Current treatments for neuromyelitis optica spectrum disorder (NMOSD) highlight recurrence management, while little attention is paid to the relief of residual neurological dysfunction. Here we aimed to evaluate the safety and efficacy of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in reducing relapses and mitigating neurological impairments. This trial, hUC-MSC-NMOSD (ChiCTR-INR-16008037), a single-arm, dose-escalation, open-label study, included 31 NMOSD patients of three dose groups received four infusions every three months, with 15-month follow-up. Primary outcome was time to first recurrence; secondary outcomes focused on clinical scores, MRI lesions and exploratory findings. HUC-MSC infusion was well tolerated in all groups of patients. Adverse events were mostly mild, with urinary tract infections being the most common. Severe adverse events were rare and unrelated to the treatment. The median relapse-free interval increased significantly post-treatment from 305 (95%CI 226-382·5) to 760 (589-1016·5) (p < 0·001), especially in the medium- and high-dose groups. During the two years before and after therapy, the mean Annualized Relapse Rate (ARR) dropped considerably from 1 (0·75-1) to 0 (0-0·5) (p < 0·001). Clinical scores improved in the low and medium-dose groups. The total volume of high-signal white matter lesions in brain significantly decreased after therapy from 4144·5 (2857·2-5508·6) to 2914·4 (2453-3684·11) (p = 0·016). Exploratory single-cell RNA sequencing and metabolomics detection revealed a potential participation of thioredoxin and oxidative phosphorylation (OXPHOS)-mediated boosting of Treg differentiation and suppressive capacity. This trial indicates that intravenous hUC-MSC administration is safe and shows potential efficacy in treating NMOSD. Medium dose might be the best possible compromise between safety and effectiveness.

Ovarian cancer poses a significant clinical challenge due to its asymptomatic onset and poor prognosis, highlighting the critical need for effective early detection strategies. This study developed a framework that integrates serum proteomic profiling with machine learning algorithms. Serum samples from 188 patients and 208 healthy controls were analysed via Matrix-Assisted Laser Desorption/Ionization Time - of - Flight (MALDI - TOF) mass spectrometry, revealing 43 differentially expressed peptides (17 upregulated, 26 downregulated). An ensemble pipeline incorporating eight machine learning algorithms showed favorable discriminatory ability in the study cohort, with the area under the receiver operating characteristic curve (AUC) of the integrated models approaching 1.00 for distinguishing ovarian cancer samples from healthy controls. We identified three consensus biomarkers [mass-to-charge ratio (m/z) = 4211.41, 2881.50, 2662.15] through feature importance analysis, and their diagnostic reliability was supported by receiver operating characteristic curves optimization and decision curve analysis. Interpretability approaches integrating Shapley values and LIME indicated that the model's high performance (AUC ≈ 1) was driven by robust multi-dimensional feature contributions. Cross-referencing with existing datasets suggested the PDE11A as a potential diagnostic biomarker. Collectively, this ensemble machine learning algorithms leveraged on serum proteomics shows promising potential for early detection of ovarian cancer, offering a strategy to mitigate the limitations of single-analyte biomarkers.

N6-methyladenosine (m6A), the most prevalent RNA modification, plays a pivotal role in regulating mRNA metabolism and cellular processes such as immune responses. Although the m6A methyltransferase METTL3 is known to regulate T-cell homeostasis and influence experimental autoimmune encephalomyelitis (EAE, a model for multiple sclerosis (MS)), its function within B cells remains poorly defined. Crucially, we observed that METTL3 expression is significantly downregulated in peripheral blood mononuclear cells (PBMCs) from MS patients and within B cells isolated from EAE mice. To directly investigate the functional consequences of this B-cell-specific METTL3 reduction in neuroinflammation, we generated B cell-specific METTL3 knockout mice (Mettl3flox/floxCD19Cre). Strikingly, this targeted deletion of METTL3 in B cells markedly exacerbated EAE severity, demonstrated by significantly worsened clinical disease scores, increased spinal cord inflammation, and greater demyelination. Further mechanistic dissection revealed how B-cell METTL3 deficiency drives this exacerbated pathology: it promoted B cell apoptosis, inhibited the differentiation of regulatory B cell (Breg) subpopulations, increased the proportion of pro-inflammatory iNOS+ macrophages, and elevated the production of IL-6, BAFF, and BCMA. In the central nervous system, it promotes neurological damage by affecting axonal function and facilitating the loss of neurons. Collectively, these findings demonstrate that METTL3 functions as a critical negative regulator within B cells, restraining their contribution to neuroinflammation in the EAE model. Importantly, therapeutically relevant overexpression of METTL3 specifically in B cells significantly reduced both the clinical severity and incidence of EAE, underscoring its potential as a novel therapeutic target for MS and similar autoimmune disorders involving pathogenic B-cell responses.

