Neuropharmacological insights into Gardenia jasminoides Ellis: Harnessing therapeutic potential for central nervous system disorders.

BACKGROUND: In China, Gardenia jasminoides Ellis (GJE) has a longstanding history of application. The Ministry of Health has listed it as one of the first pharmaceutical or food resources. In ethnic, traditional, and folk medicine, GJE has been used to treat fever and cold and relieve nervous anxiety. Recent studies have confirmed the significant efficacy of GJE for treating central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, and major depressive disorder; however, GJE has not been systematically evaluated. PURPOSE: This research systematically summarizes global studies on the use of GJE for treating CNS disorders and explores the potential applications and underlying mechanisms via intestinal flora analysis and network pharmacology, aiming to establish a scientific basis for innovative CNS disorder treatment with GJE. METHODS: The PRISMA guidelines were used, and electronic databases such as the Web of Science, PubMed, and China National Knowledge Infrastructure were searched using the following search terms: "Gardenia jasminoides Ellis" with "central nervous system disease," "neuroprotection," "Alzheimer's disease," "Parkinson's disease," "ischemic stroke," "Epilepsy," and "major depressive disorder." The published literature up to September 2023 was searched to obtain relevant information on the application of GJE for treating CNS disorders. RESULTS: There has been an increase in research on the material formulation and mechanisms of action of GJE for treating CNS disorders, with marked effects on CNS disorder treatment in different countries and regions. We summarized the research results related to the role of GJE in vitro and in vivo via multitargeted interventions in response to the complex mechanisms of action of CNS disorders. CONCLUSION: We systematically reviewed the research progress on traditional treatment for GJE and preclinical mechanisms of CNS disorders and explored the potential of optimizing network pharmacology strategies and intestinal flora analysis to elucidate the mechanisms of action of GJE. The remarkable therapeutic efficacy of GJE, an important resource in traditional medicine, has been well documented in the literature, highlighting its significant medicinal potential.

The effect of vine tea (Ampelopsis grossedentata) extract on fatigue alleviation via improving muscle mass.

ETHNOPHARMACOLOGICAL RELEVANCE: Vine Tea (VT, Ampelopsis grossedentata), boasts a venerable tradition in China, with a recorded consumption history exceeding 1200 years. Predominantly utilized by ethnic groups in southwest China, this herbal tea is celebrated for its multifaceted therapeutic attributes. Traditionally, VT has been employed to alleviate heat and remove toxins, exhibit anti-inflammatory properties, soothe sore throats, lower blood pressure, and fortify bones and muscles. In the realm of functional foods derived from plant resources, VT has garnered attention for its potential in crafting anti-fatigue beverages or foods, attributed to its promising efficacy and minimal side effects. Currently, in accordance with the Food Safety Standards set forth by the Monitoring and Evaluation Department of the National Health and Family Planning Commission in China, VT serves as a raw material in various beverages. AIM OF THE STUDY: VT has an anti-fatigue or similar effect in folk. However, the underlying molecular mechanisms contributing to VT's anti-fatigue effects remain elusive. This study endeavors to investigate the influence of Vine Tea Aqueous Extract (VTE) on fatigue mitigation and to elucidate its operative mechanisms, with the objective of developing VTE as a functional beverage. MATERIALS AND METHODS: The preparation of VTE involved heat extraction and freeze-drying processes, followed by the identification of its metabolites using UPLC-QTOF-MS to ascertain the chemical composition of VTE. A fatigue model was established using a forced swimming test in mice. Potential molecular targets were identified through network pharmacology, transcriptome analysis, and molecular docking. Furthermore, RT-PCR and Western blot techniques were employed to assess mRNA and protein expressions related to the AMPK and FoxO pathways. RESULTS: VTE significantly prolonged the duration of swimming time in an exhaustive swimming test in a dose-dependent manner, while simultaneously reducing the concentrations of blood lactic acid (LA), lactate dehydrogenase (LDH), serum urea nitrogen (SUN), and creatine kinase (CK). Notably, the performance of the high-dose VTE group surpassed that of the well-recognized ginsenoside. VTE demonstrated a regulatory effect akin to ginsenoside on the AMPK energy metabolism pathway and induced downregulation in the expression of Gadd45α, Cdkn1a, FOXO1, and Fbxo32 genes, suggesting an enhancement in skeletal muscle mass. These findings indicate that VTE can improve energy metabolism and muscle mass concurrently. CONCLUSIONS: VTE exhibits significant anti-fatigue effects, and its mechanism is intricately linked to the modulation of the AMPK and FoxO pathways. Crucially, no caffeine or other addictive substances with known side effects were detected in VTE. Consequently, vine tea shows substantial promise as a natural resource for the development of anti-fatigue beverages within the food industry.

