Disrupted de novo pyrimidine biosynthesis impairs adult hippocampal neurogenesis and cognition in pyridoxine-dependent epilepsy.

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

Storax Attenuates Cardiac Fibrosis following Acute Myocardial Infarction in Rats via Suppression of AT1R-Ankrd1-P53 Signaling Pathway.

Myocardial fibrosis following acute myocardial infarction (AMI) seriously affects the prognosis and survival rate of patients. This study explores the role and regulation mechanism of storax, a commonly used traditional Chinese medicine for treatment of cardiovascular diseases, on myocardial fibrosis and cardiac function. The AMI rat model was established by subcutaneous injection of Isoproterenol hydrochloride (ISO). Storax (0.1, 0.2, 0.4 g/kg) was administered by gavage once/d for 7 days. Electrocardiogram, echocardiography, hemodynamic and cardiac enzyme in AMI rats were measured. HE, Masson, immunofluorescence and TUNEL staining were used to observe the degree of pathological damage, fibrosis and cardiomyocyte apoptosis in myocardial tissue, respectively. Expression of AT1R, CARP and their downstream related apoptotic proteins were detected by WB. The results demonstrated that storax could significantly improve cardiac electrophysiology and function, decrease serum cardiac enzyme activity, reduce type I and III collagen contents to improve fibrosis and alleviate myocardial pathological damage and cardiomyocyte apoptosis. It also found that storax can significantly down-regulate expression of AT1R, Ankrd1, P53, P-p53 (ser 15), Bax and cleaved Caspase-3 and up-regulate expression of Mdm2 and Bcl-2. Taken together, these findings indicated that storax effectively protected cardiomyocytes against myocardial fibrosis and cardiac dysfunction by inhibiting the AT1R-Ankrd1-P53 signaling pathway.

The Metabolite Saccharopine Impairs Neuronal Development by Inhibiting the Neurotrophic Function of Glucose-6-Phosphate Isomerase.

Mutations in the Aminoadipate-Semialdehyde Synthase (AASS) gene encoding α-aminoadipic semialdehyde synthase lead to hyperlysinemia-I, a benign metabolic variant without clinical significance, and hyperlysinemia-II with developmental delay and intellectual disability. Although both forms of hyperlysinemia display biochemical phenotypes of questionable clinical significance, an association between neurologic disorder and a pronounced biochemical abnormality remains a challenging clinical question. Here, we report that Aass mutant male and female mice carrying the R65Q mutation in α-ketoglutarate reductase (LKR) domain have an elevated cerebral lysine level and a normal brain development, whereas the Aass mutant mice carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain exhibit elevations of both cerebral lysine and saccharopine levels and a smaller brain with defective neuronal development. Mechanistically, the accumulated saccharopine, but not lysine, leads to impaired neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). While extracellular supplementation of GPI restores defective neuronal development caused by G498E mutation in SDH of Aass. Altogether, our findings not only unravel the requirement for saccharopine degradation in neuronal development, but also provide the mechanistic insights for understanding the neurometabolic disorder of hyperlysinemia-II.SIGNIFICANCE STATEMENT The association between neurologic disorder and a pronounced biochemical abnormality in hyperlysinemia remains a challenging clinical question. Here, we report that mice carrying the R65Q mutation in lysine α-ketoglutarate reductase (LKR) domain of aminoadipate-semialdehyde synthase (AASS) have an elevated cerebral lysine levels and a normal brain development, whereas those carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain of AASS exhibit an elevation of both cerebral lysine and saccharopine and a small brain with defective neuronal development. Furthermore, saccharopine impairs neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). These findings demonstrate saccharopine degradation is essential for neuronal development.

Conservation Genomics of Wild Red Sage (Salvia miltiorrhiza) and Its Endangered Relatives in China: Population Structure and Interspecific Relationships Revealed From 2b-RAD Data.

