolysis (BTH) was first described in patients with PNH treated with terminal complement C5 inhibitors when intravascular hemolysis reoccurred despite treatment. Pegcetacoplan, the first proximal complement C3 inhibitor, offers broad hemolysis control in patients with PNH. While experience of managing BTH on C5 inhibitors is documented, very limited guidance exists for proximal complement inhibitors. This interim analysis assessed the effect of intensive treatment with pegcetacoplan following an acute BTH event in a subset of patients enrolled in the ongoing open-label extension (OLE) study of pegcetacoplan in PNH. Thirteen patients with acute BTH included in the analysis received either a single intravenous (IV) dose of 1080 mg (n=4) or 1080 mg subcutaneous (SC) dosing on 3 consecutive days (n=9). A potential clinically relevant complement amplifying condition, such as infection or vaccination, was reported in nearly half of the patients experiencing an acute BTH. Lactate dehydrogenase (LDH) levels decreased between day 1 and day 2 in 8 of 12 evaluable patients and in all 13 patients at day 7-12. Nine of 13 patients (69%) achieved LDH <2x the upper limit of normal by day 14-19. All AEs associated with the acute BTH event were considered resolved by the investigators. Overall, intensive treatment with pegcetacoplan was safe and well tolerated. These novel data support effective management of acute BTH events in patients on pegcetacoplan with intensive IV or SC pegcetacoplan dosing. ClinicalTrials.gov identifier: NCT03531255.

17.
Am J Hematol ; 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38348608

RESUMO

Pegcetacoplan significantly improves outcomes for patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing extravascular hemolysis (EVH) on eculizumab, leading to approval in 2021/2022 (USA/Europe). We report the first collaborative real-world evidence on pegcetacoplan use in UK and France. A total of 48 patients were either currently receiving or previously received pegcetacoplan (2019-2023). A total of 12 patients had participated in the PEGASUS clinical trial, continuing treatment after trial completion. Five patients were on combination treatment of C5 inhibition and pegcetacoplan. Mean pegcetacoplan duration was 20.2 months. Indication for pegcetacoplan was EVH on C5 inhibitors (Eculizumab, n = 29, Ravulizumab n = 16, others n = 3) with 35/48 patients requiring blood transfusion within the previous 12 months. Mean hemoglobin and reticulocyte count at pegcetacoplan commencement and after 3 months: 91 g/L and 205 × 109 /L and 115.8 g/L and 107 × 109 /L, respectively, resulting in mean Hb change of 22.3 g/L. Mean LDH pre- and post-pegcetacoplan was unchanged. Six patients have stopped pegcetacoplan. A total of 32 breakthrough hemolysis (BTH) events occurred in 13/48 patients. A total of 14 events were within clinical trials (reported separately). Six patients experienced 18 acute BTH events outside clinical trials, 7/18 associated with complement activating conditions. Successful clinical management included daily pegcetacoplan subcutaneously for 3 days or single eculizumab doses; these events are manageable with prompt intervention. Pegcetacoplan is effective for patients with PNH experiencing EVH. In this large patient cohort, treatment was well tolerated with improved hemoglobin and reticulocytes and maintained LDH control. Although BTH occurs, this is manageable by acute dose modification, with the majority of patients being maintained on pegcetacoplan.

