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Marine Drugs Apr 2024Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and accumulating evidence suggests a link between dysbiosis of the gut microbiota and the onset and...
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 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 , Verrucomicrobiota, and , while promoting the abundance of and 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.
Topics: Animals; Gastrointestinal Microbiome; Mice; Oligosaccharides; Disease Models, Animal; Male; Mice, Inbred C57BL; Neuroprotective Agents; Dysbiosis; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Dopaminergic Neurons; Parkinson Disease; Mannose; Glucuronates
PubMed: 38786584
DOI: 10.3390/md22050193 -
Biomolecules Apr 2024Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting a growing number of elderly people. In order to improve the early and differential...
Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting a growing number of elderly people. In order to improve the early and differential diagnosis of AD, better biomarkers are needed. Glycosylation is a protein post-translational modification that is modulated in the course of many diseases, including neurodegeneration. Aiming to improve AD diagnosis and differential diagnosis through glycan analytics methods, we report the glycoprotein glycome of cerebrospinal fluid (CSF) isolated from a total study cohort of 262 subjects. The study cohort consisted of patients with AD, healthy controls and patients suffering from other types of dementia. CSF free-glycans were also isolated and analyzed in this study, and the results reported for the first time the presence of 19 free glycans in this body fluid. The free-glycans consisted of complete or truncated N-/O-glycans as well as free monosaccharides. The free-glycans Hex and HexNAcHexNeu5Ac were able to discriminate AD from controls and from patients suffering from other types of dementia. Regarding CSF N-glycosylation, high proportions of high-mannose, biantennary bisecting core-fucosylated N-glycans were found, whereby only about 20% of the N-glycans were sialylated. O-Glycans and free-glycan fragments were less sialylated in AD patients than in controls. To conclude, this comprehensive study revealed for the first time the biomarker potential of free glycans for the differential diagnosis of AD.
Topics: Alzheimer Disease; Humans; Biomarkers; Polysaccharides; Male; Female; Aged; Glycosylation; Middle Aged; Aged, 80 and over; Glycoproteins; Case-Control Studies
PubMed: 38785920
DOI: 10.3390/biom14050512 -
IScience Jun 2024[This corrects the article DOI: 10.1016/j.isci.2019.09.028.].
[This corrects the article DOI: 10.1016/j.isci.2019.09.028.].
PubMed: 38784014
DOI: 10.1016/j.isci.2024.110004 -
The Journal of General Virology May 2024Porcine reproductive and respiratory syndrome (PRRSV) is an enveloped single-stranded positive-sense RNA virus and one of the main pathogens that causes the most...
Porcine reproductive and respiratory syndrome (PRRSV) is an enveloped single-stranded positive-sense RNA virus and one of the main pathogens that causes the most significant economical losses in the swine-producing countries. PRRSV is currently divided into two distinct species, PRRSV-1 and PRRSV-2. The PRRSV virion envelope is composed of four glycosylated membrane proteins and three non-glycosylated envelope proteins. Previous work has suggested that PRRSV-linked glycans are critical structural components for virus assembly. In addition, it has been proposed that PRRSV glycans are implicated in the interaction with host cells and critical for virus infection. In contrast, recent findings showed that removal of N-glycans from PRRSV does not influence virus infection of permissive cells. Thus, there are not sufficient evidences to indicate compellingly that N-glycans present in the PRRSV envelope play a direct function in viral infection. To gain insights into the role of N-glycosylation in PRRSV infection, we analysed the specific contribution of the envelope protein-linked N-glycans to infection of permissive cells. For this purpose, we used a novel strategy to modify envelope protein-linked N-glycans that consists of production of monoglycosylated PRRSV and viral glycoproteins with different glycan states. Our results showed that removal or alteration of N-glycans from PRRSV affected virus infection. Specifically, we found that complex N-glycans are required for an efficient infection in cell cultures. Furthermore, we found that presence of high mannose type glycans on PRRSV surface is the minimal requirement for a productive viral infection. Our findings also show that PRRSV-1 and PRRSV-2 have different requirements of N-glycan structure for an optimal infection. In addition, we demonstrated that removal of N-glycans from PRRSV does not affect viral attachment, suggesting that these carbohydrates played a major role in regulating viral entry. In agreement with these findings, by performing immunoprecipitation assays and colocalization experiments, we found that N-glycans present in the viral envelope glycoproteins are not required to bind to the essential viral receptor CD163. Finally, we found that the presence of N-glycans in CD163 is not required for PRRSV infection.
