Integrating network pharmacology and transcriptomic omics reveals that akebia saponin D attenuates neutrophil extracellular traps-induced neuroinflammation via NTSR1/PKAc/PAD4 pathway after intracerebral hemorrhage.

Neutrophils and their production of neutrophil extracellular traps (NETs) significantly contribute to neuroinflammation and brain damage after intracerebral hemorrhage (ICH). Although Akebia saponin D (ASD) demonstrates strong anti-inflammatory activities and blood-brain barrier permeability, its role in regulating NETs formation and neuroinflammation following ICH is uncharted. Our research focused on unraveling the influence of ASD on neuroinflammation mediated by NETs and the mechanisms involved. We found that increased levels of peripheral blood neutrophils post-ICH are correlated with worse prognostic outcomes. Through network pharmacology, we identified ASD as a promising therapeutic target for ICH. ASD administration significantly improved neurobehavioral performance and decreased NETs production in neutrophils. Furthermore, ASD was shown to upregulate the membrane protein NTSR1 and activate the cAMP signaling pathway, confirmed through transcriptome sequencing, western blot, and immunofluorescence. Interestingly, the NTSR1 inhibitor SR48692 significantly nullified ASD's anti-NETs effects and dampened cAMP pathway activation. Mechanistically, suppression of PKAc via H89 negated ASD's anti-NETs effects but did not affect NTSR1. Our study suggests that ASD may reduce NETs formation and neuroinflammation, potentially involving the NTSR1/PKAc/PAD4 pathway post-ICH, underlining the potential of ASD in mitigating neuroinflammation through its anti-NETs properties.

Temperature-Controllable Liquid Crystalline Medium for Stereochemical Elucidation of Organic Compounds via Residual Chemical Shift Anisotropies.

The configuration elucidation of organic molecules continues to pose significant challenges in studies involving stereochemistry. Nuclear magnetic resonance (NMR) techniques are powerful for obtaining such structural information. Anisotropic NMR techniques, such as measurement of residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs), complementing isotropic NMR parameters, provide relative configuration information. RCSAs provide valuable structural information, especially for nonprotonated carbons, yet have been severely underutilized due to the lack of an easily operational alignment medium capable of rapid transition from anisotropic to isotropic environments, especially in aqueous conditions. In this study, an oligopeptide-based alignment media (FK)4 is presented for RCSA measurements. Temperature variation manipulates the assembly of (FK)4, yielding tunable anisotropic and isotropic phases without the requirement of any special devices or time-consuming correction procedures during data analysis. Decent observed ΔΔRCSA values from sp3 carbons benefit the utilization of RCSA measurements in the structural elucidation of organic molecules highly composed with sp3 carbons. Moreover, the (FK)4 alignment medium is applicable for both RDC and RCSA measurements in one sample, further advancing the configuration analysis of molecules of interest.

Phosphorylation of WRKY16 by MPK3-1 is essential for its transcriptional activity during fiber initiation and elongation in cotton (Gossypium hirsutum).

Cotton, one of the most important crops in the world, produces natural fiber materials for the textile industry. WRKY transcription factors play important roles in plant development and stress responses. However, little is known about whether and how WRKY transcription factors regulate fiber development of cotton so far. In this study, we show that a fiber-preferential WRKY transcription factor, GhWRKY16, positively regulates fiber initiation and elongation. GhWRKY16-silenced transgenic cotton displayed a remarkably reduced number of fiber protrusions on the ovule and shorter fibers compared to the wild-type. During early fiber development, GhWRKY16 directly binds to the promoters of GhHOX3, GhMYB109, GhCesA6D-D11, and GhMYB25 to induce their expression, thereby promoting fiber initiation and elongation. Moreover, GhWRKY16 is phosphorylated by the mitogen-activated protein kinase GhMPK3-1 at residues T-130 and S-260. Phosphorylated GhWRKY16 directly activates the transcription of GhMYB25, GhHOX3, GhMYB109, and GhCesA6D-D11 for early fiber development. Thus, our data demonstrate that GhWRKY16 plays a crucial role in fiber initiation and elongation, and that GhWRKY16 phosphorylation by GhMPK3-1 is essential for the transcriptional activation on downstream genes during the fiber development of cotton.

