2-Deoxyglucose alleviates migraine-related behaviors by modulating microglial inflammatory factors in experimental model of migraine

BackgroundTargeting metabolic pathways has emerged as a new migraine treatment strategy as researchers realize the critical role metabolism plays in migraine. Activated inflammatory cells undergo metabolic reprogramming and rely on glycolysis to function. The objective of this study was to investigate the glycolysis changes in the experimental model of migraine and the effect of glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) in the pathophysiology of migraine.MethodsWe used a rat model of migraine that triggered migraine attacks by applying inflammatory soup (IS) to the dura and examined changes in glycolysis. 2-DG was used to inhibit glycolysis, and the effects of 2-DG on mechanical ectopic pain, microglial cell activation, calcitonin gene-related peptides (CGRP), c-Fos, and inflammatory factors induced by inflammatory soup were observed. LPS stimulated BV2 cells to establish a model in vitro to observe the effects of 2-DG on brain-derived neurotrophic factor (BDNF) after microglia activation.ResultsIn the experimental model of migraine, key enzymes involved in glycolysis such as phosphofructokinase platelet (PFKP), hexokinase (HK2), hypoxia inducible factor-1α (HIF-1α), lactate dehydrogenase (LDH) and pyruvate kinase (PKM2) were expressed in the medullary dorsal horn. While the expression of electronic respiratory transport chain complex IV (COXIV) decreased. There were no significant changes in glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. The glycolysis inhibitor 2-DG alleviated migraine-like symptoms in an experimental model of migraine, reduced the release of proinflammatory cytokines caused by microglia activation, and decreased the expression of CGRP and c-Fos. Further experiments in vitro demonstrated that glycolysis inhibition can reduce the release of Iba-1/proBDNF/BDNF and inhibit the activation of microglia.ConclusionThe migraine rat model showed enhanced glycolysis. This study suggests that glycolytic inhibitor 2-DG is an effective strategy for alleviating migraine-like symptoms. Glycolysis inhibition may be a new target for migraine treatment

Purkinje Cell Degeneration and Motor Coordination Deficits in a New Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disorder. In 2007, a novel locus, SAX2, which is located on chromosome 17p13 and contains 3 genes, ankyrin repeat and FYVE domain-containing 1 (ANKFY1), β-arrestin 2 (ARRB2) and kinesin family member 1C (KIF1C), was linked to ARSACS. We generated Ankfy1 heterozygous (Ankfy1/+) mice to establish an animal model and examine the pathophysiological basis of ARSACS. The transgenic mice displayed an abnormal gait with progressive motor and cerebellar nerve dysfunction that was highly reminiscent of ARSACS. These clinical features were accompanied by an early-onset and progressive loss of Purkinje cells, followed by gliosis. Additionally, the loss of Ankfy1 function resulted in an abnormal expression of neurotrophic factors (NTFs) in the Ankfy1/+ mouse cerebellum. Moreover, Purkinje cells cultured from neonatal Ankfy1/+ mice exhibited a shorter dendritic length and decreased numbers of dendritic spines. Importantly, cerebellar Purkinje cells from Ankfy1/+ mice and cells transfected with a lentiviral Ankfy1 shRNA underwent apoptosis. We propose that transgenic Ankfy1/+ mice are a useful model for studying the pathogenesis of ARSACS and for exploring the molecular mechanisms involved in this neurodegenerative disease

Unraveling Mechanisms and Impact of Microbial Recruitment on Oilseed Rape (<i>Brassica napus</i> L.) and the Rhizosphere Mediated by Plant Growth-Promoting Rhizobacteria

Plant growth-promoting rhizobacteria (PGPR) are noticeably applied to enhance plant nutrient acquisition and improve plant growth and health. However, limited information is available on the compositional dynamics of rhizobacteria communities with PGPR inoculation. In this study, we investigated the effects of three PGPR strains, Stenotrophomonas rhizophila, Rhodobacter sphaeroides, and Bacillus amyloliquefaciens on the ecophysiological properties of Oilseed rape (Brassica napus L.), rhizosphere, and bulk soil; moreover, we assessed rhizobacterial community composition using high-throughput Illumina sequencing of 16S rRNA genes. Inoculation with S. rhizophila, R. sphaeroides, and B. amyloliquefaciens, significantly increased the plant total N (TN) (p R. sphaeroides and B. amyloliquefaciens selectively enhanced the growth of Pseudomonadacea and Flavobacteriaceae, whereas S. rhizophila could recruit diazotrophic rhizobacteria, members of Cyanobacteria and Actinobacteria, whose abundance was positively correlated with inoculation, and improved the transformation of organic nitrogen into inorganic nitrogen through the promotion of ammonification. Initial colonization by PGPR in the rhizosphere affected the rhizobacterial community composition throughout the plant life cycle. Network analysis indicated that PGPR had species-dependent effects on niche competition in the rhizosphere. These results provide a better understanding of PGPR-plant-rhizobacteria interactions, which is necessary to develop the application of PGPR

