Structure relationship of non-covalent interactions between lotus seedpod oligomeric procyanidins and glycated casein hydrolysate during digestion.

Procyanidin-amino acid interactions during transmembrane transport cause changes in the structural and physical properties of peptides, which limits further absorption of oligopeptide-advanced glycation end products (AGEs). In this study, glycated casein hydrolysates (GCSHs) were employed to investigate the structure and interaction mechanism of GCSH with lotus seedpod oligomeric procyanidin (LSOPC) complexes in an intestinal environment. LSOPC can interact with GCSH under certain conditions to form hydrogen bonds and hydrophobic interactions to form GCSH-LSOPC complexes. Results showed that procyanidin further leads to the transformation of a GCSH secondary structure and the increase of surface hydrophobicity (H0). The strongest non-covalent interaction between GCSH and (-)-epigallocatechin gallate (EGCG) was due to the polyhydroxy structure of EGCG. Binding site analysis showed that EGCG binds to the internal cavity of P1 to maintain the relative stability of the binding conformation. The antioxidant capacity of GCSH was remarkably elevated by GCSH-LSOPC. This study will provide a new reference for the accurate control of oligopeptide-AGEs absorption by LSOPC in vivo.

Phosphate interactions with iron-titanium oxide composites: Implications for phosphorus removal/recovery from wastewater.

Understanding the interactions between phosphate (P) and mineral adsorbents is critical for removing and recovering P from wastewater, especially in the presence of both cationic and organic components. To this end, we investigated the surface interactions of P with an iron-titanium coprecipitated oxide composite in the presence of Ca (0.5-3.0 mM) and acetate (1-5 mM), and quantified the molecular complexes and tested the possible removal and recovery of P from real wastewater. A quantitative analysis of P K-edge X-ray absorption near edge structure (XANES) confirmed the inner-sphere surface complexation of P with both Fe and Ti, whose contribution to P adsorption relies on their surface charge determined by pH conditions. The effects of Ca and acetate on P removal were highly pH-dependent. At pH 7, Ca (0.5-3.0 mM) in solution significantly increased P removal by 13-30% by precipitating the surface-adsorbed P, forming hydroxyapatite (14-26%). The presence of acetate had no obvious influence on P removal capacity and molecular mechanisms at pH 7. At pH 4, the removal amount of P was not obviously affected by the presence of Ca and acetate. However, acetate and high Ca concentration jointly facilitated the formation of amorphous FePO4 precipitate, complicating the interactions of P with Fe-Ti composite. In comparison with ferrihydrite, the Fe-Ti composite significantly decreased the formation of amorphous FePO4 probably by decreasing Fe dissolution due to the coprecipitated Ti component, facilitating further P recovery. An understanding of these microscopic mechanisms can lead to the successful use and simple regeneration of the adsorbent to recover P from real wastewater.

Sorafenib-Loaded Cu2-xSe Nanoparticles Boost Photothermal-Synergistic Targeted Therapy against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for the predominant form of liver malignancy and presents a leading cause of cancer-related death globally. Sorafenib (SOR), a first-line targeted drug for advanced HCC treatment, has a battery of untoward side effects. Photothermal therapy (PTT) has been utilized as an effective adjuvant in synergy with other approaches. However, little is known about the tumoricidal efficacy of combining SOR with PTT for HCC. Herein, a novel versatile nanoparticle, Cu2-xSe@SOR@PEG (CSP), that is based on a photothermal Cu2-xSe core and SOR for simultaneously reinforcing PTT and reducing the adverse effects of SOR was constructed. The synthesized CSP exhibited a remarkably enhanced therapeutic effect upon 808 nm laser irradiation via dampening HCC cell propagation and metastasis and propelling cell apoptosis. The intravenous administration of CSP substantially suppressed tumor growth in a xenograft tumor mouse model. It was noted that the CSP manifested low toxicity and excellent biocompatibility. Together, this work indicates a promising and versatile tool that is based on synergistic PTT and molecular-targeted therapy for HCC management.

Potential molecular mechanisms of Ermiao san in the treatment of hyperuricemia and gout based on network pharmacology with molecular docking.

