RESUMEN
Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and accumulating evidence suggests a link between dysbiosis of the gut microbiota and the onset and progression of PD. In our previous investigations, we discovered that intraperitoneal administration of glucuronomannan oligosaccharides (GMn) derived from Saccharina japonica exhibited neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. However, the complicated preparation process, difficulties in isolation, and remarkably low yield have constrained further exploration of GMn. In this study, we optimized the degradation conditions in the preparation process of GMn through orthogonal experiments. Subsequently, an MPTP-induced PD model was established, followed by oral administration of GMn. Through a stepwise optimization, we successfully increased the yield of GMn, separated from crude fucoidan, from 1~2/10,000 to 4~8/1000 and indicated the effects on the amelioration of MPTP-induced motor deficits, preservation of dopamine neurons, and elevation in striatal neurotransmitter levels. Importantly, GMn mitigated gut microbiota dysbiosis induced by MPTP in mice. In particular, GM2 significantly reduced the levels of Akkermansia, Verrucomicrobiota, and Lactobacillus, while promoting the abundance of Roseburia and Prevotella compared to the model group. These findings suggest that GM2 can potentially suppress PD by modulating the gut microbiota, providing a foundation for the development of a novel and effective anti-PD marine drug.
Asunto(s)
Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Oligosacáridos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Oligosacáridos/farmacología , Masculino , Fármacos Neuroprotectores/farmacología , Disbiosis/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Manosa/farmacología , Manosa/química , Manosa/análogos & derivados , Glucuronatos/farmacologíaRESUMEN
RATIONALE: Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α-synuclein (α-syn) in the brain. There is a significant clinical unmet need for disease-modifying treatments for synucleinopathies. Recently, a seaweed-derived mixture of oligosaccharides sodium oligomannate, GV-971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms. METHODS: α-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating α-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1 kg-1 ). RESULTS: GV-971 effectively prevented α-syn aggregation and even disassembled pre-aggregated α-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue α-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCAA53T mouse model, when treated at the age of 5 months, GV-971 significantly decreased α-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions. CONCLUSIONS: Our results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced α-syn accumulation and aggregation in Prnp-SNCAA53T mice. Furthermore, GV-971 corrected α-syn-induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV-971 as a promising disease-modifying therapy for PD and other synucleinopathies.
Asunto(s)
Manosa , Enfermedad de Parkinson , Sinucleinopatías , Animales , Humanos , Lactante , Ratones , alfa-Sinucleína/metabolismo , Neuronas Dopaminérgicas/metabolismo , Manosa/análogos & derivados , Oligosacáridos/farmacología , Oligosacáridos/uso terapéutico , Enfermedad de Parkinson/metabolismo , Sinucleinopatías/metabolismo , Sinucleinopatías/patologíaRESUMEN
Rhoifolin (ROF) is a bioactive plant flavonoid with potent antioxidant and anti-inflammatory activity. However, no delivery system has yet been developed for ROF to overcome its biopharmaceutical limitations. The purpose of this study was to design a ROF-loaded polymeric nanocarrier as a potential anti-inflammatory nanomedicine. ROF was isolated from Jordanian Teucrium polium L. and entrapped into poly(lactide-co-glycolide) nanoparticles (PLGA NPs), followed by tannic acid-mediated surface modification with poly(ethylene glycol) (PEG). The optimal ROF NPs were highly monodisperse with an average diameter of 204 nm, a zeta potential of -28 mV, an entrapment efficiency of 45%, and drug loading of 9% w/w. The NPs exhibited excellent colloidal stability during storage and in the presence of serum and achieved sustained drug release for up to 96 h at physiologic (7.4) and acidic pH (5.0). In vitro cell-free antioxidant assays confirmed the potent radical scavenging activity of free ROF and ROF NPs. Moreover, ROF NPs were superior to free ROF in relieving oxidative stress in stimulated RAW 264.7 murine macrophages, which was attributed to enhanced cellular uptake of the NPs as confirmed by confocal microscopy and fluorimetry. In vivo anti-inflammatory activity was evaluated in a formalin-induced rat paw edema model. The results showed that ROF NPs were superior to free ROF in mitigating the histopathological changes in the inflamed paw tissues. Moreover, the NPs were equally potent to free ROF and the nonsteroidal anti-inflammatory drug diclofenac in terms of inhibiting the increase in paw thickness, normalizing nitric oxide levels, and modulating the gene expression of pro-inflammatory cytokines in the inflamed paw tissues. Our findings present a promising nanocarrier platform that can enhance the solubility and control the release of ROF, which will facilitate its administration in the treatment of inflammatory diseases.
