-
Revista Iberoamericana de Micologia Jun 2024Paracoccidioidomycosis is a neglected tropical disease caused by fungi of the genus Paracoccidioides. A wide range of symptoms is related to the disease; however, lungs...
BACKGROUND
Paracoccidioidomycosis is a neglected tropical disease caused by fungi of the genus Paracoccidioides. A wide range of symptoms is related to the disease; however, lungs and skin are the sites predominantly affected. The disease is mostly seen in people living in rural areas in Latin America.
CASE REPORT
We present a pediatric case of severe disseminated paracoccidioidomycosis that slowly responded to the antifungal treatment. Within three months, symptoms evolved into hepatosplenomegaly, necrotic cervical and abdominal lymph nodes, and splenic abscess. Clinical response to amphotericin B deoxycholate and itraconazole was slow, resulting in pleural and peritoneal cavity effusions, heart failure and shock. Amphotericin B deoxycholate was replaced by the liposomal formulation, with no response. Subsequently, prednisone was added to the treatment, which led to improvement in the clinical response. Serological Paracoccidioides antibody titers were atypical, with very low titers in the critical phase and significant increase during the convalescence phase. The infection was finally cleared up with amphotericin B deoxycholate, liposomal amphotericin B and the use of corticosteroids. Paracoccidioidomycosis serology was non-reactive two years post-discharge.
CONCLUSIONS
Due to the intense inflammatory response triggered by Paracoccidioides cells, giving low-dose prednisone for a short period of time modulated the inflammatory response and supported antifungal treatment.
PubMed: 38897873
DOI: 10.1016/j.riam.2024.04.001 -
Nature Communications Jun 2024Nuclear receptors (NRs) regulate transcription in response to ligand binding and NR modulation allows pharmacological control of gene expression. Although some NRs are...
Nuclear receptors (NRs) regulate transcription in response to ligand binding and NR modulation allows pharmacological control of gene expression. Although some NRs are relevant as drug targets, the NR1 family, which comprises 19 NRs binding to hormones, vitamins, and lipid metabolites, has only been partially explored from a translational perspective. To enable systematic target identification and validation for this protein family in phenotypic settings, we present an NR1 chemogenomic (CG) compound set optimized for complementary activity/selectivity profiles and chemical diversity. Based on broad profiling of candidates for specificity, toxicity, and off-target liabilities, sixty-nine comprehensively annotated NR1 agonists, antagonists and inverse agonists covering all members of the NR1 family and meeting potency and selectivity standards are included in the final NR1 CG set. Proof-of-concept application of this set reveals effects of NR1 members in autophagy, neuroinflammation and cancer cell death, and confirms the suitability of the set for target identification and validation.
Topics: Humans; Animals; Autophagy; Ligands; Receptors, Cytoplasmic and Nuclear; Mice; HEK293 Cells; Genomics; Cell Line, Tumor
PubMed: 38890295
DOI: 10.1038/s41467-024-49493-6 -
The Journal of Clinical Investigation Jun 2024The β-secretase BACE1 is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet,...
The β-secretase BACE1 is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, non-human primates and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for a safer prevention of Alzheimer's disease.
PubMed: 38888964
DOI: 10.1172/JCI170550 -
Neural Regeneration Research Mar 2025JOURNAL/nrgr/04.03/01300535-202503000-00033/figure1/v/2024-06-17T092413Z/r/image-tiff The organotypic retinal explant culture has been established for more than a decade...
JOURNAL/nrgr/04.03/01300535-202503000-00033/figure1/v/2024-06-17T092413Z/r/image-tiff The organotypic retinal explant culture has been established for more than a decade and offers a range of unique advantages compared with in vivo experiments and cell cultures. However, the lack of systematic and continuous comparison between in vivo retinal development and the organotypic retinal explant culture makes this model controversial in postnatal retinal development studies. Thus, we aimed to verify the feasibility of using this model for postnatal retinal development studies by comparing it with the in vivo retina. In this study, we showed that postnatal retinal explants undergo normal development, and exhibit a consistent structure and timeline with retinas in vivo. Initially, we used SOX2 and PAX6 immunostaining to identify retinal progenitor cells. We then examined cell proliferation and migration by immunostaining with Ki-67 and doublecortin, respectively. Ki-67- and doublecortin-positive cells decreased in both in vivo and explants during postnatal retinogenesis, and exhibited a high degree of similarity in abundance and distribution between groups. Additionally, we used Ceh-10 homeodomain-containing homolog, glutamate-ammonia ligase (glutamine synthetase), neuronal nuclei, and ionized calcium-binding adapter molecule 1 immunostaining to examine the emergence of bipolar cells, Müller glia, mature neurons, and microglia, respectively. The timing and spatial patterns of the emergence of these cell types were remarkably consistent between in vivo and explant retinas. Our study showed that the organotypic retinal explant culture model had a high degree of consistency with the progression of in vivo early postnatal retina development. The findings confirm the accuracy and credibility of this model and support its use for long-term, systematic, and continuous observation.
PubMed: 38886961
DOI: 10.4103/NRR.NRR-D-23-01557 -
Journal of Medicinal Chemistry Jun 2024The human orphan G protein-coupled receptor GPR18, activated by Δ-tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and cancer. However,...