Red sage (Salvia miltiorrhiza) is a widely used medicinal plant for treatment of cardiovascular and cerebrovascular diseases. Because of excessive excavation by huge market demand and habitat loss by human activities, the wild population resources of S. miltiorrhiza have reduced drastically in recent years. Meanwhile, population status of two closely related species S. bowleyana and S. paramiltiorrhiza were in a trend of decreasing due to their potential replacement of S. miltiorrhiza. Particularly, S. paramiltiorrhiza was threatened and endemic to a small region in eastern China. However, to date there has been no conservation genetic research reported for wild S. miltiorrhiza population and its endangered relatives. Assess the wild germplasm diversity for S. miltiorrhiza and its related species would provide fundamental genetic background for cultivation and molecular breeding of this medicinally important species. In the present study, we investigated the genetic diversity, population structure, and intra/inter-specific differentiation of S. miltiorrhiza and above two relatives using 2b-RAD genome-wide genotyping method. By investigating 81 individuals of S. miltiorrhiza, 55 individuals of S. bowleyana and 15 individuals of S. paramiltiorrhiza from 23 locations in China, we obtained 23,928 SNPs in total. A comparatively high genetic diversity was observed in S. miltiorrhiza (π = 0.0788, H e = 0.0783 ± 0.0007). The observed and expected heterozygosity in populations of these three species ranged from 0.0297 to 0.1481 and 0.0251 to 0.831, respectively. Two major lineage groups were detected in the examined S. miltiorrhiza populations. The results indicated that Dabie Mountain as a genetic diversity center of S. miltiorrhiza and possible complex inter-specific genetic exchange/hybridization occurred between S. miltiorrhiza and the two relatives. We suggest that strategic conservation and germplasm preservation should be considered not only for wild populations of S. miltiorrhiza, but also for its related S. bowleyana and S. paramiltiorrhiza.

Microstructure and physiochemical properties of meat sausages based on nanocellulose-stabilized emulsions.

Here we prepared some meat sausages using soybean oil in pure liquid form or pre-emulsified form stabilized with nanocelluloses (NCs) to partially replace pork back-fat and investigated the effects of NC types (sisal cellulose nanofiber, cotton cellulose nanofiber, and cotton cellulose nanocrystal) on the physicochemical properties and microstructure of the sausages. The physicochemical properties, including cooking loss, water holding capacity (WHC), textural properties, and rheological behavior, were evaluated. The results show that the sausages with pre-emulsified oil exhibited much-improved water and fat binding capacities, with significantly increased hardness, springiness, and chewiness. Additionally, pre-emulsifying soybean oil provided a more compact structure with smaller cavities. The sausages with different NCs had no significant difference in textural and microstructural properties, whereas they presented different water and fat binding capacities. From the results, it is concluded that NC-based emulsions are a viable fat replacer for meat sausages by providing similar stability and textural attributes.

Comparative Transcriptome Analysis Reveals Differentially Expressed Genes and Signaling Pathways Between Male and Female Red-Tail Catfish (Mystus wyckioides).

Sexual dimorphism is widespread in fish species. The red-tail catfish (Mystus wyckioides) is a commercially important catfish in the lower reaches of the Lancang River and the Mekong basin, and it shows a growth advantage in males. Here, RNA-seq was for the first time used to explore the gene expression difference between the sexes in the hypothalamus and pituitary of red-tail catfish, respectively. In the hypothalamus, 5732 and 271 unigenes have significantly higher and lower expressions, respectively, in males compared with females. KEGG analysis showed that 212 DEGs were annotated to 216 signaling pathways, and enrichment analysis suggested different levels of cAMP and glutamatergic synapse signaling between male and female hypothalami and some of the DEGs appear involved in gonad development and growth. In the pituitary, we found only 19 differentially expressed unigenes, which were annotated to 32 signaling pathways, most of which play important roles in gonad development.

The complete chloroplast genome of Mexican marigold (Tagetes erecta L., Asteraceae).