Asunto(s)
Productos Biológicos , Nanopartículas , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apigenina , Citocinas , Diclofenaco , Disacáridos , Portadores de Fármacos , Flavonoides , Formaldehído , Glucosa/análogos & derivados , Inflamación/tratamiento farmacológico , Manosa/análogos & derivados , Ratones , Óxido Nítrico , Estrés Oxidativo , Tamaño de la Partícula , Polietilenglicoles , Poliglactina 910 , Ratas , TaninosRESUMEN
Human cytomegalovirus (HCMV) remains a major public health burden worldwide. The anti-HCMV activity of glucuronomannan oligosaccharides (Gs) and sulphated glucuronomannan oligosaccharides (SGs) was investigated. Among these Gs and SGs, G4S1 and G6S1 (higher sulphated glucuronomannan tetramer and hexamer) showed satisfactory anti-HCMV activity starting at 50 µg/mL and 10 µg/mL, respectively. The results of the morphology, western blotting, qPCR and TCID50 assay showed that they prevented lytic cytopathic changes, inhibited the expression of IE1/2 and UL44, and reduced the UL123 copy number and virus titre significantly. It was interesting to note that degree of sulphation and polymerization was more important for anti-HCMV activity. Moreover, the anti-HCMV activities of G4S1 and G6S1 were stable when stored at 4 °C, -20 °C, and -80 °C for at least three months and mainly occurred in the early stage of HCMV infection through the negative charge of the sulphate groups and the interaction between SGs and the host cells.
Asunto(s)
Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Glucuronatos/farmacología , Manosa/análogos & derivados , Sargassum/química , Sulfatos/química , Internalización del Virus/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Infecciones por Citomegalovirus/virología , Glucuronatos/química , Humanos , Manosa/química , Manosa/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
Most polysaccharides used in polysaccharide-based block copolymers are attached to the second block through the reducing end, due to the few and highly polysaccharide specific non-reducing end (NRE) functionalisation methods available. Chitin oligomers, prepared by nitrous acid degradation of chitosan (AnM) can, however, be selectively oxidised by periodate since they only possess a single vicinal diol in the NRE residue. Here, we show that both aldehydes formed after oxidation are highly reactive towards bifunctional oxyamines and hydrazide linkers. Sub-stochiometric amounts of linkers resulted in conjugation of AnM oligomers through both chain termini to yield a discrete distribution of 'polymerised' oligomers. Such chitin-based block polymers were, in contrast to chitins of the same chain lengths, water-soluble. Oxidised AnM oligomers, functionalised at both termini can also enable the preparation of more complex block polysaccharides such as ABA- or ABC-type.
Asunto(s)
Quitina/química , Ácido Peryódico/química , Agua/química , Adipatos/química , Aldehídos/síntesis química , Aldehídos/química , Secuencia de Carbohidratos , Quitina/síntesis química , Hidroxilaminas/química , Manosa/análogos & derivados , Manosa/química , Oxidación-Reducción , SolubilidadRESUMEN
The C-type lectin receptor DC-SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS-CoV-2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS-CoV-2 pandemic, involvement of DC-SIGN has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents. Here, we demonstrate that mannose-functionalized poly-l-lysine glycoconjugates efficiently inhibit the attachment of viral glycoproteins to DC-SIGN-presenting cells with picomolar affinity. Treatment of these cells leads to prolonged receptor internalization and inhibition of virus binding for up to 6â h. Furthermore, the polymers are fully bio-compatible and readily cleared by target cells. The thermodynamic analysis of the multivalent interactions reveals enhanced enthalpy-driven affinities and promising perspectives for the future development of multivalent therapeutics.
Asunto(s)
Antivirales/farmacología , Moléculas de Adhesión Celular/antagonistas & inhibidores , Glicoconjugados/farmacología , Lectinas Tipo C/antagonistas & inhibidores , Receptores de Superficie Celular/antagonistas & inhibidores , Acoplamiento Viral/efectos de los fármacos , Antivirales/síntesis química , Antivirales/metabolismo , Moléculas de Adhesión Celular/metabolismo , Glicoconjugados/síntesis química , Glicoconjugados/metabolismo , Humanos , Lectinas Tipo C/metabolismo , Manosa/análogos & derivados , Manosa/metabolismo , Manosa/farmacología , Pruebas de Sensibilidad Microbiana , Polilisina/análogos & derivados , Polilisina/metabolismo , Polilisina/farmacología , Unión Proteica/efectos de los fármacos , Receptores de Superficie Celular/metabolismo , SARS-CoV-2/efectos de los fármacos , Células THP-1 , Termodinámica , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Proteínas del Envoltorio Viral/metabolismoRESUMEN
BACKGROUND: New therapies are urgently needed for Alzheimer's disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. RESULTS: A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was - 2.15 points (95% confidence interval, - 3.07 to - 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group. CONCLUSIONS: GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0229391 5. Registered on November 19, 2014.
Asunto(s)
Enfermedad de Alzheimer , Preparaciones Farmacéuticas , Actividades Cotidianas , Enfermedad de Alzheimer/tratamiento farmacológico , China , Inhibidores de la Colinesterasa , Método Doble Ciego , Humanos , Manosa/análogos & derivados , Oligosacáridos , Sodio , Resultado del TratamientoRESUMEN
Parkinson's disease (PD), one of the most common neurodegenerative disorders, is caused by dopamine depletion in the striatum and dopaminergic neuron degeneration in the substantia nigra. In our previous study, we hydrolyzed the fucoidan from Saccharina japonica, obtaining three glucuronomannan oligosaccharides (GMn; GM1, GM2, and GM3) and found that GMn ameliorated behavioral deficits in Parkinsonism mice and downregulated the apoptotic signaling pathway, especially with GM2 showing a more effective role in neuroprotection. However, the neuroprotective mechanism is unclear. Therefore, in this study, we aimed to assess the neuroprotective effects of GM2 in vivo and in vitro. We applied GM2 in 1-methyl-4-phenylpyridinium (MPP+)-treated PC12 cells, and the results showed that GM2 markedly improved the cell viability and mitochondrial membrane potential, inhibited MPP+-induced apoptosis, and enhanced autophagy. Furthermore, GM2 contributed to reducing the loss of dopaminergic neurons in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice through enhancing autophagy. These data indicate that a possible protection of mitochondria and upregulation of autophagy might underlie the observed neuroprotective effects, suggesting that GM2 has potential as a promising multifunctional lead disease-modifying therapy for PD. These findings might pave the way for additional treatment strategies utilizing carbohydrate drugs in PD.
Asunto(s)
Autofagia/efectos de los fármacos , Glucuronatos/uso terapéutico , Manosa/análogos & derivados , Mitocondrias/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Phaeophyceae , Animales , Autofagia/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Glucuronatos/aislamiento & purificación , Glucuronatos/farmacología , Masculino , Manosa/aislamiento & purificación , Manosa/farmacología , Manosa/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/patología , Células PC12 , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Phaeophyceae/aislamiento & purificación , RatasRESUMEN
To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV-971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slowdown LOAD. However, regardless of the origin of the disease, the end goal of LOAD-related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.
