[Pathogenesis of Fuchs endothelial corneal dystrophy, the fibrillar layer and individualized treatment]. / Pathogenese der Fuchs-Endotheldystrophie, die fibrilläre Schicht und individualisierte Therapie.

Fuchs endothelial corneal dystrophy (FECD) is a genetic and age-associated corneal disease characterized by an accelerated loss of corneal endothelial cells and an increased subendothelial deposition of extracellular matrix (ECM). Clinically, advanced disease leads to corneal edema with subsequent reduction in visual acuity. In the majority of patients with advanced FECD, a fibrillar layer (FL) appears on the posterior corneal surface. This FL is mostly localized in the inferotemporal corneal quadrant, marks areas with significantly reduced endothelial cell density and increased corneal thickness in the sense of edema and can be visualized and measured using Scheimpflug backscatter analysis due to increased backscatter. FECD is currently the most common indication for corneal transplantation worldwide, usually in the form of Descemet membrane endothelial keratoplasty (DMEK). New treatment approaches include variations of DMEK surgery such as hemi- or quarter DMEK with individualized and smaller grafts or Descemet membrane stripping only (DSO). In the future, clinical imaging of the FL as a particularly affected endothelial area could be important for FECD progression assessment and planning of surgical interventions. This article provides an overview of the current state of research on the clinical aspects, pathogenesis, fibrillar layer and individualized treatment of FECD.

Associations between endothelial cell characteristics and corneal topography findings in different stages of keratoconus.

PURPOSE: This study aimed to compare and correlate specular microscope indices and corneal topography indices in different stages of keratoconus. METHODS: Two hundred forty-six eyes of 123 participants were enrolled in the study. Corneal topography was performed using Sirius (CSO, Italy), with a rotating Scheimpflug camera and a Placido disc topographer. Corneal endothelial cell indices were assessed using a specular microscope (Nidek CEM-530, Japan). Eyes were graded as keratoconus stages 0-4 according to the Amsler-Krumeich classification. Corneal topography and endothelial cell indices were compared among the groups, and the correlations between them were analyzed. RESULTS: The mean age of the patients was 23.26 ± 6.75 years (range, 14-47 years). Forty-eight cases were male (39%) and 75 were female (61%). There were no statistically significant age (p = 0.578) or sex ratio (p = 0.529) differences between the groups. Twenty-nine eyes were included in the control group (11.78%), while 41 (16.67%) had stage 1 keratoconus, 88 (35.77%) had stage 2, and 88 (35.77%) had stage 3. Measurement was not possible in stage 4 keratoconus. No statistically significant difference was determined in specular microscopy values according to the stage of keratoconus, except for the number of analyzed cells (NUM) (p > 0.05). The lowest NUM values were observed in stages 1, 2, and 3, with values of 184.34 ± 67.62 cells/mm2, 155.07 ± 59.48 cells/mm2, and 127.06 ± 64.39 cells/mm2, respectively (p = 0.001). In the keratoconus group, weak statistically significant negative correlations were observed between NUM and SimK1, SimK2, KVf, BCVf, KVb, and BCVb, while a weak positive correlation was noted between NUM and central corneal thickness (p < 0.05). CONCLUSIONS: NUM seems to decrease, while endothelial cell density exhibits no significant changes, with the progression of keratoconus. It appears that as keratoconus index values increase, NUM may decrease in different stages of keratoconus.

The Role of Neutrophils in ANCA-Associated Vasculitis.

Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare systemic autoimmune diseases characterised by necrotising inflammation of small blood vessels and usually associated with circulating ANCA. The pathophysiology of AAV is complex, involving many aspects of the innate and adaptive immune system. Neutrophils are central to the pathogenesis of AAV as they are both the target of the autoantibody and effector cells mediating vascular injury. We describe mechanisms for ANCA induced activation of neutrophils, the pathogenic mechanisms by which this leads to endothelial cell injury, and how neutrophil crosstalk modulates other aspects of the immune system in AAV.

Targeting ICAM1 to Ameliorate Vaso-Occlusion and Inflammation in Sickle Cell Disease.