Genetic diversity of diazotrophs and total bacteria in the phyllosphere of Pyrus serotina, Prunus armeniaca, Prunus avium, and Vitis vinifera

Phyllosphere, which supports a large number of microorganisms, represents the interface between the aboveground parts of plants and air. In this study, four nifH clone libraries were constructed from the phyllosphere of Pyrus serotina (L), Vitis vinifera (P), Prunus armeniaca (X), and Prunus avium (Y). Clones related to Skermanella (L, 12.1%; X, 15.6%; Y, 62.5%; P 70.8%), Bradyrhizobium (L, 63.7%; P, 15.1%; X, 2.1%), Erwinia (X, 68.8%), Pseudomonas (L, 3.3%; P, 7.6%), and Chroococcidiopsis (L, 4.4%, X; 5.2%, Y; 19.6%, P, 0.9%) occurred at high percentage, highlighting their critical role in contributing nitrogen to phyllosphere ecosystem. The 16S rDNA sequence analysis suggested that bacteria associated with phyllosphere affiliated with a wide range of taxa, encompassing members from Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Deltaproteobacteria, Actinobacteria, Bacteroidetes, Firmicutes, Cyanobacteria, Tenericutes, and Deinococcus-Thermus. Additionally, the abundance of nifH gene and 16S rDNA was assessed with quantitative PCR. Copy numbers of nifH and 16S rDNA ranged from 1.14 × 103 to 1.49 × 104 and 3.72 × 106 to 7.02 × 107 (copies/g fresh leaf sample), respectively. In conclusion, our work sheds light on the microbe communities in phyllosphere, which were important for pant growth. Moreover, we observed the unique composition of nitrogen-fixing bacteria in each phyllosphere sample, suggesting specific interactions between these functional microorganism and plants, and may provide information or reference for developing bacterial fertilizer.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Unraveling Mechanisms and Impact of Microbial Recruitment on Oilseed Rape (Brassica napus L.) and the Rhizosphere Mediated by Plant Growth-Promoting Rhizobacteria

Plant growth-promoting rhizobacteria (PGPR) are noticeably applied to enhance plant nutrient acquisition and improve plant growth and health. However, limited information is available on the compositional dynamics of rhizobacteria communities with PGPR inoculation. In this study, we investigated the effects of three PGPR strains, Stenotrophomonas rhizophila, Rhodobacter sphaeroides, and Bacillus amyloliquefaciens on the ecophysiological properties of Oilseed rape (Brassica napus L.), rhizosphere, and bulk soil; moreover, we assessed rhizobacterial community composition using high-throughput Illumina sequencing of 16S rRNA genes. Inoculation with S. rhizophila, R. sphaeroides, and B. amyloliquefaciens, significantly increased the plant total N (TN) (p &lt; 0.01) content. R. sphaeroides and B. amyloliquefaciens selectively enhanced the growth of Pseudomonadacea and Flavobacteriaceae, whereas S. rhizophila could recruit diazotrophic rhizobacteria, members of Cyanobacteria and Actinobacteria, whose abundance was positively correlated with inoculation, and improved the transformation of organic nitrogen into inorganic nitrogen through the promotion of ammonification. Initial colonization by PGPR in the rhizosphere affected the rhizobacterial community composition throughout the plant life cycle. Network analysis indicated that PGPR had species-dependent effects on niche competition in the rhizosphere. These results provide a better understanding of PGPR-plant-rhizobacteria interactions, which is necessary to develop the application of PGPR

Comparison Between the Fecal Bacterial Microbiota of Healthy and Diarrheic Captive Musk Deer

