RARE DISEASE
Nephrogenic systemic fibrosis
Nephrogenic systemic fibrosis
Nephrogenic systemic fibrosis
Synonyms: Nephrogenic fibrosing dermopathy
Synonyms: Nephrogenic fibrosing dermopathy
Synonyms: Nephrogenic fibrosing dermopathy
Drug discovery
0
drugs
With orphan designations
Overview
Nephrogenic systemic fibrosis (NSF) is a rare, progressive fibrosing disorder linked to gadolinium-based contrast agent (GBCA) exposure in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²). It manifests as skin induration, joint contractures, and systemic fibrosis involving organs like the heart, lungs, and diaphragm [1][6][11]. Mortality rates reach 31%, often due to respiratory failure or complications of immobility [7][12]. Incidence has declined since 2006 due to restricted use of high-risk GBCAs [4][6].
Therapies
Renal function optimization: Transplantation or medical management (most effective intervention) [3][14]
Symptomatic care: Extracorporeal photopheresis, physical therapy, and immunosuppressants (limited efficacy) [2][3][14]
Prevention: Avoidance of group I GBCAs in renal impairment; use safer group II agents if essential [1][6][13]
Categories: rare skin diseases
Research Papers
254 drug discovery papers about Nephrogenic systemic fibrosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
254 drug discovery papers about Nephrogenic systemic fibrosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Dual-Radical Gardenia Blue Conjugated Polymers with High Relaxivity and Bioreductive Stability as Metal-Free MRI Contrast Agents
Abstract T 1-weighted MRI contrast agents are essential for accurate diagnosis. However, clinical gadolinium-based contrast agents (Gd-CAs) are increasingly questioned because of risks of nephrogenic systemic fibrosis (NSF) and long-term tissue accumulation. Metal-free organic nitroxides like TEMPO emerge as safer alternatives but are limited by rapid in vivo bioreduction and suboptimal r1 relaxivity. Here, we report TEMPO-PROXY@pGen, a dual-radical, bio-based, π-conjugated polymer synthesized through mechanochemical copolymerization of 4-amino-TEMPO with 4-amino-PROXYL (3,3,5,5-tetramethyl-1-pyrroline N-oxide) on genipin-crosslinked scaffolds. TEMPO-PROXY@pGen integrates rigid π-conjugated backbone anchoring with possible intramolecular biradical interactions, causing the apparent rotational correlation time (τR,app) to approach the regime where Solomon–Bloembergen–Morgan (SBM) theory predicts enhanced relaxivity for simple monoradical systems while preserving high effective spin density (>80 radicals per chain). This yields a longitudinal relaxivity (r1) of 4.35 mM–1s–1 at 1.4 T and 3.69 mM–1s–1 at 3.0 T, 33.5-fold higher than TEMPO and comparable per-molecule r1 to clinically approved gadobutrol at the same field strength. The polymeric architecture confers high resistance to bioreduction and lower cell toxicity. Preliminary biosafety evaluation, including histopathology, serum biomarkers, and functional imaging, in both healthy and cisplatin-induced renal impairment models, suggests an improved safety profile relative to Gd-CAs under the tested conditions. This work establishes a rational molecular engineering framework for fully organic, metal-free MRI contrast agents that separates high relaxivity from heavy metal dependence for safe imaging in patients with compromised renal function.
2026-08-11 | Chelating molecular imaging probe amino polycarboxylic acid-manganese (II) complexes: as potent photoluminescent materials for imaging
Background: The most used gadolinium and manganese-based contrast agents improve the visibility of internal cell body structures in MRI. To overcome the nephrogenic systemic fibrosis (NSF) related to renal impairment, we are in the race to find safer MRI contrast agents. The utilization of some paramagnetic transition metal ions, Mn2+ and Fe3+ that may effectively relax the water protons is a potential strategy for developing substitute contrast agents for Gd3+chelates and these metals are less harmful than Gd3+. This investigation concentrates on synthesis of DTPA and EDTA-based manganese complexes with two different poly amino carboxylic acids to enhance as potential contrast agents with further studies. Methods: DTPA/EDTA anhydrides and respective amino substituted ligands were prepared under nitrogen atmosphere and complexes were prepared by reflux method at pH 8.4 using 1N NaHCO3 solution which was characterized by UV-visible, FTIR, 1H NMR, ESR, and TGA studies. Results: FT-IR analysis shown 510 cm-1 M-O bond and shifting of the ranges observed on comparing ligand and metal studies which confirmed the metal complex formation. 10.5 – 10.6 ppm for COOH group and 5.8 – 5.9 ppm for N-H group confirm the formation of poly amino carboxylic acid ligands with DTPA/EDTA. Nuclear spin I=5/2 reveals the 3d5 electronic configuration for Mn. The Mn complexes have shown good thermal stability, and EDTA complexes have good bacterial-resistant activity. Both DTPA/EDTA complexes have good fluorescence activities. Conclusion: The manganese-based complexes showed good resistance against both Gram positive and Gram negative bacteria which are well-suited to human body, with excellent emissions of complexes that may lead to further studies for imaging agents.