The human orphan G protein-coupled receptor GPR18, activated by Δ-tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and cancer. However, studies on GPR18 are hampered by the lack of suitable tool compounds. In the present study, potent and selective GPR18 agonists were developed showing low nanomolar potency at human and mouse GPR18, determined in β-arrestin recruitment assays. Structure-activity relationships were analyzed, and selectivity versus cannabinoid (CB) and CB-like receptors was assessed. Compound (PSB-KK1415, EC 19.1 nM) was the most potent GPR18 agonist showing at least 25-fold selectivity versus CB receptors. The most selective GPR18 agonist (PSB-KK1445, EC 45.4 nM) displayed >200-fold selectivity versus both CB receptor subtypes, GPR55, and GPR183. The new GPR18 agonists showed minimal species differences, while THC acted as a weak partial agonist at the mouse receptor. The newly discovered compounds represent the most potent and selective GPR18 agonists reported to date.
Topics: Receptors, G-Protein-Coupled; Humans; Animals; Structure-Activity Relationship; Mice; Neoplasms; HEK293 Cells; Receptors, Cannabinoid; Dronabinol
PubMed: 38885438
DOI: 10.1021/acs.jmedchem.3c02423 -
Advanced Science (Weinheim,... Jun 2024Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic...
Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP-activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF-3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF-3758309 shows activity in pre-clinical PDAC models, including primary patient-derived organoids. Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC.
PubMed: 38885414
DOI: 10.1002/advs.202307695 -
Organic phosphate but not inorganic phosphate regulates expression through MAPK and TGF-ꞵ signaling.IScience Jun 2024One of the main regulators of phosphate homeostasis is fibroblast growth factor 23 (FGF23), secreted by osteocytes. The effects of organic versus inorganic dietary...
One of the main regulators of phosphate homeostasis is fibroblast growth factor 23 (FGF23), secreted by osteocytes. The effects of organic versus inorganic dietary phosphate on this homeostasis are unclear. This study used MC3T3-E1 FGF23-producing cells to examine the transcriptomic responses to these phosphates. Most importantly, the expression and secretion of FGF23 were only increased in response to organic phosphate. Gene ontology terms related to a response to environmental change were only enriched in cells treated with organic phosphate while cells treated with inorganic phosphate were enriched for terms associated with regulation of cellular phosphate metabolism. Inhibition of MAPK signaling diminished the response of to organic phosphate, suggesting it activates FGF23. TGF-β signaling inhibition increased expression after the addition of organic phosphate, while the negative TGF-β regulator decreased this response. In summary, the observed differential response of FGF23-producing to phosphate types may have consequences for phosphate homeostasis.
PubMed: 38883842
DOI: 10.1016/j.isci.2024.109625 -
Planta Jun 2024We generated transplastomic tobacco lines that stably express a human Basic Fibroblast Growth Factor (hFGFb) in their chloroplasts stroma and purified a biologically...
We generated transplastomic tobacco lines that stably express a human Basic Fibroblast Growth Factor (hFGFb) in their chloroplasts stroma and purified a biologically active recombinant hFGFb. MAIN: The use of plants as biofactories presents as an attractive technology with the potential to efficiently produce high-value human recombinant proteins in a cost-effective manner. Plastid genome transformation stands out for its possibility to accumulate recombinant proteins at elevated levels. Of particular interest are recombinant growth factors, given their applications in animal cell culture and regenerative medicine. In this study, we produced recombinant human Fibroblast Growth Factor (rhFGFb), a crucial protein required for animal cell culture, in tobacco chloroplasts. We successfully generated two independent transplastomic lines that are homoplasmic and accumulate rhFGFb in their leaves. Furthermore, the produced rhFGFb demonstrated its biological activity by inducing proliferation in HEK293T cell lines. These results collectively underscore plastid genome transformation as a promising plant-based bioreactor for rhFGFb production.
Topics: Nicotiana; Humans; Plants, Genetically Modified; Fibroblast Growth Factor 2; Chloroplasts; Recombinant Proteins; HEK293 Cells; Cell Proliferation; Plant Leaves
PubMed: 38878167
DOI: 10.1007/s00425-024-04456-5 -
ACS Nano Jun 2024The cellular environment, characterized by its intricate composition and spatial organization, hosts a variety of organelles, ranging from membrane-bound ones to...
The cellular environment, characterized by its intricate composition and spatial organization, hosts a variety of organelles, ranging from membrane-bound ones to membraneless structures that are formed through liquid-liquid phase separation. Cells show precise control over the position of such condensates. We demonstrate that organelle movement in external concentration gradients, , is distinct from the one of colloids because fluxes can remain finite inside the liquid-phase droplets and movement of the latter arises from incompressibility. Within cellular domains diffusiophoresis naturally arises from biochemical reactions that are driven by a chemical fuel and produce waste. Simulations and analytical arguments within a minimal model of reaction-driven phase separation reveal that the directed movement stems from two contributions: Fuel and waste are refilled or extracted at the boundary, resulting in concentration gradients, which (i) induce product fluxes via incompressibility and (ii) result in an asymmetric forward reaction in the droplet's surroundings (as well as asymmetric backward reaction inside the droplet), thereby shifting the droplet's position. We show that the former contribution dominates and sets the direction of the movement, toward or away from fuel source and waste sink, depending on the product molecules' affinity toward fuel and waste, respectively. The mechanism thus provides a simple means to organize condensates with different composition. Particle-based simulations and systems with more complex reaction cycles corroborate the robustness and universality of this mechanism.
PubMed: 38875706
DOI: 10.1021/acsnano.3c12842 -
Journal of Translational Medicine Jun 2024
Correction: Real‑world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC‑FFM in ruxolitinib‑refractory acute graft‑versus‑host disease.
PubMed: 38872104
DOI: 10.1186/s12967-024-05348-8