Structures of the NDP-pyranose mutase belonging to glycosyltransferase family 75 reveal residues important for Mn2+ coordination and substrate binding.

Members of glycosyltransferase family 75 (GT75) not only reversibly catalyze the autoglycosylation of a conserved arginine residue with specific NDP-sugars but also exhibit NDP-pyranose mutase activity that reversibly converts specific NDP-pyranose to NDP-furanose. The latter activity provides valuable NDP-furanosyl donors for glycosyltransferases and requires a divalent cation as a cofactor instead of FAD used by UDP-D-galactopyranose mutase. However, details of the mechanism for NDP-pyranose mutase activity are not clear. Here we report the first crystal structures of GT75 family NDP-pyranose mutases. The novel structures of GT75 member MtdL in complex with Mn2+ and GDP, GDP-D-glucopyranose, GDP-L-fucopyranose, GDP-L-fucofuranose, respectively, combined with site-directed mutagenesis studies, reveal key residues involved in Mn2+ coordination, substrate binding, and catalytic reactions. We also provide a possible catalytic mechanism for this unique type of NDP-pyranose mutase. Taken together, our results highlight key elements of an enzyme family important for furanose biosynthesis.

Short-chain fatty acids ameliorate experimental anti-glomerular basement membrane disease.

BACKGROUND: Short-chain fatty acids (SCFAs), as the link between gut microbiota and the immune system, had been reported to be protective in many autoimmune diseases by the modulation of T cell differentiation. The pathogenic role of autoreactive Th1 and Th17 cells and the protective role of Treg cells in the pathogenesis of anti-GBM disease have been fully demonstrated. Thus, the present study aimed to investigate the therapeutic effects of SCFAs in a rat model of anti-GBM disease. MATERIALS AND METHODS: Experimental anti-GBM disease was constructed by immunizing Wistar Kyoto rats with a nephrogenic T cell epitope α3127-148, and intervened by sodium acetate, sodium propionate, or sodium butyrate, 150 mM in the drinking water from day 0 to 42. Kidney injury was accessed by the biochemical analyzer, immunofluorescence, and immunohistochemistry. Antibody response was detected by ELISA. T cell clustering and proliferation were detected by flow cytometry. Human kidney 2 (HK2) cells were stimulated in vitro and cytokines were assessed by quantitative real-time PCR. RESULTS: Treatment with sodium acetate, sodium propionate, or sodium butyrate ameliorated the severity of kidney impairment in rats with anti-GBM glomerulonephritis. In the sodium butyrate-treated rats, the urinary protein, serum creatinine, and blood urea nitrogen levels were significantly lower; the percentage of crescent formation in glomeruli was significantly reduced; and the kidneys showed reduced IgG deposition, complement activation, T cell, and macrophage infiltration as well as the level of circulating antibodies against anti-α3(IV)NC1. The treatment of sodium butyrate reduced the α3127-148-specific T cell activation and increased the Treg cells differentiation and the intestinal beneficial bacteria flora. It also alleviated the damage of HK2 cells treated with inflammatory factors and complement. CONCLUSION: Treatment with SCFAs, especially butyrate, alleviated anti-GBM nephritis in rat model, indicating its potential therapeutic effects in clinical usage.

Chemical and Structural Engineering of Gelatin-Based Delivery Systems for Therapeutic Applications: A Review.

