A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans.

Candida albicans, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals against C. albicans is hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug's target, modulation of stress responses, and overexpression of efflux pumps. Thus, the need to identify novel antifungal strategies is dire. To address this challenge, we screened 3,049 structurally-diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library against a C. albicans clinical isolate and identified 17 molecules that inhibited C. albicans growth by >80% relative to controls. Among the most potent compounds were CMLD013360, CMLD012661, and CMLD012693, molecules representing two distinct chemical scaffolds, including 3-hydroxyquinolinones and a xanthone natural product. Based on structural insights, CMLD013360, CMLD012661, and CMLD012693 were hypothesized to exert antifungal activity through metal chelation. Follow-up investigations revealed all three compounds exerted antifungal activity against non-albicans Candida, including Candida auris and Candida glabrata, with the xanthone natural product CMLD013360 also displaying activity against the pathogenic mould Aspergillus fumigatus. Media supplementation with metallonutrients, namely ferric or ferrous iron, rescued C. albicans growth, confirming these compounds act as metal chelators. Thus, this work identifies and characterizes two chemical scaffolds that chelate iron to inhibit the growth of the clinically relevant fungal pathogen C. albicansIMPORTANCEThe worldwide incidence of invasive fungal infections is increasing at an alarming rate. Systemic candidiasis caused by the opportunistic pathogen Candida albicans is the most common cause of life-threatening fungal infection. However, due to the limited number of antifungal drug classes available and the rise of antifungal resistance, an urgent need exists for the identification of novel treatments. By screening a compound collection from the Boston University Center for Molecular Discovery (BU-CMD), we identified three compounds representing two distinct chemical scaffolds that displayed activity against C. albicans. Follow-up analyses confirmed these molecules were also active against other pathogenic fungal species including Candida auris and Aspergillus fumigatus. Finally, we determined that these compounds inhibit the growth of C. albicans in culture through iron chelation. Overall, this observation describes two novel chemical scaffolds with antifungal activity against diverse fungal pathogens.

The effect of Saccharomyces boulardii supplementation on Helicobacter pylori eradication in children: a systematic review and meta-analysis of Randomized controlled trials.

BACKGROUND: It is unclear whether Saccharomyces boulardii (S. boulardii) supplementation in standard triple therapy (STT) is effective in eradicating Helicobacter pylori (H. pylori) infection in children. We therefore conducted a meta-analysis of randomized controlled trials (RCTs) to assess the effect of S. boulardii supplementation on H. pylori eradication in children. METHODS: We conducted electronic searches in PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure and Wanfang database from the beginning up to September 2023. A random-effects model was employed to calculate the pooled relative risk (RR) with 95% confidence intervals (CI) through a meta-analysis. RESULTS: Fifteen RCTs (involving 2156 patients) were included in our meta-analysis. Results of the meta-analysis indicated that S. boulardii in combination with STT was more effective than STT alone (intention-to-treat analysis : 87.7% vs. 75.9%, RR = 1.14, 95% CI: 1.10-1.19, P < 0.00001; per-protocol analysis : 88.5% vs. 76.3%, RR = 1.15, 95% CI: 1.10-1.19, P < 0.00001). The S. boulardii supplementation group had a significantly lower incidence of total adverse events (n = 6 RCTs, 9.2% vs. 29.2%, RR = 0.32, 95% CI: 0.21-0.48, P < 0.00001), diarrhea (n = 13 RCTs, 14.7% vs. 32.4%, RR = 0.46, 95% CI: 0.37-0.56, P < 0.00001), and nausea (n = 11 RCTs, 12.7% vs. 21.3%, RR = 0.53, 95% CI: 0.40-0.72, P < 0.0001) than STT group alone. Similar results were also observed in the incidence of vomiting, constipation, abdominal pain, abdominal distention, epigastric discomfort, poor appetite and stomatitis. CONCLUSIONS: Current evidence indicated that S. boulardii supplementing with STT could improve the eradication rate of H. pylori, and concurrently decrease the incidence of total adverse events and gastrointestinal adverse events in children.

Effect of light intensity on growth performance and bone development of tibia in broilers.

Light management affects the health outcomes and growth performance of broiler chickens. However, the effects of different light intensities on growth performance and its association with tibia development of broilers remain unclear. In the present study, 462 Ross male broilers were divided into seven treatment groups with 6 replicates (11 birds per replicate), and then were subjected to different light intensity levels (0.5, 2, 5, 7, 9, 13 or 19 Lx) for 42 days. The results demonstrated that broilers under lower light intensity (2, 5Lx) obtained higher body weight (p < 0.05) and feed conversion ratio (p < 0.05). Lower light intensity exposure had no effects on the length, width, weight, breaking strength and the mineral density of the tibia (p > 0.05), but led to increased ash content and phosphorus during the starter phase (p < 0.05). Also, plasma levels of calcium (Ca), phosphorus (P) and alkaline phosphatase were increased in response to lower light intensity conditions (p < 0.05), but decreased under higher light intensity (p < 0.05), indicating dynamic mineral metabolic and depositional activity to light intensity. In addition, broilers exposed to lower intensity (0.5 Lx, 2 Lx and 5 Lx) during the starter phase had decreased hypertrophic chondrocytes (p < 0.05), but did not affect resting zone chondrocytes and proliferative chondrocytes of the growth plate (p > 0.05). In contrast, the light intensity did not affect the growth performance and the development of the tibia of broilers during the finishing phase. In summary, we demonstrated that lower light intensity promoted the growth performance and the bone development of broilers. Application of lower light intensity at the starter phase might be a management strategy for broiler industries.