Exosomal microRNAs (miRNAs) have emerged as promising biomarkers for gastric cancer (GC) prognosis. In this study, 76 GC patients treated at Changzhou Second People's Hospital (October 2020-May 2022) were prospectively enrolled, with monthly telephone follow-up to collect mortality and survival data for calculating overall survival. Exosomal miRNAs and clinical and pathological data from these patients constituted the training cohort, while validation was performed using a 400-patient cohort from The Cancer Genome Atlas database. A novel five-exosomal miRNA signature (miR-652-3p, miR-184, miR-340-3p, miR-96-5p, and miR-29a-3p) was identified as associated with overall survival. The resulting nomogram, which integrates this miRNA signature with key clinicopathological factors, achieved prognostic discrimination (C-index: 0.82). These findings demonstrate the clinical utility of this tool for individualized risk stratification.

BACKGROUND:Diabetic kidney disease (DKD), characterized by mesangial fibrosis and renal dysfunction, is a major microvascular complication of diabetes. Studies have shown that miRNAs are closely related to the progression of DKD. Therefore, in this study, we aimed to explore whether miR-1225-3p can regulate Smad ubiquitin regulatory factor 2 (SMURF2)-mediated carbohydrate response element binding protein (ChREBP) ubiquitination through Rho GTPase-activating protein 5 (ARHGAP5) to affect fibrosis in DKD. METHODS:DKD mice were established by intraperitoneally injecting streptozocin (STZ), and a DKD cell model was generated by culturing in media supplemented with 25 mmol/L glucose (high glucose, HG). StarBase was used to predict the target binding sites between miR-1225-3p and ARHGAP5, and a dual-luciferase reporter gene assay was used to verify this relationship. Western blotting, RT-qPCR, flow cytometry, immunoprecipitation, ELISAs, HE staining, and Masson staining were used to detect relevant indicators. RESULTS:ARHGAP5 and SMURF2 expression was decreased, but ChREBP was highly expressed in the renal tissue of DKD mice and HG-induced mouse mesangial cells (MMCs). miR-1225-3p could target and regulate the transcription of ARHGAP5, and an association between ARHGAP5 and SMURF2 was revealed. miR-1225-3p facilitated fibrosis and oxidative stress in MCCs by inhibiting ARHGAP5. In addition, SMURF2 promoted the ubiquitination of HA-ChREBP, and miR-1225-3p facilitated fibrosis and oxidative stress by mediating the ARHGAP5/SMURF2-mediated ubiquitination of ChREBP in MCCs. Furthermore, the miR-1225-3p inhibitor inhibited fibrosis and inflammation in the renal tissues of DKD mice. CONCLUSION:miR-1225-3p facilitates fibrosis and oxidative stress by mediating ARHGAP5/SMURF2-mediated ubiquitination of ChREBP.

OBJECTIVE:In the fight against Colorectal Cancer (CRC), chemotherapy resistance is a major obstacle. Therefore, it is imperative to identify effective biomarker therapeutics. Despite microRNAs (miRs) playing a crucial role in drug resistance, the mechanisms comprising miR-519d-3p's role in CRC drug resistance have not been fully understood. Therefore, the present study aimed to investigate the biological function of miR-519d-3p in the chemosensitivity of CRC cells to 5-Fluorouracil (5-FU). METHODS:CRC cells were treated with 5-FU and transfected. Cellular proliferation, invasion, and apoptosis were evaluated. The relationship between miR-519d-3p and 6-Phosphofructokinase-2/Frucose-2, 6-Biphosphatase-3 (PFKFB3) was analyzed, and their interaction in CRC was further investigated. In vivo tumor experiments were conducted to investigate the function of miR-519d-3p and 5-FU in CRC. RESULTS:As determined, CRC cells overexpressing miR-519d-3p were more sensitive to 5-FU in vitro, as miR-519d-3p inhibits proliferation and invasion and stimulates apoptosis. miR-519d-3p directly targeted PFKFB3. In CRC cells, PFKFB3 overexpression rescued miR-519d-3p-induced 5-FU toxicity. In vivo results showed that mice co-treated with miR-519d-3p mimics and 5-FU showed higher antitumor activity. CONCLUSION:Overall, it may be possible to improve 5-FU chemosensitivity of CRC cells by targeting miR-519d-3p and PFKFB3.