Metabolites-Based Network Pharmacology to Preliminarily Verify In Vitro Anti-Inflammatory Effect of Ardisiacrispin B.

Ardisiae Crenatae Radix is an ethnic medicinal herb with good anti-inflammatory activity. Ardisiacrispin B is one of the main components in Ardisiae Crenatae Radix extract, with a content of up to 16.27%, and it may be one of the pharmacological components through which Ardisiae Crenatae Radix exerts anti-inflammatory activity. At present, reports on ardisiacrispin B mainly focus on anti-tumor effects, and there have been no reports on anti-inflammatory activities. As a triterpenoid saponin, due to its large molecular weight and complex structure, the composition of substances that function in the body may include other forms after metabolism, in addition to compounds with original structures. Exploring the anti-inflammatory effects on the prototypes and metabolites of the compound may provide a more comprehensive response to the characteristics of ardisiacrispin B's anti-inflammatory action. In this study, ardisiacrispin B was analyzed for metabolites to explore its metabolic processes in vivo. Subsequently, the anti-inflammatory effects of the prototypes and metabolites were further analyzed through network pharmacology, with the expectation of discovering the signaling metabolic pathways through which they may act. Finally, the anti-inflammatory effects of ardisiacrispin B in vitro and the effects on key signaling pathways at the protein level were explored. The results of this study showed that the isolated compounds were confirmed to be ardisiacrispin B. After the metabolite analysis, a total of 26 metabolites were analyzed, and the metabolism process in rats mainly involves oxidation, dehydration, glucuronide conjugation, and others. Speculation as to the anti-inflammatory molecular mechanisms of the prototypes and metabolites of ardisiacrispin B revealed that it may exert its anti-inflammatory effects mainly by affecting the PI3K-AKT pathway. Further anti-inflammatory mechanisms demonstrated that ardisiacrispin B had a good anti-inflammatory effect on LPS-induced RAW264.7 cells and a strong inhibitory effect on NO, TNF-α, and IL-1ß release in cells. Furthermore, it had significant inhibitory effects on the expression of PI3K, P-PI3K, AKT, and P-AKT. This study supplements the gaps in the knowledge on the in vivo metabolic process of ardisiacrispin B and explores its anti-inflammatory mechanism, providing an experimental basis for the development and utilization of pentacyclic triterpenoids.

Jiang-Tang-San-Huang pill alleviates type 2 diabetes mellitus through modulating the gut microbiota and bile acids metabolism.

BACKGROUND: Jiang-Tang-San-Huang (JTSH) pill, a traditional Chinese medicine (TCM) prescription, has long been applied to clinically treat type 2 diabetes mellitus (T2DM), while the underlying antidiabetic mechanism remains unclarified. Currently, it is believed that the interaction between intestinal microbiota and bile acids (BAs) metabolism mediates host metabolism and promotes T2DM. PURPOSE: To elucidate the underlying mechanisms of JTSH for treating T2DM with animal models. METHODS: In this study, male SD rats received high-fat diet (HFD) and streptozotocin (STZ) injection to induce T2DM and were treated with different dosages (0.27, 0.54 and 1.08 g/kg) of JTSH pill for 4 weeks; metformin was given as a positive control. Alterations of gut microbiota and BA profiles in the distal ileum were assessed by 16S ribosomal RNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), respectively. Additionally, we conducted quantitative Real Time-PCR and western blotting to determine the mRNA and protein expression levels of intestinal farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), Takeda G-protein-coupled receptor 5 (TGR5) and glucagon-like peptide 1 (GLP-1) as well as hepatic cytochrome P450, family 7, subfamily a, poly-peptide 1 (CYP7A1) and cytochrome P450, family 8, subfamily b, poly-peptide 1 (CYP8B1), which are involved in BAs metabolism and enterohepatic circulation. RESULTS: Here, the results revealed that JTSH treatment significantly ameliorated hyperglycaemia, insulin resistance (IR), hyperlipidaemia, and pathological changes in the pancreas, liver, kidney and intestine and reduced the serum levels of pro-inflammatory cytokines in T2DM model rats. 16S rRNA sequencing and UPLC-MS/MS showed that JTSH treatment could modulate gut microbiota dysbiosis by preferentially increasing bacteria (e.g., Bacteroides, Lactobacillus, Bifidobacterium) with bile-salt hydrolase (BSH) activity, which might in turn lead to the accumulation of ileal unconjugated BAs (e.g., CDCA, DCA) and further upregulate the intestinal FXR/FGF15 and TGR5/GLP-1 signaling pathways. CONCLUSION: The study demonstrated that JTSH treatment could alleviate T2DM by modulating the interaction between gut microbiota and BAs metabolism. These findings suggest that JTSH pill may serve as a promising oral therapeutic agent for T2DM.

