Guillain-Barré Syndrome.

OBJECTIVE: This article summarizes the clinical features, diagnostic criteria, differential diagnosis, pathogenesis, and prognosis of Guillain-Barré syndrome (GBS), with insights into the current and future diagnostic and therapeutic interventions for this neuromuscular syndrome. LATEST DEVELOPMENTS: GBS is an acute, inflammatory, immune-mediated polyradiculoneuropathy that encompasses many clinical variants and divergent pathogenic mechanisms that lead to axonal, demyelinating, or mixed findings on electrodiagnostic studies. The type of antecedent infection, the development of pathogenic cross-reactive antibodies via molecular mimicry, and the location of the target gangliosides affect the subtype and severity of the illness. The data from the International GBS Outcome Study have highlighted regional variances, provided new and internationally validated prognosis tools that are beneficial for counseling, and introduced a platform for discussion of GBS-related open questions. New research has been undertaken, including research on novel diagnostic and therapeutic biomarkers, which may lead to new therapies. ESSENTIAL POINTS: GBS is among the most frequent life-threatening neuromuscular emergencies in the world. At least 20% of patients with GBS have a poor prognosis and significant residual deficits despite receiving available treatments. Research is ongoing to further understand the pathogenesis of the disorder, find new biomarkers, and develop more effective and specific treatments.

Anti-GD2 immunoliposomes loaded with oxamate for neuroblastoma.

Oncometabolism can be targeted for the development of less myelotoxic oncotherapeutics. Lactate dehydrogenase A (LDHA) is central to the Warburg effect, a potential oncometabolic shift in neuroblastoma (NBL). Advanced surgical, cytotoxic and cell-differentiating therapies improved survival of children with NBL. Anti-GD2 monoclonal antibodies (mAb) effectively targeting NBL are also incorporated into complex therapies. However, poor clinical outcomes of high-risk NBL require improvements. Here, we verified the pre-reported prognostic value of LDHA expression in NBL using the R2 onco-genomics platform. Kaplan-Meier curves re-demonstrated that higher tumor LDHA expression correlates with worse survival. Multivariate statistics confirmed LDHA is independent from age, stage, and MYCN amplification. In conclusion, a molecular construct is proposed with anti-GD2 mAbs utilized for the targeted delivery of liposomes containing an LDHA inhibitor, Oxamate. Development and preclinical testing of this immunoliposome may validate targeted inhibition of the Warburg effect for NBL. IMPACT: Development of therapeutics against oncometabolism. Targeted specified drug-delivery with mAb. Sparing normal tissues from profound LDHA inhibition. Immunoliposome loaded with an anti-metabolite. If preclinically successful, has translational potential.

Effect of Oral ß-Glucan on Antibody Response to Ganglioside Vaccine in Patients With High-Risk Neuroblastoma: A Phase 2 Randomized Clinical Trial.

Importance: Among patients with high-risk relapsed metastatic neuroblastoma, oral ß-glucan adjuvant during GD2/GD3 ganglioside vaccine boost has stimulated IgG antibody response, which was associated with improved survival; however, the effectiveness of oral ß-glucan during the vaccine priming phase remains unproven. Objective: To isolate the adjuvant effect of oral ß-glucan on antibody response to GD2/GD3 ganglioside vaccine in patients with high-risk neuroblastoma. Design, Setting, and Participants: In this phase 2 randomized clinical trial, enrolled patients with high-risk neuroblastoma were randomized to 2 groups to receive the GD2/GD3 vaccine at a large cancer center in a major metropolitan area from October 2018 to September 2020. Data were analyzed from October 7, 2021, to February 28, 2022. Interventions: Eligible patients receiving GD2/GD3 vaccine were randomly assigned to group 1 (n = 54) to receive no ß-glucan or group 2 (n = 53) to receive an oral ß-glucan regimen during the first 5 weeks of vaccine priming. From week 6 onwards, all 107 patients received oral ß-glucan during vaccine boost for 1 year or until disease progression. Main Outcomes and Measures: Primary end point was comparison of anti-GD2 IgG1 response before vaccine injection 6 (week 32) in group 1 vs group 2. Seroconversion rate and the association of antibody titer with ß-glucan receptor dectin-1 single nucleotide polymorphism (SNP) rs3901533 were also assessed. Results: In all, 107 patients with high-risk neuroblastoma were randomized to the 2 groups: 54 patients (median [range] age, 5.2 [1.0-17.3] years; 28 [52%] male and 26 [48%] female) in group 1; and 53 patients (median [range] age, 6.2 [1.9-18.4] years; 25 [47%] male and 28 [53%] female) in group 2; both groups were also comparable in their first remission status at study entry (70% vs 70%). Adding oral ß-glucan during the first 5 weeks of vaccine priming elicited a higher anti-GD2 IgG1 antibody response in group 2 (1.80; 90% CI, 0.12-3.39; P = .08; planned type I error, 0.10). Anti-GD2 IgG1 titer of 230 ng/mL or greater by week 8 was associated with statistically favorable PFS. Antibody titer correlated significantly with dectin-1 SNP. The genotype frequency, seroconversion rates, and vaccine-related toxic effects were similar in the 2 groups. Conclusions and Relevance: This phase 2 randomized clinical trial found that adding oral ß-glucan during vaccine priming increased anti-GD2 IgG1 titer among genetic responders without added toxic effects. Because responder dectin-1 SNP was identical in the 2 randomized groups, no difference was detected in seroconversion rates. Alternative or additional adjuvants may be needed to enhance seroconversion. Trial Registration: ClinicalTrials.gov Identifier: NCT00911560.