As a biodegradable and biocompatible protein derived from collagen, gelatin has been extensively exploited as a fundamental component of biological scaffolds and drug delivery systems for precise medicine. The easily engineered gelatin holds great promise in formulating various delivery systems to protect and enhance the efficacy of drugs for improving the safety and effectiveness of numerous pharmaceuticals. The remarkable biocompatibility and adjustable mechanical properties of gelatin permit the construction of active 3D scaffolds to accelerate the regeneration of injured tissues and organs. In this Review, we delve into diverse strategies for fabricating and functionalizing gelatin-based structures, which are applicable to gene and drug delivery as well as tissue engineering. We emphasized the advantages of various gelatin derivatives, including methacryloyl gelatin, polyethylene glycol-modified gelatin, thiolated gelatin, and alendronate-modified gelatin. These derivatives exhibit excellent physicochemical and biological properties, allowing the fabrication of tailor-made structures for biomedical applications. Additionally, we explored the latest developments in the modulation of their physicochemical properties by combining additive materials and manufacturing platforms, outlining the design of multifunctional gelatin-based micro-, nano-, and macrostructures. While discussing the current limitations, we also addressed the challenges that need to be overcome for clinical translation, including high manufacturing costs, limited application scenarios, and potential immunogenicity. This Review provides insight into how the structural and chemical engineering of gelatin can be leveraged to pave the way for significant advancements in biomedical applications and the improvement of patient outcomes.

Relationship between Vitamin D Concentration and Lipid Concentration in Patients with NAFLD in the Hulunbuir Region of China.

BACKGROUND: We aimed to characterize the relationship between the serum 25-hydroxyvitamin D concentration and the circulating lipid concentrations of patients with NAFLD in the Hulunbuir region of China. METHODS: One hundred fifty-six patients, who were diagnosed with NAFLD in the Physical Examination Department of the Second Clinical College of Inner Mongolia University for the Nationalities between January 2021 and March 2023, were recruited as NAFLD group, and 160 healthy people were recruited as a control group during the same period. The serum 25(OH)VitD, TBIL, TG, TC, LDL-C, HDL-C, AST, ALT, GGT, and FPG activities of the participants were measured, and hepatic ultrasonography was performed. RESULTS: The BMI of the NAFLD group was higher than of the control group (p < 0.05). The serum 25(OH)VitD3 (p < 0.05) and the HDL-C concentrations of the NAFLD group were lower than those of the normal control group. However, the AST (p < 0.05), ALT (p < 0.05), and GGT (p < 0.05) activities, and the serum TG (p < 0.05), TC (p < 0.05), LDL-C (p < 0.05), and the fasting glucose (p < 0.05) concentrations of the NAFLD group were higher than those of the normal control group. The serum 25(OH)VitD3 concentrations of the NAFLD group significantly cor-related negatively with BMI (r = -0.302, p < 0.01), TG (r = -0.221, p < 0.05), and fasting glucose (r = -0.236, p < 0.05). The BMI, TG, and fasting glucose of vitamin D-deficient participants were higher than of the participants with adequate or insufficient levels of vitamin D (p < 0.05). Finally, the BMI of vitamin D-deficient participants was higher than of those with an adequate vitamin D status (p < 0.05). CONCLUSIONS: A deficiency of 25(OH)VitD is more common in people from the Hulunbuir region of China than elsewhere. In addition, the vitamin D status is significantly associated with NAFLD; as the serum vitamin D concentration decreases, patients with NAFLD show greater dyslipidemia and hyperglycemia and a higher BMI.

Reversible Electrical Control of Interfacial Charge Flow across van der Waals Interfaces.

Bond-free integration of two-dimensional (2D) materials yields van der Waals (vdW) heterostructures with exotic optical and electronic properties. Manipulating the splitting and recombination of photogenerated electron-hole pairs across the vdW interface is essential for optoelectronic applications. Previous studies have unveiled the critical role of defects in trapping photogenerated charge carriers to modulate the photoconductive gain for photodetection. However, the nature and role of defects in tuning interfacial charge carrier dynamics have remained elusive. Here, we investigate the nonequilibrium charge dynamics at the graphene-WS2 vdW interface under electrochemical gating by operando optical-pump terahertz-probe spectroscopy. We report full control over charge separation states and thus photogating field direction by electrically tuning the defect occupancy. Our results show that electron occupancy of the two in-gap states, presumably originating from sulfur vacancies, can account for the observed rich interfacial charge transfer dynamics and electrically tunable photogating fields, providing microscopic insights for optimizing optoelectronic devices.