Sickle cell disease (SCD) is a hereditary disorder characterized by vaso-occlusion, inflammation, and tissue damage. Intercellular adhesion molecule 1 (ICAM-1) plays a crucial role in the pathophysiology of SCD by promoting the adhesion of sickle cells to the endothelium, contributing to vaso-occlusion and tissue damage. The ICAM-1 gene encodes a glycoprotein that interacts with lymphocyte function-associated antigen 1 (LFA-1) and macrophage 1-antigen (Mac-1) receptors, perpetuating inflammation, and oxidative stress. The NF-κB signaling pathway regulates ICAM-1 expression, which is elevated in patients with SCD, leading to increased endothelial cell activation and damage. Targeting ICAM-1 and its interactions with sickle cells and the endothelium has emerged as a potential therapeutic strategy for managing SCD. This review highlights the complex interplay between ICAM-1, sickle cells, and the endothelium, and discusses the potential of ICAM-1-targeted therapies for mitigating VOC and improving the quality of life for patients with SCD.

Metabolomic signature identifies HDL and apolipoproteins as potential biomarker for systemic sclerosis with interstitial lung disease.

BACKGROUND: High-density lipoproteins (HDL) affect endothelial functions such as the expression of endothelial cell adhesion molecules and exert anti-apoptotic/-thrombotic functionalities. Therefore, profound analysis of lipoproteins may unveil biomarkers for (micro-)vasculopathy in systemic sclerosis (SSc) and mortality determining disease manifestations like interstitial lung disease (SSc-ILD). Because nuclear magnetic resonance (NMR) spectroscopy provides a wide range of lipoprotein parameters beyond the capabilities of classical analyses it has been used herein to examine lipoprotein profiles in SSc. METHODS: To detect the metabolic and lipidomic profile serum samples from clinically well-characterized SSc patients (n = 100) and age-and sex-matched healthy controls (n = 40) were analyzed by 1H NMR spectroscopy using Bruker's in-vitro diagnostic research (IVDr) protocol. Statistical analyses were performed to validate significant findings and to search for associations between lipoproteins and clinical phenotypes. RESULTS: Patients with SSc-ILD and lung fibrosis displayed reduced HDL levels. Furthermore, a reduction in apolipoprotein A1 + A2 and its HDL fractions reflected a distinct lipoprotein profile for SSc-ILD patients. This association was independent of potential clinical confounders for dyslipidemia. Notably, in SSc-ILD HDL levels correlate with FVC (forced vital capacity), DLCO (diffusion capacity of the lungs for carbon monoxide), and the modified Rodnan-Skin-Score. CONCLUSION: These results suggest HDL and its lipoproteins may be considered as potential new biomarkers for SSc-ILD. Immune-mediated HDL effects on the endothelium facilitate microvasculopathy - one of the pathophysiological hallmarks in SSc. Therefore, a closer prospective evaluation of the capability of HDL-determination and its lipoproteins regarding a more individualized evaluation of SSc-ILD is warranted.

[Innovative surgical treatment approaches for endothelial dysfunction : Descemet stripping only (DSO) and endothelial cell injection]. / Innovative chirurgische Therapieansätze der endothelialen Dysfunktion : "Descemet stripping only" (DSO) und Endothelzellinjektion.

Currently, due to a rising number of patients Germany and many other countries experience a large deficit of donor eyes for posterior lamellar keratoplasty procedures in the treatment of corneal endothelial diseases. To address this unmet need there is an ongoing investigation of treatment modalities which do not rely on donor tissue or enable clinicians to treat more patient eyes per donor eye. The authors introduce a promising approach for both treatment principles. First, the technique of Descemet stripping only (DSO) is detailed, in which a central part of the Descemet's membrane including the endothelium is surgically removed without replacement with donor tissue. This then allows endothelial cells from the periphery of the cornea to migrate into the central area and can reduce corneal opacification and swelling. As a representative technique of the second group, the authors introduce endothelial cell injection, in which human corneal endothelial cells are cultivated in vitro and then, after removal of the diseased endothelium, injected into the anterior chamber of the recipient's eye to form a new and healthy endothelium. This is supported by injection of Rho kinase inhibitors and a face-down positioning of the patient after surgery. It is postulated that endothelial cell injection could possibly enable clinicians to treat up to 300 patient eyes with the tissue generated from 1 donor eye. Whether and how these novel approaches will become established in Europe remains to be seen.

N-Acetyl-L-Cysteine (NAC) Blunts Axitinib-Related Adverse Effects in Preclinical Models of Glioblastoma.