Development of minimally invasive cancer immunotherapy using anti-disialoganglioside GD2 antibody-producing mesenchymal stem cells for a neuroblastoma mouse model.

PURPOSE: Mouse IgG anti-disialoganglioside GD2 antibody-secreting mouse mesenchymal stem cells (anti-GD2-MSCs) were developed, and their anti-tumor effects were validated in an in vivo neuroblastoma mouse model. METHODS: Anti-GD2 antibody constructs were generated, incorporating FLAG-tagged single-chain fragment variables against GD2 fused to a linker sequence, and a fragment of a stationary portion was changed from human IgG to mouse IgG and GFP protein. The construct was lentivirally introduced into mouse MSCs. A syngeneic mouse model was established through the subcutaneous transplantation of a tumor tissue fragment from a TH-MYCN transgenic mouse, and the homing effects of anti-GD2-MSCs were validated by In vivo imaging system imaging. The syngeneic model was divided into three groups according to topical injection materials: anti-GD2-MSCs with IL-2, IL-2, and PBS. The tumors were removed, and natural killer (NK) cells were counted. RESULTS: Anti-GD2-MSCs showed homing effects in syngeneic models. The growth rate of subcutaneous tumors was significantly suppressed by anti-GD2-MSCs with IL-2 (p < 0.05). Subcutaneous tumor immunostaining showed an increased NK cell infiltration in the same group (p < 0.01). CONCLUSION: Anti-GD2-MSCs using mouse IgG showed a homing effect and significant tumor growth suppression in syngeneic models. Anti-GD2-MSC-based cellular immunotherapy could be a novel therapeutic strategy for intractable neuroblastoma.

Translational immunoPET imaging using a radiolabeled GD2-specific antibody in neuroblastoma.

Background: Antibodies targeting surface expressed disialoganglioside GD2 are increasingly used in neuroblastoma immunotherapy and might also have potential for use in radioimmunotherapy. As such targeted treatments might benefit from a dedicated theranostic approach, we studied the influence of radiolabeling on the binding characteristics of ch14.18 antibodies produced by Chinese hamster ovary (CHO) cells and evaluated the benefit of GD2-ImmunoPET as a potential tool for therapy planning. Methods:64Cu was used to reduce radiation burden, which is of high importance especially in a pediatric patient population. 64Cu-labeling was accomplished using the chelators NOTA- or DOTAGA-NCS. Radiolabeled antibodies were characterized in vitro. [64Cu]Cu-DOTAGA-ch14.18/CHO was studied in a neuroblastoma mouse model (subcutaneous CHP-134 xenografts). In vivo PET and MR images were acquired at 3 h, 24 h, and 48 h p.i. The specificity of binding was verified using GD2-negative tumors (HEK-293 xenografts), a control antibody and in vivo blocking. A first translational application was performed by PET/MRI in a patient with metastasized neuroblastoma. Results: Radiolabeling at an antibody-to-chelator ratio ≥1:10 yielded a product with a radiochemical purity of ≥90% and a specific activity of 0.2-1.0 MBq/µg. Radiochelation was stable over 48 h in PBS, mouse serum or EDTA, and 50.8 ± 3.5% and 50.8 ± 2.0% of the radiolabeled conjugates, prepared at antibody-to-chelator ratios of 1:10 or 1:15, were immunoreactive. In vivo, highly specific accumulation (31.6 ± 5.8% ID/g) in neuroblastoma was shown preclinically. Clinical PET/MR scans using [64Cu]Cu-NOTA-ch14.18/CHO (NOTA used for safety reasons) could visualize neuroblastoma metastases. Conclusions:In vivo,64Cu-labeled ch14.18/CHO is suitable for specific identification of neuroblastoma in PET. A first patient PET indicated the feasibility of the method for clinical translation and the potential utility in image-guided therapy.

TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy.

Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in TH-MYCN-driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.

Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer.

BACKGROUND: We explored whether the disialoganglioside GD2 (GD2) is expressed in small cell lung cancer (SCLC) and non-SCLC (NSCLC) and can be targeted by GD2-specific chimeric antigen receptor (CAR) T cells. METHODS: GD2 expression was evaluated in tumor cell lines and tumor biopsies by flow cytometry and immunohistochemistry. We used a GD2.CAR that coexpress the IL-15 to promote T-cell proliferation and persistence, and the inducible caspase 9 gene safety switch to ablate GD2.CAR-T cells in case of unforeseen toxicity. The antitumor activity of GD2.CAR-T cells was evaluated using in vitro cocultures and in xenograft models of orthotopic and metastatic tumors. The modulation of the GD2 expression in tumor cell lines in response to an epigenetic drug was also evaluated. RESULTS: GD2 was expressed on the cell surface of four of fifteen SCLC and NSCLC cell lines (26.7%) tested by flow cytometry, and in 39% of SCLC, 72% of lung adenocarcinoma and 56% of squamous cell carcinoma analyzed by immunohistochemistry. GD2 expression by flow cytometry was also found on the cell surface of tumor cells freshly isolated from tumor biopsies. GD2.CAR-T cells exhibited antigen-dependent cytotoxicity in vitro and in vivo in xenograft models of GD2-expressing lung tumors. Finally, to explore the applicability of this approach to antigen low expressing tumors, we showed that pretreatment of GD2low/neg lung cancer cell lines with the Enhancer of zeste homolog 2 inhibitor tazemetostat upregulated GD2 expression at sufficient levels to trigger GD2.CAR-T cell cytotoxic activity. CONCLUSIONS: GD2 is a promising target for CAR-T cell therapy in lung cancer. Tazemetostat treatment could be used to upregulate GD2 expression in tumor cells, enhancing their susceptibility to CAR-T cell targeting.

Ganglioside GD2: a novel therapeutic target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by lack of hormone receptor expression and is known for high rates of recurrence, distant metastases, and poor clinical outcomes. TNBC cells lack targetable receptors; hence, there is an urgent need for targetable markers for the disease. Breast cancer stem-like cells (BCSCs) are a fraction of cells in primary tumors that are associated with tumorigenesis, metastasis, and resistance to chemotherapy. Targeting BCSCs is thus an effective strategy for preventing cancer metastatic spread and sensitizing tumors to chemotherapy. The CD44hi CD24lo phenotype is a well-established phenotype for identification of BCSCs, but CD44 and CD24 are not targetable markers owing to their expression in normal tissues. The ganglioside GD2 has been shown to be upregulated in primary TNBC tumors compared with normal breast tissue and has been shown to identify BCSCs. In this review, we discuss GD2 as a BCSC- and tumor-specific marker in TNBC; epithelial-to-mesenchymal transition and the signaling pathways that are upstream and downstream of GD2 and the role of these pathways in tumorigenesis and metastasis in TNBC; direct and indirect approaches for targeting GD2; and ongoing clinical trials and treatments directed against GD2 as well as future directions for these strategies.

Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma.

