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Kidney International Aug 2023The complement system plays a key role in the pathophysiology of kidney thrombotic microangiopathies (TMA), as illustrated by atypical hemolytic uremic syndrome. But...
The complement system plays a key role in the pathophysiology of kidney thrombotic microangiopathies (TMA), as illustrated by atypical hemolytic uremic syndrome. But complement abnormalities are not the only drivers of TMA lesions. Among other potential pathophysiological actors, we hypothesized that alteration of heparan sulfate (HS) in the endothelial glycocalyx could be important. To evaluate this, we analyzed clinical and histological features of kidney biopsies from a monocentric, retrospective cohort of 72 patients with TMA, particularly for HS integrity and markers of local complement activation. The role of heme (a major product of hemolysis) as an HS-degrading agent in vitro, and the impact of altering endothelial cell (ECs) HS on their ability to locally activate complement were studied. Compared with a positive control, glomerular HS staining was lower in 57 (79%) patients with TMA, moderately reduced in 20 (28%), and strongly reduced in 37 (51%) of these 57 cases. Strongly reduced HS density was significantly associated with both hemolysis at the time of biopsy and local complement activation (C3 and/or C5b-9 deposits). Using primary endothelial cells (HUVECs, Glomerular ECs), we observed decreased HS expression after short-term exposure to heme, and that artificial HS degradation by exposure to heparinase was associated with local complement activation. Further, prolonged exposure to heme modulated expression of several key genes of glycocalyx metabolism involved in coagulation regulation (C5-EPI, HS6ST1, HS3ST1). Thus, our study highlights the impact of hemolysis on the integrity of endothelial HS, both in patients and in endothelial cell models. Hence, acute alteration of HS may be a mechanism of heme-induced complement activation.
Topics: Humans; Glycocalyx; Hemolysis; Endothelial Cells; Retrospective Studies; Thrombotic Microangiopathies; Complement Activation; Atypical Hemolytic Uremic Syndrome; Complement System Proteins; Kidney Diseases; Heparitin Sulfate; Heme
PubMed: 37164260
DOI: 10.1016/j.kint.2023.03.039 -
RSC Advances May 2024Porphyrin and porphyrinoid derivatives have been extensively studied in the assembly of catalysts and sensors, seeking biomimetic and bioinspired activity. In...
Porphyrin and porphyrinoid derivatives have been extensively studied in the assembly of catalysts and sensors, seeking biomimetic and bioinspired activity. In particular, Fe and Ni porphyrins can be used for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) by immobilization of these molecular catalysts on semiconductor materials. In this study, we designed a hybrid material containing a crystalline mesoporous TiO thin film in which the catalytic centres are Ni-porphyrin (NiP), Fe-porphyrin (FeP), and a NiP/FeP bimetallic system to assess whether the coexistence of both metalloporphyrins improves the OER activity. The obtained photoelectrodes were physicochemically and morphologically characterized through high-resolution FE-SEM images, UV-vis and Raman spectroscopies, cyclic voltammetry, and impedance measurements. The results show a differential behavior of the mono- and bimetallic porphyrin systems, where the Fe(iii) centre in FeP may increase the acidity and lower the reduction potential of the Ni couple when co-deposited with NiP leading to an improved photoelectrochemical water-oxidation performance. We have validated the cooperative effect of both metal complexes within this novel system, where the μ-peroxo-bridged interaction between Fe and Ni is integrated into a supramolecular heterometallic structure of porphyrins.
PubMed: 38756854
DOI: 10.1039/d3ra08047a -
Scientific Reports Sep 2023Soy leghemoglobin is one of the most important and key ingredients in plant-based meat substitutes that can imitate the colour and flavour of the meat. To improve the...
