Protective effects of Radix Stellariae extract against Alzheimer's disease via autophagy activation in Caenorhabditis elegans and cellular models.

Enhancing the clearance of proteins associated with Alzheimer's disease (AD) emerges as a promising approach for AD therapeutics. This study explores the potential of Radix Stellariae, a traditional Chinese medicine, in treating AD. Utilizing transgenic C.

Ameliorative effect of Luffa cylindrica fruits on Caenorhabditis elegans and cellular models of Alzheimer's disease-related pathology via autophagy induction.

Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder without an effective cure. Natural products, while showing promise as potential therapeutics for AD, remain underexplored.

Aims: This study was conducted with the goal of identifying potential anti-AD candidates from natural sources using Caenorhabditis elegans (C.

Piezoelectric Effect and Ignition Characteristics of Coal Mine Gob Roof Collapse.

Existing studies of coal self-ignition and impact frictional sparks do not provide valid support for the analysis of ignition sources in all cases of methane explosions in the gob. In this paper, the explosion in the gob of the Renlou coal mine is used to investigate the piezoelectric effect and ignition characteristics of roof collapse in identifying a new ignition source of gas explosion. Experimental and theoretical analyses conclude that the piezoelectric effect is produced by quartz, which is the main constituent of the roof sandstone.

Effect of intrathecal lipophilic opioids on the incidence of shivering in women undergoing cesarean delivery after spinal anesthesia: a systematic review and bayesian network meta- analysis of randomized controlled trials.

Background: Shivering is a common side effect in women having cesarean delivery (CD) under spinal anesthesia, which can be bothersome to the patient, and it can also interfere with perioperative monitoring. In several studies, the intrathecal (IT) addition of a lipophilic opioid to local anesthetics has been shown to decrease the incidence of shivering.

Objective: We performed this network meta-analysis to evaluate the effects of intrathecal lipophilic opioids in preventing the incidence of shivering in patients undergoing CD.

Effects of chemotherapeutic agent bendamustine for non-hodgkin lymphoma on spermatogenesis in mice.

Non-Hodgkin lymphoma (NHL) is one of the most common cancers affecting men of reproductive age. The high response rate of bendamustine as first-line treatment for NHL, coupled with young age of patients, makes elucidation of the impact of treatment on male reproduction important. Our aim was to determine the effects of bendamustine on male reproduction by animal model.

The physiological cold tolerance of warm-climate plants is correlated with their latitudinal range limit.

Plants are moving poleward and upward in response to climate warming. However, such movements lag behind the expanding warming front for many reasons, including the impediment of plant movement caused by unusual cold events. In this study, we measured the maximum photochemical efficiency of photosystem II () in 101 warm-climate angiosperm species to assess their cold tolerance at the end of a severe chilling period of 49 days in a southern subtropical region (Nanning) in China.

Effect of a mentor-based, supportive-expressive program, Be Resilient to Breast Cancer, on survival in metastatic breast cancer: a randomised, controlled intervention trial.

Background: Because of medical advances, metastatic breast cancer (MBC) is now viewed as a chronic disease, rather than an imminent death sentence. Helping women live with this disease requires more than a medical approach to symptoms. Thus, a mentor-based and supportive-expressive program 'Be Resilient to Breast Cancer' (BRBC) was designed to help Chinese women with MBC enhance their resilience levels, biopsychosocial functions, and potentially extend their life span.

Predicting changes in quality of life and emotional distress in Chinese patients with lung, gastric, and colon-rectal cancer diagnoses: the role of psychological resilience.

Background: Patients with cancer often experience considerable emotional distress, which decreases their quality of life (QOL). Resilience is defined as the psychological characteristics that promote positive adaptation in the face of stress and adversity; however, the relationships among QOL, resilience, and emotional distress in patients with cancer, especially Chinese patients with cancer, are under-researched in the literature.

Methods: Quality of Life Questionnaire Core 30 items, Zung Self-Rating Anxiety Scale, and the Zung Self-Rating Depression Scale were applied in this study.

Effect of a multidiscipline mentor-based program, Be Resilient to Breast Cancer (BRBC), on female breast cancer survivors in mainland China-A randomized, controlled, theoretically-derived intervention trial.

