Bioinformatics and LC-QTOF-MS based discovery of pharmacodynamic and Q-markers of Pitongshu against functional dyspepsia.

ETHNOPHARMACOLOGICAL RELEVANCE: Pitongshu (PTS) is a clinically effective empirical formula for the treatment of FD. The efficacy and safety of PTS have been demonstrated in randomized, controlled, double-blind trials, but there is a lack of understanding of the systematic evaluation of the efficacy of PTS and its material basis. OBJECTIVE: To investigate the efficacy of PTS in Functional dyspepsia (FD) mice and possible Q-markers. METHOD: In this study, we used "irregular feeding + chronic unpredictable chronic stimulation" to establish a mice model of FD with hepatogastric disharmony. The efficacy of PTS was assessed from hair condition, behavioral, pain, gastrointestinal function, and serum 5-HT, GAS, MTL levels in mice by instillation of different doses of PTS. In addition, the composition of drugs in blood was analyzed by LC-QTOF-MS and potential Q-markers were selected by combining network pharmacology, molecular docking and actual content. RESULT: Our study showed that different doses of PTS increased pain threshold and writhing latency, decreased the number of writhings, increased gastric emptying rate and small intestinal propulsion rate, decreased total acidity of gastric contents and gastric acid secretion, and increased serum levels of 5-HT, GAS, and MTL in mice to different degrees. Enrichment analysis showed that PTS may be anti-FD through multiple pathways such as Serotonergic synapse, thyroid hormone signaling pathway, cholinergic synapse, and dopaminergic synapse. In addition, potential active ingredient substances were explored by LC-QTOF-MS combined with bioinformatics. Combined with the actual contentselected six constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol, possible as Q-markers. CONCLUSION: PTS may exert its anti-FD effects through multi-component, multi-target and multi-pathway". Constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol may be the Q-markers of its anti-FD effects.

The potential mechanism of Choulingdan mixture in improving acute lung injury based on HPLC-Q-TOF-MS, network pharmacology and in vivo experiments.

Choulingdan mixture (CLDM) is an empirical clinical prescription for the adjuvant treatment of acute lung injury (ALI). CLDM has been used for almost 30 years in the clinic. However, its mechanism for improving ALI still needs to be investigated. In this study, high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS) was applied to characterize the overall chemical composition of CLDM. A total of 93 ingredients were characterized, including 25 flavonoids, 20 organic acids, 11 saponins, nine terpenoids, seven tannins and 21 other compounds. Then network pharmacology was applied to predict the potential bioactive components, target genes and signaling pathways of CLDM in improving ALI. Additionally, molecular docking was performed to demonstrate the interaction between the active ingredients and the disease targets. Finally, animal experiments further confirmed that CLDM significantly inhibits pulmonary inflammation, pulmonary edema and oxidative stress in lipopolysaccharide-induced ALI mice by inhibiting the PI3K-AKT signaling pathway. This study enhanced the amount and accuracy of compounds of CLDM and provided new insights into CLDM preventing and treating ALI.

Lactobacillus plantarum LP45 inhibits the RANKL/OPG signaling pathway and prevents glucocorticoid-induced osteoporosis.

Objective: To examine the potential effect of the probiotic strain Lactobacillus plantarum LP45 on osteoporosis and to explore the involved molecular mechanisms. Methods: A rat model of glucocorticoid-induced osteoporosis (GIO) was established, which was also orally administered with increasing doses of LP45 for 8 weeks. After the termination of the 8-week treatment, the tibia and femur bones of rats were analyzed for bone histomorphometry, bone mineral content (BMC), and bone mineral density (BMD). Femoral biomechanics were assessed. In addition, levels of osteocalcin, tartrate-resistant acid phosphatase 5 (TRAP5), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) in the serum and bone marrow were also measured using ELISA, Western blot, and real time-polymerase chain reaction. Results: GIO caused obvious defects in tibia and femur bone structures, in terms of tissue/bone volume, trabecular separation, trabecular thickness, and trabecular number, which could be rescued by LP45 dose dependently. The GIO-induced reductions in BMC, BMD, osteoblast surfaces per bone surface (BS), as well as elevated osteoclast surface per BS were largely restored by LP45 administration dose-dependently. LP45 also increased femoral biomechanics of GIO rats. Importantly, LP45 dose-dependently restored the changes of osteocalcin, TRAP5, OPG, and RANKL in the serum as well as bone marrow of GIO rats. Conclusion: Oral LP45 administration could significantly prevent bone defects in GIO rats, suggesting its potential as a dietary supplement with beneficial effects against osteoporosis, which might involve the RANKL/OPG signaling pathway.

pH-responsive black phosphorus quantum dots for tumor-targeted photodynamic therapy.