Disialoganglioside (GD2)-specific chimeric antigen receptor (CAR)-T cells (GD2-CAR-T cells) have been developed and tested in early clinical trials in patients with relapsed/refractory neuroblastoma. However, the effectiveness of immunotherapy using these cells is limited, and requires improvement. Combined therapy with CAR-T cells and molecular targeted drugs could be a promising strategy to enhance the antitumor efficacy of CAR T cell immunotherapy. Here, we generated GD2-CAR-T cells through piggyBac transposon (PB)-based gene transfer (PB-GD2-CAR-T cells), and analyzed the combined effect of these cells and a MEK inhibitor in vitro and in vivo on neuroblastoma. Trametinib, a MEK inhibitor, ameliorated the killing efficacy of PB-GD2-CAR-T cells in vitro, whereas a combined treatment of the two showed superior antitumor efficacy in a murine xenograft model compared to that of PB-GD2-CAR-T cell monotherapy, regardless of the mutation status of the MAPK pathway in tumor cells. The results presented here provide new insights into the feasibility of combined treatment with CAR-T cells and MEK inhibitors in patients with neuroblastoma.

Gangliosides combined with mild hypothermia provides neuroprotection in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) remains a major cause of disability and death in modern society. In this study, we explored the neuroprotection role of the combination of gangliosides (GM) and mild hypothermia (MH) and the potential effect on oxidative stress injuries in a rat model of TBI. All 50 rats were randomized to five groups: (1) NC group: undergoing surgery without hit; (2) TBI group: undergoing surgery with hit; (3) GM group: TBI treated with gangliosides; (4) MHT group: TBI treated with MH; (5) GM+MHT group: TBI treated with gangliosides and MH. Spatial learning impairments, neurological function injury, Evans Blue leakage, brain MRI and oxidative stress injuries were assessed. The protein levels of Cleaved-caspase 3 and CytC were also detected. Both GM and MHT could rescue TBI-induced spatial learning impairments, improve neurological function injury and brain edema. In addition, the combination of them has a better therapeutic effect. Through the MRI, we found that compared with the TBI group, the brain tissue edema area of GM group, MHT group, and GM+MHT group was smaller, the occupancy effect was weakened, and the midline was slightly shifted. Compared with the GM group and MHT group, these changes in the GM+MHT group were much smaller. GM combined with MH-alleviated TBI-induced oxidative stress injuries and apoptosis. Our study reveals that GM and MH potentially provide neuroprotection via the suppression of oxidative stress injuries and apoptosis after TBI in rats.

Intranasal Administration of Insulin and Gangliosides Improves Spatial Memory in Rats with Neonatal Type 2 Diabetes Mellitus.

We analyzed the effects of intranasal administration of insulin (0.48 U/rat) and gangliosides (6 mg/kg) on spatial memory in rats with the neonatal model of the type 2 diabetes mellitus. The development of diabetes was verified by the glucose tolerance test. Insulin and gangliosides improved training and reversal training in diabetic rats in a modified version of Morris water maze test and reduced the time of finding the hidden platform. High effectiveness of intranasal administration of gangliosides to animals for the normalization of cognitive functions was shown for the first time. The effects of insulin and gangliosides were similar during training, but during reversal training, gangliosides were more effective. At the same time, intranasally administered insulin, unlike gangliosides, partially normalized glucose tolerance in rats with type 2 diabetes mellitus.

The Effects of Ganglioside-Monosialic Acid in Taxane-Induced Peripheral Neurotoxicity in Patients with Breast Cancer: A Randomized Trial.

BACKGROUND: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting adverse effect. Ganglioside-monosialic acid (GM1) functions as a neuroprotective factor. We assessed the effects of GM1 on the prevention of TIPN in breast cancer patients. METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 206 patients with early-stage breast cancer planning to receive taxane-based adjuvant chemotherapy with a follow-up of more than 1 year. Subjects were randomly assigned to receive GM1 (80 mg, day -1 to day 2) or placebo. The primary endpoint was the Functional Assessment of Cancer Treatment Neurotoxicity subscale score after four cycles of chemotherapy. Secondary endpoints included neurotoxicity evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and the Eastern Cooperative Oncology Group neuropathy scale. All statistical tests were two-sided. RESULTS: In 183 evaluable patients, the GM1 group reported better mean Functional Assessment of Cancer Treatment Neurotoxicity subscale scores than patients in the placebo group after four cycles of chemotherapy (43.27, 95% confidence interval [CI] = 43.05 to 43.49 vs 34.34, 95% CI = 33.78 to 34.89; mean difference = 8.96, 95% CI = 8.38 to 9.54, P < .001). Grade 1 or higher peripheral neurotoxicity in Common Terminology Criteria for Adverse Events v4.0 scale was statistically significantly lower in the GM1 group (14.3% vs 100.0%, P < .001). Additionally, the GM1 group had a statistically significantly lower incidence of grade 1 or higher neurotoxicity assessed by Eastern Cooperative Oncology Group neuropathy scale sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001). CONCLUSIONS: The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after four cycles of taxane-containing chemotherapy in patients with breast cancer.