Diarrhea constitutes one of the most common diseases affecting the survival of captive musk deer and is usually caused by an imbalance in intestinal microbiota. Currently, research regarding the structure and function of intestinal microbiota in diarrheic musk deer is lacking. Therefore, in the present study, high-throughput 16S-rRNA gene sequencing was used to analyze the intestinal microbiota in feces of healthy captive musk deer (HMD) (n = 8) and musk deer with mild (MMD) (n = 8), and severe (n = 5) (SMD) diarrhea to compare the difference in intestinal microbiota of musk deer under various physiological conditions. The results showed that the diversity of HMD fecal microbiota was significantly higher than that of the two diarrhea samples. β Diversity results indicated that there were extremely significant differences in bacterial communities between the HMD sample and the MMD and SMD samples. However, no significant difference was found between the two diarrhea samples. LefSe analysis showed that the degree of intestinal physiological dysfunction in musk deer was correlated with the types of major pathogens. The main pathogen in the MMD group is Escherichia–Shigella, whereas Fusobacterium is the main pathogen in the SMD group. PICRUSt functional profile prediction indicated that the intestinal microbiota disorder could also lead to changes in the abundance of genes in metabolic pathways of the immune system. Altogether, this study provides a theoretical basis for the exploration of treatments for diarrhea in captive musk deer, which is of considerable significance to the implementation of the musk deer release into the wild program

Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function

MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors) are synaptic cell surface molecules that regulate the formation of trans-synaptic bridges between neurexins (NRXNs) and neuroligins (NLGNs), which promote synaptic development. Mutations in MDGAs are implicated in various neuropsychiatric diseases. MDGAs bind NLGNs in cis on the postsynaptic membrane and physically block NLGNs from binding to NRXNs. In crystal structures, the six immunoglobulin (Ig) and single fibronectin III domains of MDGA1 reveal a striking compact, triangular shape, both alone and in complex with NLGNs. Whether this unusual domain arrangement is required for biological function or other arrangements occur with different functional outcomes is unknown. Here, we show that WT MDGA1 can adopt both compact and extended 3D conformations that bind NLGN2. Designer mutants targeting strategic molecular elbows in MDGA1 alter the distribution of 3D conformations while leaving the binding affinity between soluble ectodomains of MDGA1 and NLGN2 intact. In contrast, in a cellular context, these mutants result in unique combinations of functional consequences, including altered binding to NLGN2, decreased capacity to conceal NLGN2 from NRXN1β, and/or suppressed NLGN2-mediated inhibitory presynaptic differentiation, despite the mutations being located far from the MDGA1-NLGN2 interaction site. Thus, the 3D conformation of the entire MDGA1 ectodomain appears critical for its function, and its NLGN-binding site on Ig1-Ig2 is not independent of the rest of the molecule. As a result, global 3D conformational changes to the MDGA1 ectodomain via strategic elbows may form a molecular mechanism to regulate MDGA1 action within the synaptic cleft

Comparative Analysis of Gut Microbiota Changes in Père David's Deer Populations in Beijing Milu Park and Shishou, Hubei Province in China

This study used 16S rRNA high-throughput sequencing technology to examine the differences in gut microbiota between the Père David's deer populations in the Beijing and Shishou areas of China in order to understand the effects of ex situ conservation on the intestinal microflora in the Père David's deer.Results: On the phylum level, the main bacteria found in the Père David's deer populations from both areas were similar: Firmicutes and Bacteroidetes. However, the relative abundances of the two groups were significantly different. Alpha diversity results indicated that there was a difference in the evenness of the microflora between the two groups, and the beta diversity results further indicated that there was a significant difference in the microflora structure between the two groups.Conclusions: During the ex situ conservation process of the Père David's deer, their food sources may change, resulting in differences in the gut microbiota. The intestinal microflora in the Père David's deer from the same area are clustered. Therefore, the impact of changes in food on the gut microbiota of the Père David's deer should be taken into consideration during ex situ conservation

Comparative Analysis of the Gut Microbiota Composition between Captive and Wild Forest Musk Deer

The large and complex gut microbiota in animals has profound effects on feed utilization and metabolism. Currently, gastrointestinal diseases due to dysregulated gut microbiota are considered important factors that limit growth of the captive forest musk deer population. Compared with captive forest musk deer, wild forest musk deer have a wider feeding range with no dietary limitations, and their gut microbiota are in a relatively natural state. However, no reports have compared the gut microbiota between wild and captive forest musk deer. To gain insight into the composition of gut microbiota in forest musk deer under different food-source conditions, we employed high-throughput 16S rRNA sequencing technology to investigate differences in the gut microbiota occurring between captive and wild forest musk deer. Both captive and wild forest musk deer showed similar microbiota at the phylum level, which consisted mainly of Firmicutes and Bacteroidetes, although significant differences were found in their relative abundances between both groups. α-Diversity results showed that no significant differences occurred in the microbiota between both groups, while β-diversity results showed that significant differences did occur in their microbiota compositions. In summary, our results provide important information for improving feed preparation for captive forest musk deer and implementing projects where captive forest musk deer are released into the wild