Serum AQP4 antibody (AQP4-IgG) is the causative antibody of neuromyelitis optica spectrum disorder (NMOSD) but AQP4-IgG in cerebrospinal fluid (CSF) has been seldom studied. We aimed to explore the clinical value and influencing factors of CSF AQP4-IgG in NMOSD. In this study, we screened 137 patients with NMOSD diagnosed according to the 2015 International Consensus Diagnostic Criteria (IPND criteria). From this cohort, paired CSF and serum samples were simultaneously collected from 82 patients (including seropositive and seronegative subgroups) for antibody titer measurement. We explored the relationship between CSF AQP4-IgG and patient’s clinical features. Their demographic, clinical, laboratory data and MRI images were collected and analyzed. 74 patients were seropositive for AQP4-IgG and 8 patients were seronegative. Among the 74 patients seropositive for AQP4-IgG, 46 were CSF-positive and 28 were CSF-negative, while none of the 8 seronegative patients were CSF-positive. CSF AQP4-IgG positive and negative patients showed significant differences in EDSS and relapse status. Out of the 82 patients, 67 patients were during relapse and only patients during relapse were included in the next analysis. Between the CSF-positive and CSF-negative patients, no significant differences were found in EDSS, relapse manifestation, CSF indicators, serum cytokine levels, lymphocyte subsets or MRI lesions. Responses to treatment during relapse and length of hospital stay showed no significant differences either. A positive correlation between the serum and CSF titers (rs: 0.64, p < 0.001) was found. Further binary logistic regression analysis revealed that CSF AQP4-IgG positivity was associated with serum AQP4-IgG titers and EDSS scores. CSF AQP4-IgG positivity primarily results from passive diffusion of serum antibodies across the blood-brain barrier, which is different from the CNS-restricted antibody production in MOG-IgG associated disorders (MOGAD). Limited prognostic value of CSF AQP4-IgG was revealed in this study.

Recurrent immune-mediated peripheral neuropathy is a rare immune disorder that presents significant therapeutic challenges. Ofatumumab (OFA) is a fully humanized anti-CD20 monoclonal antibody with low immunogenicity. We report a patient with recurrent immune-mediated peripheral neuropathy who achieved sustained remission following OFA treatment after multiple relapses. Over a two-year period, the patient experienced over 20 episodes of bilateral upper and lower limb weakness. Furthermore, the patient was unresponsive to intravenous immunoglobulin, plasma exchange, corticosteroids, mycophenolate mofetil, and Telitacicept. Subcutaneous OFA administration resulted in marked reductions in CD19+ and CD20+ B-cell counts and a relapse-free period exceeding 20 months, with no adverse events observed. This case provides early evidence supporting OFA as a safe and effective alternative for recurrent immune-mediated peripheral neuropathy.