Ferrodifferentiation regulates neurodevelopment via ROS generation.

Iron is important for life, and iron deficiency impairs development, but whether the iron level regulates neural differentiation remains elusive. In this study, with iron-regulatory proteins (IRPs) knockout embryonic stem cells (ESCs) that showed severe iron deficiency, we found that the Pax6- and Sox2-positive neuronal precursor cells and Tuj1 fibers in IRP1-/-IRP2-/- ESCs were significantly decreased after inducing neural differentiation. Consistently, in vivo study showed that the knockdown of IRP1 in IRP2-/- fetal mice remarkably affected the differentiation of neuronal precursors and the migration of neurons. These findings suggest that low intracellular iron status significantly inhibits neurodifferentiation. When supplementing IRP1-/-IRP2-/- ESCs with iron, these ESCs could differentiate normally. Further investigations revealed that the underlying mechanism was associated with an increase in reactive oxygen species (ROS) production caused by the substantially low level of iron and the down-regulation of iron-sulfur cluster protein ISCU, which, in turn, affected the proliferation and differentiation of stem cells. Thus, the appropriate amount of iron is crucial for maintaining normal neural differentiation that is termed ferrodifferentiation.

Fuzheng Jiedu Xiaoji formulation inhibits hepatocellular carcinoma progression in patients by targeting the AKT/CyclinD1/p21/p27 pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with limited treatment options. Conventional antitumor therapy combined with traditional Chinese medicine (TCM) to limit tumor progression has gradually become the focus of complementary and alternative therapies for HCC treatment. The Fuzheng Jiedu Xiaoji formulation (FZJDXJ) alleviates the clinical symptoms of patients and inhibits tumor progression, but its curative effect still requires extensive clinical research and mechanistic analysis. PURPOSE: To explore the effectiveness of FZJDXJ in HCC patients and investigate its biological function and mechanism underlying anticancer therapy. METHODS: This randomized controlled clinical trial enrolled 291 HCC patients receiving transcatheter arterial chemoembolization (TACE) therapy; patients received either FZJDXJ combined with standard treatment, or standard treatment alone, for 48 weeks. Statistical analyses were performed according to survival time at the end of the trial. The main constituents of the FZJDXJ extracts were identified and evaluated using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and molecular docking. The antitumor effects of FZJDXJ and its specific biological mechanism of action were studied. RESULTS: After 48 weeks of treatment, one-year overall survival (OS) and progression-free survival (PFS) were significantly different between the two groups. Co-administration of FZJDXJ and TACE prolonged the OS of HCC patients, especially in BCLC A or B stage. FZJDXJ and TACE treatment effectively extended the PFS of patients, especially in the BCLC B stage. HPLC-MS/MS identified 1619 active constituents of FZJDXJ, including formononetin, chlorogenic acid (CGA), caffeic acid, luteolin, gallic acid, diosgenin, ergosterol endoperoxide, and lupeol, which may function through the AKT/CyclinD1/p21/p27 pathways. Through molecular docking, CGA and gallic acid could effectively combine with Thr308, an important phosphorylation site of AKT1. FZJDXJ inhibited tumor growth in nude mice. In vitro, FZJDXJ-mediated serum inhibited the proliferation, migration, and invasion of liver cancer cells, and promoted cell apoptosis. CONCLUSION: Clinically, FZJDXJ combined with TACE therapy significantly prolonged OS and PFS and reduced the mortality rate of HCC patients. Mechanistically, FZJDXJ effectively inhibited the proliferation and migration of liver cancer cells through the modulation of the AKT/CyclinD1/p21/p27 pathways, and may be a promising TCM drug for anti-HCC therapy.

Comparative Study on the Chemical Components and Gastrointestinal Function on Rats of the Raw Product and Licorice-Simmered Product of Polygala tenuifolia.