A network pharmacology integrated molecular docking strategy was used to predict the underlying molecular mechanism of Ermiao san in the treatment of hyperuricemia and gout. Traditional Chinese medicine systems pharmacology (TCMSP) database and analysis platform were used to screen out the active compounds and their targets of Ermiao san. The disease target genes related to hyperuricemia (HUA) and gout were obtained by searching CTD, DisGeNET, DrugBank, GeneCards, OMIM, TTD, and PharmGKB databases with "Hyperuricemia" and "Gout" as keywords, respectively. The potential targets of Ermiao san in the treatment of HUA and gout were screened through a Venn diagram. The protein-protein interaction network was constructed using Cytoscape software. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were then conducted. Finally, some compounds and core targets were selected for molecular docking verification by Autodock Vina and Pymol software. Forty-six active compounds, such as quercetin, wogonin and beta-sitosterol, etc were identified. Ermiao san plays a therapeutic role in HUA and gout regulating various biological processes, cellular compounds, and molecular functions. The core targets of Ermiao san for treating HUA and gout are AT1 (namely Protein Kinase Bα), interleukin-1 beta, prostaglandin-endoperoxide synthase 2, JUN, etc. And the key pathways are nuclear factor-κB, interleukin-17 and tumor necrosis factor. The results of molecular docking analyses suggested that active compounds of Ermiao san could bind well to the core protein receptors. Ermiao san has a synergistic mechanism of multiple compounds, multiple targets, and multiple pathways in the treatment of HUA and gout, which provides a good theoretical basis for the clinical application.

Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

Hypothalamic modulation of adult hippocampal neurogenesis in mice confers activity-dependent regulation of memory and anxiety-like behavior.

Adult hippocampal neurogenesis plays a critical role in memory and emotion processing, and this process is dynamically regulated by neural circuit activity. However, it remains unknown whether manipulation of neural circuit activity can achieve sufficient neurogenic effects to modulate behavior. Here we report that chronic patterned optogenetic stimulation of supramammillary nucleus (SuM) neurons in the mouse hypothalamus robustly promotes neurogenesis at multiple stages, leading to increased production of neural stem cells and behaviorally relevant adult-born neurons (ABNs) with enhanced maturity. Functionally, selective manipulation of the activity of these SuM-promoted ABNs modulates memory retrieval and anxiety-like behaviors. Furthermore, we show that SuM neurons are highly responsive to environmental novelty (EN) and are required for EN-induced enhancement of neurogenesis. Moreover, SuM is required for ABN activity-dependent behavioral modulation under a novel environment. Our study identifies a key hypothalamic circuit that couples novelty signals to the production and maturation of ABNs, and highlights the activity-dependent contribution of circuit-modified ABNs in behavioral regulation.

Biochanin A from Chinese Medicine: An Isoflavone with Diverse Pharmacological Properties.

Biochanin A (BCA) is a dietary isoflavone, isolated from the leaves and stems of Trifolium pratense L and many other herbs of Chinese medicine. Recent findings indicated BCA as a promising drug candidate with diverse bioactive effects. On the purpose of evaluating the possibility of BCA in clinical application, this review is trying to provide a comprehensive summary of the pharmacological actions of BCA. The publications collected from PubMed, ScienceDirect, and Wiley databases were summarized for the last 10 years. Then, the potential therapeutic use of BCA on the treatment of various diseases was discussed according to its pharmacological properties, namely, anticancer, anti-inflammatory, anti-bacterial, anti-diabetic, and anti-obesity effects as well as neuroprotective, hepatoprotective, cardioprotective, and osteoprotective effects. BCA might mainly regulate the MAPK, PI3K, NRF2, and NF-kB pathways, respectively, to exert its bioactive effects. However, the limited definitive targets, poor biological availability, and insufficient safety evaluation might block the clinical application of BCA. This review may provide new insights for the development of BCA in the application of related diseases.

Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) turn out to be a promising source of cell-free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose-derived MSC-EVs (haMSC-EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC-EVs in healthy volunteers. DiR-labelled haMSC-EVs were used to explore the distribution of nebulized haMSC-EVs in the murine model. Pseudomonas aeruginosa-induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL-6, TNF-α and IL-10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC-EVs through the nebulized route. Twenty-four healthy volunteers were involved and received the haMSC-EVs once, ranging from 2 × 108 particles to 16 × 108 particles (MEXVT study, NCT04313647). Nebulizing haMSC-EVs improved survival rate to 80% at 96 h in P. aeruginosa-induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC-EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC-EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC-EVs in lung injury diseases.

Effects of Dingchuan Decoction on Lung Function and Clinical Effectiveness Rate in Children with Asthma: A Systematic Review and Meta-Analysis.