Selective removal of thallium from water by MnO2-doped magnetic beads: Performance and mechanism study.

Aqueous thallium has posed an increasing threat to environment as human's intensified activities in mining, refining, process and discharge. Remediation on thallium pollution has been of up-most importance to water treatment. In present work, MnO2 and magnetic Fe3O4 have been implanted to sodium alginate (SA) in presence of carboxyl methyl cellulose (CMC), and the resultant beads consisted of SA/CMC/MnO2/Fe3O4 were characterized. The materials were applied to treatment of Tl-contaminated water as adsorbent in lab. The removal results revealed that the adsorption capacity reached 38.8 mg (Tl)·g (beads)-1 and almost 100 % removal efficiency was achieved. The residual Tl was below 0.1 µg·L-1, meeting the discharge standard regulated in China. The kinetic adsorption was better described as a pseudo-second-order and three-step intra-particle diffusion model. Freundlich isotherm was well fitted the experimental data. The absorbent shown an excellent competitive specificity (KTl/M: ∼104!) over common hazardous ions Cu2+, Cd2+, Co2+, Pb2+ and Cr3+, as well as naturally abundant K+ and Na+ (KTl/M: 10-102) in mimic environmental conditions. Regeneration and reusability of the absorbent was also verified by five absorption-desorpotion cycles. XPS results revealed that a redox reaction between Mn4+ with Tl+, and an ion exchange of H+ (-O-Fe) and Tl+ were assumed to be main process for the specific capturing. This study provided an efficient SA/CMC/MnO2/Fe3O4 composite beads that could be a promising adsorbent for Tl-polluted water treatment.

[Protective effect of Albizia chinensis saponin on ethanol-induced gastric mucosal injury in rats focus on mucus and mucosal barriers].

This study aims to explore the protective effect of Albizia chinensis saponin on ethanol-induced acute gastric ulcer in rats and elucidate its mechanisms. SD rats were deprived of water for 24 hours before the experiment. The control group and model group were administered water by gavage, and the positive drug group received rabeprazole sodium solution(40 mg·kg~(-1)) by gavage. The experimental groups were given different doses of Albizia chinensis saponin solution(3, 10, and 30 mg·kg~(-1)). After 30 minutes, the control group received 1.5 mL of water by gavage, while the other groups were administered an equal volume of 95% ethanol for modeling. After six hours, the rats were killed by cervical dislocation, and the stomachs were collected. The ulcer area was measured, and the ulcer index was calculated. Hematoxylin-eosin(HE) staining was performed to assess histopathological changes in gastric tissue. Periodic acid-Schiff(PAS) staining was used to evaluate the distribution of gastric mucosal surface mucus. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of phospholipids and aminohexose in the gastric mucosa. Western blot was performed to determine the expression levels of the bicarbonate transporter, matrix metalloproteinase, and tight junction-associated proteins in gastric tissue. Immunohistochemistry(IHC) staining was conducted to quantify the number of positive cells for secreted mucin and tight junction-associated proteins. The results showed that the gastric tissue surface of rats in the control group was smooth without ulceration, and the gastric ulcer index of rats in the model group was 35±11. Albizia chinensis saponin at doses of 3, 10, and 30 mg·kg~(-1) resulted in inhibition rates of gastric ulcer of 46%(P<0.01), 85%(P<0.001), and 100%(P<0.001), respectively. Severe disruption of gastric mucosal structure and absence of the mucus layer were observed in the model group. Compared with the model group, the Albizia chinensis saponin group showed intact gastric mucosal surface mucus layer, significantly increased levels of phospholipids and aminohexose in the mucus, increased number of MUC5AC positive cells, and upregulated expression levels of the bicarbonate transporter SLC26A3 and CFTR. It also showed decreased phosphorylation of JNK and c-Jun, reduced expression levels of MMP-8, elevated expression of TIMP-1, and increased expression levels of Occludin and ZO-1. In conclusion, Albizia chinensis saponin enhances the function of the mucus-bicarbonate barrier by upregulating the content of MUC5AC, phospholipids, and aminohexose and increasing the expression levels of the bicarbonate transporter SLC26A3 and CFTR. Moreover, Albizia chinensis saponin exerts its protective effects on gastric ulcers by inhibiting the JNK signaling pathway to prevent excessive activation of MMP-8, thereby reducing the degradation of Occludin and ZO-1 and enhancing the mucosal barrier function. In summary, Albizia chinensis saponin exerts its anti-gastric ulcer effects by simultaneously enhancing the mucus barrier and the mucosal barrier.