2026-05-15 | Pheomelanin and PEG Coatings on Superparamagnetic Fe 3 O 4 Nanoparticles: Reduced T 2 in MRI for Early Cancer Diagnosis
High Resolution Image Download MS PowerPoint Slide Nanotechnology is a field that is widely accepted as improving breast cancer diagnosis and making it safer from a clinical perspective. The use of superparamagnetic iron oxide nanoparticles as negative contrast agents (SPION-CAs) can be a favorable alternative to gadolinium-based contrast agents (Gd-CAs) because the latter can cause nephrogenic systemic fibrosis in patients with renal impairment. The main advantages of SPION-CAs over Gd-CAs are their biocompatibility, including low cytotoxicity, long blood circulation times, and efficient elimination through natural metabolic pathways or via storage and degradation of iron oxide (ferritinophagy). Recently, ultrasmall SPION-CAs coated with polyethylene glycol (PEG) for vascular imaging were approved in China. In this work, we synthesized PEG-coated SPIONs (SPION-A01) and compared them with pheomelanin-coated SPIONs (SPION-C01), as pheomelanin is a biocompatible bio-oligomer with a high affinity for iron coordination sites. Analyses by TEM and XRD showed an average core diameter of approximately 6.0 nm (SPION-A01) and 10.0 nm (SPION-C01), and superparamagnetic behavior was expected. VSM measurement confirmed this prediction, with SPION-C01 exhibiting a saturation magnetization approximately twice that of SPION-A01. Zeta-potential measurements indicated good colloidal stability of the samples, with SPION-C01 showing higher stability than SPION-A01. Indeed, the DLS analysis showed that SPION-C01 is thinner than SPION-A01, which is consistent with the presence of pheomelanin monomeric units. The in vitro assays, such as cytotoxicity, Prussian blue staining, and TEM (analysis in MCF-7 cells), showed their low cytotoxicity and positive uptake in human breast carcinoma (MCF-7) and normal fibroblast cells (McCoy). Moreover, the ex vivo hemolytic activity assay showed that both samples were negative, confirming their hemocompatibility. Indeed, the in vitro MRI measurements showed that the transverse relaxivity values ( r 2 ), which measure the MRI efficiency, were similar for both samples, but SPION-C01 exhibited a slightly higher r 2, supporting its potential as a negative SPION-CA.
2026-05-13 | Precision-Engineered Bismuth-Based Nanocomposites as Next-Generation Biocompatible Contrast Agents: A Rigorous Multi-Scale Theoretical, Computational, and Translational Framework
Background. Iodinated contrast agents (ICAs) for computed tomography (CT) and gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) remain the clinical standard, yet impose documented risks---contrast-induced acute kidney injury (CI-AKI) and nephrogenic systemic fibrosis (NSF)---particularly in renally compromised patients.Objective. This perspective establishes a rigorous, multi-scale theoretical and computational framework to evaluate bismuth-based nanocomposites (Bi₂S₃, Bi/Bi₂O₃) as precision-engineered alternatives, integrating first-principles X-ray physics, advanced three-compartment pharmacokinetics (PK), colloidal stability theory, and the Proposed Integrative Design--Validation--Translation (PI-DVT) pipeline.Methods. A systematic review of >70 peer-reviewed studies (2006--2025) was conducted. Geant4 Monte Carlo and COMSOL Multiphysics simulations were parameterized from established literature benchmarks. Sensitivity analyses (±20% parameter perturbations) and Monte Carlo uncertainty propagation quantify model robustness. The three-compartment PK model explicitly accounts for reticuloendothelial system (RES) sequestration, protein corona dynamics, and sigmoidal renal elimination gated on hydrodynamic diameter.Results. Simulations forecast that Bi₂S₃ nanoparticles (3--6 nm, PEGylated) yield X-ray mass attenuation coefficients of ~5.74 cm²/g at 100 keV---approximately 3× that of iodine---and Hounsfield unit (HU) enhancements of 350 at 3 mg/mL. The PK model predicts >85% renal clearance within 24 hours under idealized conditions, with RES retention <2% under optimized PEG densities (0.8 chains/nm², 2--5 kDa); the 95% credible clearance interval is 83.2--92.4%. These are theoretical projections from analogous systems; no Bi₂S₃-specific human PK data exist. Recent (2025) ultrasmall Bi/Bi₂O₃ nanoparticles corroborate >2-fold attenuation and 95% cell viability in vitro. Radiosensitizer enhancement ratios (SER) up to 4.93 and combined radiotherapy--chemodynamic therapy (RT-CDT) synergy projecting >70% tumor regression in murine models substantiate theranostic potential.Conclusions. Bismuth-based nanocomposites present a physically and chemically coherent rationale as alternatives to conventional agents. All safety, efficacy, and cost projections are computational predictions extrapolated from first principles and analogous nanomaterial data; they must not be interpreted as clinical evidence. Empirical validation through staged in vitro/in vivo studies and Phase I clinical trials is the critical next milestone, guided by the PI-DVT framework. No clinical conclusions should be drawn from computational predictions alone.