Dingchuan decoction (DCD) is a traditional Chinese prescription for asthma that remains popular today. To systematically evaluate the effect of DCD on lung function, clinical effectiveness rate, and safety in children with asthma, significant databases were searched for randomized controlled trials from their inception to September 9, 2019. Randomized controlled trials assessing the effect of DCD on lung function and clinical effectiveness rate in children with asthma were included in this meta-analysis. The methodological quality of the included trials was assessed using the Cochrane risk of bias tool. RevMan 5.3 was used for data analysis. Fourteen studies with 1,384 children were reviewed. FEV1 improvement rate (mean difference [MD] 12.50, 95% confidence interval [CI] 8.72-16.29), PEF improvement rate (MD 14.28, 95% CI 11.08-17.49), and clinical effectiveness rate (relative risk 1.19, 95% CI 1.14-1.25) significantly increased in the DCD group when compared to simple conventional medication. Four trials suggest that DCD is safe for children. In conclusion, the use of DCD combined with conventional medication improves lung function and clinical effectiveness rate better than simple conventional medication. However, the selected trials lack blinding and large-scale studies. Therefore, to better manage DCD in clinical practice, more randomized controlled trials and large-scale studies are required for further evaluation.

Gamma Knife Radiosurgery for Cavernous Malformations of Basal Ganglia and Thalamus: A Retrospective Study of 53 Patients.

INTRODUCTION: Gamma Knife radiosurgery (GKRS) has been used to treat cavernous malformations (CMs) located in basal ganglia and thalamus. However, previous reports are limited by small patient population. METHODS: We retrospectively reviewed the clinical and radiological data of 53 patients with CMs of basal ganglia and thalamus who underwent GKRS at West China Hospital between May 2009 and July 2018. All patients suffered at least once bleeding before GKRS. The mean volume of these lesions was 1.77 cm3, and the mean marginal dose was 13.2 Gy. After treatment, patients were followed to determine the change in symptom and hemorrhage event. RESULTS: The mean follow-up period was 52.1 months (6.2-104.3 months). The calculated annual hemorrhage rate (AHR) was 48.5% prior to GKRS and 3.0% after treatment (p < 0.001). The Kaplan-Meier analysis revealed that 2-, 3-, and 5-year hemorrhage-free survival were 88, 80.9, and 80.9%, respectively. Preexisting symptoms were resolved in 11 patients, improved in 14, and stable in 5. Only 2 patients (3.8%) developed new neurological deficit. CONCLUSION: Our study suggests that AHR after GKRS was comparable to the recorded AHR of natural history (3.1-4.1%) in previous studies. GKRS is a safe and effective treatment modality for CMs of basal ganglia and thalamus. Considering the relative insufficient understanding of natural history of CMs, future study warrants longer follow-up.

Enzymolysis peptides from Mauremys mutica plastron improve the disorder of neurotransmitter system and facilitate sleep-promoting in the PCPA-induced insomnia mice.

ETHNOPHARMACOLOGY RELEVANCY: For many centuries, Mauremys mutica is highly valued as a food homologous Chinese herbal medicine. It has been considered useful to sedate, nourish brain and promote sleep. However, the animal experimental evidence of its sleep-promoting activity is missing in literature. AIM OF THE STUDY: In this study, PCPA-induced insomnia model was used to explore the sleep-promoting mechanism of enzymolysis peptides from PMM, and its main composition and chemical structure were analyzed. MATERIALS AND METHODS: Experiments were performed using PCPA-induced insomnia model, all animals were intraperitoneally injected with PCPA (350 mg/kg·d) for two days. The sleep-promoting effect evaluated using measuring content of 5-HT, GABA, DA, IL-1, BDNF and expression of 5-HT1A receptor and GABAA receptor α1-subunit in mice brain. Primary structure of peptides was identified by HPLC-ESI-QqTOF-MS/MS. RESULTS: Compared with the model group, the content of 5-HT, GABA, IL-1, BDNF in mice brain of PMM peptide groups was increased to varying degrees, the content of DA was decreased, and the gene transcription and protein expression of 5-HT1A receptor and GABAA receptor α1-subunit were almost all returned to normal levels. In addition, the primary structures of most abundant nine typical peptides in PMM peptides were identified. CONCLUSIONS: The results showed that PMM peptides could improve the disorder of neurotransmitter system, restore compensatory over-expression 5-HT1A receptor and GABAA receptor α1-subunit, and have a good sleep-promoting effect. The specific amino acid composition, sequence and glycosylation modification of PMM peptides may be the key reason for their activity, which lays a foundation for the subsequent development of sleep-promoting peptide products.