Ultrafast Surface-Specific Spectroscopy of Water at a Photoexcited TiO2 Model Water-Splitting Photocatalyst.

A critical step in photocatalytic water dissociation is the hole-mediated oxidation reaction. Molecular-level insights into the mechanism of this complex reaction under realistic conditions with high temporal resolution are highly desirable. Here, we use femtosecond time-resolved, surface-specific vibrational sum frequency generation spectroscopy to study the photo-induced reaction directly at the interface of the photocatalyst TiO2 in contact with liquid water at room temperature. Thanks to the inherent surface specificity of the spectroscopic method, we can follow the reaction of solely the interfacial water molecules directly at the interface at timescales on which the reaction takes place. Following the generation of holes at the surface immediately after photoexcitation of the catalyst with UV light, water dissociation occurs on a sub-20 ps timescale. The reaction mechanism is similar at pH 3 and 11. In both cases, we observe the conversion of H2 O into Ti-OH groups and the deprotonation of pre-existing Ti-OH groups. This study provides unique experimental insights into the early steps of the photo-induced dissociation processes at the photocatalyst-water interface, relevant to the design of improved photocatalysts.

Autoantibodies against laminin-521 are pathogenic in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against GBM components. Evidence from human inherited kidney diseases and animal models suggests that the α, ß, and γ chains of laminin-521 are all essential for maintaining the glomerular filtration barrier. We previously demonstrated that laminin-521 is a novel autoantigen within the GBM and that autoantibodies to laminin-521 are present in about one-third of patients. In the present study, we investigated the pathogenicity of autoantibodies against laminin-521 with clinical and animal studies. Herein, a rare case of anti-GBM disease was reported with circulating autoantibodies binding to laminin-521 but not to the NC1 domains of α1-α5(IV) collagen. Immunoblot identified circulating IgG from this patient bound laminin α5 and γ1 chains. A decrease in antibody levels was associated with improved clinical presentation after plasmapheresis and immunosuppressive treatments. Furthermore, immunization with laminin-521 in female Wistar-Kyoto rats induced crescentic glomerulonephritis with linear IgG deposits along the GBM, complement activation along with infiltration of T cells and macrophages. Lung hemorrhage occurred in 75.0% of the rats and was identified by the presence of erythrocyte infiltrates and hemosiderin-laden macrophages in the lung tissue. Sera and kidney-eluted antibodies from rats immunized with laminin-521 demonstrated specific IgG binding to laminin-521 but not to human α3(IV)NC1, while the opposite was observed in human α3(IV)NC1-immunized rats. Thus, our patient data and animal studies imply a possible independent pathogenic role of autoantibodies against laminin-521 in the development of anti-GBM disease.