[Compound porcine cerebroside and ganglioside relieves brain injury and promotes expression of cerebellin 4 in neonatal mice with intrauterine hypoxia].

Objective To study the effects of compound porcine cerebroside and ganglioside injection (CPCGI) on brain injury and expression of cerebellin 4 (CBLN4) in neonatal mice after intrauterine hypoxia. Methods A total of 15 healthy adult pregnant mice were randomly divided into 3 groups: control group with 3 mice, model group and CPCGI treatment group with 6 mice in each group. From the 14th day of pregnancy, the pregnant mice in the CPCGI treatment group and model group were put into the animal hypoxia box to produce the intrauterine hypoxia fetal mouse models. After the delivery of mother, the neonatal mice in the CPCGI treatment group and model group were given CPCGI (1 mL/kg) and PBS via abdominal cavity, respectively, while the control group received no treatment. At 40 days postpartum, the memory ability of mice was trained with a platform jumper test. After the platform test, the brain tissue of the mice was taken out. The expression of neurogenolase (NSE), interleukin-1 beta (IL-1ß), CBLN4 and synaptophsin (SYN) were detected by immunofluorescence staining. The relative expression of CBLN4 protein in the hippocampus of mice was detected by Western blot analysis. Results Compared with the control group, hypoxia caused a significant decrease in learning and memory ability of newborn mice, and CPCGI could significantly improve the memory of mice. After hypoxia, the expression of NSE, CBLN4 and SYN in the neonatal cerebellum significantly decreased, and the expression of IL-1ß significantly increased. The expression of NSE, CBLN4 and SYN in CPCGI treatment group was significantly higher than those in the model group, and the expression of IL-1ß was significantly lower than that in the model group. Conclusion CPCGI can reduce neuronal damage in neonatal mice after hypoxia, which may be related to the reduction of IL-1ß expression and the promotion of synaptic reconstruction.

Characterization of myeloid-derived suppressor cells and cytokines GM-CSF, IL-10 and MCP-1 in dogs with malignant melanoma receiving a GD3-based immunotherapy.

Melanoma in humans and canines is an aggressive and highly metastatic cancer. The mucosal forms in both species share genetic and histopathologic features, making dogs a valuable spontaneous disease animal model. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells of myeloid origin with immunosuppressive capabilities, which are increased in many human cancers and contribute to tumor immune evasion. They are a possible target to improve immunotherapy outcomes. Current information regarding MDSCs in canines is minimal, limiting their use as translational model for the study of MDSCs. The objective of this study was to characterize major MDSCs subsets (monocytic and polymorphonuclear) and the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) in canines with malignant melanoma and to evaluate changes in MDSCs and the cytokines over time in response to a GD3-based active immunotherapy. Whole blood and serum collected from 30 healthy controls and 33 patients enrolled in the University of Florida melanoma vaccine trial were analyzed by flow cytometry with canine specific CD11b, MHCII and anti-human CD14 antibodies to assess ostensibly polymorphonuclear-MDSC (CD11b+ MHCII- CD14-) and monocytic-MDSC (CD11b+ MHCII- CD14+) subsets. IL-10, MCP-1 and both MDSCs subsets were significantly elevated in melanoma dogs versus controls. Both MDSCs subsets decreased significantly following GD3-based immunotherapy administration but no significant changes in cytokines were seen over time. To our knowledge, this is the first report documenting increased monocytic-MDSCs in canine melanoma. This is consistent with human malignant melanoma data, supporting dogs as a valuable model for therapeutic intervention studies.