2026-03-03 | Exploring manganese-loaded nanoparticle formulations as contrast agents: A comprehensive in vitro and in vivo study.
Magnetic Resonance Imaging (MRI) is a crucial diagnostic modality in modern medical practice, offering non-invasive insight into internal structures and functions of the human body. The development of MRI contrast agents has significantly improved imaging sensitivity and precision. Traditional gadolinium-based agents, while effective, have been linked to nephrogenic systemic fibrosis (NSF), necessitating the exploration of alternative contrast agents. Nanoparticle-based systems have emerged as promising candidates for new contrast media, leveraging the unique properties of nanoparticles to address technological and medical challenges. Manganese has garnered attention due to its potential as a safe and effective alternative to gadolinium-based agents. This study delves into the synthesis of manganese loaded nanoparticles using poly (lactic-co-glycolic acid) (PLGA), a biodegradable polymer with proven biocompatibility. Two distinct manganese nanoencapsulation methods were devised and evaluated for their toxicity profiles. The method demonstrating superior biocompatibility, designated as PLGA-MN, was selected for in vivo assessments. Comparative analysis was performed against a control group administered manganese acetate (MnAc) (PBS) solution. In vivo MR imaging was performed on Sprague-Dawley rats, while the distribution of PLGA-MNs in blood, brain, liver, and spleen was determined through inductively coupled plasma mass spectrometry (ICP-MS). The results lay the foundation for advancing contrast agent development, harnessing nanotechnology to elevate diagnostic imaging capabilities and simultaneously addressing the safety considerations linked to conventional agents such as gadolinium.
proteins
2022-03-01 | Human Recombinant Relaxin (Serelaxin) as Anti-fibrotic Agent: Pharmacology, Limitations and Actual Perspectives
: Relaxin (recombinant human relaxin-2 hormone; RLX-2; serelaxin) had raised expectations as a new medication for fibrotic diseases. A plethora of in vitro and in vivo studies have offered convincing demonstrations that relaxin promotes remodelling of connective tissue extracellular matrix mediated by inhibition of multiple fibrogenic pathways, especially the downstream signalling of transforming growth factor (TGF)-β1, a major pro-fibrotic cytokine, and the recruitment and activation of myofibroblast, the main fibrosis-generating cells. However, all clinical trials with relaxin in patients with fibrotic diseases gave inconclusive results. In this review, we have summarized the molecular mechanisms of fibrosis, highlighting those which can be effectively targeted by relaxin. Then, we have performed a critical reappraisal of the clinical trials performed to-date with relaxin as anti-fibrotic drug, in order to highlight their key points of strength and weakness and to identify some future opportunities for the therapeutic use of relaxin, or its analogues, in fibrotic diseases and pathologic scarring which, in our opinion, deserve to be investigated.
2021-05-31 | Anti-fibrotic potential of erythropoietin signaling on bone marrow derived fibrotic cell
Abstract Introduction The number of patients with end stage kidney disease (ESKD) are increasing world-side. While interstitial fibrosis (IF) is a common step for the progression to ESKD, therapeutic options for IF is still limited in clinical settings. We have reported that bone marrow-derived fibrotic cell, fibrocyte, is involved in the pathogenesis of kidney fibrosis. Also recent studies revealed that erythropoietin has protective effect on kidney diseases. However, it is unknown whether erythropoietin (EPO) inhibits fibrosis in progressive kidney injury. Therefore, we explored the impacts of EPO on kidney fibrosis with focusing on fibrocyte. Method Fibrocyte was differentiated from peripheral mononuclear cells of healthy donor. Fibrocyte was stimulated with transforming growth factor beta (TGF) - β with/without EPO treatment. Moreover, the therapeutic effect of EPO was evaluated in murine unilateral ureteral obstruction (UUO) model. Result TGF-β stimulation increased the expression of COL1 mRNA in fibrocyte. EPO signal reduced the expression of COL1 mRNA in dose dependent manner. EPO reduced mitochondrial oxidative stress and ameliorated mitochondrial membrane depolarization induced by TGF-β stimulation. Moreover, EPO reduced the mRNA expression of mitochondria related molecules, TRAF6 , in fibrocyte. In addition, the count of CD45+/αSMA + double-positive fibrocyte was decreased in the EPO-administered UUO kidneys. Conclusion EPO signals function to prevent kidney fibrosis, particularly in fibrocyte. Regulating the renal accumulation of fibrocyte is a part of the anti-fibrotic functions of EPO.