Resource Value Discovery and Utilization of Wastes in Industrialization of Rhei Radix et Rhizoma / 中国实验方剂学杂志

The recycling of traditional Chinese medicine （TCM） wastes is an important research topic to be solved urgently in the industrialization of TCM resources. Rhei Radix et Rhizoma is a bulk Chinese herb mainly derived from Rheum palmatum，R. tanguticum，and R. officinale. At present，these three medicinal plants have been cultivated on a large scale and widely used in the fields of medicine，health care，food，cosmetics，and veterinary medicine，with an annual demand of more than 5 500 tons（1 ton=1 000 kg）. However，a large number of wastes such as non-medicinal parts and residues produced in the production and deep processing are discarded because there is no effective way of utilization，resulting in serious waste of resources and environmental pollution. The non-medicinal parts contain not only the chemical components and pharmacological effects similar to those of roots and rhizomes but also a variety of amino acids，mineral elements，and conventional nutrients. They have a long history of use，and the content of some resource components is higher than that in roots and rhizomes. In particular，their stems and leaves exhibit great potential to be consumed as food and medicine due to high safety. Besides，the content of anthraquinones in Rhei Radix et Rhizoma residue is high and it possesses good antibacterial activity. It can be seen that the waste from the industrialization of Rhei Radix et Rhizoma has high utilization value. Hence，based on the relevant literature and investigation on the application of producing areas in China and abroad，the paper summarized the utilization status of their medicinal and non-medicinal parts，the waste production in the industrialization，as well as the active substances and utilization ways and put forward the multi-level and multi-path utilization strategy of Rhei Radix et Rhizoma wastes，in order to provide reference for the rational development and application of Rhei Radix et Rhizoma resources and promote the effective utilization and green development of the corresponding wastes.

[Preparation of Cangyi nanoemulsion in situ gel and drug release mechanism of nasal mucosa in vitro].

To prepare Cangyi nanoemulsion in situ gel and study its nasal mucosa release mechanism in vitro. After proper treatment of different drugs in the compound, the prescription of nanoemulsion was determined by pseudo-ternary phase diagram method. With the ratio of mixed emulsifier to oil phase [(S+COS)/O], the ratio of mixed emulsifier(K_m), the ratio of water phase to mixed emulsifier and oil phase[W/(S+COS+O)] as investigation factors and the normalized value(OD) as evaluation index, the prescription of Cangyi nanoemulsion was optimized by central composite design-response surface method. With the ratio of poloxamer 407(P407) and poloxamer 188(P188) as the investigation factors and the gelation temperature as the evaluation index, the in situ gel prescription of Cangyi nanoemulsion was optimized. The improved Franz diffusion cell was used to explore the nasal mucosa drug-release mechanism of Cangyi nanoemulsion in situ gel with oxymatrine, ferulic acid and salvianolic acid B content as indexes. The optimal prescription of Cangyi nanoemulsion in situ gel was as follows: 6.862% castor oil polyoxyl(EL), 4.262% absolute ethanol, 1.392% ethyl oleate, 7% P407 and 6% P188. The average pH was 5.55 and the average gelation temperature was 32.8 ℃. In vitro release studies showed that oxymatrine, ferulic acid and salvianolic acid B were released simultaneously and the drug release behavior was consistent with that in Higuchi model. The preparation process of Cangyi nanoemulsion in situ gel is stable, with suitable pH value, gelation temperature and viscosity. It has a certain slow-release effect, and can meet the needs of local nasal drug use.

[Systematic review and trial sequential analysis of randomized clinical trial of Hongjin Xiaojie Capsules for treatment of hyperplastic disease of breast].