Asunto(s)
Enfermedad de Alzheimer/terapia , Espinas Dendríticas/fisiología , Microbioma Gastrointestinal/efectos de los fármacos , Manosa/análogos & derivados , Oligosacáridos/administración & dosificación , Sinapsis/fisiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Dieta Saludable/métodos , Dieta Saludable/psicología , Ejercicio Físico/fisiología , Ejercicio Físico/psicología , Microbioma Gastrointestinal/fisiología , Humanos , Manosa/administración & dosificación , Sinapsis/efectos de los fármacos , Sinapsis/patologíaRESUMEN
BACKGROUND: Sodium oligomannate (GV-971), a marine-derived oligosaccharide, is a novel agent that may improve cognition in AD patients. METHODS: The 24-week multicenter, randomized, double-blind, placebo parallel controlled clinical trial was conducted in AD in China between 24 October 2011 and 10 July 2013. The study included a 4-week screening/washout period, followed by a 24-week treatment period. Patients were randomized in a 1:1:1 ratio to receive GV-971 900 mg, 600 mg, or placebo capsule in treatment period, respectively. The primary outcome was cognitive improvement as assessed by changes in Alzheimer's Disease Assessment Scale-cognitive subscale 12-item (ADAS-cog12) scores from baseline to week 24. The secondary efficacy outcomes included CIBIC-Plus, ADCS-ADL, and NPI at 24 weeks after treatment compared with baseline. A subgroup study was assessment of the change in cerebral glucose metabolism by fluorodeoxyglucose positron emission tomography measurements. RESULTS: Comparing with the placebo group (n = 83, change - 1.45), the ADAS-cog12 score change in the GV-971 600-mg group (n = 76) was - 1.39 (p = 0.89) and the GV-971 900-mg group (n = 83) was - 2.58 (p = 0.30). The treatment responders according to CIBIC-Plus assessment were significantly higher in the GV-971 900-mg group than the placebo group (92.77% vs. 79.52%, p < 0.05). The GV-971 900-mg subgroup showed a lower decline of cerebral metabolic rate for glucose than the placebo subgroup at the left precuneus, right posterior cingulate, bilateral hippocampus, and bilateral inferior orbital frontal at uncorrected p = 0.05. The respective rates of treatment-related AEs were 5.9%, 14.3%, and 3.5%. CONCLUSIONS: GV-971 was safe and well tolerated. GV-971 900 mg was chosen for phase III clinical study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01453569 . Registered on October 18, 2011.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , China , Inhibidores de la Colinesterasa , Método Doble Ciego , Humanos , Manosa/análogos & derivados , Oligosacáridos , Sodio , Resultado del TratamientoRESUMEN
The SARS-CoV-2 spike glycoproteins (SGPs) and human angiotensin converting enzyme 2 (ACE2) are the two key targets for the prevention and treatment of COVID-19. Host cell surface heparan sulfate (HS) is believed to interact with SARS-CoV-2 SGPs to facilitate host cell entry. In the current study, a series of polysaccharides from Saccharina japonica were prepared to investigate the structure-activity relationship on the binding abilities of polysaccharides (oligosaccharides) to pseudotype particles, including SARS-CoV-2 SGPs, and ACE2 using surface plasmon resonance. Sulfated galactofucan (SJ-D-S-H) and glucuronomannan (Gn) displayed strongly inhibited interaction between SARS-CoV-2 SGPs and heparin while showing negligible inhibition of the interaction between SARS-CoV-2 SGPs and ACE2. The IC50 values of SJ-D-S-H and Gn in blocking heparin SGP binding were 27 and 231 nM, respectively. NMR analysis showed that the structure of SJ-D-S-H featured with a backbone of 1, 3-linked α-L-Fucp residues sulfated at C4 and C2/C4 and 1, 3-linked α-L-Fucp residues sulfated at C4 and branched with 1, 6-linked ß-D-galacto-biose; Gn had a backbone of alternating 1, 4-linked ß-D-GlcAp residues and 1, 2-linked α-D-Manp residues. The sulfated galactofucan and glucuronomannan showed strong binding ability to SARS-CoV-2 SGPs, suggesting that these polysaccharides might be good candidates for preventing and/or treating SARS-CoV-2.
Asunto(s)
Infecciones por Coronavirus/virología , Glucuronatos/metabolismo , Manosa/análogos & derivados , Neumonía Viral/virología , Polisacáridos/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Enzima Convertidora de Angiotensina 2 , Betacoronavirus/química , Betacoronavirus/metabolismo , Sitios de Unión , COVID-19 , Glucuronatos/química , Heparina/química , Heparina/metabolismo , Humanos , Manosa/química , Manosa/metabolismo , Oligosacáridos/química , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Phaeophyceae/química , Polisacáridos/química , Unión Proteica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/química , Relación Estructura-ActividadRESUMEN
The anti-lung cancer activity of oligosaccharides derived from glucuronomannan was investigated. The inhibition of A549 cell proliferation by glucuronomannan (Gn) and its oligomers (dimer (G2), tetramer (G4) and hexamer (G6)) were concentration dependent. In vivo activities on the A549-derived tumor xenografts showed the tumor inhibition of G2, G4 and G6 were 17 %, 40 % and 46 %, respectively. Organ coefficients in nude mice showed an increase in the kidney with G4, the brain with G6, and the spleen with G6. An advanced tandem mass tag labeled proteomics approach was performed. A significant differential expression was found in 59 out of the 4371 proteins, which involved the immune system. Surface plasmon resonance (SPR) studies revealed G6 was strongly bound to immunoglobulin G. This suggests that glucuronomannan hexamer inhibits the proliferation of lung cancer through its binding to immunoglobulin.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Glucuronatos/farmacología , Inmunoglobulina G/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Manosa/análogos & derivados , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Células A549 , Animales , Dimerización , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Glucuronatos/química , Glucuronatos/metabolismo , Humanos , Inmunoglobulina G/química , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Manosa/química , Manosa/metabolismo , Manosa/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Unión Proteica , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genéticaRESUMEN
Parkinson's disease (PD), characterized by dopaminergic neuron degeneration in the substantia nigra and dopamine depletion in the striatum, affects up to 1% of the global population over 50 years of age. Our previous study found that a heteropolysaccharide from Saccharina japonica exhibits neuroprotective effects through antioxidative stress. In view of its high molecular weight and complex structure, we degraded the polysaccharide and subsequently obtained four oligosaccharides. In this study, we aimed to further detect the neuroprotective mechanism of the oligosaccharides. We applied MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to induce PD, and glucuronomannan oligosaccharides (GMn) was subsequently administered. Results showed that GMn ameliorated behavioral deficits in Parkinsonism mice. Furthermore, we observed that glucuronomannan oligosaccharides contributed to down-regulating the apoptotic signaling pathway through enhancing the expression of tyrosine hydroxylase (TH) in dopaminergic neurons. These results suggest that glucuronomannan oligosaccharides protect dopaminergic neurons from apoptosis in PD mice.
Asunto(s)
Antiparkinsonianos/farmacología , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Glucuronatos/farmacología , Manosa/análogos & derivados , Oligosacáridos/farmacología , Trastornos Parkinsonianos/prevención & control , Algas Marinas , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Antiparkinsonianos/aislamiento & purificación , Proteínas Reguladoras de la Apoptosis/metabolismo , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Glucuronatos/aislamiento & purificación , Masculino , Manosa/aislamiento & purificación , Manosa/farmacología , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Oligosacáridos/aislamiento & purificación , Prueba de Campo Abierto/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Algas Marinas/química , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Starch/cellulose has become the major feedstock for manufacturing biofuels and biochemicals because of their abundance and sustainability. In this study, we presented an artificially designed "starch-mannose-fermentation" biotransformation process through coupling the advantages of in vivo and in vitro metabolic engineering strategies together. Starch was initially converted into mannose via an in vitro metabolic engineering biosystem, and then mannose was fermented by engineered microorganisms for biomanufacturing valuable mannosyl compounds. The in vitro metabolic engineering biosystem based on phosphorylation/dephosphorylation reactions was thermodynamically favorable and the conversion rate reached 81%. The mannose production using whole-cell biocatalysts reached 75.4 g/L in a 30-L reactor, indicating the potential industrial application. Furthermore, the produced mannose in the reactor was directly served as feedstock for the fermentation process to bottom-up produced 19.2 g/L mannosyl-oligosaccharides (MOS) and 7.2 g/L mannosylglycerate (MG) using recombinant Corynebacterium glutamicum strains. Notably, such a mannose fermentation process facilitated the synthesis of MOS, which has not been achieved under glucose fermentation and improved MG production by 2.6-fold than that using the same C-mole of glucose. This approach also allowed access to produce other kinds of mannosyl derivatives from starch.