OBJECTIVE: Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH-wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo-angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib-dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. METHODS: We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N-Acetyl-L-Cysteine (NAC) might be used to reduce senescence-associated adverse effects of axitinib treatment without altering its anti-tumor activity. RESULTS: We demonstrate that the use of the antioxidant molecule N-Acetyl-Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib-dependent toxicity. CONCLUSION: Overall, we found that NAC co-treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib-dependent toxicity.

Growth hormone - releasing hormone in the immune system.

GHRH is a neuropeptide associated with a diverse variety of activities in human physiology and immune responses. The present study reviews the latest information on the involvement of GHRH in the immune system and inflammation, suggesting that GHRH antagonists may deliver a new therapeutic possibility in disorders related to immune system dysfunction and inflammation.

Vascular-endothelial adaptations following low and high volumes of high-intensity interval training in patients after myocardial infarction.

BACKGROUND: Determinants of coronary artery disease, such as endothelial dysfunction and oxidative stress, could be attenuated by high-intensity aerobic interval exercise training (HIIT). However, the volume of this type of training is not well established. OBJECTIVE: To assess the impact of two volumes of HIIT, low (LV-HIIT, <10 min at high intensity) and high (HV-HIIT, >10 min at high intensity), on vascular-endothelial function in individuals after an acute myocardial infarction (AMI). MATERIALS AND METHODS: Clinical trial in 80 AMI patients (58.4 ± 8.3 years, 82.5% men) with three study groups: LV-HIIT (n = 28) and HV-HIIT (n = 28) with two sessions per week for 16 weeks and control group (CG, n = 24) with unsupervised physical activity recommendations. Endothelial function (brachial flow-mediated dilation, FMD), atherosclerosis (carotid intima-media thickness ultrasound, cIMT), and levels of oxidized low-density lipoprotein (ox-LDL) as a marker of oxidative stress were determined before and after the intervention period. RESULTS: After the intervention, in the exercise groups, there was an increase in FMD (LV-HIIT, ↑58.8%; HV-HIIT, ↑94.1%; p < 0.001) concurrently with a decrease in cIMT (LV-HIIT, ↓3.0%; HV-HIIT, ↓3.2%; p = 0.019) and LDLox (LV-HIIT, ↓5.2%; HV-HIIT, ↓8.9%; p < 0.001), with no significant changes in the CG. Furthermore, a significant inverse correlation was observed between ox-LDL and endothelial function related to the volume of HIIT training performed (LV-HIIT: r = -0.376, p = 0.031; HV-HIIT: r = -0.490, p < 0.004), with no significance in the CG (r = 0.021, p = 0.924). CONCLUSION: In post-AMI patients, HIIT may lead to a volume-dependent enhancement in endothelial function, attributed to a decrease in oxidative stress, with added beneficial effects in reducing vascular wall thickness. An LV-HIIT program, with less than 10 min at high intensity per session, has proven enough efficiency to initiate favorable vascular-endothelial adaptations, potentially reducing cardiovascular risk among patients with coronary artery disease. TRIAL REGISTRATION: INTERFARCT, ClinicalTrials.gov: NCT02876952.

Endothelial Dysfunction Does Not Occur after Acute, Elevated Homocysteine Exposure of the Lumen of the Iliac Artery of the Anaesthetised Pig.

INTRODUCTION: Elevated luminal homocysteine has been linked with cardiovascular disease; however, whether there is a direct effect of homocysteine on blood vessel endothelium is not clear. In this study, the acute effect of luminal homocysteine on iliac artery endothelial function was assessed in the anaesthetised pig. METHODS: Hyperhomocysteinaemic blood was injected into an occluded segment of the iliac in the anaesthetised pig for 20 min, and the effect on atrial diameter during the occlusion and during the reactive hyperaemia assessed. RESULTS: No significant changes in arterial diameter or pressure were observed during the incubation period at homocysteine concentrations of 10, 20, 40 and 100 µM. There was also no difference in the magnitude of the iliac diameter increase in the response to reactive hyperaemia when the incubation period was completed. CONCLUSION: There is no evidence of endothelial dysfunction in response to an acute 20-min elevation in homocysteine in an intact conduit artery.

Microvascular Engineering for the Development of a Nonembedded Liver Sinusoid with a Lumen: When Endothelial Cells Do Not Lose Their Edge.