2018-12-11 | Roles of the TGF-β⁻VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis.
Lymphatic vessels drain excess tissue fluids to maintain the interstitial environment. Lymphatic capillaries develop during the progression of tissue fibrosis in various clinical and pathological situations, such as chronic kidney disease, peritoneal injury during peritoneal dialysis, tissue inflammation, and tumor progression. The role of fibrosis-related lymphangiogenesis appears to vary based on organ specificity and etiology. Signaling via vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor (VEGFR)-3 is a central molecular mechanism for lymphangiogenesis. Transforming growth factor-β (TGF-β) is a key player in tissue fibrosis. TGF-β induces peritoneal fibrosis in association with peritoneal dialysis, and also induces peritoneal neoangiogenesis through interaction with VEGF-A. On the other hand, TGF-β has a direct inhibitory effect on lymphatic endothelial cell growth. We proposed a possible mechanism of the TGF-β⁻VEGF-C pathway in which TGF-β promotes VEGF-C production in tubular epithelial cells, macrophages, and mesothelial cells, leading to lymphangiogenesis in renal and peritoneal fibrosis. Connective tissue growth factor (CTGF) is also involved in fibrosis-associated renal lymphangiogenesis through interaction with VEGF-C, in part by mediating TGF-β signaling. Further clarification of the mechanism might lead to the development of new therapeutic strategies to treat fibrotic diseases.
2015-12-01 | Balanced regulation of the CCN family of matricellular proteins: a novel approach to the prevention and treatment of fibrosis and cancer
The CCN family of matricellular signaling proteins is emerging as a unique common link across multiple diseases and organs related to injury and repair. They are now being shown to play a central role in regulating the pathways to the initiation and resolution of normal wound healing and fibrosis in response to multiple forms of injury. Similarly, it is also emerging that they play a key role in regulating the establishment, growth, metastases and tissue regeneration in many forms of cancer via the interaction of cancer cells with the tumor stroma. Evidence has been recently provided that these proteins do not act independently but are co-regulated working in a yin/yang manner to alter the outcome of both normal physiological processes as well as pathology. The purpose of this review is to twofold. First, it will summarize work to date supporting CCN2 as a therapeutic target in the formation and progression of renal, skin, and other organ fibrosis, as well as cancer stroma formation. Second, it will highlight recent evidence for CCN3 as a counter-regulator and a potential therapeutic agent in these diseases with an exciting, novel potential to both treat and then restore tissue homeostasis in those afflicted by these devastating disorders.
2014-12-08 | Fibroblasts secrete Slit2 to inhibit fibrocyte differentiation and fibrosis
Monocytes leave the blood and enter tissues. In healing wounds and fibrotic lesions, some of the monocytes differentiate into fibroblast-like cells called fibrocytes. In healthy tissues, even though monocytes enter the tissue, for unknown reasons, very few monocytes differentiate into fibrocytes. In this report, we show that fibroblasts from healthy human tissues secrete the neuronal guidance protein Slit2 and that Slit2 inhibits human fibrocyte differentiation. In mice, injections of Slit2 inhibit bleomycin-induced lung fibrosis. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, Slit2 has a widespread distribution whereas, in patients with advanced disease, there is less Slit2 in the fibrotic lesions. These data may explain why fibrocytes are rarely observed in healthy tissues, may suggest that the relative levels of Slit2 present in healthy tissue and at sites of fibrosis may have a significant effect on the decision of monocytes to differentiate into fibrocytes, and may indicate that modulating Slit2 signaling may be useful as a therapeutic for fibrosis.
gene therapies
2022-05-02 | Delineating toxicity mechanisms associated with MRI contrast enhancement through a multidimensional toxicogenomic profiling of gadolinium.
Gadolinium is a metal used in contrast agents for magnetic resonance imaging. Although gadolinium is widely used in clinical settings, many concerns regarding its toxicity and bioaccumulation after gadolinium-based contrast agent administration have been raised and published over the last decade. To date, most toxicological studies have focused on identifying acute effects following gadolinium exposure, rather than investigating associated toxicity mechanisms. In this study, we employ functional toxicogenomics to assess mechanistic interactions of gadolinium with Saccharomyces cerevisiae. Furthermore, we determine which mechanisms are conserved in humans, and their implications for diseases related to the use of gadolinium-based contrast agents in medicine. A homozygous deletion pool of 4291 strains were screened to identify biological functions and pathways disturbed by the metal. Gene ontology and pathway enrichment analyses showed endocytosis and vesicle-mediated transport as the main yeast response to gadolinium, while certain metabolic processes, such as glycosylation, were the primary disrupted functions after the metal treatments. Cluster and protein-protein interaction network analyses identified proteins mediating vesicle-mediated transport through the Golgi apparatus and the vacuole, and vesicle cargo exocytosis as key components to reduce the metal toxicity. Moreover, the metal seemed to induce cytotoxicity by disrupting the function of enzymes (e.g. transferases and proteases) and chaperones involved in metabolic processes. Several of the genes and proteins associated with gadolinium toxicity are conserved in humans, suggesting that they may participate in pathologies linked to gadolinium-based contrast agent exposures. We thereby discuss the potential role of these conserved genes and gene products in gadolinium-induced nephrogenic systemic fibrosis, and propose potential prophylactic strategies to prevent its adverse health effects.