Autoimmunity in Anti-Glomerular Basement Membrane Disease: A Review of Mechanisms and Prospects for Immunotherapy.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against the glomerular and alveolar basement membranes, leading to rapidly progressive glomerulonephritis and severe alveolar hemorrhage. The noncollagenous domain of the α3 chain of type IV collagen, α3(IV)NC1, contains the main target autoantigen in this disease. Epitope mapping studies of α3(IV)NC1 have identified several nephritogenic epitopes and critical residues that bind to autoantibodies and trigger anti-GBM disease. The discovery of novel target antigens has revealed the heterogeneous nature of this disease. In addition, both epitope spreading and mimicry have been implicated in the pathogenesis of anti-GBM disease. Epitope spreading refers to the development of autoimmunity to new autoepitopes, thus worsening disease progression, whereas epitope mimicry, which occurs via sharing of critical residues with microbial peptides, can initiate autoimmunity. An understanding of these autoimmune responses may open opportunities to explore potential new therapeutic approaches for this disease. We review how current advances in epitope mapping, identification of novel autoantigens, and the phenomena of epitope spreading and mimicry have heightened the understanding of autoimmunity in the pathogenesis of anti-GBM disease, and we discuss prospects for immunotherapy.

Primary membranous nephropathy in two siblings with one combined with anti-glomerular basement membrane disease: a case report.

BACKGROUND: The phospholipase A2 receptor (PLA2R) associated with membranous nephropathy (MN) is an organ-specific autoimmune disease associated with PLA2R and human leukocyte antigen (HLA) genes. Familial PLA2R-related MN is rarely reported. The combination of anti-GBM disease and MN has been well documented, though the mechanism behind it remains unclear. CASE PRESENTATION: We describe two siblings diagnosed with pathology-confirmed PLA2R-related MN 1 year apart. And one of the two siblings developed an anti-GBM disease. The high-resolution HLA typing showed identical alleles in both siblings, specifically heterozygotes of DRB1*15:01/*03:01. CONCLUSION: We describe a familial case of PLA2R-related MN supporting the role of genetic factors that HLA-DRB1*15:01 and DRB1*03:01 predispose patients in the development of PLA2R-related MN in the Han Chinese population. The combination of MN and anti-GBM disease may also partially be associated with the same susceptible HLA allele DRB1*15:01.

Rhomboid intercostal block or thoracic paravertebral block for postoperative recovery quality after video-assisted thoracic surgery: A prospective, non-inferiority, randomised controlled trial.

BACKGROUND: The analgesic characteristics of rhomboid intercostal block (RIB) remain unclear. Before it can be fully recommended, we compared the recovery quality and analgesic effects of RIB and thoracic paravertebral block (TPVB) for video-assisted thoracoscopic surgery (VATS). OBJECTIVE: The current study aimed to investigate whether there is a difference in postoperative recovery quality between TPVB and RIB. DESIGN: A prospective, non-inferiority, randomised controlled trial. SETTING: Affiliated Hospital of Jiaxing University in China from March 2021 to August 2022. PATIENTS: Eighty patients aged 18 to 80 years, with ASA physical status I to III, and scheduled for elective VATS were enrolled in the trial. INTERVENTION: Ultrasound-guided TPVB or RIB was performed with 20 ml 0.375% ropivacaine. MAIN OUTCOME MEASURES: The primary outcome of the study was the mean difference of quality of recovery-40 scores 24 h postoperatively. The non-inferiority margin was defined as 6.3. Numeric rating scores (NRS) for pain at 0.5, 1, 3, 6, 12, 24 and 48 h postoperatively in all patients were also recorded. RESULTS: A total of 75 participants completed the study. The mean difference of quality of recovery-40 scores 24 h postoperatively was -1.6 (95% CI, -4.5 to 1.3), demonstrating the non-inferiority of RIB to TPVB. There was no significant difference between the two groups in the area under the curve for pain NRS over time, at rest and on movement, at 6, 12, 24 and 48 h postoperatively (all P  > 0.05), except for the area under the curve pain NRS over time on movement at 48 h postoperatively ( P  = 0.046). There were no statistical differences between the two groups in the postoperative sufentanil use at 0 to 24 h or 24 to 48 h (all P  > 0.05). CONCLUSION: Our study suggests that RIB was non-inferior to TPVB for the quality of recovery, with almost the same postoperative analgesic effect as TPVB after VATS. CLINICAL TRIAL REGISTRATION: chictr.org.cn: ChiCTR2100043841.