To reduce the risk of adjustment problems for breast cancer patients in mainland China, we examined the efficacy of a multidiscipline mentor-based program, Be Resilient to Breast Cancer (BRBC), delivered after breast surgery to (a) increase protective factors of social support, hope for the future, etc.; (b) decrease risk factors of Physical and Emotional Distress; and (c) increase outcomes of Resilience, Transcendence and Quality of Life (QOL). A multisite randomized controlled trial was conducted at 6 specialist cancer hospitals.

Changes of major tea polyphenols and production of four new B-ring fission metabolites of catechins from post-fermented Jing-Wei Fu brick tea.

HPLC analysis of samples from four major fermentation procedures of Jing-Wei Fu brick tea showed that the level of major tea catechins epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) dropped increasingly to about 1/3 in the final product. Phytochemical study of the final product led to the discovery of four new B-ring fission metabolites of catechins (BRFCs) Fuzhuanin C-F (1-4) together with three known BRFCs (5-7), six known catechins (8-13), five simple phenols (14-18), seven flavones and flavone glycosides (19-25), two alkaloids (26, 27), three triterpenoids (28-30) and one steroid (31). The structures were elucidated by spectroscopic methods including 1D and 2D NMR, LC-HR-ESI-MS, IR, and CD spectra.

New limonoids and a dihydrobenzofuran norlignan from the roots of Toona sinensis.

Two new limonoids, toonins A (1) and B (2), and one new dihydrobenzofuran norlignan, toonin C (3), were isolated from the roots of Toona sinensis together with the ten known compounds 4-methoxy-6-(2',4'-dihydroxy-6'-methylphenyl)-pyran-2-one (4), bourjotinolone A (5), proceranone (6), matairesinol (7), 4-hydroxy-3-methoxybenzene-ethanol (8), syringic acid (9), isoscopoletin (10), lyoniresinol (11), aloeemodin (12), and β-sitosterol (13). Their structures were elucidated on the basis of one- and two-dimensional spectroscopic analysis. Isolation of compounds 4, 6-13 from this plant is reported here for the first time.

Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor.

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist.

Zwitterionic uracil derivatives as potent GnRH receptor antagonists with improved pharmaceutical properties.

A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.

Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity.

Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.

5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers.

Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II.

Selection, synthesis, and structure-activity relationship of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists.

The present article describes a selection of a new class of small molecule antagonists for the h-GnRH receptor, their preparation, and evaluation in vitro. Three computational methods were combined into a consensus score, to rank order virtual templates. The top 5% of templates were further evaluated in silico and assessed for novelty and synthetic accessibility.

Identification of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives as novel GnRH receptor antagonists.

A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats.

Trapping of a nonpeptide ligand by the extracellular domains of the gonadotropin-releasing hormone receptor results in insurmountable antagonism.

Drugs that exhibit insurmountable antagonism are proposed to provide improved clinical efficacy through extended receptor blockade. Long-term suppression of the gonadotropin-releasing hormone receptor (GnRHR) is an important therapeutic approach for a number of sex hormone-dependent diseases. In this study, we describe the mechanism and structural components required for insurmountable activity of a GnRHR antagonist.

Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902.

Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902, that suppresses serum LH concentrations in postmenopausal women after oral administration. Here we report the in vitro and in vivo pharmacological characterization of this compound.

Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling.

We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6.

Kinetics of nonpeptide antagonist binding to the human gonadotropin-releasing hormone receptor: Implications for structure-activity relationships and insurmountable antagonism.

Numerous nonpeptide ligands have been developed for the human gonadotropin-releasing hormone (GnRH) receptor as potential agents for treatment of disorders of the reproductive-endocrine axis. While the equilibrium binding of these ligands has been studied in detail, little is known of the kinetics of their receptor interaction. In this study we evaluated the kinetic structure-activity relationships (SAR) of uracil-series antagonists by measuring their association and dissociation rate constants.

Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil.

1-(2,6-Difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (6), a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor, exists as a pair of atropisomers in solution, which was detected by NMR spectroscopy, and separable by HPLC. In addition to a (R)-configured benzylamine, there is a second stereogenic element due to the presence of a chiral axis between the substituted 5-phenyl group and the uracil core. The rate constant of the interconversion (k = 5.

1-(4-Amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine derivatives as melanin-concentrating hormone receptor-1 antagonists.

Derivatives of 1-(4-amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine were identified as potent and functionally active MCH-R1 antagonists. One compound with Ki = 2.3 nM demonstrated good oral bioavailability (32%) and in vivo efficacy in rats.

Structure-activity relationships of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists.

SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM.