Inhibitory Effect of Hernandezine on the Proliferation of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) causes 830000 deaths every year and is becoming the third malignant tumor worldwide. One of the primary reasons is the lack of effective drugs. Hernandezine (HER), a bisbenzylisoquinoline alkaloid of Thalictrum simplex, has been confirmed to have antitumor activity. But there are few reports about its effect on HCC and the underlying mechanisms still remain unclear. Therefore, the antitumor effects and mechanisms of HER on HCC were evaluated in HepG2 and Hep3B cells. The in vitro experiments demonstrated that HER significantly induced G0/G1 phase arrest, inhibited the proliferation and promoted cell apoptosis in liver cancer cell lines. In the mechanisms, the antitumor effects of HER on liver cancer cells were mediated by phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) pathway and reactive oxygen species (ROS), simultaneously. In one way, HER inhibited the activities of PI3K-AKT pathway, which interrupt the dimer formation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1) and result to G0/G1 phase arrest. In another way, after HER treatment, ROS accumulated in liver cancer cells and caused mitochondria injury which further influenced the expression of apoptosis-related proteins and eventually resulted to HepG2 and Hep3B cell apoptosis. In addition, HER showed a tumor restrain function in HepG2 and Hep3B bearing nude mice. Overall, these findings indicated that HER is a promising antitumor drug, which may provide a new direction for clinical HCC treatment.

The application of the MM/GBSA method in the binding pose prediction of FGFR inhibitors.

The success of a structure-based drug is highly dependent on a known binding pose of the protein-ligand system. However, this is not always available. In this study, we set out to explore the applicability of the popular and easy-to-use MD-based MM/GBSA method to determine the binding poses of known FGFR inhibitors. It was found that MM/GBSA combined with 100 ns of MD simulation significantly improved the success rate of docking methods from 30-40% to 70%. This work demonstrates a way that the MM/GBSA method can be more accurate than it is in ligand ranking, filling a gap in structure-based drug discovery when the binding pose is unknown.

In Silico and In Vitro Anti-Helicobacter Pylori Effects of Combinations of Phytochemicals and Antibiotics.

Helicobacter pylori infection is a WHO class 1 carcinogenic factor of gastric adenocarcinoma. In the past decades, many studies have demonstrated the increasing trend of antibiotic resistance and pointed out the necessity of new effective treatment. This study was aimed at identifying phytochemicals that can inhibit H. pylori and possibly serve as adjuvant treatments. Here, in silico molecular docking and drug-like properties analyses were performed to identify potential inhibitors of urease, shikimate kinase and aspartate-semialdehyde dehydrogenase. These three enzymes are targets of the treatment of H. pylori. Susceptibility and synergistic testing were performed on the selected phytochemicals and the positive control antibiotic, amoxicillin. The in-silico study revealed that oroxindin, rosmarinic acid and verbascoside are inhibitors of urease, shikimate kinase and aspartate-semialdehyde dehydrogenase, respectively, in which, oroxindin has the highest potency against H. pylori, indicated by a minimum inhibitory concentration (MIC) value of 50 µg/mL. A combination of oroxindin and amoxicillin demonstrated additive effects against H. pylori, as indicated by a fractional inhibitory concentration (FIC) value of 0.75. This study identified phytochemicals that deserve further investigation for the development of adjuvant therapeutic agents to current antibiotics against H. pylori.

Nursing shortage: the facts and strategies in Macao society.

Historically, Macao, a Special Administrative Region (SAR) in the People's Republic of China, has been troubled by a shortage of nurses. This shortage became especially severe during the period immediately after the handover of Macao from Portugal to the People's Republic of China in 1999. A fast-growing population, an aging population, the risk of epidemics, and competition for personnel with other industries have all contributed to this shortage. In recent years, Macao has implemented the following successful strategies to address the shortage: increased school enrollments, benefits, and professional development, along with the development of a clinical specialist program, a transition program for new graduates, and training for more certified nursing assistants. Strong government support and collaboration among all stakeholders have also served to enhance the nursing work force. In this article, the authors describe the nursing shortage in Macao SAR, discuss factors contributing to the shortage, and present strategies used to manage the shortage. They conclude by emphasizing the importance of increasing salary and professional status and providing transition programs for new graduates.