Black phosphorus quantum dots(BPQDs) have shown a good application prospect in the field of tumor therapy due to their photoelectric effect and good biodegradability. Due to the active endocytosis and fast metabolic efficiency of tumor cells, BPQDs are easy to be absorbed by tumor cells. However, this does not guarantee that BPQDs will be completely targeted to tumor cells, and normal cells will also absorb BPQDs. Because the cell membrane is negatively charged, BPQDs are also negatively charged and are not easily absorbed by cells under the action of electrostatic repulsion. Surface pegylation is the most common modification method of black phosphorus at present. However, surface pegylation can reduce the uptake of BPQDs by tumor cells. Positive PEG is also easy to be recognized and swallowed by the reticuloendothelial system. The inherent instability and poor tumor targeting of BPQDs under physiological conditions limit further research and clinical application. For this purpose, we selected cationic polymer polyethylenimine (PEI) to modify BPQDs and then added RGD peptides targeting tumor cells. An outer layer of negatively charged PEG+DMMA makes the nanosystem more stable . In the acidic environment of the tumor, the PEG layer has a charge reversal, and the positively charged PEI and the RGD polypeptide BPQDs targeted by the tumor cells are released into the tumor cells. It provides a new method for efficiently and accurately transporting BPQDs, a novel photosensitive nanomaterial, into tumor cells for photodynamic therapy.

Effect of three different proteases on horsemeat tenderness during postmortem aging.

In this study, the semitendinosus of horse meat was used as the raw material. The study assessed the variation of the tenderness of horse meat during postmortem aging through the injection of papain, bromelain and fungal protease. The cooking loss of the horse meat became worse during postmortem aging. Low concentration of protease improved water retention properties of horse meat. Papain, bromelain and fungal protease had significant influence on MFI and shear force. MFI increased obviously but the shear force decreased significantly with the addition of more protease (p <0.05). During postmortem aging, many small molecules popeptide appeared in treatment group. Myosin light chain 2, 20 KDa, 32 KDa and 75 KDa bands appeared at first, however later they disappeared in the group with high concentration of protease treatment in addition to the disappearance of Desmin and Troponin I. The muscle fiber, perimysium and endomysium were degraded because of papain, bromelain and fungal protease treatment. More muscle fiber fragments appeared during postmortem aging.Thus, the tenderness and eating quality of horse meat were improved by adding three kinds of protease.

Different impacts of the zero-markup drug policy on county general and traditional Chinese medicine hospitals: evidence from Shandong province, China.

BACKGROUND: As a key part of the new round of health reform, the zero-markup drug policy (ZMDP) removed the profit margins of drug sales at public health care facilities, and had some effects to the operation of these institutions. This study aims to assess whether the ZMDP has different impacts between county general and traditional Chinese medicine (TCM) hospitals. METHODS: We obtained longitudinal data from all county general and TCM hospitals of Shandong province in 2007-2017. We used difference-in-difference (DID) method to identify the overall and dynamic effects of the ZMDP. RESULTS: On average, after the implementation of the ZMDP, the share of revenue from medicine sales reduced by 16.47 and 10.42%, the revenue from medicine sales reduced by 24.04 and 11.58%, in county general and TCM hospitals, respectively. The gross revenue reduced by 5.07% in county general hospitals. The number of annual outpatient visits reduced by 11.22% in county TCM hospitals. Government subsidies increased by 199.22 and 89.3% in county general and TCM hospitals, respectively. The ZMDP reform was not significantly associated with the revenue and expenditure surplus, the number of annual outpatient visits and the number of annual inpatient visits in county general hospitals, the gross revenue, the revenue and expenditure surplus and the number of annual inpatient visits in county TCM hospitals. In terms of dynamic effects, the share of revenue from medicine sales, revenue from medicine sales, and gross revenue decreased by 20.20, 32.58 and 6.08% respectively, and up to 28.53, 63.89 and 17.94% after adoption, while government subsidies increased by around 170 to 200% in county general hospitals. The number of annual outpatient visits decreased by 9.70% and up to 18.84% in county TCM hospitals. CONCLUSION: The ZMDP achieved its some initial goals of removing the profits from western medicines in county hospitals' revenue without disrupting the normal operation, and had different impacts between county general and TCM hospitals. Meanwhile, some unintended consequences were also recognized through the analysis, such as the decline of the utilization of the TCM.

Comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder in children and adolescents: study protocol for a systematic review and network meta-analysis.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is common among children and adolescents who are exposed to trauma, and it is often associated with significant negative impacts on their psychosocial functioning and quality of life. Many types of psychotherapies have been found to be effective for PTSD in children and adolescents. However, due to the lack of direct comparisons between different psychotherapies, the hierarchy of treatment efficacy is still unclear. Therefore, we plan to conduct a systematic review and network meta-analysis to evaluate the efficacy and acceptability of various types of psychotherapies for PTSD in children and adolescents. METHODS AND ANALYSIS: A systematic search will be conducted among eight electronic databases, including PubMed, Cochrane, Embase, Web of Science, PsycINFO, Cumulative Index of Nursing and Allied Health, Published International Literature on Traumatic Stress (PILOTS) and ProQuest Dissertations, from inception to October 2017. Randomised controlled trials, regardless of language, publication year and publication type, comparing any psychotherapies for PTSD to any control condition or alternative treatment in children and adolescents (18 years old or less) diagnosed with full or subclinical PTSD will be included. Study duration and the number of treatment sessions will not be limited. The primary outcome will be PTSD symptom severity at post-treatment as measured by a rating scale reported by the child, parent or a clinician. The secondary outcomes will include: (1) efficacy at follow-up; (2) acceptability (all-cause discontinuation); (3) anxiety symptom severity; (4) depressive symptom severity and (5) quality of life and functional improvement. Bayesian network meta-analyses for all relative outcome measures will be performed. We will conduct subgroup and sensitivity network meta-analyses to determine whether the findings are affected by study characteristics. The quality of the evidence contributing to network estimates of the primary outcome will be evaluated by the Grading of Recommendations, Assessment, Development and Evaluations framework. ETHICS AND DISSEMINATION: No ethical issues are foreseen. The results will be published in a peer-reviewed journal, which will be disseminated electronically and in print. This network meta-analysis may be updated to inform and guide the clinical management of PTSD in children and adolescents. PROSPERO REGISTRATION NUMBER: CRD42016051786.

A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor.

Glucocorticoids (GCs)-ligands of the glucocorticoid receptor (GR)-are widely used to treat inflammatory diseases, but suffer from significant side effects and poor responsiveness in certain patient populations. Identification of chemical GR modulators may provide insights into the regulatory mechanisms of anti-inflammatory functions of GR and help improve GC-based therapy. Here we report the development and application of a high-throughput screening to identify compounds that either enhance or suppress the anti-inflammatory effect of GR function. Using a cell-based GR activity assay that measures Dexamethasone (Dex)-mediated NF-κB repression, we have screened ~8,000 compounds and identified several compounds that suppressed GR activity, including multiple GSK3ß inhibitors and anti-cancer agent camptothecin. Notably, we also identified two kinase IKK2 inhibitors, including TPCA-1, as GR enhancers that improve the anti-inflammatory effect of GR. In particular, TPCA-1 augmented the activity of Dex in NF-κB repression by attenuating GR down-regulation. Consistent with the observation, siRNA-mediated IKK2 knockdown decreased GR down-regulation and increased GR expression. Together, our results identified chemical compounds as novel modulators of GR and revealed an unexpected role for IKK2 in GR down-regulation. Furthermore, we have established a high-throughput screening platform for discovering GR-modulating compounds that may be repurposed to improve current GC-based therapies.

Can arbuscular mycorrhiza and fertilizer management reduce phosphorus runoff from paddy fields?

Our study sought to assess how much phosphorus (P) runoff from paddy fields could be cut down by fertilizer management and inoculation with arbuscular mycorrhizal fungi. A field experiment was conducted in Lalin River basin, in the northeast China: six nitrogen-phosphorus-potassium fertilizer levels were provided (0, 20%, 40%, 60%, 80%, and 100% of the recommended fertilizer supply), with or without inoculation with Glomus mosseae. The volume and concentrations of particle P (PP) and dissolved P (DP) were measured for each runoff during the rice growing season. It was found that the seasonal P runoff, including DP and PP, under the local fertilization was 3.7 kg/ha, with PP, rather than DP, being the main form of P in runoff water. Additionally, the seasonal P runoff dropped only by 8.9% when fertilization decreased by 20%; rice yields decreased with declining fertilization. We also found that inoculation increased rice yields and decreased P runoff at each fertilizer level and these effects were lower under higher fertilization. Conclusively, while rice yields were guaranteed arbuscular mycorrhizal inoculation and fertilizer management would play a key role in reducing P runoff from paddy fields.

[Screening of glucosidase inhibitors from various fractions of Mulberry leaves].

OBJECTIVE: To search for glucosidase inhibitors of various fractions extracted from mulberry leaves. METHOD: The constituents of mulberry leaves water fraction were prepared by the process of boiling, condensing, precipitating, exchanging with resins and rinsing. In vitro glucosidase inhibitory activities were examined by photometric bioassay derived from rats. To investigate in vivo effect of lowering blood glucose, the mouse blood glucose level was assayed by glucose tolerance experiments. RESULT: The glucosidase inhibitory activities were found in all the constituents of alkaloids, flavones and amyloses, the alkaloid constituent being the strongest. CONCLUSION: The effect of reducing blood glucose of mulberry leaves is related to the inhibitory activities against glucosidase of different constituents.