Soy leghemoglobin is one of the most important and key ingredients in plant-based meat substitutes that can imitate the colour and flavour of the meat. To improve the high-yield production of leghemoglobin protein and its main component-heme in the yeast Pichia pastoris, glycerol and methanol cultivation conditions were studied. Additionally, in-silico metabolic modelling analysis of growth-coupled enzyme quantity, suggests metabolic gene up/down-regulation strategies for heme production. First, cultivations and metabolic modelling analysis of P. pastoris were performed on glycerol and methanol in different growth media. Glycerol cultivation uptake and production rates can be increased by 50% according to metabolic modelling results, but methanol cultivation-is near the theoretical maximum. Growth-coupled metabolic optimisation results revealed the best feasible upregulation (33 reactions) (1.47% of total reactions) and 66 downregulation/deletion (2.98% of total) reaction suggestions. Finally, we describe reaction regulation suggestions with the highest potential to increase heme production yields.
Topics: Glycerol; Leghemoglobin; Methanol; Heme
PubMed: 37739976
DOI: 10.1038/s41598-023-42865-w -
Journal of Nanobiotechnology Jul 2023Wound healing is a common occurrence. However, delayed healing and aberrant scarring result in pathological wound healing. Accordingly, a scarless wound healing remains...
Hyaluronic acid-modified and verteporfin-loaded polylactic acid nanogels promote scarless wound healing by accelerating wound re-epithelialization and controlling scar formation.
Wound healing is a common occurrence. However, delayed healing and aberrant scarring result in pathological wound healing. Accordingly, a scarless wound healing remains a significant clinical challenge. In this study, we constructed hyaluronic acid (HA)-modified and verteporfin (VP)-loaded polylactic acid (PLA) nanogels (HA/VP-PLA) to promote scarless wound healing by accelerating wound re-epithelialization and controlling scar formation. Owing to the unique structure of HA incorporating and coating in VP-loaded PLA nanoparticles, HA/VP-PLA could be topically applied on wound to achieve targeted delivery to fibroblasts. Then, HA/VP-PLA released HA and lactic acid (LA) to stimulate the proliferation and migration of fibroblasts, as well as VP to inhibit Yes-associated protein (YAP) expression and nuclear localization to suppress fibrosis. In vitro (skin fibroblasts) and in vivo (rat and rabbit models) experiments strongly suggested that HA/VP-PLA promoted scarless wound healing by accelerating wound re-epithelialization and controlling scar formation. Therefore, our work provides a feasible strategy for scarless wound healing, and the sophisticated HA/VP-PLA exhibit a great potential for clinical applications.
Topics: Rats; Animals; Rabbits; Cicatrix; Hyaluronic Acid; Re-Epithelialization; Nanogels; Verteporfin; Wound Healing; Polyesters; Skin
PubMed: 37496007
DOI: 10.1186/s12951-023-02014-x -
JCI Insight Nov 2023Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including...
Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including the most common form of human dwarfism, achondroplasia (ACH). Targeting FGFR3 activity holds great promise as a therapeutic approach for treatment of these diseases. Here, we established a receptor/adaptor translocation assay system that can specifically monitor FGFR3 activation, and we applied it to identify FGFR3 modulators from complex natural mixtures. An FGFR3-suppressing plant extract of Amaranthus viridis was identified from the screen, and 2 bioactive porphyrins, pheophorbide a (Pa) and pyropheophorbide a, were sequentially isolated from the extract and functionally characterized. Further analysis showed that Pa reduced excessive FGFR3 signaling by decreasing its half-life in FGFR3-overactivated multiple myeloma cells and chondrocytes. In an ex vivo culture system, Pa alleviated defective long bone growth in humanized ACH mice (FGFR3ACH mice). Overall, our study presents an approach to discovery and validation of plant extracts or drug candidates that target FGFR3 activation. The compounds identified by this approach may have applications as therapeutics for FGFR3-associated cancers and skeletal dysplasias.
