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 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.

Synthesis of pyrimidines from dinitrogen and carbon.

The element nitrogen and nitrogenous compounds are vital to life. The synthesis of nitrogen-containing compounds using dinitrogen as the nitrogen source, not through ammonia, is of great interest and great value but remains a grand challenge. Herein, we describe a strategy to realize this transformation by combining the heterogeneous approach with the homogeneous methodology. The N2 molecule was first fixed with carbon and LiH through a one-pot heterogeneous process, forming Li2CN2 as an 'activated' nitrogen source with high efficiency. Then subsequent homogeneous treatments of Li2CN2 to construct the organic synthon carbodiimide and the RNA/DNA building block pyrimidines were fulfilled. By using 15N2 as the feedstock, their corresponding 15N-labeled carbodiimide and pyrimidines were readily obtained. This homogeneous-heterogeneous synergy strategy will open a new chapter for N2 transformation.

Zhuang-Gu-Fang Treats Osteoporosis in Ovariectomized Rats by Increasing the Osteogenesis-Related Factors Leptin, Ghrelin, and PYY.

Zhuang-Gu-Fang is a Chinese medicinal compound mixture, which is mainly composed of traditional remedies like the Epimedium Herb, Astragalus, and Eucommia among many others. The study is aimed at investigating the therapeutic effect of Zhuang-Gu-Fang in ovariectomized rats. Fifty six-month-old Wistar rats were randomly selected and divided into 5 groups (n = 10), namely, model group, positive group, low-dose Chinese medicine group, medium-dose group, and high-dose group. Another 10 sham operation Wistar rats were taken as a negative control group. After 3 months of intervention, the bone mineral density (BMD), procollagen type I N-peptide (PINP), beta C-terminal cross-linked telopeptides of type I collagen carboxyl-terminal peptide (ß-CTX), Leptin, Ghrelin, and Peptide YY (PYY) of each group were measured. Besides, the ultrastructure of bone structure and osteoblasts was also observed by transmission electron microscopy. Western blot method was used to detect the expression levels of Leptin and Ghrelin in bone tissue, and RT-PCR detected the mRNA expression levels of Leptin and Ghrelin. BMD test indicated that Zhuang-Gu-Fang could effectively prevent the loss of tibia bone in ovariectomized rats. Histomorphology analysis showed that Zhuang-Gu-Fang could preserve trabecular bone structure integrity and improve osteoblast ultrastructure. Notably, the study found out that Zhuang-Gu-Fang worked through balancing the bone metabolism via increasing bone formation/resorption ratio. Additionally, Zhuang-Gu-Fang highlighted the recovery effects in multiple levels of osteogenesis- and osteanagenesis-related factors Leptin, Ghrelin, and PYY. Conclusively, the study proved the therapeutic potential of the Zhuang-Gu-Fang for postmenopausal osteoporosis (PMOP) and further revealed that its therapeutic effect was related to the balance of bone metabolism and the recovery effects of bone-related factors Leptin, Ghrelin, and PYY.

Cobalt-Catalyzed Three-Component Difluoroalkylation-Peroxidation of Alkenes.

The Co(acac)2-catalyzed three-component difluoroalkylation-peroxidation of alkenes with difluorohaloactates and hydroperoxides has been developed. The protocol provides an efficient and selective access to various ß-peroxyl difluoroalkyl derivatives, which can be transformed into α-amino acid and pyrimidine derivatives by the reactions with amines and amidines. The mild reaction conditions, broad substrate scopes, gram-scale synthesis, and synthetic applications exemplified the utility and practicability of this method. In addition, this methodology can be extended to other halide compounds to give the alkylation-peroxidation products.

Nitration-Peroxidation of Alkenes: A Selective Approach to ß-Peroxyl Nitroalkanes.

Nitration-peroxidation of alkenes for the synthesis of ß-peroxyl nitroalkanes has been developed by using tert-butyl nitrite and tert-butyl hydroperoxide. The method presents a new and selective difunctionalization of alkenes to introduce a nitro group and a peroxyl group across the double bonds of alkenes under mild conditions. A radical reaction pathway is proposed by experimental and theoretical studies.

The inhibitory effect of sodium baicalin on oseltamivir-resistant influenza A virus via reduction of neuraminidase activity.

Baicalin was identified as a neuraminidase (NA) inhibitor displaying anti-influenza A virus (IAV) activity. However, its poor solubility in saline has limited its use in the clinic. We generated sodium baicalin and showed that it exhibited greatly increased solubility in saline. Its efficacy against oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) was evaluated in vitro and in vivo. Results showed that 10 µM of sodium baicalin inhibited A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and H1N1-H275Y in MDCK cells in a dose-dependent manner, with inhibitory rates of 83.9, 75.9 and 47.7%, respectively. Intravenous administration of sodium baicalin at 100 mg/kg/d enabled the survival of 20% of H1N1-H275Y-infected mice. The treatment alleviated body weight loss and lung injury. Moreover, sodium baicalin exerted a clear inhibitory effect on NAs. The IC50 values of sodium baicalin against H1N1-H275Y and cells-expressing A/Anhui/1/2013-R294K (H7N9-R294K) NA protein (N9-R294K) were 214.4 µM and 216.3 µM. Direct interactions between sodium baicalin and NA were observed, and we simulated the interactions of sodium baicalin with N9-R294K and N9 near the active sites of OC-N9-R294K and OC-N9. The residues responsible for the sodium baicalin-N9-R294K and sodium baicalin-N9 interactions were the same, confirming that sodium baicalin exerts effects on wild-type and oseltamivir-resistant viral strains.

Oroxylin A suppresses influenza A virus replication correlating with neuraminidase inhibition and induction of IFNs.

Because it is highly contagious, the influenza A virus (IAV) has the potential to cause pandemics in humans. The emergence of drug-resistant strains requires the development of new chemical therapeutics. Oroxylin A (OA) is a flavonoid which has been shown to have antioxidant and antitumor effects. However, intensive studies in which OA fights against different influenza virus strains and the underlying antiviral mechanisms have not been reported. In our study, the antiviral activities in cells and in mice, the preliminary mechanisms of OA were investigated. Our data show that it can inhibit A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant A/FM/1/47-H275Y (H1N1-H275Y) viruses in MDCK cells in a dose-dependent manner with inhibitory rates of 70.9%, 59.5% and 23.2%, respectively, at 50µM doses. Orally administered OA effectively protected mice from H1N1 virus-induced death, body weight loss and lung injury, with a survival rate of 60.0% at 100mg/kg/d dose. In addition, the H1N1 M1 gene transcription and protein synthesis were suppressed by 43.7% and 33.2%, respectively, in the late biosynthesis stage. This resulted in inhibition of viral replication. Furthermore, we found that OA has a neuraminidase (NA) inhibitory effect with IC50 values for H1N1-H275Y and A/Anhui/1/2013-R294K (H7N9-R294K) of 241.4µM and 203.6µM, respectively. Interferons (IFNs) produced by the virally infected cells play important roles in antiviral defense, therefore, IFN levels in the blood were also tested in mice. We found that IFN-ß and IFN-γ in the OA 100mg/kg/d group were markedly increased by 24.5pg/mL and 859.9pg/mL, respectively, compared with those in the model group. This indicated that OA could induce the secretion of IFNs. The potent inhibition of virus replication and NA inhibitory activity, as well as the promotion of IFN production suggest that OA could be a drug candidate to fight against IAVs including oseltamivir-resistant strains.