Background:Autoimmune encephalitis (AE) is a severe neurological disorder, but limited evidence comparing the efficacy of double filtration plasmapheresis (DFPP) and intravenous methylprednisolone (IVMP) as first-line treatments in the acute phase. This study aimed to evaluate the clinical outcomes of DFPP versus IVMP in antibody-positive patients with AE. Methods:A prospective observational cohort study was conducted at Renji Hospital from July 2018 to May 2024. Thirty-eight patients with antibody-confirmed AE in the acute phase who received either DFPP (n=22) or IVMP (n=16) as first-line therapy were included. The primary outcome was improvement in the Modified Rankin Scale (mRS), and the secondary outcome was improvement in the Clinical Assessment Scale for Autoimmune Encephalitis (CASE). Adverse events were recorded for safety assessment. Univariate and multivariate logistic regression analyses were performed. Results:The DFPP group demonstrated significantly higher rates of functional improvement, with 68.2% (15/22) achieving mRS reduction compared to 31.3% (5/16) in the IVMP group (p=0.047). Similarly, symptomatic improvement (CASE score reduction) was observed in 72.7% (17/22) of DFPP patients versus 43.8% (7/16) with IVMP (p=0.099). Multivariate analysis identified DFPP as the sole independent predictor of better outcomes (OR: 5.234, 95% CI: 1.179-23.235, p=0.030). Adverse events were limited to the DFPP group (3/22), including manageable deep venous thrombosis and hepatic impairment. Conclusion:DFPP demonstrated superior short-term efficacy compared to IVMP in improving functional and symptomatic outcomes in acute-phase AE, suggesting its potential as a preferred first-line therapy. Further large-scale randomized trials are warranted to validate these findings.

This study investigates distinct neuroinflammatory patterns in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using multi-tracer PET and MR imaging. Eight NMOSD (5F/3M; median age 36.5) and six MOGAD patients (2F/4M; median age 34.0) underwent PET scans with [18F]FDG (glucose metabolism), the translocator protein (TSPO) ligand [18F]PBR06 (glial activation), and [11C]acetate (astrocyte metabolism), integrated with synchronous 3T MRI sequences. Standardized uptake value ratios (SUVRs) referenced to contralateral white matter (WM) or whole brain were statistically compared across specific anatomic regions: active lesions, normal-appearing WM (NAWM), and periventricular zones. Both groups exhibited elevated [18F]PBR06 SUVR within lesions compared to contralateral WM, marking microgliosis. Crucially, NMOSD lesions showed significantly lower [18F]FDG SUVR (p ​= ​0.01; metabolic impairment) and [11C]acetate SUVR (astrocyte dysfunction) than MOGAD lesions. Lesional [18F]PBR06 uptake correlated significantly with [18F]FDG uptake. Beyond lesions, NMOSD patients had higher [18F]FDG SUVR in cerebellar WM (p ​< ​0.01) and periventricular regions near the fourth ventricle (p ​= ​0.01), and higher [18F]PBR06 SUVR in cerebral WM (p ​= ​0.03), contrasted with MOGAD. With lesions in both disorders demonstrating microgliosis, NMOSD exhibited more severe lesion-specific metabolic suppression and astrocyte dysfunction, reflected in reduced [11C]acetate uptake, coupled with regional inflammation (microgliosis) and hypermetabolism. These differential multi-tracer PET patterns, especially the combined reduction in lesional astrocytic ([11C]acetate) and metabolic ([18F]FDG) markers in NMOSD versus MOGAD, highlight multimodal PET/MRI as a powerful tool for differentiating NMOSD and MOGAD pathophysiology.

Telitacicept, a novel recombinant fusion protein comprising the ligand-binding domain of the TACI receptor and the Fc component of human IgG, has rarely been studied for the treatment of neuromyelitis optica spectrum disorders (NMOSD). This study aimed to explore the effects of telitacicept in NMOSD mice. An NMOSD mouse model was constructed. Fifty microliters of 0.8 mg/mL telitacicept was injected intravenously on Days 4, 8, 12 and 16 postimmunization (p.i.). Behavioral scoring, magnetic resonance imaging and histopathological evaluation were conducted on Day 19. B lymphocytes and their subgroups were analyzed by flow cytometry. Concentration of serum IgM was measured using an ELISA kit. Concentrations of B lymphocyte stimulator (BLyS) and IL-6 were measured via LEGENDplex. Differentially expressed genes of B lymphocytes were screened via mRNA sequencing and verified by qPCR. Behavioral score of telitacicept-treated NMOSD mice significantly decreased (p < 0.0001). Inflammation, demyelination, loss of AQP4 and GFAP in the spinal cord were markedly alleviated (p < 0.05). B lymphocytes and their subsets were reduced to varying degrees (p < 0.05). Telitacicept treatment significantly reduced serum IgM levels (p < 0.01), as well as BLyS and IL-6 concentrations (p < 0.05). Telitacicept induced differential gene expression in B lymphocytes, inhibiting the expression of transcription factors related to B lymphocyte maturation, such as IRF8, BLIMP1, and Pou2af1, as well as cell surface receptors such as CD19 and CD21. Telitacicept has a therapeutic effect on NMOSD mice by regulating the differentiation of B lymphocyte subsets and inhibiting the production of pathogenic antibodies.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) have great potential for treating autoimmune diseases for their immunomodulatory and tissue-regenerative abilities; however, their therapeutic role in neuromyelitis optica spectrum disorder (NMOSD) remains uncertain. 106 hUC-MSCs prepared in 200 μl PBS were intravenously administered to a systemic NMOSD model on day 10 and day 14 after immunization. Then, disease progression, immune responses, and blood–brain barrier integrity were evaluated. Additionally, we tested the effects of hUC-MSCs on astrocyte viability and apoptosis using an aquaporin 4 (AQP4) IgG and complement-induced cytotoxicity model in vitro. hUC-MSCs alleviated NMOSD progression in vivo with improved motor function, reduced inflammatory infiltration, myelin loss, and preservation of astrocytes and neurons. hUC-MSC treatment did not affect autoimmune reactions in the spleen, however, decreased cytokine release in the spinal cord and mitigated blood–brain barrier disruption. Furthermore, in vitro studies revealed that co-culture with hUC-MSCs significantly restored astrocyte viability and reduced apoptosis in AQP4 IgG and complement-mediated damage. Our results revealed that hUC-MSCs displayed therapeutic efficacy in NMOSD and showed potential in attenuating blood–brain barrier disruption, as well as AQP4 IgG and complement-induced astrocyte apoptosis.

Background: The relationship between serum low-density lipoprotein cholesterol (LDL-C) and the risk of relapse in neuromyelitis optica spectrum disorder (NMOSD) remains uncertain. We aimed to examine the association between serum LDL-C level and relapse in NMOSD patients. Methods: We conducted an analysis of the prospective observational NMOSD cohort study with consecutive 184 hospitalized NMOSD patients from department of neurology. Blood samples were collected to measure LDL-C level upon admission. Primary and relapse were evaluated during hospitalization. The relationship between serum LDL-C level and relapse were analyzed by linear curve fitting analyses. Crude and adjusted odds ratios (OR) of LDL-C for relapse with 95% confidence intervals were analyzed using multiple logistic regression models. ROC curve analysis was used to identify the target lipid-lowering value of LDL-C and the probability of relapse was evaluated by the Kaplan-Meier Plot. Results: Over a mean disease course of 100 +/- 87 days, 59.24% (n=109) participants developed relapse with higher LDL-C than the primary group (n=75) (p<0.001). Adjusted smoothed plots suggested that there were linear relationships between serum LDL-C level and relapse (p< 0.001). The OR (95% CI) between serum LDL-C level and relapse were 2.67 (1.76-4.04, p<0.001), and 2.38 (1.48-3.83, p<0.001) respectively in NMOSD patients before and after adjusting for potential confounders. The target LDL-C lowering values were 2.795 mmol/L with potential benefits to prevent relapse in NMOSD. Conclusion: In this sample of NMOSD patients, we found that the elevated serum LDL-C was independently and positively associated with the relapse, and serum LDL-C should be well-controlled to prevent the relapse of NMOSD.

Purpose: To investigate the risk factors associated with subclinical diabetic peripheral neuropathy (sDPN) in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: This cross-sectional, retrospective study involved 311 patients with T2DM who were successively admitted from January 2018 to December 2021 without any neurological symptoms. All participants underwent a nerve conduction study (NCS), and those asymptomatic patients with abnormal nerve conduction were diagnosed with sDPN. Differences between groups were evaluated by the chi -squared, Wilcoxon, or Fisher's exact test. Binary logistic regression analysis was performed to determine the independent risk factors for sDPN. Receiver operating characteristic (ROC) curves were constructed, and the areas under curves (AUCs) were detected. Results: Among 311 asymptomatic patients with T2DM, 142 (45.7%) with abnormal nerve conduction were diagnosed with sDPN. Patients with sDPN significantly differed from those without diabetic peripheral neuropathy (DPN) in age, history of hypertension, duration of diabetes, anemia, neutrophil-to-lymphocyte ratio, fasting C -peptide level, serum creatinine level, and albuminuria (all p<0.05). Furthermore, the duration of diabetes (odds ratio [OR]: 1.062, 95% confidence interval [CI]: 1.016-1.110), fasting C -peptide level (OR: 2.427, 95% CI: 1.126-5.231), and presence of albuminuria (OR: 2.481, 95% CI: 1.406-4.380) were independently associated with the development of sDPN (all p<0.05). The AUCs for fasting C -peptide level, duration of diabetes, and the two factors combined were 0.6229 (95% CI: 0.5603-0.6855, p=0.0002), 0.6738 (95% CI: 0.6142-0.7333, p<0.0001), and 0.6808 (95% CI: 0.6212-0.7404, p<0.0001), respectively. Conclusion: For patients with T2DM and longer duration of diabetes, lower fasting C -peptide levels, and presence with albuminuria, the risk for developing DPN is higher even if they have no clinical signs or symptoms. Identifying potential risk factors for the development of sDPN and effectively controlling them early are critical for the successful management of DPN.