Microvascular engineering seeks to exploit known cell-cell and cell-matrix interactions in the context of vasculogenesis to restore homeostasis or disease development of reliable capillary models in vitro. However, current systems generally focus on recapitulating microvessels embedded in thick gels of extracellular matrix, overlooking the significance of discontinuous capillaries, which play a vital role in tissue-blood exchanges particularly in organs like the liver. In this work, we introduce a novel method to stimulate the spontaneous organization of endothelial cells into nonembedded microvessels. By creating an anisotropic micropattern at the edge of a development-like matrix dome using Marangoni flow, we achieved a long, nonrandom orientation of endothelial cells, laying a premise for stable lumenized microvessels. Our findings revealed a distinctive morphogenetic process leading to mature lumenized capillaries, demonstrated with both murine and human immortalized liver sinusoidal endothelial cell lines (LSECs). The progression of cell migration, proliferation, and polarization was clearly guided by the pattern, initiating the formation of a multicellular cord that caused a deformation spanning extensive regions and generated a wave-like folding of the gel, hinged at a laminin-depleted zone, enveloping the cord with gel proteins. This event marked the onset of lumenogenesis, regulated by the gradual apico-basal polarization of the wrapped cells, leading to the maturation of vessel tight junctions, matrix remodeling, and ultimately the formation of a lumen─recapitulating the development of vessels in vivo. Furthermore, we demonstrate that the process strongly relies on the initial gel edge topography, while the geometry of the vessels can be tuned from a curved to a straight structure. We believe that our facile engineering method, guiding an autonomous self-organization of vessels without the need for supporting cells or complex prefabricated scaffolds, holds promise for future integration into microphysiological systems featuring discontinuous, fenestrated capillaries.

The time dependent influence of curvature and topography of biomaterials in the behavior of corneal endothelial cells.

Among the different layers of the cornea, the corneal endothelium, which is composed of corneal endothelial cells (CEC), plays a key role in the maintenance of cornea transparency. Based on the donor shortages and the limitations associated with transplantation, in this work we have developed collagen hydrogels with different patterned structures on the surface to provide topographies in ranges similar to the natural environment that CEC sense. This aimed at stimulating cells to maintain a typical CEC phenotype and provide alternatives to corneal transplantation. In this sense, we have elaborated curved collagen hydrogels (concave and convex) with three different topographies (50, 200 and 300 µm grooves), with the help of 3D printed mold and replicating the mold with the collagen hydrogel, onto which CEC were cultured in order to analyze its behavior. Flat hydrogels were used as controls. Cell morphology, cell circularity and gene expression of ATP1A1 and ZO-1 genes were analyzed after 3 and 6 days. Results showed an effect of the curvature and the topography compared to flat collagen hydrogels, showing higher expression of ZO-1 and ATP1A1 in curved non-patterned hydrogels at day 3. The patterned hydrogels did not have such a significant effect on gene expression compared to flat hydrogels, showing stronger effect of the curvature compared to the topography. The effect was opposite at day 6, showing higher gene expression at days 6 on the patterned hydrogels, especially for the ZO-1 gene. The gene expression results were in accordance with the cell morphology observed at the different time points, showing circularities closer to hexagon like morphology at shorter time points. Overall, this platform can serve as a system to culture cell under proper environment to further be able to transplant a CEC monolayer or to allow transplantation of thin collagen layers with cultured CEC.

TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss. FECD pathogenesis is linked to impaired response to oxidative stress and environmental ultraviolet A (UVA) exposure. Although UVA is known to cause nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation, ferroptosis has not been characterized in FECD. We investigated the roles of genetic background and UVA exposure in causing CEC degeneration in FECD. Using ungenotyped FECD patient surgical samples, we found increased levels of cytosolic ferrous iron (Fe2+) and lipid peroxidation in end-stage diseased tissues compared with healthy controls. Using primary and immortalized cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found altered gene and protein expression involved in ferroptosis compared to controls including elevated levels of Fe2+, basal lipid peroxidation, and the ferroptosis-specific marker transferrin receptor 1. Increased cytosolic Fe2+ levels were detected after physiologically relevant doses of UVA exposure, indicating a role for ferroptosis in FECD disease progression. Cultured cells were more prone to ferroptosis induced by RSL3 and UVA than controls, indicating ferroptosis susceptibility is increased by both FECD genetic background and UVA. Finally, cell death was preventable after RSL3 induced ferroptosis using solubilized ubiquinol, indicating a role for anti-ferroptosis therapies in FECD. This investigation demonstrates that genetic background and UVA exposure contribute to iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated disease progression in FECD.