Changes in the water environment and its major driving factors in Poyang Lake from 2016 to 2019, China.

The hydrological exchange process between Poyang Lake (PYL), the largest freshwater lake in China, and the Yangtze River leads to drastic changes in water area (WA) and water level (WL), as well as apparent fluctuations in lake nutrients, algal organisms, and trophic level index. This study investigated the current status of the PYL water environment and the influence of hydrological changes on the nutrient status of the floodplain of the lake. Based on monthly measured data from six hydrological stations from 2016 to 2019, it was hypothesized that WA and WL were the key regulators of the spatial and temporal distribution patterns of lake water quality and algal growth, including water temperature, water clarity (Secchi depth [SD]), and nutrient levels. The results revealed that (1) the spatial and temporal distribution characteristics of major nutrients in PYL were influenced by dynamic changes in hydrological characteristics (SD, total nitrogen [TN], and total phosphorus [TP]); (2) the eutrophication level in PYL has been in a steady state in recent years, while the central area has been more prone to the risk of eutrophication (e.g., the peak eutrophication index during Period 1 [January to April] in the water near the Duchang station reached 70); and (3) there were significant correlations among environmental variables, nutrients, and algal organisms, with different spatial and temporal distribution characteristics (p < 0.05), while the changes in WA and WL considerably influenced the water environment in the PYL.

A strategy to comprehensively analyze the bioactivity of complex herbal prescriptions via peak-by-peak cutting and knock-out chromatography: Qiliqiangxin capsule as an example.

An herbal prescription is usually composed of several herbal medicines. The complex and diverse components bring great challenges to its bioactivity study. To comprehensively analyze the bioactivity of an herbal prescription, a new strategy based on peak-by-peak cutting and knock-out chromatography was proposed. In this strategy, active compounds were screened out via peak-by-peak cutting from an herbal extract, and the influence of a compound on the overall activity of the herbal extract was evaluated by knock-out chromatography. Qiliqiangxin capsule is an herbal prescription composed of 11 herbal medicines for the treatment of chronic heart failure. A total of 71 peaks were collected through peak-by-peak cutting, and each peak was identified by a high-resolution mass spectrum. The bioassay against 1,1-diphenyl-2-picrylhydrazyl showed that two types of compounds namely salvianolic acids and caffeoylquinic acids were potent scavengers. Knock-out chromatography suggested that the removal of one single compound had no obvious influence on the overall activity of the Qiliqiangxin capsule. After all the main peaks in the Qiliqiangxin capsule were knocked out, the remaining part still exhibited a potent activity, indicating high activity stability of the Qiliqiangxin capsule. The proposed strategy is helpful for the comprehensive analysis of the bioactivity of other herbal prescriptions.

Dietary hydrolyzed wheat gluten supplementation ameliorated intestinal barrier dysfunctions of broilers challenged with Escherichia coli O78.

This study aimed to investigate a protective effect of hydrolyzed wheat gluten (HWG) on Escherichia coli (E. coli)-induced intestinal barrier dysfunctions in broilers. Broilers fed a basal diet unsupplemented or supplemented with HWG (0.5% or 1%) were intraperitoneally injected with either E. coli O78 suspension (108 CFU/mL) or equal volume of vehicle on d 18 of age. Blood and tissue samples were collected 3rd d post infection. The results showed that E. coli-infection increased immune-organ indexes of spleen and thymus, enhanced serum diamine oxidase (DAO) level, impaired ileal villus structure and reduced tight junction mRNA levels (Occludin, Claudin-1, ZO-1, P < 0.05), while increased mRNA levels of inflammatory cytokines (TNF-α, IFN-γ, IL-1ß, IL-6, IL-8) and TLR4 in the ileum of broilers (P < 0.05). The effects of E. coli O78 challenge on organ indexes of spleen and thymus, serum DAO level, mRNA levels of tight junctions were alleviated by 1% HWG supplementation, the upregulations of IL-1ß and TLR4 were prevented by 0.5% HWG supplementation (P < 0.05). In addition, increased IFN-γ of E. coli-infected broilers was abrogated by 0.5% or 1% HWG supplementation (P < 0.05). In summary, dietary HWG supplementation ameliorated intestinal barrier dysfunctions triggered by E. coli-infection in the ileum of broilers. HWG supplementation might be a nutritional strategy to improve the intestinal mucosal barrier function of broilers.

Designing mindfulness information for interaction in social media: The role of information framing, health risk perception and lay theories of health.