Modeling and optimizing of an actual municipal sewage plant: A comparison of diverse multi-objective optimization methods.

The activated sludge process of an actual municipal sewage treatment plant was systematically modeled, calibrated, and verified in this study. Identified multi-objective optimization (MOO) methods were employed to optimize the process parameters of the validated model, and the optimal MOO algorithm was obtained by comparing Pareto solution sets. The optimization model consisted of three key evaluation indicators (objective functions), which are the average effluent quality (AEQ), overall cost index (OCI), and total volume (TV) of the biochemical tank, along with 12 more process parameters (decision variables). Three optimization algorithms, i.e., adaptive non-dominated sorting genetic algorithm III (ANSGA-III), non-dominated sorting genetic algorithm II (NSGA-II), and particle swarm algorithm (PSO), were adopted using MATLAB. The comparison of these algorithms demonstrated that the ANSGA-III algorithm had better Pareto solution sets under the triple objective optimization, and the effluent quality of COD, TN, NH4+-N, and TP after optimization decreased by 2.22, 0.47, 0.13, and 0.02 mg/L, respectively. Additionally, the simulated AEQ was reduced by 13% compared to the original effluent, and the OCI and TV decreased from 21,023 kWh d-1 and 17,065 m3 to 20,226 kWh d-1 and 16,530 m3, respectively. The reported ANSGA-III algorithm and the proposed multi-objective method have a promising ability for energy conservation, emission reduction, and upgrading of municipal sewage treatment plants.

Preliminary Structural Characterization of Selenium Nanoparticle Composites Modified by Astragalus Polysaccharide and the Cytotoxicity Mechanism on Liver Cancer Cells.

Astragalus alcohol soluble polysaccharide (AASP) could present superior water solubility and antitumor activity with high concentration. Selenium nanoparticles (SeNPs) have received growing attention in various fields, but their unstable property increases the application difficulties. In the present study, functionalized nano-composites (AASP-SeNPs) were synthesized through SeNPs using AASP (average molecular weight of 2.1 × 103 Da) as a surface modifier, and the preliminary structural characteristics and inhibitory mechanism on liver cancer (HepG2) cells were investigated. Results showed that AASP-SeNPs prepared under a sodium selenite/AASP mass ratio of 1/20 (w/w) were uniformly spherical with a mean grain size of 49.80 nm and exhibited superior dispersivity and stability in water solution. Moreover, the composites could dose-dependently inhibit HepG2 cell proliferation and induce apoptosis through effectively regulating mitochondria-relevant indicators including ΔΨm depletion stimulation, intracellular ROS accumulation, Bax/Bcl-2 ratio improvement, and Cytochrome c liberation promotion. These results provide scientific references for future applications in functional food and drug industries.

Predictors of Kidney Outcomes of Anti-Glomerular Basement Membrane Disease in a Large Chinese Cohort.

INTRODUCTION: Anti-glomerular basement membrane (GBM) disease is a rare but the most aggressive form of glomerulonephritis. To dissect the prognostic factors, we retrospectively analyzed the clinical features of a large cohort and compared the clinical features and prognosis during decades. METHODS: Data on clinical manifestation, treatment, and prognosis were collected. Cox models and receiver operating characteristic (ROC) curve were used to investigate the predictors for outcomes. The Kaplan-Meier curve and log-rank test were used to compare kidney and patient survival. RESULTS: A total of 448 patients were enrolled. Patient survival and kidney survival at 1 year was 69.4% and 37.7%, respectively. During the past 3 decades, mortality at 3 months and 1 year significantly dropped from 37.5% and 57.1% in 1991-2000 to 2.8% and 6.9% in 2011-2020 (p < 0.001), respectively; kidney prognosis showed a tendency of improvement as well. Serum creatinine (Scr) on diagnosis (HR, 1.16; 95% CI, 1.05-1.29) and crescent percentage (HR, 1.73; 95% CI, 1.34-2.24) were independent predictors for end-stage kidney disease. ROC curve showed that the optimal cutoff point of Scr on diagnosis for prediction of dialysis dependency at 1 year was 536.4 µmol/L (sensitivity 88.3% and specificity 80.8%). Antineutrophil cytoplasmic antibodies (ANCAs) positivity (HR, 4.43; 95% CI, 1.72-11.38) was a predictor for mortality. Plasma exchange was associated with a better patient prognosis (HR, 0.40; 95% CI 0.16-0.95). CONCLUSION: Scr on diagnosis and percentage of crescents were predictors for kidney outcomes. Positive ANCA was a predictor for mortality. Overall patient prognosis of anti-GBM disease was improved during the past 3 decades.