Extraction of antibacterial peptides against Helicobacter pylori from bovine milk casein.

Introduction: More than half of the world's population is infected with Helicobacter pylori, which may cause gastritis, peptic ulcer and even gastric cancer. The World Health Organization (WHO) has announced that H. pylori infection is a class I carcinogen and hence eradication of it is highly important. Bovine milk contains caseins, which can be digested by various enzymes in the human stomach to produce antibacterial peptides. Material and methods: This study used in vitro methods to extract anti-H. pylori peptides from caseins by the gastric protease pepsin under environments with similar pH values to those found in the human stomach. The molecular weights and sequences of the peptides were identified by MALDI-TOF mass spectrometry and MS/MS Ion Search, respectively. Antibacterial activity tests were performed to calculate the minimum inhibitory concentration (MIC90) of the extracts. Results: The findings of this study revealed that the major products of bovine milk casein digestion by pepsin are casecidin 17 and ß-casein 207-224. The extracts produced promising anti-H. pylori effects with the lowest MIC90 found at pH values of 1.5 and 2.0. Conclusions: This study identified the anti-H. pylori effects of casecidin 17 and ß-casein 207-224, which may help in developing therapeutic agents to modulate the effect of antibiotics on H. pylori infections.

Association of suicidal ideation and depression with the use of proton pump inhibitors in adults: a cross-sectional study.

Proton pump inhibitors (PPIs) were found to be associated with depression. This study aimed to find the cross-sectional association between recent PPI use and suicidal ideation. Item 9 of Patient Health Questionnaire-9 (PHQ-9) of the US National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018 was used to categorize whether or not the participants had suicidal ideation. The secondary outcome of this study was depression and the scores of the PHQ-9 were used as the depression diagnostic instrument. The study population included 16,881 participants who were over 20 years old. The bivariate Rao-Scott χ2 test showed a significant association between PPI use and suicidal ideation (P < 0.001) and a stronger association was observed between PPIs and depression (P < 0.001). Multiple logistic regression analysis of the education, gender, race and age-adjusted model revealed that the PPI users had a 2.34 (95% CI 1.66-3.31) greater risk of having suicidal ideation than the non-PPI users. Middle-aged participants (40-49 years) showed the greatest number of differences in suicidal ideation between PPI and non-PPI users (P < 0.001). Future research should continue to consider the psychiatric effects of taking PPIs.

Experimental and In Silico Analysis of Cordycepin and its Derivatives as Endometrial Cancer Treatment.

The aim of this study was to investigate the inhibition effects of cordycepin and its derivatives on endometrial cancer cell growth. Cytotoxicity MTT assays, clonogenic assays, and flow cytometry were used to observe the effects on apoptosis and regulation of the cell cycle of Ishikawa cells under various concentrations of cordycepin, cisplatin, and combinations of the two. Validated in silico docking simulations were performed on 31 cordycepin derivatives against adenosine deaminase (ADA) to predict their binding affinities and hence their potential tendency to be metabolized by ADA. Cordycepin has a significant dose-dependent inhibitory effect on cell proliferation. The combination of cordycepin and cisplatin produced greater inhibition effects than did cordycepin alone. Apoptosis investigations confirmed the ability of cordycepin to induce the apoptosis of Ishikawa cells. The in silico results indicate that compound MRS5698 is least metabolized by ADA and has acceptable drug likeness and safety profiles. This is the first study to confirm the cytotoxic effects of cordycepin on endometrial cancer cells. This study also identified cordycepin derivatives with promising pharmacological and pharmacokinetic properties for further investigation in the development of new treatments for endometrial cancer.

Synergistic antibacterial effects of herbal extracts and antibiotics on methicillin-resistant Staphylococcus aureus: A computational and experimental study.