Tagetes erecta is an important ornamental and medicinal plant indigenous to Mexico and Guatemala. The complete chloroplast genome of T. erecta was newly sequenced in this study. The total chloropalst genome size of T. erecta was 152,055 bp. In total, 123 genes were indetified, including 79 protein-coding genes, 8 rRNA genes, and 37 tRNA genes. Twelve genes are containing introns (ycf3 and clpP contained two introns). The overall GC content of this genome was 37.4%. A further phylogenomic analysis of Asteraceae, including 23 taxa, was conducted for the placement of genus Tagetes. The complete plastome of T. erecta will provide a valuable resource for further genetic conservation, evolution, and molecular breading studies in Asteraceae.

Hemostasis and uterine contraction promoting effect of the extract from drugs in the Zi-Yin-Tiao-Jing granule, a traditional Chinese compound preparation.

ETHNOPHARMACOLOGICAL RELEVANCE: Zi-Yin-Tiao-Jing granule (ZG) is a traditional Chinese medicine compound preparation for perimenopausal dysfunctional uterine bleeding. It is made from 9 Chinese crude drugs based on a modified traditional Chinese prescription recorded in Fu Qingzhu Nvke as Guben Zhibeng Tang. AIM OF THE STUDY: This study aimed to investigate the hemostasis and uterine contraction promoting effect of quality controlled ZG extract on animals as a preclinical study. MATERIALS AND METHODS: ZG extract was quality controlled by determining the contents of asperosaponin Ⅵ and tetrahydroxystilbene glucoside (TSG) with high-performance liquid chromatography (HPLC) and the contents of total tannins, total saponins and total flavonoids with ultraviolet spectrophotometry (UV). Bleeding time, clotting time, prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen (FIB) content were assayed to test the hemostasis effect of ZG extract on sixty healthy female Kunming mice. In addition, ten healthy female Sprague-Dawley rats were used to test the effect of ZG extract on uterine contractions in vitro with the BL-420 Biological Function Experiment System. RESULTS: The ZG extract contained 0.81mgg-1 asperosaponin Ⅵ, 0.15mgg-1 TSG, 1.98mgg-1 total tannins, 1.83mgg-1 total saponins, and 4.09mgg-1 total flavonoids. Compared with placebo, the ZG extract shortened the bleeding time at a dosage of 1.2gkg-1 and 2.4gkg-1, and shortened the clotting time at 0.6gkg-1, 1.2gkg-1 and 2.4gkg-1 in mice (P < 0.01). It also decurtated the APTT at a dosage of 0.6gkg-1 (P < 0.05) and raised the content of FIB in the plasma at a dosage of 2.4gkg-1 (P < 0.05). However, the PT showed no changes after the administration of ZG extract (P > 0.05). In addition, ZG extract at the doses of 1.8mgmL-1, 3.6mgmL-1, and 5.4mgmL-1 increased the amplitude and motoricity of uterine contractions of rats (P < 0.05 or P < 0.01) but maintained the frequency as unchanged. CONCLUSIONS: The ZG extract was quality controllable by assaying for asperosaponin Ⅵ, TSG, total tannins, total saponins and total flavonoids. It could promote the hemostasis of mice in vivo, as well as the uterine contractions of rats in vitro. Therefore, it may be a promising preparation for clinical treatment of perimenopausal dysfunctional uterine bleeding.

Characterization of the complete chloroplast genome of summer snowflake (Leucojum aestivum, Amaryllidaceae).

Leucojum aestivum (Amaryllidaceae) is an important medicinal plant native to Europe, North Africa, and Central Asia. Its wild resources are Endangered because of excavation. In the present study, the chloroplast genome of L. aestivum was sequenced. The plastome length is 157,241 bp. A total of 132 genes were identified, consisting of 86 protein-coding genes, eight rRNA genes, and 38 tRNA genes. Thirty-four species from Asparagales were used for phylogenomic analysis.

[Effect factors and mechanisms of borneol's bidirectional regulation on blood-brain barrier permeability].