Highly Accurate and Explainable Predictions of Small-Molecule Antioxidants for Eight In Vitro Assays Simultaneously through an Alternating Multitask Learning Strategy.

Small molecule antioxidants can inhibit or retard oxidation reactions and protect against free radical damage to cells, thus playing a key role in food, cosmetics, pharmaceuticals, the environment, as well as materials. Experimentally driven antioxidant discovery is a major paradigm, and computationally assisted antioxidants are rarely reported. In this study, a functional-group-based alternating multitask self-supervised molecular representation learning method is proposed to simultaneously predict the antioxidant activities of small molecules for eight commonly used in vitro antioxidant assays. Extensive evaluation results reveal that compared with the baseline models, the multitask FG-BERT model achieves the best overall predictive performance, with the highest average F1, BA, ROC-AUC, and PRC-AUC values of 0.860, 0.880, 0.954, and 0.937 for the test sets, respectively. The Y-scrambling testing results further demonstrate that such a deep learning model was not constructed by accident and that it has reliable predictive capabilities. Additionally, the excellent interpretability of the multitask FG-BERT model makes it easy to identify key structural fragments/groups that contribute significantly to the antioxidant effect of a given molecule. Finally, an online antioxidant activity prediction platform called AOP (freely available at https://aop.idruglab.cn/) and its local version were developed based on the high-quality multitask FG-BERT model for experts and nonexperts in the field. We anticipate that it will contribute to the discovery of novel small-molecule antioxidants.

MMSyn: A New Multimodal Deep Learning Framework for Enhanced Prediction of Synergistic Drug Combinations.

Combination therapy is a promising strategy for the successful treatment of cancer. The large number of possible combinations, however, mean that it is laborious and expensive to screen for synergistic drug combinations in vitro. Nevertheless, because of the availability of high-throughput screening data and advances in computational techniques, deep learning (DL) can be a useful tool for the prediction of synergistic drug combinations. In this study, we proposed a multimodal DL framework, MMSyn, for the prediction of synergistic drug combinations. First, features embedded in the drug molecules were extracted: structure, fingerprint, and string encoding. Then, gene expression data, DNA copy number, and pathway activity were used to describe cancer cell lines. Finally, these processed features were integrated using an attention mechanism and an interaction module and then input into a multilayer perceptron to predict drug synergy. Experimental results showed that our method outperformed five state-of-the-art DL methods and three traditional machine learning models for drug combination prediction. We verified that MMSyn achieved superior performance in stratified cross-validation settings using both the drug combination and cell line data. Moreover, we performed a set of ablation experiments to illustrate the effectiveness of each component and the efficacy of our model. In addition, our visual representation and case studies further confirmed the effectiveness of our model. All results showed that MMSyn can be used as a powerful tool for the prediction of synergistic drug combinations.

Optimization and biological evaluation of l-DOPA derivatives as potent influenza PAN endonuclease inhibitors with multi-site binding characteristics.

Emerging and potential influenza pandemics still are an enormous worldwide public health challenge. The PAN endonuclease has been proved to be a promising target for anti-influenza drug design. Here, we report the discovery and optimization of potent Y-shaped PAN inhibitors featuring multi-site binding characteristics with l-DOPA as a starting point. We systematically modified the hit 1 bearing two-binding characteristics based on structure-based rational design combined with multisite binding and conformational constraint strategies, generating four families of l-DOPA derivatives for SARs analysis. Among these substances, N, 3-di-substituted 1, 2, 3, 4-tetrahydroisoquinoline derivative T-31 displayed superior properties as a lead PAN endonuclease inhibitor and antiviral agent. The lead T-31 inhibited PAN endonuclease activity with an IC50 value of 0.15 µM and showed broad and submicromolar anti-influenza potency in cell-based assays. More importantly, T-31 could simultaneously target both influenza HA and the RdRp complex, thus interfering with virus entry into host cells and viral replication. This study offers a set of novel PAN endonuclease inhibitors with multi-site binding characteristics starting from the l-DOPA skeleton.