Topics: Mice; Humans; Animals; Receptor, Fibroblast Growth Factor, Type 3; Porphyrins; Achondroplasia; Signal Transduction; Neoplasms
PubMed: 37824212
DOI: 10.1172/jci.insight.171257 -
Frontiers in Immunology 2024Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express... (Review)
Review
Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express HMOX1 and 2 and are critical sites of heme degradation in healthy and diseased states. Here we review the functions of the macrophage heme oxygenase system and its clinical relevance in discrete groups of pathologies where heme has been demonstrated to play a driving role. HMOX1 function in macrophages is essential for limiting oxidative tissue damage in both acute and chronic hemolytic disorders. By degrading pro-inflammatory heme and releasing anti-inflammatory molecules such as carbon monoxide, HMOX1 fine-tunes the acute inflammatory response with consequences for disorders of hyperinflammation such as sepsis. We then discuss divergent beneficial and pathological roles for HMOX1 in disorders such as atherosclerosis and metabolic syndrome, where activation of the HMOX system sits at the crossroads of chronic low-grade inflammation and oxidative stress. Finally, we highlight the emerging role for HMOX1 in regulating macrophage cell death via the iron- and oxidation-dependent form of cell death, ferroptosis. In summary, the importance of heme clearance by macrophages is an active area of investigation with relevance for therapeutic intervention in a diverse array of human diseases.
Topics: Humans; Heme Oxygenase (Decyclizing); Heme; Clinical Relevance; Macrophages; Iron; Inflammation
PubMed: 38585264
DOI: 10.3389/fimmu.2024.1379967 -
Molecules (Basel, Switzerland) Jul 2023This review presents a strategy for obtaining various functional derivatives of tetrapyrrole compounds based on transformations of unsaturated carbon-oxygen and... (Review)
Review
This review presents a strategy for obtaining various functional derivatives of tetrapyrrole compounds based on transformations of unsaturated carbon-oxygen and carbon-carbon bonds of the substituents at the position (-formyl, vinyl, and ethynyl porphyrins). First, synthetic approaches to the preparation of these precursors are described. Then diverse pathways for the transformations of the multipotent synthons are discussed, revealing a variety of products of such reactions. The structures, electronic, and optical properties of the compounds obtained by the methods under consideration are analyzed. In addition, there is an overview of the applications of the products obtained. Biomedical use of the compounds is among the most important. Finally, the advantages of using the reviewed synthetic strategy to obtain dyes with targeted properties are highlighted.
PubMed: 37570752
DOI: 10.3390/molecules28155782 -
Scientific Reports Oct 2023This study investigated aniseikonia after reduced-fluence photodynamic therapy (RFPDT) for central serous chorioretinopathy (CSC). We examined 48 eyes of 48 patients (38...
This study investigated aniseikonia after reduced-fluence photodynamic therapy (RFPDT) for central serous chorioretinopathy (CSC). We examined 48 eyes of 48 patients (38 men; mean age, 49.2 ± 9.9 years) with CSC resolved after RFPDT. Horizontal and vertical aniseikonia were measured using the New Aniseikonia Test at baseline, 6 months, and 12 months after RFPDT. The maximum absolute value of the horizontal and vertical measurements indicated the aniseikonia score. The aniseikonia score was 2.2 ± 2.3 at 6 months and 2.2 ± 2.0 at 12 months after RFPDT, both of which improved significantly from the baseline score of 4.1 ± 2.9 (P < 0.05 and P < 0.01, respectively). The 12-month aniseikonia score significantly correlated with the baseline aniseikonia score (P = 0.047), outer nuclear thickness at baseline (P = 0.027) and 12 months after RFPDT (P = 0.014), baseline SRD area (P = 0.005), and ellipsoid zone disruption at 12 months after RFPDT (P = 0.021). In multivariate analysis, baseline serous retinal detachment (SRD) area (P = 0.034) was significantly associated with aniseikonia score at 12 months after RFPDT. Eyes with a larger SRD area might have higher aniseikonia scores even after SRD resolution following RFPDT.
Topics: Male; Humans; Adult; Middle Aged; Central Serous Chorioretinopathy; Photosensitizing Agents; Aniseikonia; Photochemotherapy; Retinal Detachment; Tomography, Optical Coherence; Fluorescein Angiography; Retrospective Studies; Porphyrins
PubMed: 37816824
DOI: 10.1038/s41598-023-44415-w -
International Journal of Molecular... Nov 2023Hemolytic disorders, like malaria and sickle cell disease (SCD), are responsible for significant mortality and morbidity rates globally, specifically in the Americas and...