To systemically evaluate the clinical efficacy and safety of Hongjin Xiaojie Capsules for hyperplastic disease of breast(HDBA), so as to provide the evidence for its clinical application. The inclusion criteria are the RCT of single administration of Hongjin Xiaojie Capsules for treatment of HDBA. We retrieved following databases(CNKI, WanFang, VIP, SinoMed, Cochrane Library and PubMed) from their inception to October 1, 2019. Two researchers independently screened out literatures and extracted data, and assessed the methodological quality of eligible RCT according to the criteria in Cochrane Handbook for Systematic Reviews of Interventions. RevMan 5.3 was used for data analysis, binary data was summarized by risk ratio(RR) with confidence intervals(CI) of 95%, and continuous data were summarized by mean difference(MD) with CI of 95%. To estimate the sample size of systematic review, trial sequential analysis(TSA) was performed base on software TSA v0.9 version. Totally 14 RCTs were included, involving 3 057 patients. The results of Meta-analysis showed a significantly higher cure rate(RR=1.13, 95%CI[1.03, 1.25], P=0.01) and higher total effective rate(RR=1.09, 95%CI[1.05, 1.13], P<0.000 1) in Hongjin Xiaojie Capsules group than those in the Juyuansuan Tamoxifen group. The incidence of adverse events was significantly higher in Juyuansuan Tamoxifen group than that in Hongjin Xiaojie Capsules group(RR=0.28 95%CI[0.16, 0.49], P<0.001), and the adverse events included nausea, vomiting, abdominal pain, diarrhea, irregular menstruation, amenorrhea, unclear vision, dizziness and headache. The TSA for the cure rate demonstrated that the current available data reached the expected value. However, due to the low effect intensity of evidence, the pooled results might be affected by high risk bias of trials. The quality of evidence of included trials was generally low or very low. Inverted funnel diagram showed possible publication bias. This review suggested that Hongjin Xiaojie Capsules were potentially effective and safe in treatment of HDBA, especially, the incidences of drug-related adverse events from Hongjin Xiaojie Capsules were significantly lower than those from tamoxifen. However, because of lack of high-quality evidence for drawing a conclusion, more rigorously designed and high-quality trials are needed to confirm the efficacy and safety of Hongjin Xiaojie Capsules.

Comparative Assessment of the Antioxidant Activities among the Extracts of Different Parts of Clausena lansium (Lour.) Skeels in Human Gingival Fibroblast Cells.

Clausena lansium (Lour.) Skeels (wampee) is an outstanding natural plant with medicinal properties. The aim of this study was to compare the cytoprotective effects of four parts of wampee under oxidative stress. The aqueous extracts of leaf, peel, pulp, and seed were tested for the proliferation effects on human gingival fibroblast (HGF) cells and the protective effects in the hydrogen peroxide-induced HGF model. Furthermore, the total glutathione assay and identification of rutin by high-performance liquid chromatography were carried out to attempt to determine whether the cytoprotective effects were related to the total glutathione (GSH) stability and rutin content. The results showed that all of the extracts had no cytotoxicity to HGF at tested concentrations ranging from 50 to 5000 µg/ml during 24 h, and the leaf, pulp, and seed extracts increased proliferation of HGF at relatively high concentrations. All the extracts except for the seed extract significantly decreased the production of reactive oxygen species, and the peel extracts exhibited the most effective antioxidant effect. The leaf extract had the highest anticytotoxicity and GSH stabilization effect in the HGF challenged with hydrogen peroxide. In addition, the relative content of rutin in peel and leaf extracts was higher than that in pulp and seed. The results of GSH assay and rutin identification suggest that different cellular protective effects among the four parts of wampee are partially related to the GSH stabilization and rutin content. These findings provide a scientific basis for the antioxidant effect-related biological activities of wampee extracts.

Effect of melatonin for the management of endometriosis: A protocol of systematic review and meta-analysis.

BACKGROUND: This study aims to explore the effect of melatonin for the management of endometriosis. METHODS: We will search electronic databases (Cochrane Library, MEDLINE, EMBASE, CINAHL, Web of Science, Scopus, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure) from their inceptions to the February 29, 2020 without language and publication time limitations. The study identification, study quality assessment, and data extraction will be undertaken by two separate researchers. We will also appraise evidence quality of main outcomes by Grading of Recommendations Assessment Development and Evaluation, and statistical analysis performance by RevMan 5.3 Software. RESULTS: This study will summarize up-to-date clinical evidence to investigate the effect of melatonin for the management of endometriosis. CONCLUSION: This study may provide helpful evidence of melatonin for the management of endometriosis. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040093.

Supplemental Nicotinamide Dose-Dependently Regulates Body Phosphorus Excretion via Altering Type II Sodium-Phosphate Co-Transporter Expressions in Laying Hens.

