Serum and urine metabolomics based on UPLC-QTOF/MS reveal the effect and potential mechanism of "schisandra-evodia" herb pair in the treatment of Alzheimer's disease.

The "schisandra-evodia" herb pair (S-E) is a herbal preparation to treat Alzheimer's disease (AD). This study aims to investigate the therapeutic efficacy and potential mechanism of S-E in AD rats, utilizing pharmacodynamic assessments and serum- and urine-based metabolomic analyses. Pharmacodynamic assessments included Morris water maze test, hematoxylin-eosin staining and immunohistochemistry experiments. The results of the study showed that the AD model was successful; the S-E significantly enhanced long-term memory and spatial learning in AD rats. Meanwhile, S-E notably ameliorated Aß25-35-induced cognitive impairment, improved hippocampal neuron morphology, decreased Aß deposition in the hippocampus and mitigated inflammatory damage. We then analyzed serum and urine samples using UPLC-MS/MS to identify potential biomarkers and metabolic pathways. Metabolomic analysis revealed alterations in 40 serum metabolites and 38 urine metabolites following S-E treatment, predominantly affecting pathways related to taurine and hypotaurine metabolism, linoleic acid metabolism, α-linolenic acid metabolism, glycerophospholipid metabolism and arachidonic acid metabolism. This study elucidates the biochemical mechanism underlying AD and the metabolic pathway influenced by S-E, laying the groundwork for future clinical applications.

The ENG/VEGFα Pathway Is Likely Affected by a Nonsense Variant of Endoglin (ENG)/CD105, Causing Hereditary Hemorrhagic Telangiectasia Type 1 (HHT1) in a Chinese Family.

Hereditary hemorrhagic telangiectasia (HHT), also called Rendu-Osler syndrome, is a group of rare genetic diseases characterized by autosomal dominance, multisystemic vascular dysplasia, and age-related penetrance. This includes arteriovenous malformations (AVMs) in the skin, brain, lung, liver, and mucous membranes. The correlations between the phenotype and genotype for HHT are not clear. An HHT Chinese pedigree was recruited. Whole exome sequencing (WES) analysis, Sanger verification, and co-segregation were conducted. Western blotting was performed for monitoring ENG/VEGFα signaling. As a result, a nonsense, heterozygous variant for ENG/CD105: c.G1169A:p. Trp390Ter of the proband with hereditary hemorrhagic telangiectasia type 1 (HHT1) was identified, which co-segregated with the disease in the M666 pedigree. Western blotting found that, compared with the normal levels associated with non-carrier family members, the ENG protein levels in the proband showed approximately a one-half decrease (47.4% decrease), while levels of the VEGFα protein, in the proband, showed approximately a one-quarter decrease (25.6% decrease), implying that ENG haploinsufficiency, displayed in the carrier of this variant, may affect VEGFα expression downregulation. Pearson and Spearman correlation analyses further supported TGFß/ENG/VEGFα signaling, implying ENG regulation in the blood vessels. Thus, next-generation sequencing including WES should provide an accurate strategy for gene diagnosis, therapy, genetic counseling, and clinical management for rare genetic diseases including that in HHT1 patients.

Protective effect and mechanism of different proportions of "Danggui-Kushen" herb pair on ischemic heart disease.

This study aims to investigate the protective effect and mechanism of "Danggui-Kushen" herb pair (DKHP) on ischemic heart disease (IHD). The rat model of myocardial reperfusion injury (MIRI) was established by ligation of the left anterior descending coronary artery. Rats were randomly divided into seven groups and administered orally for 7 days: control group, IHD group, DKHP1:1 group, DKHP1:2 group, DKHP2:1 group, DKHP1:3 group, DKHP3:1 group, the dosage was 2.7 g/kg. Measure electrocardiogram (ECG), myocardial infarction and injury assessment, Hematoxylin and eosin (HE) staining to evaluate myocardial injury and the protective effect of DKHP. Lactate dehydrogenase (LDH), Reactive oxygen species (ROS), IL-1ß and IL-6 kit detection, immunohistochemical analysis, establishment of H9c2 cardiomyocyte hypoxia (Hypoxia) model, DKHP pretreatment for 3 h, MTT method to detect cell survival rate, cell immunofluorescence to observe NF- The expression of TLR-4, NF-κB, p-NF-κB, IKßα, p-IKßα, HIF-1α, VEGF and other genes and proteins were detected by κB nuclear translocation, mitochondrial membrane potential measurement, Western blot and Polymerase Chain Reaction (PCR). Compared with the model group, DKHP can reduce the size of myocardial infarction, reduce the levels of factors such as LDH, ROS, IL-1ß and IL-6, and improve the cell survival rate; Compared with the model group, DKHP can inhibit the nuclear transfer of NF-κB and reduce mitochondrial damage; the results of immunohistochemical analysis, PCR and Western blot showed that compared with the model group, DKHP can reduce TLR-4, p-NF-κB, Expression levels of p-IKßα, HIF-1α, VEGF and other proteins. Reveal that DKHP may play a protective role in ischemic heart disease by reducing inflammation and oxidative stress damage. DKHP may have protective effect on ischemic heart disease, and its mechanism may be through reducing inflammatory response and oxidative stress damage to achieve this protective effect.