Laminin-521 is a Novel Target of Autoantibodies Associated with Lung Hemorrhage in Anti-GBM Disease.

BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is characterized by GN and often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within α345(IV) collagen-a major component of the glomerular and alveolar basement membranes. Laminin-521 is another major GBM component and a proven target of pathogenic antibodies mediating GN in animal models. Whether laminin-521 is a target of autoimmunity in human anti-GBM disease is not yet known. METHODS: A retrospective study of circulating autoantibodies from 101 patients with anti-GBM/Goodpasture's disease and 85 controls used a solid-phase immunoassay to measure IgG binding to human recombinant laminin-521 with native-like structure and activity. RESULTS: Circulating IgG autoantibodies binding to laminin-521 were found in about one third of patients with anti-GBM antibody GN, but were not detected in healthy controls or in patients with other glomerular diseases. Autoreactivity toward laminin-521 was significantly more common in patients with anti-GBM GN and lung hemorrhage, compared with those with kidney-limited disease (51.5% versus 23.5%, P=0.005). Antilaminin-521 autoantibodies were predominantly of IgG1 and IgG4 subclasses and significantly associated with lung hemorrhage (P=0.005), hemoptysis (P=0.008), and smoking (P=0.01), although not with proteinuria or serum creatinine at diagnosis. CONCLUSIONS: Besides α345(IV) collagen, laminin-521 is another major autoantigen targeted in anti-GBM disease. Autoantibodies to laminin-521 may have the potential to promote lung injury in anti-GBM disease by increasing the total amount of IgG bound to the alveolar basement membranes.

Rituximab for the treatment of refractory anti-glomerular basement membrane disease.

BACKGROUND: Anti-glomerular basement membrane (anti-GBM) disease is a rare but severe autoantibody-mediated immune disorder. The typical clinical presentation includes rapidly progressive glomerulonephritis and often concurrent pulmonary hemorrhage. The present study is aimed to investigate the therapeutic effects of rituximab either used alone or with other immunosuppressants. METHODS: Eight patients diagnosed with anti-GBM disease and treated with rituximab from 2014 to 2020 were retrospectively reviewed. RESULTS: Eight patients included 5 males and 3 females with a median age of 58.5 years. They all presented severe kidney injuries and 1 patient had lung hemorrhage. At diagnosis, the median of serum creatinine was 246 µmol/L (ranging from 91 to 850 µmol/L), with 3 patients requiring dialysis. All of them received corticosteroids and plasmapheresis. Rituximab was given as either standard four weekly doses or one pulse ranging from 100 to 600 mg. After a median follow-up of 34.5 months, kidney function was partially recovered or stabilized in 5/8 (62.5%) patients, free of dialysis. Anti-GBM antibodies remained undetected in all patients during follow-up. No severe adverse effect associated with rituximab was observed. CONCLUSION: Rituximab may be an alternative therapy in the treatment of patient with severe or refractory anti-GBM disease.

Down-regulated in renal cell carcinoma 1 (DRR1) regulates axon outgrowth during hippocampal neuron development.