The Application of Rho Kinase Inhibitors in the Management of Glaucoma.

Glaucoma is a chronic neurodegenerative disease that poses a significant threat of irreversible blindness worldwide. Current treatments for glaucoma focus on reducing intraocular pressure (IOP), which is the only modifiable risk factor. Traditional anti-glaucomatous agents, including carbonic anhydrase inhibitors, beta-blockers, alpha-2 agonists, and prostaglandin analogs, work by either improving uveoscleral outflow or reducing aqueous humor production. Rho kinase (ROCK) inhibitors represent a novel class of anti-glaucomatous drugs that have emerged from bench to bedside in the past decade, offering multifunctional characteristics. Unlike conventional medications, ROCK inhibitors directly target the trabecular meshwork outflow pathway. This review aims to discuss the mechanism of ROCK inhibitors in reducing IOP, providing neuroprotection, and preventing fibrosis. We also highlight recent studies and clinical trials evaluating the efficacy and safety of ROCK inhibitors, compare them with other clinical anti-glaucomatous medications, and outline future prospects for ROCK inhibitors in glaucoma treatment.

Ion Exchange-mediated 3D Cross-linked ZIF-L Superstructure for Flexible Electrochemical Energy Storage.

Metal-organic frameworks (MOFs) are considered as a promising candidate for advancing energy storage owing to their intrinsic multi-channel architecture, high theoretical capacity, and precise adjustability. However, the low conductivity and poor structural stability lead to unsatisfactory rate and cycling performance, greatly hindering their practical application. Herein, we propose a sea urchin-like Co-ZIF-L superstructure using molecular template to induce self-assembly followed by ion exchange method, which shows improved conductivity, successive channels, and high stability. The ion exchange can gradually etch the superstructure, leading to the reconstruction of Co-ZIF-L with three-dimensional (3D) cross-linked ultrathin porous nanosheets. Moreover, the precise control of Co to Ni ratios can construct effective micro-electric field and synergistically enhance the rapid transfer of electrons and electrolyte ions, improving the conductivity and stability of CoNi-ZIF-L. The Co6.53Ni-ZIF-L electrode exhibits a high specific capacity (602 F g-1 at 1 A g-1) and long cycling stability (95.3% retention after 4,000 cycles at 5 A g-1). The Co6.53Ni-ZIF-L//AC asymmetric flexible supercapacitor employing gel electrolyte also exhibits excellent cycling stability (93.3% retention after 4000 cycles at 5 A g-1). This discovery provides valuable insights for electrode material selection and energy storage efficiency improvement.

Myelin Debris Impairs Tight Junctions and Promotes the Migration of Microvascular Endothelial Cells in the Injured Spinal Cord.

Clearance of myelin debris caused by acute demyelination is an essential process for functional restoration following spinal cord injury (SCI). Microvascular endothelial cells, acting as "amateur" phagocytes, have been confirmed to engulf and degrade myelin debris, promoting the inflammatory response, robust angiogenesis, and persistent fibrosis. However, the effect of myelin debris engulfment on the function of endothelial tight junctions (TJs) remains unclear. Here, we demonstrate that myelin debris uptake impairs TJs and gap junctions of endothelial cells in the lesion core of the injured spinal cord and in vitro, resulting in increased permeability and leakage. We further show that myelin debris acts as an inducer to regulate the endothelial-to-mesenchymal transition in a dose-dependent manner and promotes endothelial cell migration through the PI3K/AKT and ERK signaling pathways. Together, our results indicate that myelin debris engulfment impairs TJs and promotes the migration of endothelial cells. Accelerating myelin debris clearance may help maintain blood-spinal cord barrier integrity, thus facilitating restoration of motor and sensory function following SCI.

A machine learning approach for predicting perihematomal edema expansion in patients with intracerebral hemorrhage.