Antibiotic resistance has become a serious global concern, and the discovery of antimicrobial herbal constituents may provide valuable solutions to overcome the problem. In this study, the effects of therapies combining antibiotics and four medicinal herbs on methicillin-resistant Staphylococcus aureus (MRSA) were investigated. Specifically, the synergistic effects of Magnolia officinalis, Verbena officinalis, Momordica charantia, and Daphne genkwa in combination with oxacillin or gentamicin against methicillin-resistant (ATCC43300) and methicillin-susceptible (ATCC25923) S. aureus were examined. In vitro susceptibility and synergistic testing were performed to measure the minimum inhibitory concentration and fractional inhibitory concentration (FIC) index of the antibiotics and medicinal herbs against MRSA and methicillin-susceptible S. aureus. To identify the active constituents in producing these synergistic effects, in silico molecular docking was used to investigate the binding affinities of 139 constituents of the four herbs to the two common MRSA inhibitory targets, penicillin binding proteins 2a (PBP2a) and 4 (PBP4). The physicochemical and absorption, distribution, metabolism, and excretion properties and drug safety profiles of these compounds were also analyzed. D. genkwa extract potentiated the antibacterial effects of oxacillin against MRSA, as indicated by an FIC index value of 0.375. M. officinalis and V. officinalis produced partial synergistic effects when combined with oxacillin, whereas M. charantia was found to have no beneficial effects in inhibiting MRSA. Overall, tiliroside, pinoresinol, magnatriol B, and momorcharaside B were predicted to be PBP2a or PBP4 inhibitors with good drug-like properties. This study identifies compounds that deserve further investigation with the aim of developing therapeutic agents to modulate the effect of antibiotics on MRSA. Impact statement Antibiotic resistant is a well-known threat to global health and methicillin-resistant Staphylococcus aureus is one of the most significant ones. These resistant bacteria kill thousands of people every year and therefore a new effective antimicrobial treatment is necessary. This study identified the herbs and their associated bioactive ingredients that can potential the effects of current antibiotics. These herbs have long history of human usage in China and have well-defined monograph in the Chinese Pharmacopeia. These indicate their relatively high clinical safety and may have a quicker drug development process than that of a new novel antibiotic. Based on the results of this study, the authors will perform further in vitro and animal studies, aiming to accumulate significant data for the application of clinical trial.

In silico prediction of prostaglandin D2 synthase inhibitors from herbal constituents for the treatment of hair loss.

ETHNOPHARMACOLOGICAL RELEVANCE: Many herbal topical formulations have been marketed worldwide to prevent hair loss or promote hair growth. Certain in vivo studies have shown promising results among them; however, the effectiveness of their bioactive constituents remains unknown. AIM OF THE STUDY: Recently, prostaglandin D2 (PGD2) inhibition has been discovered as a pharmacological mechanism for treating androgenic alopecia (AGA). This present study was aimed to identify prostaglandin D2 synthase (PTGDS) inhibitors in traditional Chinese medicines (TCMs) for treating AGA. MATERIALS AND METHODS: In this study, 389 constituents of 12 selected herbs were docked into 6 different crystal structures of PTGDS. The accuracy of the docking methods was successfully validated with experimental data from the ZINC In Man (Zim) database using receiver operating characteristic (ROC) studies. Seven essential drug properties were predicted for topical formulation: skin permeability, sensitisation, irritation, corrosion, mutagenicity, tumorigenicity and reproductive effects. RESULTS: Many constituents of the twelve herbs were found to have more advanced binding energies than the experimentally proved PTGDS inhibitors, but many of them were indicative of at least one type of skin adverse reactions, and exhibited poor skin permeability. CONCLUSIONS: Overall, ricinoleic acid, acteoside, amentoflavone, quercetin-3-O-rutinoside and hinokiflavone were predicted to be PTGDS inhibitors with good pharmacokinetic properties and minimal adverse skin reactions. These compounds have the highest potential for further in vitro and in vivo investigation with the aim of developing safe and high-efficacy hair loss treatment.

Effect of mTOR inhibitors in nude mice with endometrial carcinoma and variable PTEN expression status.

BACKGROUND: The aim of this study was to investigate the sensitivity to rapamycin of endometrial cancer cells with different phosphatase and tensin homologue (PTEN) expression to understand the mechanism of resistance to mammalian target of rapamycin (mTOR) inhibitors in the treatment of endometrial cancer. MATERIAL AND METHODS: Twenty specific pathogen-free female BALB/c mice received transplants of either HEC-1A (PTEN-positive) or Ishikawa (PTEN-negative) cells. Mice in the treatment group were injected intraperitoneally once a week for 4 consecutive weeks. The control group was injected weekly with phosphate buffer saline (PBS) for 4 consecutive weeks. Tumor volume, tumor mass, growth curves, and inhibition rate were measured, after which the mice were killed. RESULTS: Both tumor growth rate and size were slower in the treatment group than in the control group for all mice that received transplants of either HEC-1A or Ishikawa cells. The tumor inhibition rates in the treatment group were 48.1% and 67.1% in mice transplanted with HEC-1A and Ishikawa cells, respectively. CONCLUSIONS: The inhibitory effects of rapamycin were enhanced in PTEN-negative Ishikawa tumor cells compared with PTEN-positive HEC-1A cells, which could explain the reduced effect of rapalogues in some endometrial cancer patients and help to understand the mechanism of resistance to this drug.