Rift Valley fever virus is able to cross the human blood-brain barrier in vitro by direct infection with no deleterious effects.

Rift Valley fever (RVF) is a zoonotic arboviral disease that causes recurrent epidemics in Africa that may trigger fatal neurological disorders. However, the mechanisms of neuroinvasion by which the RVF virus (RVFV) reaches the human central nervous system (CNS) remain poorly characterized. In particular, it is not clear how RVFV is able to cross the human blood-brain barrier (hBBB), which is a neurovascular endothelium that protects the brain by regulating brain and blood exchanges. To explore these mechanisms, we used an in vitro hBBB model to mimic in vivo hBBB selectiveness and apicobasal polarity. Our results highlight the ability of RVFV to cross the hBBB by direct infection in a non-structural protein S (NSs)-independent but strain-dependent manner, leading to astrocyte and pericyte infections. Interestingly, RVFV infection did not induce hBBB disruption and was associated with progressive elimination of infected cells with no impairment of the tight junction protein scaffold and barrier function. Our work also shows that NSs, a well described RVFV virulence factor, limited the establishment of the hBBB-induced innate immune response and subsequent lymphocyte recruitment. These results provide in vitro confirmation of the ability of RVFV to reach human CNS by direct infection of the hBBB without altering its barrier function, and provide new directions to explore human RVFV neurovirulence and neuroinvasion mechanisms.IMPORTANCEThe RVF virus (RVFV) is capable of infecting humans and inducing severe and fatal neurological disorders. Neuropathogenesis and human central nervous system (CNS) invasion mechanisms of RVFV are still unknown, with only historical studies of autopsy data from fatal human cases in the 1980s and exploration studies in rodent models. One of the gaps in understanding RVFV human pathogenesis is how RVFV is able to cross the blood-brain barrier (BBB) in order to reach the human CNS. For the first time, we show that RVFV is able to directly infect cells of the human BBB in vitro to release viral particles into the human CNS, a well-characterized neuroinvasion mechanism of pathogens. Furthermore, we demonstrate strain-dependent variability of this neuroinvasion mechanism, identifying possible viral properties that could be explored to prevent neurological disorders during RVFV outbreaks.

Laminin Beta 2 Is Localized at the Sites of Blood-Brain Barrier and Its Disruption Is Associated With Increased Vascular Permeability, Histochemical, and Transcriptomic Study.

Heterotrimeric extracellular matrix proteins laminins are mostly deposited at basal membranes and are important in repair and neoplasia. Here, we localize laminin beta 2 (LAMB2) at the sites of blood-brain barrier (BBB). Microvasculature (MV) of normal brain is endowed with complete LAMB2 coverage. In contrast, its cognate protein laminin beta 1 (LAMB1) is absent in MV of normal brain but emerges at the sprouting tip of a growing vessels. Similarly, vascular proliferation in high-grade gliomas (HGG) is accompanied by marked overexpression of LAMB1, whereas LAMB2 shows deficient deposition. We find that many brain pathologies with presence of post-gadolinium enhancement (PGE) on magnetic resonance imaging (MRI) show disruption of LAMB2 vascular ensheathment. Inhibition of vascular endothelial growth factor signaling in HGG blocks angiogenesis, suppresses PGE in HGG, prevents expression of LAMB1, and restores LAMB2 vascular coverage. Analysis of single-cell RNA sequencing (scRNA-seq) databases shows that in quiescent brain LAMB2 is predominantly expressed by BBB-associated pericytes (PCs) and endothelial cells (ECs), whereas neither cell types produce LAMB1. In contrast, in HGG, both LAMB1 and 2 are overexpressed by endothelial precursor cells, a phenotypically unique immature group, specific to proliferating hyperplastic MV.

Busin Glide-Assisted Pull-Through Insertion of Artificial Corneal Endothelium (EndoArt).