OBJECTIVES: Preventing the expansion of perihematomal edema (PHE) represents a novel strategy for the improvement of neurological outcomes in intracerebral hemorrhage (ICH) patients. Our goal was to predict early and delayed PHE expansion using a machine learning approach. METHODS: We enrolled 550 patients with spontaneous ICH to study early PHE expansion, and 389 patients to study delayed expansion. Two imaging researchers rated the shape and density of hematoma in non-contrast computed tomography (NCCT). We trained a radiological machine learning (ML) model, a radiomics ML model, and a combined ML model, using data from radiomics, traditional imaging, and clinical indicators. We then validated these models on an independent dataset by using a nested 4-fold cross-validation approach. We compared models with respect to their predictive performance, which was assessed using the receiver operating characteristic curve. RESULTS: For both early and delayed PHE expansion, the combined ML model was most predictive (early/delayed AUC values were 0.840/0.705), followed by the radiomics ML model (0.799/0.663), the radiological ML model (0.779/0.631), and the imaging readers (reader 1: 0.668/0.565, reader 2: 0.700/0.617). CONCLUSION: We validated a machine learning approach with high interpretability for the prediction of early and delayed PHE expansion. This new technique may assist clinical practice for the management of neurocritical patients with ICH. KEY POINTS: • This is the first study to use artificial intelligence technology for the prediction of perihematomal edema expansion. • A combined machine learning model, trained on data from radiomics, clinical indicators, and imaging features associated with hematoma expansion, outperformed all other methods.

Effect of the Host Lattice Environment on the Expression of 5s2 Lone-Pair Electrons in a 0D Bismuth-Based Metal Halide.

ns2-Metal halide perovskites have attracted wide attention due to their fascinating photophysical properties. However, achieving high photoluminescence (PL) properties is still an enormous challenge, and the relationship between the lattice environment and ns2-electron expression is still elusive. Herein, an organic-inorganic Bi3+-based halide (C5H14N2)2BiCl6·Cl·2H2O (C5H14N22+ = doubly protonated 1-methylpiperazine) with a six-coordinated structure has been successfully prepared, which, however, exhibits inferior PL properties due to the chemically inert expression of Bi3+-6s2 lone-pair electrons. After reasonably embedding Sb3+ with 5s2 electrons into the lattice of (C5H14N2)2BiCl6·Cl·2H2O, the host lattice environment induces the Sb-Cl moiety to change from the original five-coordinated to six-coordinated structure, thereby resulting in a broad-band yellow emission with a PL efficiency up to 50.75%. By utilizing the host lattice of (C5H14N2)2BiCl6·Cl·2H2O, the expression of Sb3+-5s2 lone-pair electrons is improved and thus promotes the radiative recombination from the Sb3+-3P1 state, resulting in the enhanced PL efficiency. This work will provide an in-depth insight into the effect of the local structure on the expression of Sb3+-5s2 lone-pair electrons.

Ventriculoperitoneal shunt for tuberculous meningitis-associated hydrocephalus: long-term outcomes and complications.

BACKGROUND: Hydrocephalus is a frequent complication of tuberculous meningitis (TBM), and ventriculoperitoneal shunt (VPS) has been shown to improve short-term prognosis for patients with TBM-associated hydrocephalus. However, questions remain about long-term prognosis and shunt-related complications. This study aims to provide a comprehensive assessment of both long-term prognosis and shunt-related complications in patients with TBM-induced hydrocephalus who have undergone VPS treatment. METHODS: This retrospective study analyzed the clinical data of TBM patients with hydrocephalus treated with VPS at Peking Union Medical College Hospital between December 1999 and February 2023. Both short-term outcomes at discharge and long-term outcomes during follow-up were examined. Prognosis and shunt-related complications were assessed using the modified Rankin Scale (mRS) and the Activity of Daily Living (ADL) score to evaluate neurological function and autonomic living ability, respectively. RESULTS: A total of 14 patients with TBM-associated hydrocephalus were included in this study. Of these, 92.9% (13/14) exhibited favorable short-term outcomes, while 57.1% (8/14) showed positive long-term outcomes. Initial results indicated 6 complete recoveries (CR), 7 partial recoveries (PR), and 1 treatment failure. No catheter-related complications were observed initially. Long-term results included 4 CRs, 4 PRs, and 6 treatment failures. A variety of shunt surgery-related complications were noted, including three instances of catheter obstruction, one of incision infection, one of catheter-related infection, one of acute cerebral infarction, and one of transient peritoneal irritation accompanied by diarrhea. CONCLUSIONS: VPS appears to be an effective and well-tolerated treatment for TBM-associated hydrocephalus, efficiently alleviating acute intracranial hypertension. Nonetheless, continuous long-term monitoring and proactive management are essential to mitigate the risk of catheter-related complications.