small molecules
2026-08-13 | Dual-Radical Gardenia Blue Conjugated Polymers with High Relaxivity and Bioreductive Stability as Metal-Free MRI Contrast Agents
Abstract T 1-weighted MRI contrast agents are essential for accurate diagnosis. However, clinical gadolinium-based contrast agents (Gd-CAs) are increasingly questioned because of risks of nephrogenic systemic fibrosis (NSF) and long-term tissue accumulation. Metal-free organic nitroxides like TEMPO emerge as safer alternatives but are limited by rapid in vivo bioreduction and suboptimal r1 relaxivity. Here, we report TEMPO-PROXY@pGen, a dual-radical, bio-based, π-conjugated polymer synthesized through mechanochemical copolymerization of 4-amino-TEMPO with 4-amino-PROXYL (3,3,5,5-tetramethyl-1-pyrroline N-oxide) on genipin-crosslinked scaffolds. TEMPO-PROXY@pGen integrates rigid π-conjugated backbone anchoring with possible intramolecular biradical interactions, causing the apparent rotational correlation time (τR,app) to approach the regime where Solomon–Bloembergen–Morgan (SBM) theory predicts enhanced relaxivity for simple monoradical systems while preserving high effective spin density (>80 radicals per chain). This yields a longitudinal relaxivity (r1) of 4.35 mM–1s–1 at 1.4 T and 3.69 mM–1s–1 at 3.0 T, 33.5-fold higher than TEMPO and comparable per-molecule r1 to clinically approved gadobutrol at the same field strength. The polymeric architecture confers high resistance to bioreduction and lower cell toxicity. Preliminary biosafety evaluation, including histopathology, serum biomarkers, and functional imaging, in both healthy and cisplatin-induced renal impairment models, suggests an improved safety profile relative to Gd-CAs under the tested conditions. This work establishes a rational molecular engineering framework for fully organic, metal-free MRI contrast agents that separates high relaxivity from heavy metal dependence for safe imaging in patients with compromised renal function.
2026-08-11 | Chelating molecular imaging probe amino polycarboxylic acid-manganese (II) complexes: as potent photoluminescent materials for imaging
Background: The most used gadolinium and manganese-based contrast agents improve the visibility of internal cell body structures in MRI. To overcome the nephrogenic systemic fibrosis (NSF) related to renal impairment, we are in the race to find safer MRI contrast agents. The utilization of some paramagnetic transition metal ions, Mn2+ and Fe3+ that may effectively relax the water protons is a potential strategy for developing substitute contrast agents for Gd3+chelates and these metals are less harmful than Gd3+. This investigation concentrates on synthesis of DTPA and EDTA-based manganese complexes with two different poly amino carboxylic acids to enhance as potential contrast agents with further studies. Methods: DTPA/EDTA anhydrides and respective amino substituted ligands were prepared under nitrogen atmosphere and complexes were prepared by reflux method at pH 8.4 using 1N NaHCO3 solution which was characterized by UV-visible, FTIR, 1H NMR, ESR, and TGA studies. Results: FT-IR analysis shown 510 cm-1 M-O bond and shifting of the ranges observed on comparing ligand and metal studies which confirmed the metal complex formation. 10.5 – 10.6 ppm for COOH group and 5.8 – 5.9 ppm for N-H group confirm the formation of poly amino carboxylic acid ligands with DTPA/EDTA. Nuclear spin I=5/2 reveals the 3d5 electronic configuration for Mn. The Mn complexes have shown good thermal stability, and EDTA complexes have good bacterial-resistant activity. Both DTPA/EDTA complexes have good fluorescence activities. Conclusion: The manganese-based complexes showed good resistance against both Gram positive and Gram negative bacteria which are well-suited to human body, with excellent emissions of complexes that may lead to further studies for imaging agents.