Background: Currently, the push-in technique through the corneal tunnel using a blunt-tip spatula is used to insert an artificial corneal endothelium (EndoArt) into the anterior chamber (AC). The device is useful for patients with bullous keratopathy; however, it may be difficult to manipulate the very thin implant through hazy cornea. Unlike DMEK graft, it cannot be stained and the F-mark is faint. So, visualizing and orienting the implant is a real challenge especially through a hazy cornea and inadequate AC visualization. Therefore, alternative EndoArt implantation techniques are needed in patients with advanced endothelial dysfunction to avoid complications. Purpose: To report an alternative technique for EndoArt implantation using a Busin glide. Technique: The EndoArt was loaded onto the Busin glide with the concave side of the EndoArt facing upward and was then pulled/pushed into the Busin glide opening. After the Descemet's membrane and endothelium were detached and removed in a circular fashion in a patient with advanced corneal endothelial decompensation, the Busin glide was inserted into the corneal incision, and the EndoArt was slowly pulled into the AC using retractor forceps. Finally, the air was injected into the AC. Conclusion: The Busin glide-assisted pull-through technique smoothly and securely inserted the EndoArt into the AC without upside-down attachment. This alternative technique can be useful for patients with a history of repeat intraocular surgeries or trauma with severe corneal edema to avoid potential complications such as epithelial implantation cysts or downgrowth.

Antioxidant Properties and Vasorelaxant Mechanism of Aqueous Extract of Ricinodendron heudelotii (Euphorbiaceae).

Ricinodendron heudelotii is a plant of the Euphorbiaceae family, used in traditional medicine to treat numerous diseases, including high blood pressure. The aim of this study is to evaluate the antioxidant and vasorelaxant effects of the aqueous extract of the stem bark of R. heudelotii. The pharmacological studies were carried out using the aqueous extract obtained by infusion. The antioxidant capacity of R. heudelotii was assessed by in vitro tests with DPPH (2,2-diphenyl-1-picryl-hydrazyl), ABTS (2,2'-azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid), iron-reducing capacity (FRAP), and inhibition of nitric oxide (NO) release. In vitro studies, the aortic rings obtained from adult Wistar albino rats of both sexes were used to determine the vasorelaxant effects of the extract of R. heudelotii on the NO and prostacyclin (PGI2) pathways as well as its involvement on various potassium channels were determined on intact or naked fragments of rat aorta precontracted with phenylephrine (10-6 M) or KCl (60 mM). The aqueous extract of R. heudelotii exhibited a remarkable DPPH (EC50: 1.68 µg/mL) and ABTS (EC50: 106.30 µg/mL) and nitric oxide (53.71% inhibition at 1000 µg/mL) radical scavenging activities as well as reducing power (absorbance of 1.56 at 1000 µg/mL). The nitric oxide inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and prostacyclin inhibitor, indomethacin, significantly attenuated the vasodilatory effect of R. heudelotii. Tetraethylammonium could not inhibit the vasodilatory effect of the extract, unlike glibenclamide and barium chloride. Ricinodendron heudelotii extract possesses antioxidant properties and vasorelaxing effect linked to endothelium-related factors, and this relaxation was partially mediated mainly through the inhibition of Kir and KATP channels.

Pulmonary fibrosis: pathogenesis and therapeutic strategies.

Pulmonary fibrosis (PF) is a chronic and progressive lung disease characterized by extensive alterations of cellular fate and function and excessive accumulation of extracellular matrix, leading to lung tissue scarring and impaired respiratory function. Although our understanding of its pathogenesis has increased, effective treatments remain scarce, and fibrotic progression is a major cause of mortality. Recent research has identified various etiological factors, including genetic predispositions, environmental exposures, and lifestyle factors, which contribute to the onset and progression of PF. Nonetheless, the precise mechanisms by which these factors interact to drive fibrosis are not yet fully elucidated. This review thoroughly examines the diverse etiological factors, cellular and molecular mechanisms, and key signaling pathways involved in PF, such as TGF-ß, WNT/ß-catenin, and PI3K/Akt/mTOR. It also discusses current therapeutic strategies, including antifibrotic agents like pirfenidone and nintedanib, and explores emerging treatments targeting fibrosis and cellular senescence. Emphasizing the need for omni-target approaches to overcome the limitations of current therapies, this review integrates recent findings to enhance our understanding of PF and contribute to the development of more effective prevention and management strategies, ultimately improving patient outcomes.