Memory in aging colloidal gels with time-varying attraction.

We report a combined rheology, x-ray photon correlation spectroscopy, and modeling study of gel formation and aging in suspensions of nanocolloidal spheres with volume fractions of 0.20 and 0.43 and with a short-range attraction whose strength is tuned by changing temperature. Following a quench from high temperature, where the colloids are essentially hard spheres, to a temperature below the gel point, the suspensions form gels that undergo aging characterized by a steadily increasing elastic shear modulus and slowing, increasingly constrained microscopic dynamics. The aging proceeds at a faster rate for stronger attraction strength. When the attraction strength is suddenly lowered during aging, the gel properties evolve non-monotonically in a manner resembling the Kovacs effect in glasses, in which the modulus decreases and the microscopic dynamics become less constrained for a period before more conventional aging resumes. Eventually, the properties of the gel following the decrease in attraction strength converge to those of a gel that has undergone aging at the lower attraction strength throughout. The time scale of this convergence increases as a power law with the age at which the attraction strength is decreased and decreases exponentially with the magnitude of the change in attraction. A model for gel aging in which particles attach and detach from the gel at rates that depend on their contact number reproduces these trends and reveals that the non-monotonic behavior results from the dispersion in the rates that the populations of particles with different contact number adjust to the new attraction strength.

Engineered extracellular vesicles for ischemic stroke: a systematic review and meta-analysis of preclinical studies.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the efficacy of engineered extracellular vesicles (EEVs) in the treatment of ischemic stroke (IS) in preclinical studies and to compare them with natural extracellular vesicles (EVs). The systematic review provides an up-to-date overview of the current state of the literature on the use of EEVs for IS and informs future research in this area. METHODS: We searched PubMed, EMBASE, Web of Science, Cochrane Library, and Scopus databases for peer-reviewed preclinical studies on the therapeutic effect of EEVs on IS.Databases ranged from the inception to August 1, 2023. The outcome measures included infarct volumes, neurological scores, behavioral scores, apoptosis rates, numbers of neurons, and levels of IL-1ß, IL-6, and TNF-α. The CAMARADES checklist was used to assess the quality and bias risks of the studies. All statistical analyses were performed using RevMan 5.4 software. RESULTS: A total of 28 studies involving 1760 animals met the inclusion criteria. The results of the meta-analysis showed that compared to natural EVs, EEVs reduced infarct volume (percentage: SMD = -2.33, 95% CI: -2.92, -1.73; size: SMD = -2.36, 95% CI: -4.09, -0.63), improved neurological scores (mNSS: SMD = -1.78, 95% CI: -2.39, -1.17; Zea Longa: SMD = -2.75, 95% CI: -3.79, -1.71), promoted behavioral recovery (rotarod test: SMD = 2.50, 95% CI: 1.81, 3.18; grid-walking test: SMD = -3.45, 95% CI: -5.15, -1.75; adhesive removal test: SMD = -2.60, 95% CI: -4.27, -0.93; morris water maze test: SMD = -3.91, 95% CI: -7.03, -0.79), and reduced the release of proinflammatory factors (IL-1ß: SMD = -2.02, 95% CI: -2.77, -1.27; IL-6: SMD = -3.01, 95% CI: -4.47, -1.55; TNF-α: SMD = -2.72, 95% CI: -4.30, -1.13), increasing the number of neurons (apoptosis rate: SMD = -2.24, 95% CI: -3.32, -1.16; the number of neurons: SMD = 3.70, 95% CI: 2.44, 4.96). The funnel plots for the two main outcome measures were asymmetric, indicating publication bias. The median score on the CAMARADES checklist was 7 points (IQR: 6-9). CONCLUSIONS: This meta-analysis shows that EEVs are superior to natural EVs for the treatment of IS. However, research in this field is still at an early stage, and more research is needed to fully understand the potential therapeutic mechanism of EEVs and their potential use in the treatment of IS. PROSPERO REGISTRATION NUMBER: CRD42022368744.