Topics: Porcine respiratory and reproductive syndrome virus; Glycosylation; Animals; Swine; Polysaccharides; Porcine Reproductive and Respiratory Syndrome; Viral Envelope Proteins; Cell Line; Receptors, Cell Surface; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Viral Envelope
PubMed: 38776134
DOI: 10.1099/jgv.0.001994 -
Virulence Dec 2024infection is an important cause of public health diseases, and no effective vaccine is currently available. Owing to its unique intracellular lifestyle, requires a... (Review)
Review
infection is an important cause of public health diseases, and no effective vaccine is currently available. Owing to its unique intracellular lifestyle, requires a variety of nutrients and substrates from host cells, particularly sphingomyelin, cholesterol, iron, amino acids, and the mannose-6-phosphate receptor, which are essential for inclusion development. Here, we summarize the recent advances in nutrient acquisition mechanism by hijacking host cell vesicular transport, which plays an important role in chlamydial growth and development. obtains the components necessary to complete its intracellular developmental cycle by recruiting Rab proteins (major vesicular trafficking regulators) and Rab effector proteins to the inclusion, interfering with Rab-mediated multivesicular trafficking, reorienting the nutrition of host cells, and reconstructing the intracellular niche environment. Consequently, exploring the role of vesicular transport in nutrient acquisition offers a novel perspective on new approaches for preventing and treating infection.
Topics: Humans; Chlamydia Infections; Chlamydia; Nutrients; Host-Pathogen Interactions; Animals; Biological Transport
PubMed: 38773735
DOI: 10.1080/21505594.2024.2351234 -
Ultrasonics Sonochemistry Jul 2024In this research, the extraction process of polysaccharides from Pithecellobium clypearia Benth (PCBPs) was optimized using dual-frequency ultrasound-assisted extraction...
Extraction of Pithecellobium clypearia Benth polysaccharides by dual-frequency ultrasound-assisted extraction: Structural characterization, antioxidant, hypoglycemic and anti-hyperlipidemic activities.
In this research, the extraction process of polysaccharides from Pithecellobium clypearia Benth (PCBPs) was optimized using dual-frequency ultrasound-assisted extraction (DUAE). The biological activities of PCBPs were investigated by in vitro antioxidant, hypoglycemic, and anti-hyperlipidemic assay. High-performance anion-exchange chromatography, high-performance gel permeation chromatography, SEM, UV-Vis spectroscopy, and FT-IR spectra were used to analyze the monosaccharide composition, molecular weight, microscopic morphology, and characteristic structure of PCBPs. The results showed that the maximum extraction rate of PCBPs was 9.90 ± 0.16% when the ultrasonic time was 8 min, the liquid-to-material ratio was 32 mL/g, and the ultrasonic power was 510 W. The PCBPs also possessed excellent in vitro antioxidant, hypoglycemic, and anti-hyperlipidemic activities. In addition, the average molecular weight of PCBPs was 15.07 kDa. PCBPs consisted of rhamnose, arabinose, galactose, glucose, xylose, mannose, and glucuronic acid, with the molar ratios of 11.07%, 18.54%, 48.17%, 10.44%, 4.62%, 4.96%, and 2.20%, respectively. Moreover, the results of SEM showed that PCBPs mainly showed a fine spherical mesh structure. The above studies provided a valuable theoretical basis for the subsequent in-depth study of PCBPs.