2026-05-15 | Pheomelanin and PEG Coatings on Superparamagnetic Fe 3 O 4 Nanoparticles: Reduced T 2 in MRI for Early Cancer Diagnosis
High Resolution Image Download MS PowerPoint Slide Nanotechnology is a field that is widely accepted as improving breast cancer diagnosis and making it safer from a clinical perspective. The use of superparamagnetic iron oxide nanoparticles as negative contrast agents (SPION-CAs) can be a favorable alternative to gadolinium-based contrast agents (Gd-CAs) because the latter can cause nephrogenic systemic fibrosis in patients with renal impairment. The main advantages of SPION-CAs over Gd-CAs are their biocompatibility, including low cytotoxicity, long blood circulation times, and efficient elimination through natural metabolic pathways or via storage and degradation of iron oxide (ferritinophagy). Recently, ultrasmall SPION-CAs coated with polyethylene glycol (PEG) for vascular imaging were approved in China. In this work, we synthesized PEG-coated SPIONs (SPION-A01) and compared them with pheomelanin-coated SPIONs (SPION-C01), as pheomelanin is a biocompatible bio-oligomer with a high affinity for iron coordination sites. Analyses by TEM and XRD showed an average core diameter of approximately 6.0 nm (SPION-A01) and 10.0 nm (SPION-C01), and superparamagnetic behavior was expected. VSM measurement confirmed this prediction, with SPION-C01 exhibiting a saturation magnetization approximately twice that of SPION-A01. Zeta-potential measurements indicated good colloidal stability of the samples, with SPION-C01 showing higher stability than SPION-A01. Indeed, the DLS analysis showed that SPION-C01 is thinner than SPION-A01, which is consistent with the presence of pheomelanin monomeric units. The in vitro assays, such as cytotoxicity, Prussian blue staining, and TEM (analysis in MCF-7 cells), showed their low cytotoxicity and positive uptake in human breast carcinoma (MCF-7) and normal fibroblast cells (McCoy). Moreover, the ex vivo hemolytic activity assay showed that both samples were negative, confirming their hemocompatibility. Indeed, the in vitro MRI measurements showed that the transverse relaxivity values ( r 2 ), which measure the MRI efficiency, were similar for both samples, but SPION-C01 exhibited a slightly higher r 2, supporting its potential as a negative SPION-CA.
2026-05-13 | Precision-Engineered Bismuth-Based Nanocomposites as Next-Generation Biocompatible Contrast Agents: A Rigorous Multi-Scale Theoretical, Computational, and Translational Framework
Background. Iodinated contrast agents (ICAs) for computed tomography (CT) and gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) remain the clinical standard, yet impose documented risks---contrast-induced acute kidney injury (CI-AKI) and nephrogenic systemic fibrosis (NSF)---particularly in renally compromised patients.Objective. This perspective establishes a rigorous, multi-scale theoretical and computational framework to evaluate bismuth-based nanocomposites (Bi₂S₃, Bi/Bi₂O₃) as precision-engineered alternatives, integrating first-principles X-ray physics, advanced three-compartment pharmacokinetics (PK), colloidal stability theory, and the Proposed Integrative Design--Validation--Translation (PI-DVT) pipeline.Methods. A systematic review of >70 peer-reviewed studies (2006--2025) was conducted. Geant4 Monte Carlo and COMSOL Multiphysics simulations were parameterized from established literature benchmarks. Sensitivity analyses (±20% parameter perturbations) and Monte Carlo uncertainty propagation quantify model robustness. The three-compartment PK model explicitly accounts for reticuloendothelial system (RES) sequestration, protein corona dynamics, and sigmoidal renal elimination gated on hydrodynamic diameter.Results. Simulations forecast that Bi₂S₃ nanoparticles (3--6 nm, PEGylated) yield X-ray mass attenuation coefficients of ~5.74 cm²/g at 100 keV---approximately 3× that of iodine---and Hounsfield unit (HU) enhancements of 350 at 3 mg/mL. The PK model predicts >85% renal clearance within 24 hours under idealized conditions, with RES retention <2% under optimized PEG densities (0.8 chains/nm², 2--5 kDa); the 95% credible clearance interval is 83.2--92.4%. These are theoretical projections from analogous systems; no Bi₂S₃-specific human PK data exist. Recent (2025) ultrasmall Bi/Bi₂O₃ nanoparticles corroborate >2-fold attenuation and 95% cell viability in vitro. Radiosensitizer enhancement ratios (SER) up to 4.93 and combined radiotherapy--chemodynamic therapy (RT-CDT) synergy projecting >70% tumor regression in murine models substantiate theranostic potential.Conclusions. Bismuth-based nanocomposites present a physically and chemically coherent rationale as alternatives to conventional agents. All safety, efficacy, and cost projections are computational predictions extrapolated from first principles and analogous nanomaterial data; they must not be interpreted as clinical evidence. Empirical validation through staged in vitro/in vivo studies and Phase I clinical trials is the critical next milestone, guided by the PI-DVT framework. No clinical conclusions should be drawn from computational predictions alone.
2026-03-03 | Exploring manganese-loaded nanoparticle formulations as contrast agents: A comprehensive in vitro and in vivo study.