Erythropoietin in Glaucoma: From Mechanism to Therapy.

Glaucoma can cause irreversible vision loss and is the second leading cause of blindness worldwide. The disease mechanism is complex and various factors have been implicated in its pathogenesis, including ischemia, excessive oxidative stress, neurotropic factor deprivation, and neuron excitotoxicity. Erythropoietin (EPO) is a hormone that induces erythropoiesis in response to hypoxia. However, studies have shown that EPO also has neuroprotective effects and may be useful for rescuing apoptotic retinal ganglion cells in glaucoma. This article explores the relationship between EPO and glaucoma and summarizes preclinical experiments that have used EPO to treat glaucoma, with an aim to provide a different perspective from the current view that glaucoma is incurable.

Overview of Recent Advances in Nano-Based Ocular Drug Delivery.

Ocular diseases profoundly impact patients' vision and overall quality of life globally. However, effective ocular drug delivery presents formidable challenges within clinical pharmacology and biomaterial science, primarily due to the intricate anatomical and physiological barriers unique to the eye. In this comprehensive review, we aim to shed light on the anatomical and physiological features of the eye, emphasizing the natural barriers it presents to drug administration. Our goal is to provide a thorough overview of various characteristics inherent to each nano-based drug delivery system. These encompass nanomicelles, nanoparticles, nanosuspensions, nanoemulsions, microemulsions, nanofibers, dendrimers, liposomes, niosomes, nanowafers, contact lenses, hydrogels, microneedles, and innovative gene therapy approaches employing nano-based ocular delivery techniques. We delve into the biology and methodology of these systems, introducing their clinical applications over the past decade. Furthermore, we discuss the advantages and challenges illuminated by recent studies. While nano-based drug delivery systems for ophthalmic formulations are gaining increasing attention, further research is imperative to address potential safety and toxicity concerns.

Biodegradable Polymer-Based Drug-Delivery Systems for Ocular Diseases.

Ocular drug delivery is a challenging field due to the unique anatomical and physiological barriers of the eye. Biodegradable polymers have emerged as promising tools for efficient and controlled drug delivery in ocular diseases. This review provides an overview of biodegradable polymer-based drug-delivery systems for ocular diseases with emphasis on the potential for biodegradable polymers to overcome the limitations of conventional methods, allowing for sustained drug release, improved bioavailability, and targeted therapy. Natural and synthetic polymers are both discussed, highlighting their biodegradability and biocompatibility. Various formulation strategies, such as nanoparticles, hydrogels, and microemulsions, among others, are investigated, detailing preparation methods, drug encapsulation, and clinical applications. The focus is on anterior and posterior segment drug delivery, covering glaucoma, corneal disorders, ocular inflammation, retinal diseases, age-related macular degeneration, and diabetic retinopathy. Safety considerations, such as biocompatibility evaluations, in vivo toxicity studies, and clinical safety, are addressed. Future perspectives encompass advancements, regulatory considerations, and clinical translation challenges. In conclusion, biodegradable polymers offer potential for efficient and targeted ocular drug delivery, improving therapeutic outcomes while reducing side effects. Further research is needed to optimize formulation strategies and address regulatory requirements for successful clinical implementation.

OGT Binding Peptide-Tagged Strategy Increases Protein O-GlcNAcylation Level in E. coli.