The root of Polygala tenuifolia Willd. (Polygalaceae) (PT) has been listed as a nootropic, anti-inflammatory, and antipsychotic medicine that can cure insomnia. Raw PT (RPT) is toxic and must be processed before clinical use. Licorice-simmered PT (LPT) is one of the most common processed products. We conducted this study in order to investigate the differences in chemical components and gastrointestinal function between RPT and LPT. We used principal component analysis (PCA) and quantitative analysis to study the differences in the chemical components. Animal experiments were conducted to evaluate the effects of PT on the gastrointestinal function of rats before and after simmering. Pathological sections of gastrointestinal tissues, serum hormone levels, and inflammatory cytokines were observed. The PCA results demonstrated that obvious separation was achieved between the RPT and LPT samples. Tenuifoliside B (TFSB), 3,6'-disinapoyl sucrose (DSS), tenuifoliose A (TFOA), tenuifoliose H (TFOH), onjisaponin B (OJB), onjisaponin Z (OJZ), and total saponins levels were decreased after licorice processing, while glomeratose A (GA) and 3,4,5-trimethoxycinnamic acid (TMCA) levels were markedly increased. Compared to the control group, the RPT groups exhibited dramatically lower levels of gastrin (GAS), motilin (MTL), and substance P (SP) and markedly higher levels of vasoactive intestinal peptide (VIP) and somatostatin (SS), but the LPT groups exhibited no significant differences in the above indexes. The levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) in gastrointestinal tissue were markedly increased in the low RPT (L-RPT), high RPT (H-RPT), and H-LPT groups, showing a certain inflammatory effect, but the inflammatory effect in the L-LPT group was relatively weak. Licorice simmering can effectively reduce the inhibitory effect of RPT on gastrointestinal function in rats and reduce damage to gastrointestinal tissue. This study provides a scientific basis for research on the processing mechanism and clinical application of PT.

Loss of the centrosomal protein Cenpj leads to dysfunction of the hypothalamus and obesity in mice.

Cenpj is a centrosomal protein located at the centrosomes and the base of cilia, it plays essential roles in regulating neurogenesis and cerebral cortex development. Although centrosomal and cilium dysfunction are one of the causes of obesity, insulin resistance, and type 2 diabetes, the role that Cenpj plays in the regulation of body weight remains unclear. Here, we deleted Cenpj by crossing Cenpjflox/flox mice with Nkx2.1-Cre mice. Loss of the centrosomal protein Cenpj in Nkx2.1-expressing cells causes morbid obesity in mice at approximately 4 months of age with expended brain ventricles but no change of brain size. We found that hypothalamic cells exhibited reduced proliferation and increased apoptosis upon Cenpj depletion at the embryonic stages, resulting in a dramatic decrease in the number of Proopiomelanocortin (POMC) neurons and electrophysiological dysfunction of NPY neurons in the arcuate nucleus (ARC) in adults. Furthermore, depletion of Cenpj also reduced the neuronal projection from the ARC to the paraventricular nucleus (PVN), with decreased melanocortin-4 receptors (MC4R) expression in PVN neurons. The study defines the roles that Cenpj plays in regulating hypothalamus development and body weight, providing a foundation for further understanding of the pathological mechanisms of related diseases.

Akkermansia muciniphila: A potential novel mechanism of nuciferine to improve hyperlipidemia.

BACKGROUND: Intestinal microbiota is a novel drug target of metabolic diseases, especially for those with poor oral bioavailability. Nuciferine, with poor bioavailability, has an anti-hyperlipidemic effect at low dosages. PURPOSE: In the present study, we aimed to explore the role of intestinal microbiota in the anti-hyperlipidemic function of nuciferine and identify the key bacterial targets that might confer the therapeutic actions. METHODS: The contribution of gut microbes in the anti-hyperlipidemic effect of nuciferine was evaluated by conventional and antibiotic-established pseudo-sterile mice. Whole-metagenome shotgun sequencing was used to characterize the changes in microbial communities by various agents. RESULTS: Nuciferine exhibited potent anti-hyperlipidemic and liver steatosis-alleviating effects at the doses of 7.5-30 mg/kg. The beneficial effects of nuciferine were substantially abolished when combined with antibiotics. Metagenomic analysis showed that nuciferine significantly shifted the microbial structure, and the enrichment of Akkermansia muciniphila was closely related to the therapeutic effect of nuciferine. CONCLUSIONS: Our results revealed that gut microbiota played an essential role in the anti-hyperlipidemic effect of nuciferine, and enrichment of Akkermansia muciniphila represented a key mechanism through which nuciferine exerted its therapeutic effects.