Asunto(s)
Reactores Biológicos , Corynebacterium glutamicum , Ácidos Glicéricos , Manosa/análogos & derivados , Ingeniería Metabólica , Microorganismos Modificados Genéticamente , Almidón/metabolismo , Corynebacterium glutamicum/genética , Corynebacterium glutamicum/crecimiento & desarrollo , Manosa/biosíntesis , Manosa/genética , Microorganismos Modificados Genéticamente/genética , Microorganismos Modificados Genéticamente/crecimiento & desarrolloRESUMEN
BACKGROUND: Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5'-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic. SCOPE OF REVIEW: This review covers the latest advances in the search for a treatment for PMM2-CDG. MAJOR CONCLUSIONS: Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins. GENERAL SIGNIFICANCE: The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussed.
Asunto(s)
Trastornos Congénitos de Glicosilación/terapia , Fosfotransferasas (Fosfomutasas)/deficiencia , Animales , Elementos sin Sentido (Genética)/uso terapéutico , Trastornos Congénitos de Glicosilación/tratamiento farmacológico , Trastornos Congénitos de Glicosilación/genética , Trastornos Congénitos de Glicosilación/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Glicosilación/efectos de los fármacos , Humanos , Manosa/análogos & derivados , Manosa/uso terapéutico , Fosfotransferasas (Fosfomutasas)/genética , Fosfotransferasas (Fosfomutasas)/metabolismoRESUMEN
Mannose is a monosaccharide widely distributed in body fluids and tissues, especially in the nerve, skin, testicles, retina, liver and intestines. It is used to synthesize glycoproteins and participate in immune regulation. In recent years, mannose has been applied more and more widely in the biomedical context as people have a deeper understanding of its biological effects. This review introduces the use of mannose in treating various diseases (including cancer, urinary tract infections, type 1 diabetes, and diabetic wounds), preventing pancreatic fistula, and improving magnetic resonance imaging for acute pancreatitis. We also demonstrate that mannose has the potential for clinical applications.
Asunto(s)
Fármacos Antiobesidad/farmacología , Antineoplásicos/farmacología , Portadores de Fármacos , Hipoglucemiantes/farmacología , Manosa/farmacología , Animales , Medios de Contraste/administración & dosificación , Medios de Contraste/metabolismo , Humanos , Imagen por Resonancia Magnética , Manosa/análogos & derivados , Manosa/metabolismo , Fístula Pancreática/prevención & control , Pancreatitis/diagnóstico por imagen , Cicatrización de Heridas/efectos de los fármacosRESUMEN
There has been much interest in the clinical trial of GV972 for treatment of Alzheimer's disease in that the data have indicated that the compound is protective against cognitive decline. This effect has been attributed to a remodelling of the gut microbiota. I suggest that the effect might be caused by an antiviral action of GV971 against herpes simplex virus type 1 in brain, which many studies have strongly implicated as having a major role in Alzheimer's disease. The antiviral action of GV971 is proposed on the basis that it is an acidic polysaccharide consisting of linear sodium oligomannurarate molecules of a range of sizes, derived from brown algae. Marine-derived polysaccharides are well known for possessing various bioactivities, including antiviral and antibacterial properties.