In silico prediction of tyrosinase and adenylyl cyclase inhibitors from natural compounds.

Although many herbal medicines are effective in the treatment of hyperpigmentation, the potency of different constituents remains unknown. In this work, more than 20,000 herbal ingredients from 453 herbs were docked into the crystal structures of adenylyl cyclase and a human homology tyrosinase model using Surflex-Dock. These two enzymes are responsible for melanin production and inhibition of them may attain a skin-whitening effect superior to currently available agents. The essential drug properties for topical formulation of the herbal ingredients, including skin permeability, sensitization, irritation, corrosive and carcinogenic properties were predicted by Dermwin, Skin Sensitization Alerts (SSA), Skin Irritation Corrosion Rules Estimation Tool (SICRET) and Benigni/Bossa rulebase module of Toxtree. Moreover, similarity ensemble and pharmacophore mapping approaches were used to forecast other potential targets for these herbal compounds by the software, SEArch and PharmMapper. Overall, this study predicted seven compounds to have advanced drug-like properties over the well-known effective tyrosinase inhibitors, arbutin and kojic acid. These seven compounds have the highest potential for further in vitro and in vivo investigation with the aim of developing safe and high-efficacy skin-whitening agents.

In silico prediction of the cosmetic whitening effects of naturally occurring lead compounds.

The identification of tyrosinase inhibitors is important, not only for the treatment of skin hyperpigmentation disorders, such as melasma, but also for the production of cosmetic whitening effects. The aim of this study was the in silico prediction of the naturally occurring lead compounds in three commonly used skin-whitening herbs: Ampelopsis japonica, Lindera aggregata, and Ginkgo biloba. The active ingredients responsible for the whitening effect of these herbs remain largely unknown. The tyrosinase binding affinities and skin permeation, skin irritancy, and corrosive properties of43 natural constituents of the three herbs were predicted by docking simulations using Surflex-Dock and the QSAR-based Dermal Permeability Coefficient Program (DERMWIN) and Skin Irritation Corrosion Rules Estimation Tool (SICRET) implemented in Toxtree. Nine constituents of the three herbs were found to have more advanced binding energies than the gold standard whitening agents, arbutin and kojic acid, but 40 were indicative of at least one skin sensitization alert, and many exhibited poor skin permeability. Linderagalactone c and (+)-n-methyllaurotetanine were found to have the strongest prospects for use in topical formulations, as they achieved high predicted tyrosinase binding scores and displayed good skin permeation properties and minimal potential for skin sensitization and irritation.

Assessment of QM/MM scoring functions for molecular docking to HIV-1 protease.

We explore the ability of four quantum mechanical (QM)/molecular mechanical (MM) models to accurately identify the native pose of six HIV-1 protease inhibitors and compare them with the AMBER force field and ChemScore and GoldScore scoring functions. Three QM/MM scoring functions treated the ligand at the HF/6-31G*, AM1d, and PM3 levels; the fourth QM/MM function modeled the ligand and active site at the PM3-D level. For the discrimination of native from non-native poses, solvent-corrected HF/6-31G*:AMBER and AMBER functions exhibited the best overall performance. While the electrostatic component of the MM and QM/MM functions appears important for discriminating the native pose of the ligand, the polarization contribution in the QM/MM functions was relatively insensitive to a ligand's binding mode and, for one ligand, actually hindered discrimination. The inclusion of a desolvation penalty, here using a generalized Born solvent model, improved discrimination for the MM and QM/MM methods. There appeared to be no advantage to binding mode prediction by incorporating active site polarization at the PM3-D level. Finally, we found that choice of the protonation state of the aspartyl dyad in the HIV-1 protease active site influenced the ability of scoring methods to determine the native binding pose.