Magnetic Resonance Imaging (MRI) is a crucial diagnostic modality in modern medical practice, offering non-invasive insight into internal structures and functions of the human body. The development of MRI contrast agents has significantly improved imaging sensitivity and precision. Traditional gadolinium-based agents, while effective, have been linked to nephrogenic systemic fibrosis (NSF), necessitating the exploration of alternative contrast agents. Nanoparticle-based systems have emerged as promising candidates for new contrast media, leveraging the unique properties of nanoparticles to address technological and medical challenges. Manganese has garnered attention due to its potential as a safe and effective alternative to gadolinium-based agents. This study delves into the synthesis of manganese loaded nanoparticles using poly (lactic-co-glycolic acid) (PLGA), a biodegradable polymer with proven biocompatibility. Two distinct manganese nanoencapsulation methods were devised and evaluated for their toxicity profiles. The method demonstrating superior biocompatibility, designated as PLGA-MN, was selected for in vivo assessments. Comparative analysis was performed against a control group administered manganese acetate (MnAc) (PBS) solution. In vivo MR imaging was performed on Sprague-Dawley rats, while the distribution of PLGA-MNs in blood, brain, liver, and spleen was determined through inductively coupled plasma mass spectrometry (ICP-MS). The results lay the foundation for advancing contrast agent development, harnessing nanotechnology to elevate diagnostic imaging capabilities and simultaneously addressing the safety considerations linked to conventional agents such as gadolinium.
proteins
2022-03-01 | Human Recombinant Relaxin (Serelaxin) as Anti-fibrotic Agent: Pharmacology, Limitations and Actual Perspectives
: Relaxin (recombinant human relaxin-2 hormone; RLX-2; serelaxin) had raised expectations as a new medication for fibrotic diseases. A plethora of in vitro and in vivo studies have offered convincing demonstrations that relaxin promotes remodelling of connective tissue extracellular matrix mediated by inhibition of multiple fibrogenic pathways, especially the downstream signalling of transforming growth factor (TGF)-β1, a major pro-fibrotic cytokine, and the recruitment and activation of myofibroblast, the main fibrosis-generating cells. However, all clinical trials with relaxin in patients with fibrotic diseases gave inconclusive results. In this review, we have summarized the molecular mechanisms of fibrosis, highlighting those which can be effectively targeted by relaxin. Then, we have performed a critical reappraisal of the clinical trials performed to-date with relaxin as anti-fibrotic drug, in order to highlight their key points of strength and weakness and to identify some future opportunities for the therapeutic use of relaxin, or its analogues, in fibrotic diseases and pathologic scarring which, in our opinion, deserve to be investigated.
2021-05-31 | Anti-fibrotic potential of erythropoietin signaling on bone marrow derived fibrotic cell
Abstract Introduction The number of patients with end stage kidney disease (ESKD) are increasing world-side. While interstitial fibrosis (IF) is a common step for the progression to ESKD, therapeutic options for IF is still limited in clinical settings. We have reported that bone marrow-derived fibrotic cell, fibrocyte, is involved in the pathogenesis of kidney fibrosis. Also recent studies revealed that erythropoietin has protective effect on kidney diseases. However, it is unknown whether erythropoietin (EPO) inhibits fibrosis in progressive kidney injury. Therefore, we explored the impacts of EPO on kidney fibrosis with focusing on fibrocyte. Method Fibrocyte was differentiated from peripheral mononuclear cells of healthy donor. Fibrocyte was stimulated with transforming growth factor beta (TGF) - β with/without EPO treatment. Moreover, the therapeutic effect of EPO was evaluated in murine unilateral ureteral obstruction (UUO) model. Result TGF-β stimulation increased the expression of COL1 mRNA in fibrocyte. EPO signal reduced the expression of COL1 mRNA in dose dependent manner. EPO reduced mitochondrial oxidative stress and ameliorated mitochondrial membrane depolarization induced by TGF-β stimulation. Moreover, EPO reduced the mRNA expression of mitochondria related molecules, TRAF6 , in fibrocyte. In addition, the count of CD45+/αSMA + double-positive fibrocyte was decreased in the EPO-administered UUO kidneys. Conclusion EPO signals function to prevent kidney fibrosis, particularly in fibrocyte. Regulating the renal accumulation of fibrocyte is a part of the anti-fibrotic functions of EPO.
2018-12-11 | Roles of the TGF-β⁻VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis.