The study of therapeutic efficacy and mechanisms of Schisandra chinensis and Evodia rutaecarpa combined treatment in a rat model of Alzheimer's disease.

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs used to treat neurodegenerative diseases. This study investigates the combined effects of SC and ER on learning and memory in an Alzheimer's disease rat model and their underlying mechanisms. Methods: High-performance liquid chromatography was employed to analyze the primary active constituents of Schisandra and Evodia. The effects of the combined treatment of Schisandra and Evodia on learning and memory in an Alzheimer's disease rat model were evaluated through Morris water maze and Hematoxylin-Eosin staining experiments. Immunohistochemical analysis was conducted to investigate the impact of S-E on Aß1-42 and P-tau proteins. Western blotting and real-time quantitative polymerase chain reaction were utilized to quantify the expression of pivotal proteins and genes within the BDNF/TRKB/CREB and GSK-3ß/Tau pathways. Results: The treatment group exhibited significant neuroprotective effects, ameliorating learning and memory impairments in the Alzheimer's disease rat model. The treatment regimen modulated the activity of the BDNF/TRKB/CREB and GSK-3ß/Tau pathways by influencing the expression of relevant genes, thereby reducing the generation of Aß1-42 and P-Tau proteins and inhibiting the deposition of senile plaques. Furthermore, among the three treatment groups, the combined treatment demonstrated notably superior therapeutic effects on Alzheimer's disease compared to the single-drug treatment groups.

An Enzymatic Strategy for the Selective Methylation of High-Value-Added Tetrahydroprotoberberine Alkaloids.

Tetrahydroprotoberberines (THPBs) are plant-specific alkaloids with significant medicinal value. They are present in trace amounts in plants and are difficult to chemically synthesize due to stereoselectivity and an unfavorable environment. In this study, a selective methylation strategy was developed for the biocatalysis of seven high-value-added THPB compounds using 4'-O-methyltransferase (Cj4'OMT), norcoclaurine 6-O-methyltransferase (Cj6OMT), and (S)-scoulerine 9-O-methyltransferase (SiSOMT and PsSOMT) in engineered E. coli. The methyltransferases Cj4'OMT, Cj6OMT, PsSOMT, and SiSOMT were expressed heterologously in E. coli. Compound 1 (10-methoxy-2,3,9-tetrahydroxyberbine) was synthesized using the recombinant E. coli strain Cj4'OMT and the substrate 2,3,9,10-tetrahydroxyberbine. Compound 2 (9-methoxy-2,3,10-tetrahydroxyberbine) was produced in the recombinant Escherichia coli (E. coli) strain PsSOMT, and compounds 2 and 3 (discretamine) were produced in the recombinant E. coli strain SiSOMT. Compounds 4 (9,10-methoxy-2,3-tetrahydroxyberbine) and 5 (corypalmine) were obtained by co-culturing the recombinant strains Cj4'OMT and SiSOMT with substrate. Compounds 6 (scoulerine) and 7 (isoscoulerine) were produced by co-culturing the substrate with the recombinant strains Cj4'OMT and Cj6OMT. To increase the yield of novel compound 2, the flask culture conditions of the engineered SiSOMT strain were optimized, resulting in the production of 165.74 mg/L of this compound. This study thus presents an enzymatic approach to the synthesis of high-value-added THPBs with minimum environmental wastage.

Tracing global N2O emission mitigation strategies through trade networks.

Nitrous oxide (N2O) is the third most potent greenhouse gas (GHG) and the most important ozone depleting substance. But how global N2O emissions are connected through the interwoven trade network remains unclear. This paper attempts to specifically trace anthropogenic N2O emissions via global trade networks using a multi-regional input-output model and a complex network model. Nearly one quarter of global N2O emissions can be linked to products traded internationally in 2014. The top 20 economies contribute to about 70% of the total embodied N2O emission flows. In terms of the trade embodied emissions classified by sources, cropland-, livestock-, chemistry-, and other industries-related embodied N2O emissions account for 41.9%, 31.2%, 19.9%, and 7.0%, respectively. Clustering structure of the global N2O flow network is revealed by the regional integration of 5 trading communities. Hub economies such as mainland China and the USA are collectors and distributors, and some emerging countries, such as Mexico, Brazil, India, and Russia, also exhibit dominance in different kinds of networks. This study selects the cattle sector to further verify that low production-side emission intensities and trade cooperation can lead to N2O emission reduction. In view of the impact of trade networks on global N2O emissions, achieving N2O emission reduction calls for vigorous international cooperation.