Background: Human umbilical cord mesenchymal stem cells (hUC-MSCs) have great potential for treating autoimmune diseases for their immunomodulatory and tissue-regenerative abilities; however, their therapeutic role in neuromyelitis optica spectrum disorder (NMOSD) remains uncertain. Methods: hUC-MSCs were intravenously administered to a systemic NMOSD model and evaluated disease progression, immune responses, and blood-brain barrier integrity. Additionally, we tested the effects of hUC-MSCs on astrocyte viability and apoptosis using an aquaporin 4 (AQP4) IgG and complement-induced cytotoxicity model in vitro. Results: hUC-MSCs alleviatedNMOSD progression in vivo with improved motor function, reduced inflammatory infiltration, myelin loss, and preservation of astrocytes and neurons. hUC-MSC treatment did not affect autoimmune reactions in the spleen, however, decreased cytokine release in the spinal cord and mitigated blood-brain barrier disruption. Furthermore, in vitro studies revealed that co-culture with hUC-MSCs significantly restored astrocyte viability and reduced apoptosis in AQP4 IgG and complement-mediated damage. Conclusion: Our results revealed that hUC-MSCs displayed therapeutic efficacy in NMOSD and showed potential in attenuating blood-brain barrier disruption, as well as AQP4 IgG and complement-induced astrocyte apoptosis.

Background:Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. However, few biomarkers have been found to predict the outcome of immunotherapy. We investigated the relationship between the serum albumin (S-Alb) and response to immunotherapy in acute NMOSD patients.Methods:A total of 107 consecutive Chinese patients with acute NMOSD diagnosed between January 2013 and January 2022 were included in our prospective observational study. S-Alb was measured by the use of bromocresol green and immunoturbidimetric methods on admission. The immunotherapy response was assessed by the percentage change in the expanded disability status scale (EDSS) score from admission to discharge after treatment. We evaluated the association between S-Alb and immunotherapy response through multivariate logistic regression analysis.Results:S-Alb levels were significantly lower in patients who were resistant to immunotherapy than in those who were responsive to treatment (p<0.001). S-Alb levels were positively related to a favorable response to immunotherapy (r=0.386, p<0.001). The odds ratio (95% CI) for the association between S-Alb level and response to immunotherapy was 1.27 (95% CI=1.08, 1.50; p=0.004) after adjusting for potential factors. ROC analysis showed that patients with S-Alb levels lower than 40.85 g/L were likely to be resistant to immunotherapy.Conclusion:Our study indicated that a higher S-Alb was an independent indicator of response to immunotherapy in acute NMOSD patients.