Topics: Antioxidants; Polysaccharides; Hypoglycemic Agents; Ultrasonic Waves; Hypolipidemic Agents; Chemical Fractionation; Fabaceae; Molecular Weight; Animals
PubMed: 38772313
DOI: 10.1016/j.ultsonch.2024.106918 -
Biochemistry May 2024Cyanovirin-N (CV-N) binds high-mannose oligosaccharides on enveloped viruses with two carbohydrate-binding sites, one bearing high affinity and one low affinity to...
Cyanovirin-N (CV-N) binds high-mannose oligosaccharides on enveloped viruses with two carbohydrate-binding sites, one bearing high affinity and one low affinity to Manα(1-2)Man moieties. A tandem repeat of two CV-N molecules (CVN2) was tested for antiviral activity against human immunodeficiency virus type I (HIV-1) by using a domain-swapped dimer. CV-N was shown to bind -acetylmannosamine (ManNAc) and -acetyl-d-glucosamine (GlcNAc) when the carbohydrate-binding sites in CV-N were free to interact with these monosaccharides independently. CVN2 recognized ManNAc at a of 1.4 μM and bound this sugar in solution, regardless of the lectin making amino acid side chain contacts on the targeted viral glycoproteins. An interdomain cross-contacting residue Glu41, which has been shown to be hydrogen bonding with dimannose, was substituted in the monomeric CV-N. The amide derivative of glucose, GlcNAc, achieved similar high affinity to the new variant CVN-E41T as high-mannose -glycans, but binding to CVN2 in the nanomolar range with four binding sites involved or binding to the monomeric CVN-E41A. A stable dimer was engineered and expressed from the alanine-to-threonine-substituted monomer to confirm binding to GlcNAc. In summary, low-affinity binding was achieved by CVN2 to dimannosylated peptide or GlcNAc with two carbohydrate-binding sites of differing affinities, mimicking biological interactions with the respective -linked glycans of interest and cross-linking of carbohydrates on human T cells for lymphocyte activation.
Topics: Acetylglucosamine; Binding Sites; Bacterial Proteins; Carrier Proteins; Humans; HIV-1; Protein Binding; Hexosamines; Models, Molecular; Protein Multimerization
PubMed: 38770609
DOI: 10.1021/acs.biochem.4c00113 -
Frontiers in Genetics 2024This report outlines the case of a child affected by a type of congenital disorder of glycosylation (CDG) known as ALG2-CDG (OMIM 607906), presenting as a congenital...
This report outlines the case of a child affected by a type of congenital disorder of glycosylation (CDG) known as ALG2-CDG (OMIM 607906), presenting as a congenital myasthenic syndrome (CMS) caused by variants identified in , which encodes an α1,3-mannosyltransferase (EC 2.4.1.132) involved in the early steps of N-glycosylation. To date, fourteen cases of ALG2-CDG have been documented worldwide. From birth, the child experienced perinatal asphyxia, muscular weakness, feeding difficulties linked to an absence of the sucking reflex, congenital hip dislocation, and hypotonia. Over time, additional complications emerged, such as inspiratory stridor, gastroesophageal reflux, low intake, recurrent seizures, respiratory infections, an inability to maintain the head upright, and a global developmental delay. Whole genome sequencing (WGS) revealed the presence of two variants in compound heterozygosity: a novel variant c.1055_1056delinsTGA p.(Ser352Leufs*3) and a variant of uncertain significance (VUS) c.964C>A p.(Pro322Thr). Additional studies, including determination of carbohydrate-deficient transferrin (CDT) revealed a mild type I CDG pattern and the presence of an abnormal transferrin glycoform containing a linear heptasaccharide consisting of one sialic acid, one galactose, one N-acetyl-glucosamine, two mannoses and two N-acetylglucosamines (NeuAc-Gal-GlcNAc-Man2-GlcNAc2), ALG2-CDG diagnostic biomarker, confirming the pathogenicity of these variants.