Asunto(s)
Antivirales/uso terapéutico , Encéfalo/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Manosa/análogos & derivados , Fármacos Neuroprotectores/uso terapéutico , Oligosacáridos/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/virología , Animales , Antivirales/farmacología , Encéfalo/patología , Encéfalo/virología , Disfunción Cognitiva/patología , Disfunción Cognitiva/virología , Herpesvirus Humano 1/fisiología , Humanos , Manosa/farmacología , Manosa/uso terapéutico , Fármacos Neuroprotectores/farmacología , Oligosacáridos/farmacología , Replicación Viral/efectos de los fármacos , Replicación Viral/fisiologíaRESUMEN
Although synthetic CpG oligodeoxynucleotides (ODNs) have shown substantial potential as immunotherapeutic agents, their effective intracellular delivery remains challenging. In this work, nanoparticles prepared from low-molecular weight (LMW) chitosans were investigated as CpG ODN delivery systems. Chitosan samples with a molecular weight (Mw) of 5 and 15 kDa and degree of deacetylation (DDA) of 50 and 80% were prepared. Additionally, mannosylated chitosans with a substitution degree of 15% were synthesized. The impact of LMW chitosan Mw and DDA on nanoparticle physical properties and the associated immunostimulatory effect in RAW 264.7 cells was studied. Nanoparticles prepared with chitosan of higher DDA and larger Mw exhibited better CpG ODN binding ability and intracellular uptake. Nevertheless, the most efficient immunostimulatory effect was observed while using 50% acetylated and mannosylated samples. The decreased charge density on chitosan backbone resulted in the enhanced intracellular CpG ODN release, which promoted in vitro cytokine secretion. Moreover, mannose ligand grafting promoted nanoparticle uptake through receptor-mediated recognition. Overall, this research suggests that chitosan structural parameters can be modulated to prepare LMW chitosan nanoparticles that first efficiently encapsulate CpG ODN, and then release it in immune cells, thus may be used as an efficient vector for intracellular CpG ODN delivery.
Asunto(s)
Quitosano/análogos & derivados , Islas de CpG , Liberación de Fármacos , Nanopartículas/química , Oligodesoxirribonucleótidos/química , Acetatos/química , Animales , Citocinas/química , Manosa/análogos & derivados , Ratones , Peso Molecular , Oligodesoxirribonucleótidos/administración & dosificación , Células RAW 264.7 , Electricidad EstáticaRESUMEN
Sodium oligomannate (®; GV-971) is a marine algae-derived oral oligosaccharide being developed by Shanghai Green Valley Pharmaceuticals for the treatment of Alzheimer's disease (AD). Sodium oligomannate received its first approval in November 2019 in China for the treatment of mild to moderate AD to improve cognitive function. This article summarizes the milestones in the development of sodium oligomannate leading to this first approval for AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Aprobación de Drogas , Manosa/análogos & derivados , Oligosacáridos/uso terapéutico , Animales , China , Humanos , Manosa/química , Manosa/uso terapéutico , Oligosacáridos/químicaRESUMEN
Levoglucosan, a product from thermal decomposition of cellulose, is widely known as an organic tracer of biomass burning, but has also been reported from coal smoke particulate matter (PM) including lignites. This study provides direct evidence that levoglucosan is generated not only during low-temperature burning/smoldering of xylite, but also from other lignite types including detritic and detroxylitic brown coals from Poland. Moreover, only trace amounts of mannosan and galactosan have been detected in PM of lignite smoke. The hopanes in lignite smoke PM comprise the thermodynamically unstable ßß-hopanes and hopenes, with values of the homohopane index 22S/(22S + 22R) ranging from 0.02 to 0.12. This is characteristic for immature organic matter, and combined with the presence of anhydrosaccharides can be used as tracers for lignite combustion in ambient air. Furthermore, almost all Miocene lignite smoke PM samples contain α-, ß-, γ-, and δ-tocopherols, and prist-1-ene. This is the first report of the occurrence of all four tocopherol isomers in the geological record (in lignite extracts) and in lignite smoke PM samples. Lower α-tocopherol is observed for the lignite burn-test samples than in the corresponding lignite extracts, probably due to partial chain degradation to prist-1-ene during combustion.