Demonstrating analytical similarity of a biosimilar HLX04 to bevacizumab with a panel of state-of-the-art methods and tiering of quality attributes.

Therapeutical monoclonal antibodies are structurally and functionally complex, whereas the innovator's manufacturing processes are proprietary. With respect to the similarity assessment, a proposed biosimilar product needs to demonstrate a side-by-side comparison between the reference product (RP) and candidate product in terms of physicochemical properties and biological activities, as well as nonclinical and clinical outcomes. Here, a comprehensive analytical similarity assessment was performed for in-depth comparison of HLX04, China-sourced Avastin® (CN-Avastin®), and Europe-sourced Avastin® (EU-Avastin®) following a tier-based quality attribute (QA) evaluation. A series of orthogonal and state-of-the-art analytical techniques were developed for the assessment. Ten lots of HLX04 were compared with 29 lots bevacizumab RP. Referred to the characterization results, HLX04 is highly similar to the RPs with respect to physicochemical properties and biological functions. In addition, HLX04 was found with similar stability and degradation behaviors upon multiple stressed conditions to bevacizumab. Minor differences were observed in glycosylation, aggregates, FcγRIIIa(F), and FcγRIIIa(V) binding activities; nevertheless, they were evaluated and demonstrated not to impact clinical outcomes. According to the reported clinical results, the totality of evidence, including the pharmacokinetic, efficacy, safety, and immunogenicity, further shows that HLX04 is similar to CN-/EU-Avastin®.

The Role of NF-κB in Myocardial Ischemia/Reperfusion Injury.

Acute myocardial infarction (AMI) is a threat to human life and physical health worldwide. Timely reperfusion is very important to limit infarct size and protect ischemic myocardium. Unfortunately, it has also caused severer myocardial damage, which is called "myocardial ischemia/ reperfusion injury (MIRI)". There is no effective clinical treatment for it. Over the past two decades, biological studies of NF-κB have improved the understanding of MIRI. Nuclear Factor-κB (NF-κB) is a major transcription factor associated with cardiovascular health and disease. It is involved in the release of pro-inflammatory factors and apoptosis of cardiomyocytes. Recent studies have shown that inhibition of NF-κB plays a protective role in acute hypoxia and reperfusion injury. Here we review the molecular regulation of NF-κB in MIRI, better understanding of NF-κB signaling mechanisms related to inflammation and crosstalk with endogenous small molecules. We hope this review will aid in improving therapeutic approaches to clinical diagnosing. This review provides evidence for the role of NF-κB in MIRI and supports its use as a therapeutic target.

Beneficial Effects of Mixing Kentucky Bluegrass With Red Fescue via Plant-Soil Interactions in Black Soil of Northeast China.

Continuous monoculture of cool-season turfgrass causes soil degradation, and visual turf quality decline is a major concern in black soil regions of Northeast China. Turf mixtures can enhance turfgrass resistance to biotic and abiotic stresses and increase soil microbial diversity. Understanding mechanism by plant-soil interactions and changes of black soil microbial communities in turf mixture is beneficial to restoring the degradation of urbanized black soils and maintaining sustainable development of urban landscape ecology. In this study, based on the previous research of different sowing models, two schemes of turf monoculture and mixture were conducted in field plots during 2016-2018 in a black soil of Heilongjiang province of Northeast China. The mixture turf was established by mixing 50% Kentucky bluegrass "Midnight" (Poa pratensis L.) with 50% Red fescue "Frigg" (Festuca rubra L.); and the monoculture turf was established by sowing with pure Kentucky bluegrass. Turf performance, soil physiochemical properties, and microbial composition from rhizosphere were investigated. Soil microbial communities and abundance were analyzed by Illumina MiSeq sequencing and quantitative PCR methods. Results showed that turfgrass quality, turfgrass biomass, soil organic matter (SOM), urease, alkaline phosphatase, invertase, and catalase activities increased in PF mixture, but disease percentage and soil pH decreased. The microbial diversity was also significantly enhanced under turf mixture model. The microbial community compositions were significantly different between the two schemes. Turf mixtures obviously increased the abundances of Beauveria, Lysobacter, Chryseolinea, and Gemmatimonas spp., while remarkably reduced the abundances of Myrothecium and Epicoccum spp. Redundancy analysis showed that the compositions of bacteria and fungi were related to edaphic parameters, such as SOM, pH, and enzyme activities. Since the increasing of turf quality, biomass, and disease resistance were highly correlated with the changes of soil physiochemical parameters and microbial communities in turf mixture, which suggested that turf mixture with two species (i.e., Kentucky blue grass and Red fescue) changed soil microbial communities and enhanced visual turfgrass qualities through positive plant-soil interactions by soil biota.