Analysis of chemical variations between raw and wine-processed Ligustri Lucidi Fructus by ultra-high-performance liquid chromatography-Q-Exactive Orbitrap/MS combined with multivariate statistical analysis approach.

Ligustri Lucidi Fructus (LLF) is the dried and mature fruit of Ligubtrum lucidum Ait., which has the effect of nourishing the liver and kidney, brightening the eyes and promoting the growth of black hair. Wine-processed LLF is commonly used in traditional Chinese medicine; however, the processing mechanisms are still unclear. Herein, a system data acquisition and mining strategy was designed to investigate the chemical profile differences between the raw and wine-processed LLF, based on high-performance liquid chromatography-Orbitrap high resolution mass spectrometry coupled with multivariate statistical analysis including principal component analysis and partial least square analysis. Afterwars, a total of 55 components were found to be the main contributors to the significant difference between raw and wine-processed LLF by comparison with chromatographic behaviors, intact precursor ions, and characteristic MS fragmentation patterns. In addition, 10 main constituents of raw and wine-processed LLF were simultaneously determined by UHPLC-MS/MS for analyzing the content variations. Some structural transformation mechanisms during wine processing were deduced from the results. The results may provide a scientific foundation for deeply elucidating the wine-processing mechanism of LLF.

Cellular and molecular properties of neural progenitors in the developing mammalian hypothalamus.

The neuroendocrine hypothalamus is the central regulator of vital physiological homeostasis and behavior. However, the cellular and molecular properties of hypothalamic neural progenitors remain unexplored. Here, hypothalamic radial glial (hRG) and hypothalamic mantle zone radial glial (hmRG) cells are found to be neural progenitors in the developing mammalian hypothalamus. The hmRG cells originate from hRG cells and produce neurons. During the early development of hypothalamus, neurogenesis occurs in radial columns and is initiated from hRG cells. The radial glial fibers are oriented toward the locations of hypothalamic subregions which act as a scaffold for neuronal migration. Furthermore, we use single-cell RNA sequencing to reveal progenitor subtypes in human developing hypothalamus and characterize specific progenitor genes, such as TTYH1, HMGA2, and FAM107A. We also demonstrate that HMGA2 is involved in E2F1 pathway, regulating the proliferation of progenitor cells by targeting on the downstream MYBL2. Different neuronal subtypes start to differentiate and express specific genes of hypothalamic nucleus at gestational week 10. Finally, we reveal the developmental conservation of nuclear structures and marker genes in mouse and human hypothalamus. Our identification of cellular and molecular properties of neural progenitors provides a basic understanding of neurogenesis and regional formation of the non-laminated hypothalamus.

Physiologically Based Pharmacokinetics of Dexamethasone in Rats.

Blood and multitissue concentration-time profiles for dexamethasone (DEX), a synthetic corticosteroid, were measured in male rats after subcutaneous bolus and infusion dosing. A physiologically based pharmacokinetics (PBPK) model was applied for 12 measured tissues. Tissue partition coefficients (K p ) and metabolic clearance were assessed from infusion studies. Blood cell to plasma partitioning (0.664) and plasma free fraction (0.175) for DEX were found to be moderate. DEX was extensively partitioned into liver (K p = 6.76), whereas the calculated K p values of most tissues ranged between 0.1 and 1.5. Despite the moderate lipophilicity of DEX (log P = 1.8), adipose exhibited very limited distribution (K p = 0.17). Presumably due to P-glycoprotein-mediated efflux, DEX concentrations were very low in brain compared with its expected high permeability. Infusion studies yielded K p values from male and female rats at steady state that were similar. In silico K p values calculated for different tissues by using GastroPlus software were similar to in vivo values except for adipose and liver. Glucocorticoid receptors are found in diverse tissues, and these PBPK modeling results may help provide exposure profiles driving pharmacodynamic effects of DEX. SIGNIFICANCE STATEMENT: Our physiologically based pharmacokinetics model describes the experimentally determined tissue and plasma dexamethasone (DEX) pharmacokinetics (PK) profiles in rats reasonably well. This model can serve for further investigation of DEX tissue distribution in rats as the PK driving force for PD effects in different tissues. No major sex differences were found for DEX tissue distribution. Knowledge gained in this study may be translatable to higher-order species including humans.

Wuhu Decoction Regulates Dendritic Cell Autophagy in the Treatment of Respiratory Syncytial Virus (RSV)-Induced Mouse Asthma by AMPK/ULK1 Signaling Pathway.

BACKGROUND Dendritic cell autophagy plays a pivotal role in asthma. Wuhu decoction can significantly improve respiratory syncytial virus (RSV) bronchiolitis and delay its development into asthma. The aim of the present study was to explore the therapeutic effect and mechanism of Wuhu decoction on RSV -induced asthma in mice. MATERIAL AND METHODS Establishment of asthmatic mice model was induced by RSV. Hematoxylin-eosin staining, periodic acid-Schiff (PAS) staining, and Masson trichrome staining were performed to observe pathological changes in the lungs. The levels of CD4⁺ T, CD8⁺ T, and CD4⁺ CD25⁺ T in blood were analyzed by flow cytometry. The contents of interleukin (IL)-4, interferon-gamma (IFN-γ), IL-10, and IL-13 in serum were measured by enzyme-linked immunosorbent assay (ELISA). The number of autophagosomes in dendritic cells (DCs) of lung tissue was observed by transmission electron microscope. The DCs of lung tissue were isolated by magnetic bead sorting. The levels of LC3-II, Beclin-1, and LC3-I in DCs and MMP-9, TIMP-1, AMPK, p-AMPK, ULK1, and LK1 expression in lung tissues were detected by western blot. Real-time polymerase chain reaction (PCR) detected the expression of AMPK and ULK1 genes. RESULTS Wuhu decoction can effectively alleviate chronic airway inflammation and airway remodeling and reduce airway hyperresponsiveness. Moreover, Wuhu decoction can significantly enhance the level of autophagy in DCs of lung tissue and promote the expression of AMPK and ULK1 in lung tissue. CONCLUSIONS Wuhu decoction may improve the RSV-induced asthmatic symptoms by enhancing autophagy of DCs in lung tissue dependent on the AMPK/ULK1 signaling pathway.

Molluscicidal effectiveness of Luo-Wei, a novel plant-derived molluscicide, against Oncomelania hupensis, Biomphalaria alexandrina and Bulinus truncatus.

BACKGROUND: Control of snail intermediate hosts has been proved to be a fast and efficient approach for interrupting the transmission of schistosomiasis. Some plant extracts have shown obvious molluscicidal activity, and a new compound Luo-Wei, also named tea-seed distilled saponin (TDS), was developed based on the saponins extracted from Camellia oleifera seeds. We aimed to test the molluscicidal activity of 4% TDS against the intermediate host snails in China and Egypt, and evaluate its environmental safety to non-target organisms. METHODS: In the laboratory, Oncomelania hupensis, Biomphalaria alexandrina and Bulinus truncatus were exposed to 4% TDS, and the median lethal concentration (LC50) was estimated at 24, 48 and 72 h. In the field, snail mortalities were assessed 1, 2, 3 and 7 d post-immersion with 2.5 g/m3 4% TDS and 1, 3, 7 and 15 d post-spraying with 5 g/m2 4% TDS. In addition, the acute toxicity of 4% TDS to Japanese quail (Coturnix japonica), zebrafish (Brachydanio rerio) and freshwater shrimp (Macrobrachium nipponense) was assessed by estimations of LC50 or median lethal dose (LD50). RESULTS: In the laboratory, the LC50 values of 4% TDS for O. hupensis were 0.701, 0.371 and 0.33 mg/L at 24, 48 and 72 h, respectively, and 4% TDS showed a 1.975 mg/L [corrected] 24 h LC50 against B. alexandrina, and a 1.396 mg/L 24 h LC50 against B. truncatus. Across all study regions, the pooled mortalities of O. hupensis were 72, 86, 94 and 98% at 1, 2, 3 and 7 d, following field immersion of 4% TDS at a dose of 2.5 g/m3, and were 69, 77, 85 and 88% at 1, 3, 7 and 15 d, following field spraying at 5 g/m2, respectively. 4% TDS had moderate toxicity to Japanese quail (7 d LD50 > 60 mg/kg) and to shrimp (96 h LC50 = 6.28 mg/L; 95% CI: 3.53-11.2 mg/L), whereas its toxicity to zebrafish was high (96 h LC50 = 0.15 mg/L; 95% CI: 0.14-0.17 mg/L). CONCLUSIONS: 4% TDS is active against O. hupensis, B. alexandrina and B. truncatus under laboratory and field conditions, and it may be a candidate molluscicide of plant origin.

Early Excitatory Activity-Dependent Maturation of Somatostatin Interneurons in Cortical Layer 2/3 of Mice.