PubMed: 38770420
DOI: 10.3389/fgene.2024.1363558 -
World Journal of Gastrointestinal... May 2024Limited knowledge exists regarding the casual associations linking blood metabolites and the risk of developing colorectal cancer.
BACKGROUND
Limited knowledge exists regarding the casual associations linking blood metabolites and the risk of developing colorectal cancer.
AIM
To investigate causal associations between blood metabolites and colon cancer.
METHODS
The study utilized a two-sample Mendelian randomization (MR) analysis to investigate the causal impact of 486 blood metabolites on colorectal cancer. The primary method of analysis used was the inverse variance weighted model. To further validate the results several sensitivity analyses were performed, including Cochran's Q test, MR-Egger intercept test, and MR robust adjusted profile score. These additional analyses were conducted to ensure the reliability and robustness of the findings.
RESULTS
After rigorous selection for genetic variation, 486 blood metabolites were included in the MR analysis. We found Mannose [odds ratio (OR) = 2.09 (1.10-3.97), = 0.024], N-acetylglycine [OR = 3.14 (1.78-5.53), = 7.54 × 10], X-11593-O-methylascorbate [OR = 1.68 (1.04-2.72), = 0.034], 1-arachidonoylglycerophosphocholine [OR = 4.23 (2.51-7.12), = 6.35 × 10] and 1-arachidonoylglycerophosphoethanolamine 4 [OR = 3.99 (1.17-13.54), = 0.027] were positively causally associated with colorectal cancer, and we also found a negative causal relationship between Tyrosine [OR = 0.08 (0.01-0.63), = 0.014], Urate [OR = 0.25 (0.10-0.62), = 0.003], N-acetylglycine [0.73 (0.54-0.98), = 0.033], X-12092 [OR = 0.89 (0.81-0.99), = 0.028], Succinylcarnitine [OR = 0.48 (0.27-0.84), = 0.09] with colorectal cancer. A series of sensitivity analyses were performed to confirm the rigidity of the results.
CONCLUSION
This study showed a causal relationship between 10 blood metabolites and colorectal cancer, of which 5 blood metabolites were found to be causal for the development of colorectal cancer and were confirmed as risk factors. The other five blood metabolites are protective factors.
PubMed: 38764807
DOI: 10.4251/wjgo.v16.i5.1995 -
The Journal of Biological Chemistry May 2024The stepwise addition of monosaccharides to N-glycans attached to client proteins to generate a repertoire of mature proteins involves a concerted action of many...
The stepwise addition of monosaccharides to N-glycans attached to client proteins to generate a repertoire of mature proteins involves a concerted action of many glycosidases and glycosyltransferases. Here, we report that Golgi α-mannosidase II (GMII), a pivotal enzyme catalyzing the first step in the conversion of hybrid- to complex-type N-glycans, is activated by Zn supplied by the early secretory compartment-resident ZNT5-ZNT6 heterodimers (ZNT5-6) and ZNT7 homodimers (ZNT7). Loss of ZNT5-6 and ZNT7 function results in marked accumulation of hybrid-type and complex/hybrid glycans with concomitant reduction of complex- and high-mannose-type glycans. In cells lacking the ZNT5-6 and ZNT7 functions, the GMII activity is substantially decreased. In contrast, the activity of its homolog, lysosomal mannosidase (LAMAN), is not decreased. Moreover, we show that the growth of pancreatic cancer MIA PaCa-2 cells lacking ZNT5-6 and ZNT7 is significantly decreased in a nude mouse xenograft model. Our results indicate the integral roles of ZNT5-6 and ZNT7 in N-glycosylation and highlight their potential as novel target proteins for cancer therapy.
PubMed: 38762179
DOI: 10.1016/j.jbc.2024.107378