CPCGI confers neuroprotection by enhancing blood circulation and neurological function in cerebral ischemia/reperfusion rats.

The current study used a rat middle cerebral artery occlusion (MCAO) model with the aim to explore the effects of compound porcine cerebroside and ganglioside injection (CPCGI) on brain ischemia/reperfusion injury in rats. Improvement in the infarct­side microcirculation and the overall recovery of neurological function were detected by triphenyltetrazolium chloride staining, laser speckle blood flow monitoring, latex perfusion, immunofluorescence and immunoblotting. The results revealed that administration of CPCGI for 7 consecutive days following ischemic stroke contributed to the recovery of neurological function and the reduction of cerebral infarct volume in rats. Blood flow monitoring results demonstrated that the administration of CPCGI effectively promoted cerebral blood flow following stroke, and contributed to the protection of the ischemic side blood vessels. In addition, CPCGI treatment increased the numbers of new blood vessels in the peripheral ischemic region, and upregulated the expression levels of vascular endothelial growth factor, angiopoietin 1 and its receptor TEK receptor tyrosine kinase, fibroblast growth factor and Wnt signaling pathway­associated proteins. Taken together, the present results indicated that CPCGI improved the blood circulation and neurological function following cerebral ischemia/reperfusion in rats.

Ganglioside GQ1b ameliorates cognitive impairments in an Alzheimer's disease mouse model, and causes reduction of amyloid precursor protein.

Brain-derived neurotrophic factor (BDNF) plays crucial roles in memory impairments including Alzheimer's disease (AD). Previous studies have reported that tetrasialoganglioside GQ1b is involved in long-term potentiation and cognitive functions as well as BDNF expression. However, in vitro and in vivo functions of GQ1b against AD has not investigated yet. Consequently, treatment of oligomeric Aß followed by GQ1b significantly restores Aß1-42-induced cell death through BDNF up-regulation in primary cortical neurons. Bilateral infusion of GQ1b into the hippocampus ameliorates cognitive deficits in the triple-transgenic AD mouse model (3xTg-AD). GQ1b-infused 3xTg-AD mice had substantially increased BDNF levels compared with artificial cerebrospinal fluid (aCSF)-treated 3xTg-AD mice. Interestingly, we also found that GQ1b administration into hippocampus of 3xTg-AD mice reduces Aß plaque deposition and tau phosphorylation, which correlate with APP protein reduction and phospho-GSK3ß level increase, respectively. These findings demonstrate that the tetrasialoganglioside GQ1b may contribute to a potential strategy of AD treatment.

Activated NF-κB/Nrf2 and Wnt/ß-catenin pathways are associated with lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria.

Early diagnosis of CKD patients at risk for microalbuminuria or macroalbuminuria could facilitate clinical outcomes and long-term survival. Considering the few and limited efficacy of current biomarkers in early detection, we aim to discover plasma lipids that effectively predict the development of CKD paitents with microalbuminuria or macroalbuminuria. A total of 380 healthy controls and 1156 patients with CKD stages 3 to 5 were stratified by urine albumin-creatinine ratio as microalbuminuria (30-300 mg/g) and macroalbuminuria (>300 mg/g). Fasting plasma samples were determined by UPLC-HDMS based on lipidomics. Quantitative real-time polymerase chain reaction, Western blot and immunohistochemical analyses were used to validate the lipid metabolism-associated pathways. Pathway analysis demonstrated that these lipids were closely associated with PPARγ, inflammatory mediator regulation of TRP channels and RAS signaling, which were intimately involved in activated NF-κB and Nrf2 pathways. We further carried out pathway validation and demonstrated that NF-κB pathway was activated in patients with macroalbuminuria compared with CKD patients with microalbuminuria, while Nrf2-associated protein expression was downregulated, which was accompanied by the up-regulation of Wnt/ß-catenin signaling pathway. Four lipids including DTA, 5,8-TDA, GGD3 and DHA that showed great potential in the discrimination of CKD patients with microalbuminuria and healthy controls were selected by logistic regression analysis. Additionally, six lipid species including CDCA, glucosylceramide, GGD2, TTA, DHA and EDA that contributed to the discrimination of CKD patients with microalbuminuria and macroalbuminuria were selected by logistic LASSO regression Gangliosides were first identified and might be promising therapeutic targets for CKD patients with the different degree of albuminuria. Collectively, this study first demonstrates the association of plasma inflammation, oxidative stress, Wnt/ß-catenin and lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria.