Down-regulated in renal cell carcinoma 1 (DRR1), a unique stress-induced protein, is highly expressed in the nervous system. This study investigated the roles of DRR1 in the brain by examining its expression pattern at different developmental stages of a rat brain and in cultured primary hippocampal neurons. High expression of DRR1 was observed in all developmental stages of a rat brain and cultured primary hippocampal neurons. We then focused on the role of DRR1 in promoting neurite outgrowth during the early stage of hippocampal neuron development. Results showed that down-regulation of DRR1 suppressed axon outgrowth. Mass spectrometry analysis revealed that tropomodulin-2 (Tmod2) is a novel binding partner of DRR1. Our results showed that both DRR1 and Tmod2 mediate axon formation during the early stage of hippocampal neuron development. Suppression of TMOD2 expression rescued the abnormal axon outgrowth induced by DRR1 knockdown during the early stage of hippocampal neuron development.

Spontaneous perirenal hemorrhage in systemic lupus erythematosus: a rare case report and literature review.

BACKGROUND: Spontaneous perirenal hemorrhage is relatively uncommon but may be life-threatening. There are some challenges in early diagnosis due to the lack of specific presentations. CASE PRESENTATION: We report a case of spontaneous perirenal hemorrhage in a newly diagnosed systemic lupus erythematosus patient who initially presented with non-specific flank pain. Weakness and unstable vital signs were noted on admission. Abdominal ultrasonography and computed tomography revealed a sizable perirenal hematoma over the left retroperitoneal cavity. Renal arteriography identified active extravasation of contrast media from a distant branch of the left renal artery, and selective embolization effectively obliterated the bleeding spot. After cessation of bleeding, the patient received intensive immunosuppressive therapy for acute kidney injury and encephalopathy due to lupus. Her mental status recovered successfully, and she was withdrawn from short-term hemodialysis. CONCLUSIONS: Spontaneous perirenal hemorrhage in the condition of systemic lupus erythematosus was a rare clinical entity with life-threatening potential. Early accurate diagnosis of spontaneous renal hemorrhage requires both detailed clinical examination and radiologic studies. Interventional embolization is essential and effective for both diagnosis and treatment. A high index of suspicion is necessary to avoid missing this potentially fatal syndrome, especially in patients with an increased risk of bleeding.

A Modified Peptide Derived from Goodpasture Autoantigen Arrested and Attenuated Kidney Injuries in a Rat Model of Anti-GBM Glomerulonephritis.

BACKGROUND: In Goodpasture disease, the noncollagenous domain 1 of the α3 chain (α3NC1) of type IV collagen is the main target antigen of antibodies against glomerular basement membrane (GBM). We previously identified a nephritogenic epitope, P14 (α3127-148), that could induce crescentic nephritis in WKY rats, and defined its core motif. Designing a modified peptide, replacing critical pathogenic residues with nonpathogenic ones (on the basis of homologous regions in α1NC1 chain of type IV collagen, known to be nonpathogenic), might provide a therapeutic option for anti-GBM GN. METHODS: We synthesized a modified peptide, replacing a single amino acid, and injected it into α3-P14-immunized rats from day 0 (the early-treatment group) or a later-treatment group (from days 17 to 21). A scrambled peptide administrated with the same protocol served as a control. RESULTS: The modified peptide, but not the scrambled peptide, attenuated anti-GBM GN in both treatment groups, and halted further crescent formation even after disease onset. Kidneys from the modified peptide-treated rats exhibited reductions in IgG deposits, complement activation, and infiltration by T cells and macrophages. Treatment also resulted in an anti-inflammatory cytokine profile versus a proinflammatory profile for animals not receiving the modified peptide; it also reduced α3-P14-specific T cell activation, modulated T cell differentiation by decreasing Th17 cells and enhancing the ratio of Treg/Th17 cells, and inhibited binding of α3-P14 to antibodies and MHC II molecules. CONCLUSIONS: A modified peptide involving alteration of a critical motif in a nephritogenic T cell epitope alleviated anti-GBM GN in a rat model. Our findings may provide insights into an immunotherapeutic approach for autoimmune kidney disorders such as Goodpasture disease.