18.
Toxicon ; 240: 107629, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38336277

RESUMO

INTRODUCTION: Biotoxins are toxic substances that originate from living organisms and are harmful to humans. Therefore, we need to know the symptoms of biotoxins poisoning to manage the damage. The purpose of this study is to establish a practical diagnostic protocol for dealing with poisoned patients exposed to biotoxins. MATERIALS AND METHODS: The present study is a review study. Our studied community is articles and books matching the title of the project and relevant keywords. First, by searching the key words sign, symptom, biotoxins, relevant articles were extracted and studied from valid databases. By reviewing the studies based on the search strategy, four groups of biotoxins that were studied the most were identified. These four groups are marine biotoxins, bacterial biotoxins, fungal biotoxins and plant biotoxins. In each of these biotoxin groups, important toxins were selected and studied. RESULTS: A total of 1864 articles were initially identified from the databases searched in present study. After screening titles and abstracts, 26 articles were included in the systematic review. Specifically, 7 articles were included for bacterial toxins, 9 articles for marine toxins, 5 articles for plant toxins and 5 articles for fungal toxins. CONCLUSION: The symptoms of plant biotoxins poisoning may include cardiovascular, hematologic, neurologic, respiratory, renal, and gastrointestinal symptoms, while the symptoms of fungal biotoxins poisoning may include hepatic, renal, gastrointestinal, musculoskeletal, metabolic, respiratory, neurological, and cardiovascular symptoms. marine biotoxins poisoning presents with gastrointestinal and neurological symptoms, with varying incubation periods and recovery times. bacterial biotoxins exposure can lead to a wide range of clinical symptoms, with diarrhea, vomiting, and abdominal pain being the most common, and hemoglobinuria or hematuria being a sensitive and specific clinical manifestation for diagnosing ongoing HUS in children.


Assuntos
Toxinas Marinhas , Criança , Humanos , Toxinas Marinhas/toxicidade
19.
iScience ; 27(3): 109021, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38361629

RESUMO

Nano-vesicular carriers are promising tissue-specific drug delivery platforms. Here, biomimetic proteolipid vesicles (BPLVs) were used for delivery of glycosylphosphatidylinositol (GPI)-anchored proteins to GPI deficient paroxysmal nocturnal hemoglobinuria (PNH) cells. BPLVs were assembled as single unilamellar monodispersed (polydispersity index, 0.1) negatively charged (ζ-potential, -28.6 ± 5.6 mV) system using microfluidic technique equipped with Y-shaped chip. GPI-anchored and not-GPI proteins on BPLV surface were detected by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from healthy and PNH subjects were treated with BPLVs (final concentration, 0.5 mg/mL), and cells displayed an excellent protein uptake, documented by flow cytometry immunophenotyping and confocal microscopy. BPLV-treated cells stressed with complement components showed an increased resistance to complement-mediated lysis, both healthy and PNH PBMCs. In conclusion, BPLVs could be effective nanocarriers for protein transfer to targeted cells to revert protein deficiency, like in PNH disease. However, further in vivo studies are required to validate our preclinical in vitro results.

20.
J Biol Chem ; : 105784, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38401844

RESUMO

The introduction of a therapeutic anti-C5 antibody into clinical practice in 2007 inspired a surge into the development of complement-targeted therapies. This has led to the recent approval of a C3 inhibitory peptide, an antibody directed against C1s and a full pipeline of several complement inhibitors in preclinical and clinical development. However, no inhibitor is available that efficiently inhibits all three complement initiation pathways and targets host cell surface markers as well as complement opsonins. To overcome this, we engineered a novel fusion protein combining selected domains of the three natural complement regulatory proteins decay accelerating factor (DAF), Factor H (FH) and complement receptor 1 (CR1). Such a triple fusion complement inhibitor (TriFu) was recombinantly expressed and purified alongside multiple variants and its building blocks. We analysed these proteins for ligand binding affinity and decay acceleration activity by surface plasmon resonance. Additionally, we tested complement inhibition in several in vitro/ex vivo assays using standard classical and alternative pathway restricted hemolysis assays next to hemolysis assays with PNH erythrocytes. A novel in vitro model of the alternative pathway disease C3 glomerulopathy (C3G) was established to evaluate the potential of the inhibitors to stop C3 deposition on endothelial cells. Next to the novel engineered triple fusion variants which inactivate complement convertases in an enzyme-like fashion, stoichiometric complement inhibitors targeting C3, C5, Factor B and Factor D were tested as comparators. The triple fusion approach yielded a potent complement inhibitor that efficiently inhibits all three complement initiation pathways while targeting to surface markers.

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