Lymphatic vessels drain excess tissue fluids to maintain the interstitial environment. Lymphatic capillaries develop during the progression of tissue fibrosis in various clinical and pathological situations, such as chronic kidney disease, peritoneal injury during peritoneal dialysis, tissue inflammation, and tumor progression. The role of fibrosis-related lymphangiogenesis appears to vary based on organ specificity and etiology. Signaling via vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor (VEGFR)-3 is a central molecular mechanism for lymphangiogenesis. Transforming growth factor-β (TGF-β) is a key player in tissue fibrosis. TGF-β induces peritoneal fibrosis in association with peritoneal dialysis, and also induces peritoneal neoangiogenesis through interaction with VEGF-A. On the other hand, TGF-β has a direct inhibitory effect on lymphatic endothelial cell growth. We proposed a possible mechanism of the TGF-β⁻VEGF-C pathway in which TGF-β promotes VEGF-C production in tubular epithelial cells, macrophages, and mesothelial cells, leading to lymphangiogenesis in renal and peritoneal fibrosis. Connective tissue growth factor (CTGF) is also involved in fibrosis-associated renal lymphangiogenesis through interaction with VEGF-C, in part by mediating TGF-β signaling. Further clarification of the mechanism might lead to the development of new therapeutic strategies to treat fibrotic diseases.
2015-12-01 | Balanced regulation of the CCN family of matricellular proteins: a novel approach to the prevention and treatment of fibrosis and cancer
The CCN family of matricellular signaling proteins is emerging as a unique common link across multiple diseases and organs related to injury and repair. They are now being shown to play a central role in regulating the pathways to the initiation and resolution of normal wound healing and fibrosis in response to multiple forms of injury. Similarly, it is also emerging that they play a key role in regulating the establishment, growth, metastases and tissue regeneration in many forms of cancer via the interaction of cancer cells with the tumor stroma. Evidence has been recently provided that these proteins do not act independently but are co-regulated working in a yin/yang manner to alter the outcome of both normal physiological processes as well as pathology. The purpose of this review is to twofold. First, it will summarize work to date supporting CCN2 as a therapeutic target in the formation and progression of renal, skin, and other organ fibrosis, as well as cancer stroma formation. Second, it will highlight recent evidence for CCN3 as a counter-regulator and a potential therapeutic agent in these diseases with an exciting, novel potential to both treat and then restore tissue homeostasis in those afflicted by these devastating disorders.
2014-12-08 | Fibroblasts secrete Slit2 to inhibit fibrocyte differentiation and fibrosis
Monocytes leave the blood and enter tissues. In healing wounds and fibrotic lesions, some of the monocytes differentiate into fibroblast-like cells called fibrocytes. In healthy tissues, even though monocytes enter the tissue, for unknown reasons, very few monocytes differentiate into fibrocytes. In this report, we show that fibroblasts from healthy human tissues secrete the neuronal guidance protein Slit2 and that Slit2 inhibits human fibrocyte differentiation. In mice, injections of Slit2 inhibit bleomycin-induced lung fibrosis. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, Slit2 has a widespread distribution whereas, in patients with advanced disease, there is less Slit2 in the fibrotic lesions. These data may explain why fibrocytes are rarely observed in healthy tissues, may suggest that the relative levels of Slit2 present in healthy tissue and at sites of fibrosis may have a significant effect on the decision of monocytes to differentiate into fibrocytes, and may indicate that modulating Slit2 signaling may be useful as a therapeutic for fibrosis.
gene therapies
2022-05-02 | Delineating toxicity mechanisms associated with MRI contrast enhancement through a multidimensional toxicogenomic profiling of gadolinium.
Gadolinium is a metal used in contrast agents for magnetic resonance imaging. Although gadolinium is widely used in clinical settings, many concerns regarding its toxicity and bioaccumulation after gadolinium-based contrast agent administration have been raised and published over the last decade. To date, most toxicological studies have focused on identifying acute effects following gadolinium exposure, rather than investigating associated toxicity mechanisms. In this study, we employ functional toxicogenomics to assess mechanistic interactions of gadolinium with Saccharomyces cerevisiae. Furthermore, we determine which mechanisms are conserved in humans, and their implications for diseases related to the use of gadolinium-based contrast agents in medicine. A homozygous deletion pool of 4291 strains were screened to identify biological functions and pathways disturbed by the metal. Gene ontology and pathway enrichment analyses showed endocytosis and vesicle-mediated transport as the main yeast response to gadolinium, while certain metabolic processes, such as glycosylation, were the primary disrupted functions after the metal treatments. Cluster and protein-protein interaction network analyses identified proteins mediating vesicle-mediated transport through the Golgi apparatus and the vacuole, and vesicle cargo exocytosis as key components to reduce the metal toxicity. Moreover, the metal seemed to induce cytotoxicity by disrupting the function of enzymes (e.g. transferases and proteases) and chaperones involved in metabolic processes. Several of the genes and proteins associated with gadolinium toxicity are conserved in humans, suggesting that they may participate in pathologies linked to gadolinium-based contrast agent exposures. We thereby discuss the potential role of these conserved genes and gene products in gadolinium-induced nephrogenic systemic fibrosis, and propose potential prophylactic strategies to prevent its adverse health effects.
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