BACKGROUND: Dietary supplemental nicotinamide is used to treat hyperphosphatemia in humans. However, the mechanisms of its impact on body phosphorus homeostasis remain unclear. OBJECTIVE: This study was to determine effects and molecular mechanisms of 3 dietary nicotinamide concentrations on body phosphorus homeostasis in laying hens. METHODS: Hy-Line Brown layers (total = 21; 40 wk old; body weight: 1,876 ± 24 g) were individually housed (n = 7) and fed a corn-soybean meal-based diet supplemented with nicotinamide at 20 (N20), 140 (N140), and 1000 (N1000) mg/kg for 21 d. Serum phosphorus and fibroblast growth factor 23 (FGF23) concentrations, phosphorus and calcium excretion, and mRNA and/or protein of type II sodium-phosphate co-transporters (NPt2a, NPt2ab) and FGF23 and FGF23 receptors were measured in the intestines, calvaria, kidney, and liver. RESULTS: Hens in the N1000 group had a 16% lower serum phosphorus concentration and 22% greater phosphorus excretion than those in the N20 or N140 group (P ≤ 0.05). Compared with hens in the N20 group, hens in the N140 and N1000 groups, which did not differ, had 15-21% lower serum FGF23 concentrations, 19-22% greater calcium excretion, 43-56% lower ileum NPT2b protein production, and 1.5- to 1.6-fold greater kidney NPT2a protein production, respectively (all differences at P ≤ 0.05). CONCLUSIONS: Supplementing high concentrations of nicotinamide in diets for laying hens led to accelerated phosphorus and calcium excretions and decreased serum phosphorus and FGF23 concentrations, which were associated with downregulated intestinal NPt2b protein production. Our findings exclude kidney NPt2a protein production as a primary mechanism for the nicotinamide-induced body phosphorus loss.

Black mulberry ethanol extract attenuates atherosclerosis-related inflammatory factors and downregulates PPARγ and CD36 genes in experimental atherosclerotic rats.

Atherosclerosis (AS) is the pathological basis of various vascular diseases and currently is seriously affecting human health. Numerous studies have paid more attention to natural medicines with anti-AS properties. As a traditional Uygur folk medicine, black mulberry fruits are conventionally used in the prevention and treatment of cardiovascular diseases in southern Xinjiang of China, and their underlying mechanisms remain unknown. Our previous study revealed that the ethanol extract of black mulberry (EEBM) inhibited AS development by improving lipid metabolism abnormalities, enhancing anti-oxidative activities, and reducing atherosclerotic lesions of atherosclerotic rats. Based on this, our objective was to further investigate the effects of EEBM on the expression of AS-related inflammatory factors and the key genes PPARγ and CD36 of the ox-LDL-PPARγ-CD36 feed-forward cycle in experimental atherosclerotic rats. Black mulberry fruits were extracted with acid ethanol and chromatographed on an AB-8 macroporous resin to obtain EEBM. All experimental rats were randomly divided into five groups: normal, model, model plus simvastatin (5 mg/kg d·body weight), and model plus low-dose and high-dose EEBM groups (105 and 210 mg/kg d·body weight, respectively). Serum levels of the inflammatory factors were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expression of PPARγ and CD36 in atherosclerotic rats' liver tissue and thoracic aorta were determined by Q-PCR and western blot analysis, respectively. EEBM at high dose effectively attenuated the abnormally expressed AS-related inflammatory factors of TNF-α, IL-6, MMP-9, and CRP in atherosclerotic rats by 41.5%, 66.1%, 77.5%, and 79.5%, respectively. After treatment with high dose EEBM, the elevated-expressions of PPARγ and CD36 at the mRNA and protein levels in atherosclerotic rats were found to be obviously downregulated at both levels. These results demonstrate that EEBM might lessen the AS-related inflammatory reaction, and then inhibit the formation of ox-LDL, consequently downregulating the expression of PPARγ and CD36 at the mRNA and protein levels, thus reducing macrophage-foam-cell formation and prohibiting the development of atherosclerotic plaque through the ox-LDL-PPARγ-CD36 feed-forward cycle, which can effectively prevent the occurrence and development of AS in atherosclerotic rats.

GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD). PAM treatment dose-dependently decreased the duration of the ketamine-induced loss of righting reflex (LORR). Compared with those in the KFD group, the duration of LORR and the analgesic effect of the KFD + PNF group were obviously decreased. Meanwhile, successive administration of PNF and KFD had no adverse effects on the cardiovascular and respiratory systems. Both the KFD group and the KFD + PNF group showed no changes in hepatic and renal function or cognitive function in rats. Moreover, the recovery of motor coordination of the KFD + PNF group was faster than that of the KFD group. In summary, our results suggest the potential application of the PNF combination as an antagonistic treatment strategy for anesthesia.