AIM:To investigate the molecular mechanisms underlying memory impairment induced by high-altitude (HA) hypoxia, specifically focusing on the role of cold-inducible RNA-binding protein (CIRP) in regulating the AMPA receptor subunit GluR1 and its potential as a therapeutic target. METHODS:A mouse model was exposed to 14 days of hypobaric hypoxia (HH), simulating conditions at an altitude of 6000 m. Behavioral tests were conducted to evaluate memory function. The expression, distribution, and interaction of CIRP with GluR1 in neuronal cells were analyzed. The binding of CIRP to GluR1 mRNA and its impact on GluR1 protein expression were examined. Additionally, the role of CIRP in GluR1 regulation was assessed using Cirp knockout mice. The efficacy of the Tat-C16 peptide, which consists of the Tat sequence combined with the CIRP 110-125 amino acid sequence, was also tested for its ability to mitigate HH-induced memory decline. RESULTS:CIRP was primarily localized in neurons, with its expression significantly reduced following HH exposure. This reduction was associated with decreased GluR1 protein expression on the cell membrane and increased localization in the cytoplasm. The interaction between CIRP and GluR1 was diminished under HH conditions, leading to reduced GluR1 stability on the cell membrane and increased cytoplasmic relocation. These changes resulted in a decreased number of synapses and dendritic spines, impairing learning and memory functions. Administration of the Tat-C16 peptide effectively ameliorated these impairments by modulating GluR1 expression and distribution in HH-exposed mice. CONCLUSION:CIRP plays a critical role in maintaining synaptic integrity under hypoxic conditions by regulating GluR1 expression and distribution. The Tat-C16 peptide shows promise as a therapeutic strategy for alleviating cognitive decline associated with HA hypoxia.

Aim Diabetic nephropathy (DN) is the most common complication of diabetes mellitus. We aimed to investigate the role of regulatory T cells (Tregs) and helper T cells 17 (Th17) in the development and progression of DN. Methods A mouse type 2 diabetic nephropathy (T2DN) model was established. Immunohistochemistry was used to detect the expression of HSP70 and Tim-3 in mouse kidney tissues, and western blotting was used to detect the expression levels of HSP70 and Tim-3. PAS staining and Masson's trichrome staining were used to detect the degree of kidney injury. Flow cytometry was used to detect the number of Th17 and Treg cells in blood and kidney tissues. The expression levels of interleukin 17 (IL-17) and interleukin 10 (IL-10) in the serum were measured via ELISA. Results The expression of HSP70 was significantly increased while the expression of Tim-3 was significantly decreased in the kidneys of mice in the T2DN group compared with those in the control (NC) group. Additionally, the inhibition of HSP70 upregulated the expression of Tim-3 in T2DN mice. The Th17/Treg ratio was significantly greater in the blood and kidneys of the mice in the T2DN group than in those of the NC group, the expression of serum IL-17 was increased, and the expression of IL-10 was decreased. Conclusion Increased HSP70 inhibits Tim-3 expression in T2DN mouse kidney tissues, and subsequently causes a Th17/Treg imbalance and an inflammatory response, ultimately leading to kidney injury. The inhibition of HSP70 may alleviate the progression of T2DN.

Abstract Background: Serum AQP4 antibody (AQP4-IgG) is the causative antibody of neuromyelitis optica spectrum disorder (NMOSD). AQP4-IgG in cerebrospinal fluid (CSF) of NMOSD patients were seldom studied. In this study, we measured antibody titers in time-matched paired CSF and serum samples and explored the relation between CSF AQP4-IgG and patient’s clinical features. Methods: A total of 137 NMOSD patients admitted in the department of Neurology of Renji Hospital from January 2016 to July 2022 were retrospectively reviewed. 87 patients with complete results of paired serum and CSF AQP4-IgG assay were included. Their demographic, clinical, laboratory data and MRI images were collected and analyzed. Result: In this study, 77 patients were seropositive for AQP4-IgG and 10 patients were seronegative. Among the 77 patients seropositive for AQP4-IgG, 47 were CSF-positive and 30 were CSF-negative, while no patients were CSF-positive in the 10 seronegative patients. Between the CSF-positive and CSF-negative groups, there were significant difference in expanded disability status scale (EDSS) scores, relapse proportion, CSF IgG, and CSF IgM, and these indicators were higher in CSF-positive group. We also found a positive correlation between the serum and CSF titer (r s : 0.629, p <0.001). Further logistic multi-factor regression analysis of CSF AQP4-IgG titer revealed that only serum AQP4-IgG titer was ultimately included in the regression model (OR 1.004, 95% CI: 1.001-1.007, p <0.01). Conclusion: AQP4-IgG titer in CSF is mainly affected by serum AQP4-IgG titer. Higher EDSS and a higher presence of relapse status are more common in patients with positive CSF AQP4-IgG.

Supplementary Figure S1; Supplementary Table S1.