Hemolytic disorders, like malaria and sickle cell disease (SCD), are responsible for significant mortality and morbidity rates globally, specifically in the Americas and Africa. In both malaria and SCD, red blood cell hemolysis leads to the release of a cytotoxic heme that triggers the expression of unique inflammatory profiles, which mediate the tissue damage and pathogenesis of both diseases. MicroRNAs (miRNAs), such as miR-451a and let-7i-5p, contribute to a reduction in the pro-inflammatory responses induced by circulating free hemes. MiR-451a targets both (pro-inflammatory) and (anti-inflammatory), and when this miRNA is present, is reduced and is increased. Let-7i-5p targets and reduces , which results in anti-inflammatory signaling. These gene targets regulate inflammation via regulation and increase anti-inflammatory signaling. Additionally, they indirectly regulate the expression of key heme scavengers, such as heme-oxygenase 1 (HO-1) (coded by the gene) and , to decrease circulating cytotoxic heme concentration. MiRNAs can be transported within extracellular vesicles (EVs), such as exosomes, offering insights into the mechanisms of mitigating heme-induced inflammation. We tested the hypothesis that miR-451a- or let-7i-5p-loaded artificial EVs (liposomes) will reduce heme-induced inflammation in brain vascular endothelial cells (HBEC-5i, ATCC: CRL-3245) and macrophages (THP-1, ATCC: TIB-202) in vitro. We completed arginase and nitric oxide assays to determine anti- and pro-inflammatory macrophage presence, respectively. We also assessed the gene expression of , , , and by RT-qPCR for both cell lines. Our findings revealed that the exposure of HBEC-5i and THP-1 to liposomes loaded with miR-451a or let-7i-5p led to a reduced mRNA expression of , , , and when treated with a heme. It also resulted in the increased expression of and . Finally, macrophages exhibited a tendency toward adopting an anti-inflammatory differentiation phenotype. These findings suggest that miRNA-loaded liposomes can modulate heme-induced inflammation and can be used to target specific cellular pathways, mediating inflammation common to hematological conditions, like malaria and SCD.
Topics: Humans; MicroRNAs; Hemolysis; Liposomes; Heme; Endothelial Cells; Hemopexin; Toll-Like Receptor 4; 14-3-3 Proteins; Anemia, Sickle Cell; Inflammation; Anti-Inflammatory Agents; Malaria
PubMed: 38069257
DOI: 10.3390/ijms242316934 -
Analytical Chemistry Sep 2023Multifunctional gold nanoparticles (AuNPs) are of great interest, owing to their vast potential for use in many areas including sensing, imaging, delivery, and medicine....
Multifunctional gold nanoparticles (AuNPs) are of great interest, owing to their vast potential for use in many areas including sensing, imaging, delivery, and medicine. A key factor in determining the biological activity of multifunctional AuNPs is the quantification of surface conjugated molecules. There has been a lack of accurate methods to determine this for multifunctionalized AuNPs. We address this limitation by using a new method based on the deconvolution and Levenberg-Marquardt algorithm fitting of UV-visible absorption spectrum to calculate the precise concentration and number of cytochrome (Cyt ) and zinc porphyrin (Zn Porph) bound to each multifunctional AuNP. Dynamic light scattering (DLS) and zeta potential measurements were used to confirm the functionalization of AuNPs with Cyt and Zn Porph. Transmission electron microscopy (TEM) was used in conjunction with UV-visible absorption spectroscopy and DLS to identify the AuNP size and confirm that no aggregation had taken place after functionalization. Despite the overlapping absorption bands of Cyt and Zn Porph, this method was able to reveal a precise concentration and number of Cyt and Zn Porph molecules attached per AuNP. Furthermore, using this method, we were able to identify unconjugated molecules, suggesting the need for further purification of the sample. This guide provides a simple and effective method to quickly quantify molecules bound to AuNPs, giving users valuable information, especially for applications in drug delivery and biosensors.
Topics: Gold; Metal Nanoparticles; Spectrum Analysis; Dynamic Light Scattering; Multifunctional Nanoparticles; Cytochromes c
PubMed: 37621249
DOI: 10.1021/acs.analchem.3c01649