GABAergic interneurons perform distinct functions during cortical development in the mouse brain. Among the diverse GABAergic neurons present in the brain, early-born somatostatin (SST)-expressing inhibitory interneurons, which are innervated by other interneurons and local pyramidal cells (PCs), act in a neural computational role in circuitry regulation. The synapses between the SST+ interneurons and other cells form gradually during development. Here, we traced the developmental course of the electrophysiological properties of SST+ interneurons at layer 2/3 of the neocortical secondary motor area (M2) in mouse, and the synaptic connectivity between SST+ interneurons and PCs. Also, we used toxin-mediated and genetic method to suppress the activities of PCs, and demonstrate that decreasing excitatory input at early stage (before P1) rather than late stage (after P8) would delay the functional maturation of SST+ interneurons. In conclusion, our results indicate that early functional activity of PCs is crucial for the intrinsic maturation of SST+ interneurons, following which these interneurons participate in local circuitry.

Hypolipidemic activity and mechanisms of the total phenylpropanoid glycosides from Ligustrum robustum (Roxb.) Blume by AMPK-SREBP-1c pathway in hamsters fed a high-fat diet.

The aim of this study was to evaluate the hypolipidemic effect and mechanisms of total phenylpropanoid glycosides extracted from Ligustrum robustum (Roxb.) Blume (LRTPG) in hamsters fed a high-fat diet and to discover bioactive components in HepG2 cell model induced by oleic acid. LRTPG of high (1.2 g/kg), medium (0.6 g/kg), and low (0.3 g/kg) doses was administrated daily for 21 consecutive days in hamsters. We found that in hamsters fed a high-fat diet, LRTPG effectively reduced the concentrations of plasma triglycerides (TG), free fatty acid, total cholesterol, low-density lipoprotein cholesterol, and hepatic TG and total cholesterol. And the compounds acteoside, ligupurpuroside A, ligupurpuroside C, and ligupurpuroside D significantly inhibited lipid accumulation in HepG2 cell at the concentration of 50 µmol/L. Mechanism research demonstrated that LRTPG increased the levels of phospho-AMP-activated protein kinase and phospho-sterol regulatory element binding protein-1c in liver, further to suppress the downstream lipogenic genes as stearoyl-CoA desaturase 1, glycerol-3-phosphate acyltransferase, 1-acylglycerol-3-phosphate O-acyltransferase 2, and diacylglycerol acyltransferase 2. In addition, LRTPG increased the hydrolysis of circulating TG by up-regulating lipoprotein lipase activities. These results indicate that LRTPG prevents hyperlipidemia via activation of hepatic AMP-activated protein kinase-sterol regulatory element binding protein-1c pathway.

Metabolomics reveals that vine tea (Ampelopsis grossedentata) prevents high-fat-diet-induced metabolism disorder by improving glucose homeostasis in rats.

BACKGROUND: Vine tea (VT), derived from Ampelopsis grossedentata (Hand.-Mazz.) W.T. Wang, is an alternative tea that has been consumed widely in south China for hundreds of years. It has been shown that drinking VT on a daily basis improves hyperlipidemia and hyperglycemia. However, little is known about the preventive functions of VT for metabolic dysregulation and the potential pathological mechanisms involved. This paper elucidates the preventive effects of VT on the dysregulation of lipid and glucose metabolism using rats maintained on a high-fat-diet (HFD) in an attempt to explain the potential mechanisms involved. METHODS: Sprague Dawley (SD) rats were divided into five groups: a group given normal rat chow and water (control group); a group given an HFD and water (HFD group); a group given an HFD and Pioglitazone (PIO group), 5 mg /kg; and groups given an HFD and one of two doses of VT: 500 mg/L or 2000 mg/L. After 8 weeks, changes in food intake, tea consumption, body weight, serum and hepatic biochemical parameters were determined. Moreover, liver samples were isolated for pathology histology and liquid chromatography-mass spectrometry (LC-MS)-based metabolomic research. RESULTS: VT reduced the serum levels of glucose and total cholesterol, decreased glucose area under the curve in the insulin tolerance test and visibly impaired hepatic lipid accumulation. Metabolomics showed that VT treatment modulated the contents of metabolic intermediates linked to glucose metabolism (including gluconeogenesis and glycolysis), the TCA cycle, purine metabolism and amino acid metabolism. CONCLUSION: The current results demonstrate that VT may prevent metabolic impairments induced by the consumption of an HFD. These effects may be caused by improved energy-related metabolism (including gluconeogenesis, glycolysis and TCA cycle), purine metabolism and amino acid metabolism, and reduced lipid levels in the HFD-fed rats.