In recent twenty years, there are a lot of studies about the effect of borneol on permeability of blood-brain barrier(BBB); however, it isDODOrt of regular conclusions of effect factors and in-depth analysis of functional mechanisms. The current researching data were collected and analyzed in this paper for illuminating the effect factors and mechanisms of borneol on permeability of BBB.The following conclusions were obtained: five factors about borneol influencing the permeability of BBB. First, opticity activity of borneol had no significant effect on action effects. Second, dose of borneol in the range of 50.00-200.00 mg•kg⁻¹, did not affect the effect direction, but only affect its action intensity either with use alone or combination use. Third, the borneol can increase the permeability of physiological BBB, and decrease the permeability of pathological BBB. Fourth, regardless of using singly or using compatibility with musk, borneol can decrease the permeability of BBB in different brain disease models. Fifth, when used with astragalus, catalpol or puerarin, borneol can increase the permeability of BBB and promote the drugs through BBB in pathological conditions. The target spots and mechanisms of borneol's bidirectional regulation on the permeability of BBB are related to the structure and function of cerebral endothelial cells, the exocytosis effects of P-gp and low pinocytosis internal transport effects. On one hand，borneol can down-regulate P-gp by inhibiting NF-κB to reduce the exocytosis effects of P-gp and promote the blood brain barrier pinocytosis to increase the permeability of BBB; On the other hand，borneol can reduce the degradation of basement membrane of blood vessel and tight junctions by inhibiting the expression of IL-1ß, MMP-9 to decrease the permeability of BBB；moreover，borneol has bidirectional regulation effects on blood-brain barrier permeability by influencing the signaling pathways of Ca2+-eNOS-NO, VEGF-eNOS-NO. However, the detailed mechanisms that borneol regulates and controls the permeability of BBB are so complicated, so they shall be further proved and clarified.

Characterization of a Novel α-l-Arabinofuranosidase from Ruminococcus albus 7 and Rational Design for Its Thermostability.

An α-l-arabinofuranosidase (Abf) encoding gene was obtained via genomic mining from a Ruminococcus albus strain. The specific activity of this GH 51 Abf was 73.3 U/mg at pH 6.0 and 50 °C. The modification of Abf, aimed at improving thermostability, was performed through different strategies. Structure-based rational design using the PoPMuSiC and the Enzyme Thermal Stability System (ETSS) predicted thermal stability of Abf and enhanced the half-life of thermal inactivation (t1/2) at 50 °C for K208W more than 11.1 times versus the wild-type (WT). Sequence-based rational design was also conducted by substituting histidine with lysine at various sites. Among eight mutants, the t1/2 at 50 °C of H337K was prolonged by 5.0-fold, and the specific activity of this mutant was increased to 121.8 U/mg. In addition, the mutant H337K was utilized with some enzymes to extract pectin from apple pomace. The enzymatically produced pectin got less moisture and ash, milder pH, and higher viscosity than its acid-extracted counterpart, indicating that Abf has an application prospect in pectin production.

[Borneol promotes catalpol and puerarin crossing through blood-brain barrier in focal cerebral ischemic rats].