O-GlcNAcylation is a single glycosylation of GlcNAc mediated by OGT, which regulates the function of substrate proteins and is closely related to many diseases. However, a large number of O-GlcNAc-modified target proteins are costly, inefficient, and complicated to prepare. In this study, an OGT binding peptide (OBP)-tagged strategy for improving the proportion of O-GlcNAc modification was established successfully in E. coli. OBP (P1, P2, or P3) was fused with target protein Tau as tagged Tau. Tau or tagged Tau was co-constructed with OGT into a vector expressed in E. coli. Compared with Tau, the O-GlcNAc level of P1Tau and TauP1 increased 4~6-fold. Moreover, the P1Tau and TauP1 increased the O-GlcNAc-modified homogeneity. The high O-GlcNAcylation on P1Tau resulted in a significantly slower aggregation rate than Tau in vitro. This strategy was also used successfully to increase the O-GlcNAc level of c-Myc and H2B. These results indicated that the OBP-tagged strategy was a successful approach to improve the O-GlcNAcylation of a target protein for further functional research.

A Rare Case of Orbital Castleman Disease with Overlapping IgG4-Related Disease.

Multicentric Castleman disease (MCD) is a systemic lymphoproliferative disorder that can lead to mass lesions in various body parts, including the lungs, kidneys, and extranodal sites. Meanwhile, orbital Castleman disease is extremely rare. Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized fibroinflammatory disorder and is characterized by the formation of tumor-like lesions with lymphoplasmacytic infiltrates, which are enriched in IgG4-positive plasma cells and may present with a characteristic storiform pattern of fibrosis to variable degrees. In this study, we report a case of a 67-year-old Taiwanese man with a 7-year history of bilateral eyelid swelling and proptosis. Orbital magnetic resonance imaging revealed soft tissue lesions in the bilateral intraconal region, demonstrating strong enhancement in the lacrimal glands, and extension into the bilateral infraorbital foramen, suggesting an orbital lymphoproliferative disease. The histopathological results of the intraorbital tumor excision were suggestive of a plasma-cell-predominant mixed-cell variant of MCD. However, the patient also showed definitive signs of IgG4-RD, including lacrimal gland enlargement and histopathological results of plasmacytosis, fibrosis, and germinal centers, with an increased ratio of IgG4 cells and elevated serum IgG4 levels. This case suggests a potential interacting pathway between these two disease entities that needs further studies.

SU16f inhibits fibrotic scar formation and facilitates axon regeneration and locomotor function recovery after spinal cord injury by blocking the PDGFRß pathway.

BACKGROUND: Excessively deposited fibrotic scar after spinal cord injury (SCI) inhibits axon regeneration. It has been reported that platelet-derived growth factor receptor beta (PDGFRß), as a marker of fibrotic scar-forming fibroblasts, can only be activated by platelet-derived growth factor (PDGF) B or PDGFD. However, whether the activation of the PDGFRß pathway can mediate fibrotic scar formation after SCI remains unclear. METHODS: A spinal cord compression injury mouse model was used. In situ injection of exogenous PDGFB or PDGFD in the spinal cord was used to specifically activate the PDGFRß pathway in the uninjured spinal cord, while intrathecal injection of SU16f was used to specifically block the PDGFRß pathway in the uninjured or injured spinal cord. Immunofluorescence staining was performed to explore the distributions and cell sources of PDGFB and PDGFD, and to evaluate astrocytic scar, fibrotic scar, inflammatory cells and axon regeneration after SCI. Basso Mouse Scale (BMS) and footprint analysis were performed to evaluate locomotor function recovery after SCI. RESULTS: We found that the expression of PDGFD and PDGFB increased successively after SCI, and PDGFB was mainly secreted by astrocytes, while PDGFD was mainly secreted by macrophages/microglia and fibroblasts. In addition, in situ injection of exogenous PDGFB or PDGFD can lead to fibrosis in the uninjured spinal cord, while this profibrotic effect could be specifically blocked by the PDGFRß inhibitor SU16f. We then treated the mice after SCI with SU16f and found the reduction of fibrotic scar, the interruption of scar boundary and the inhibition of lesion and inflammation, which promoted axon regeneration and locomotor function recovery after SCI. CONCLUSIONS: Our study demonstrates that activation of PDGFRß pathway can directly induce fibrotic scar formation, and specific blocking of this pathway would contribute to the treatment of SCI.