In silico Approach for Anti-Thrombosis Drug Discovery: P2Y1R Structure-Based TCMs Screening.

Cardiovascular diseases (CVDs), including thrombosis, which is induced by platelet aggregation, are the leading cause of mortality worldwide. The P2Y1 receptor (P2Y1R) facilitates platelet aggregation and is thus an important potential anti-thrombotic drug target. The P2Y1R protein structure contains a binding site for receptor antagonist MRS2500 within its seven-transmembrane bundle, which also provides suitable pockets for numerous other ligands to act as nucleotide antagonists of P2Y1R. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) comprises 499 Chinese Pharmacopoeia-registered herbs and the structure information for 29,384 ingredients. In silico docking of these compounds into the P2Y1R protein structure within the MRS2500 pocket can identify potential antithrombotic drugs from natural medicinal plants. Docking studies were performed and scored to evaluate ligand-binding affinities. In this study, a total of 8987 compounds from Traditional Chinese Medicine (TCM) were filtered by Lipinski's rule of five, and their ideal oral-intake properties were evaluated. Of these, 1656 compounds distributed in 443 herbs docked into the P2Y1R-MRS2500 structure in 16,317 poses. A total of 38 compounds were ranked with a DockScore above 70, and these may have significant potential for development into anti-thrombosis drugs. These computational results suggested that licorice (Glycyrrhiza uralensis Fisch), cimicifugae (Cimicifuga foetida L.), and ganoderma (Ganoderma lucidum Karst) and their chemical constituents, which have not previously been widely used for anti-thrombosis, may have unexpected effects on platelet aggregation. Moreover, two types of triterpene scaffolds summarized from 10 compounds were distributed in these three herbs and also docked into P2Y1R. These scaffold structures may be utilized for the development of drugs to inhibit platelet aggregation.

Profiling and multivariate statistical analysis of Panax ginseng based on ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

An ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was developed for the detection and structural analysis of ginsenosides in white ginseng and related processed products (red ginseng). Original neutral, malonyl, and chemically transformed ginsenosides were identified in white and red ginseng samples. The aglycone types of ginsenosides were determined by MS/MS as PPD (m/z 459), PPT (m/z 475), C-24, -25 hydrated-PPD or PPT (m/z 477 or m/z 493), and Δ20(21)-or Δ20(22)-dehydrated-PPD or PPT (m/z 441 or m/z 457). Following the structural determination, the UHPLC-Q-TOF-MS-based chemical profiling coupled with multivariate statistical analysis method was applied for global analysis of white and processed ginseng samples. The chemical markers present between the processed products red ginseng and white ginseng could be assigned. Process-mediated chemical changes were recognized as the hydrolysis of ginsenosides with large molecular weight, chemical transformations of ginsenosides, changes in malonyl-ginsenosides, and generation of 20-(R)-ginsenoside enantiomers. The relative contents of compounds classified as PPD, PPT, malonyl, and transformed ginsenosides were calculated based on peak areas in ginseng before and after processing. This study provides possibility to monitor multiple components for the quality control and global evaluation of ginseng products during processing.

Improving permeability and oral absorption of mangiferin by phospholipid complexation.

Mangiferin is an active ingredient of medicinal plant with poor hydrophilicity and lipophilicity. Many reports focused on improving aqueous solubility, but oral bioavailability of mangiferin was still limited. In this study, we intended to increase not only solubility, but also membrane permeability of mangiferin by a phospholipid complexation technique. The new complex's physicochemical properties were characterized in terms of scanning electron microscopy (SEM), differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), aqueous solubility, oil-water partition coefficient and in vitro dissolution. The intestinal absorption of the complex was studied by the rat in situ intestinal perfusion model. After oral administration of mangiferin-phospholipid complex and crude mangiferin in rats, the concentrations of mangiferin were determined by a validated RP-HPLC method. Results showed that the solubility of the complex in water and in n-octanol was enhanced and the oil-water partition coefficient was improved by 6.2 times and the intestinal permeability in rats was enhanced significantly. Peak plasma concentration and AUC of mangiferin from the complex (Cmax: 377.66 µg/L, AUC: 1039.94 µg/L*h) were higher than crude mangiferin (Cmax: 180 µg/L, AUC: 2355.63 µg/L*h). In view of improved solubility and enhanced permeability, phospholipid complexation technique can increase bioavailability of mangiferin by 2.3 times in comparison to the crude mangiferin.