Previous studies showed that borneol could promote some drugs crossing through the blood-brain-barrier (BBB) at certain conditions. However, the mechanism has not been clarified yet. This study aimed to investigate the effect of bornrol on promoting catalpol and puerarin through BBB and explore the relevant mechanism. The focal cerebral ischemic rats were divided into 7 groups randomly and then were administered corresponding drugs: model group (M, solvent), catalpol-puerarin group (ZG, catalpol 45 mg•kg⁻¹+puerarin 200 mg•kg⁻¹), catalpol-puerarin-bornrol group(ZGB, catalpol 45 mg•kg⁻¹+puerarin 200 mg•kg⁻¹ +bornrol 200 mg•kg⁻¹), catalpol-bornrol group(ZB, catalpol 45 mg•kg⁻¹ +bornrol 200 mg•kg⁻¹), puerarin-bornrol group(GB, puerarin 200 mg•kg⁻¹ +bornrol 200 mg•kg⁻¹), butoxamine-ZG group(BTX+ZG, butoxamine 1.5 mg•kg⁻¹+ catalpol 45 mg•kg⁻¹+puerarin 200 mg•kg⁻¹), and butoxamine-ZGB group(BTX+ZGB, butoxamine 1.5 mg•kg⁻¹+ catalpol 45 mg•kg⁻¹+puerarin 200 mg•kg⁻¹ +bornrol 200 mg•kg⁻¹). Another 10 sham-operated rats were set as control (S). Ten minutes after the administration, the cerebrospinal fluid was taken to test the content of catalpol and puerarin, and the brain tissue was taken to test the expression of ß2-adrenergic receptor, eNOS, and NO. Compared with the M group, the ZG group showed content of catalpol is 26.673 µg•L⁻¹ and the content of puerarin is below the detection limit;the expression levels of ß2-adrenergic receptor, eNOS and the contents of NO in brain tissue are no significant difference. Compared with the ZG group, the ZGB, ZB and GB groups showed significantly increased content of catalpol andpuerarin, as well as the expression of ß2-adrenergic receptor, eNOS and NO in the brain tissue (P<0.05). The content of catalpol in BTX+ZG group changed non-significantly. Compared with the ZGB group, the BTX+ZGB group presented significantly decreased content of catalpol and puerarin and reduced expression of eNOS and NO in the brain tissue (P<0.05）.The results demonstrated that borneol could dramatically promote catalpol and puerarin crossing through BBB in the focal cerebral ischemic rats. Moreover, the effect may be related to the up-regulation of ß2-adrenergic receptor and the increasing expression of eNOS and NO.

Rosiglitazone protects against palmitate-induced pancreatic beta-cell death by activation of autophagy via 5'-AMP-activated protein kinase modulation.

Promoting beta-cell survival is crucial for the prevention of beta-cell failure in diabetes. Thiazolidinediones, a widely used drug to improve insulin sensitivity in clinical practice, is found to have a protective effect on islet beta-cell. To date, the mechanism underlying the protective role of thiazolidinedione on beta-cell survival remain largely unknown. Activation of autophagy was detected by transmission electron microscopy, western blot, and GFP-LC3 transfection. Cell viability was examined by WST-8. Cell apoptosis was demonstrated by DAPI and Annexin V/PI staining. Colony formation assay was used to detect long-term cell viability. We demonstrated that rosiglitazone-treated beta-cells were more resistant to palmitate-induced apoptosis. The conversion of LC3-I to LC3-II and accumulated autophagosomes were found to be upregulated in rosiglitazone-treated cells. Inhibition of autophagy augmented palmitate-induced apoptosis with rosiglitazone treatment, suggesting that autophagy plays an important role in the survival function of rosiglitazone on beta-cells. Furthermore, we showed that rosiglitazone could induce AMP-activated protein kinase (AMPK) phosphorylation and reduce p70S6 kinase phosphorylation. Inhibition of AMPK impaired autophagy activation and enhanced palmitate-induced apoptosis during rosiglitazone treatment. These findings reveal that rosiglitazone-induced autophagy contributes to its protective function on beta-cells during palmitate treatment.

Graph theoretical analysis of EEG functional connectivity during music perception.

The present study evaluated the effect of music on large-scale structure of functional brain networks using graph theoretical concepts. While most studies on music perception used Western music as an acoustic stimulus, Guqin music, representative of Eastern music, was selected for this experiment to increase our knowledge of music perception. Electroencephalography (EEG) was recorded from non-musician volunteers in three conditions: Guqin music, noise and silence backgrounds. Phase coherence was calculated in the alpha band and between all pairs of EEG channels to construct correlation matrices. Each resulting matrix was converted into a weighted graph using a threshold, and two network measures: the clustering coefficient and characteristic path length were calculated. Music perception was found to display a higher level mean phase coherence. Over the whole range of thresholds, the clustering coefficient was larger while listening to music, whereas the path length was smaller. Networks in music background still had a shorter characteristic path length even after the correction for differences in mean synchronization level among background conditions. This topological change indicated a more optimal structure under music perception. Thus, prominent small-world properties are confirmed in functional brain networks. Furthermore, music perception shows an increase of functional connectivity and an enhancement of small-world network organizations.