Vaccination with Tumor-Ganglioside Glycomimetics Activates a Selective Immunity that Affords Cancer Therapy.

Immune targeting of (glyco)protein tumor markers has been useful to develop cancer and virus vaccines. However, the ganglioside family of tumor-associated glycolipids remains intractable to vaccine approaches. Here we show that synthetic antigens mimicking the carbohydrate moiety of GD2 or GD3 gangliosides can be used as vaccines to activate a selective humoral and cellular immunity that is therapeutic against several cancers expressing GD2 or GD3. Adoptive transfer of T cells generated after vaccination elicits tumor-infiltrating lymphocytes of the γδ T cell receptor and CD8+ phenotypes; and affords a high therapeutic index. The glycomimetic vaccine principles can be expanded to target the family of tumor gangliosides and other carbohydrates expressed primarily in pathological states.

Comparative Effects of Monosialoganglioside versus Citicoline on Apoptotic Factor, Neurological Function and Oxidative Stress in Newborns with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To determine the comparative effect of monosialoganglioside versus citicoline on the content changes of serum apoptotic factors (PDCD5, sFas and sFasL), neurological function indices (BDNF, NSE, S100-ß and NGF) and oxidative stress indices (SOD, MDA and GSH-PX) in newborns with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Emergency Department, Affiliated Children's Hospital of Zhengzhou University, China, from October 2016 to February 2018. METHODOLOGY: A total of 90 newborns with HIE were randomly divided into a treatment group and a control group, with 45 cases in each group. In addition to the conventional treatment, the treatment group was given monosialoganglioside treatment, while the control group was given citicoline treatment. Both groups were treated for 10 days. After treatment, the content differences of serum apoptosis factors (PDCD5, sFas and sFasL), neurological function indices (BDNF, NSE, S100-ß and NGF) and oxidative stress indices (SOD, MDA and GSH-PX) were observed in the two groups. RESULTS: After treatment, the levels of serum PDCD5, sFas, sFasL, MDA, NSE and S100-ß in the treatment group were lower than those in the control group (all p<0.001). The contents of serum SOD, GSH-PX, BDNF and NGF in the treatment group were higher than those in the control group (all p<0.001). CONCLUSION: Monosialoganglioside can effectively improve the apoptotic factors, neurological function and oxidative stress indices in newborns and maintain the stability of the internal environment, so it is worthy of promotion and application.

Cattle Encephalon Glycoside and Ignotin Reduce Early Brain Injury and Cognitive Dysfunction after Subarachnoid Hemorrhage in Rats.

Subarachnoid hemorrhage (SAH) is a well-known hemorrhagic stroke with high rates of morbidity and mortality where patients frequently experience cognitive dysfunction. This study explores a potential treatment for cognitive dysfunction following SAH with the demonstration that multi-target drug cattle encephalon glycoside and ignotin (CEGI) can relieve cognitive dysfunction by decreasing hippocampal neuron apoptosis following SAH in rats. Experimentally, 110 male SD rats were separated at random into Sham (20), SAH + Vehicle (30), SAH + 4 ml/kg CEGI (30), and SAH + 1 ml/kg CEGI groups (30) and an endovascular perforation model was created to induce SAH. We discovered that the number of TUNEL-positive neurons in the hippocampus was markedly decreased in SAH + 4 ml/kg and SAH + 1 ml/kg CEGI groups compared to the SAH + Vehicle group. This finding was associated with an observed decrease in Bax/Bcl-2 ratio, cytochrome-c and PUMA expression, and the suppression of caspase-3 activation following SAH. In Morris water maze tests, the SAH + 4 ml/kg CEGI group demonstrated a decreased escape latency time and increase in time spent in the target quadrant as well as crossing times of platform region. These results indicate that high doses of CEGI can decrease hippocampal neuron apoptosis and relieve cognitive dysfunction in rats, suggesting that multitarget-drug CEGI exhibits a neuroprotective effect in SAH via the mitochondrial apoptosis pathway.