In the post-pandemic era, our health is facing unprecedented challenges, and people are more willing to obtain health-related information or interact with each other than ever before. In this context, people's interest in mindfulness information is also growing. However, not enough attention has been paid to the relationship between mindfulness information design and information interaction. The purpose of this study is to assess the impact of information design based on the gain and loss framework on people's willingness to interact with mindfulness information, and to identify the framework for achieving better results. Through two experimental studies, we find that information design based on the framework of gains and losses can produce different effects. Specifically, the findings of the first experiment (N = 282) shows the individuals are more willing to interact mindfulness information when they are exposed to gain-framed information rather than loss-framed. In the second experiment (N = 308), we find that loss framing, compared with gain framing, led to greater health risk perception, which in turn make participants more likely to interact with mindfulness information with others. Additionally, our results show that the lay theories of health plays a moderating role in the direct effect of information framework on willingness to interact with mindfulness information in social media. When individuals hold incremental lay theories, they are more willing to interact with mindfulness information under the gain-framed information condition compared with the loss-framed information condition. However, when individuals are in entity condition, there is no significant difference in the willingness to interact with mindfulness information between the gain-framed and loss-framed information. Our studies of integrating information framework into designing mindfulness information suggest a promising strategy of health information interaction in social media.

[Changes in the functional connectivity of the thalamus in insomniac ED patients with yin deficiency and fire syndrome: An exploration based on functional MRI findings].

OBJECTIVE: To investigate the changes of nocturnal erectile function and functional connectivity (FC) of bilateral thalami in insomniac ED patients with yin deficiency and fire syndrome. METHODS: We enrolled 30 healthy controls and 87 ED patients with yin deficiency and fire syndrome, 41 with and the other 46 without insomnia. Using IIEF-5 and Pittsburgh Sleep Quality Index (PSQI), we evaluated the nocturnal erectile function and sleep quality of the patients and compared the clinical indicators between the two groups. Then we collected and preprocessed the MRI data on the cerebral function of the 15 ED patients with insomnia, another 15 without insomnia and the 30 healthy controls. With the thalamus as the region of interest (ROI), we calculated and compared the FC values of brain regions between the ED patients (with or without insomnia) and healthy controls, and corrected the results for multiple comparisons using the AlphaSim method. RESULTS: Compared with the patients without insomnia, those with insomnia had a lower duration of erectile episode and tumescence and rigidity activity units in the tip of the penis. With the left thalamus as the ROI, the right middle frontal gyrus and inferior parietal were shown to be the differential brain regions among the three groups. Compared with the healthy controls, the patients without insomnia showed decreased FC values between the left thalamus and left orbital part of the middle frontal gyrus, insula, putamen and right thalamus, while those with insomnia exhibited decreased FC values between the left thalamus and bilateral middle frontal gyri, inferior parietal, calcarine fissure, parahippocampal gyrus, left superior parietal gyrus, right precuneus and inferior temporal gyrus, and they also exhibited decreased FC values between the left thalamus and middle frontal gyrus in comparison with those without insomnia. With the right thalamus as the ROI, the left medial superior frontal gyrus, bilateral calcarine fissure and right thalamus were found to be the differential brain regions among the three groups. Compared with the healthy controls, the patients without insomnia showed decreased FC values between the right thalamus (including the right thalamus itself) and left medial orbital superior frontal gyrus, superior temporal gyrus (temporal pole), middle temporal gyrus, insula and right orbital part of the inferior frontal gyrus, while those with insomnia manifested decreased FC values between the right thalamus and middle frontal gyrus, inferior parietal, left superior parietal gyrus and calcarine fissure, and they also manifested increased FC values between the right thalamus and medial superior frontal gyrus, and decreased FC values between the right thalamus and left calcarine fissure in comparison with those without insomnia. CONCLUSION: ED patients with insomnia have more serious clinical symptoms, with FC changes in the thalamocortical loop, which might be the pathological mechanisms of ED with insomnia.

Phytochemicals in Cancer Immune Checkpoint Inhibitor Therapy.

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.

DrugComb update: a more comprehensive drug sensitivity data repository and analysis portal.

Combinatorial therapies that target multiple pathways have shown great promises for treating complex diseases. DrugComb (https://drugcomb.org/) is a web-based portal for the deposition and analysis of drug combination screening datasets. Since its first release, DrugComb has received continuous updates on the coverage of data resources, as well as on the functionality of the web server to improve the analysis, visualization and interpretation of drug combination screens. Here, we report significant updates of DrugComb, including: (i) manual curation and harmonization of more comprehensive drug combination and monotherapy screening data, not only for cancers but also for other diseases such as malaria and COVID-19; (ii) enhanced algorithms for assessing the sensitivity and synergy of drug combinations; (iii) network modelling tools to visualize the mechanisms of action of drugs or drug combinations for a given cancer sample and (iv) state-of-the-art machine learning models to predict drug combination sensitivity and synergy. These improvements have been provided with more user-friendly graphical interface and faster database infrastructure, which make DrugComb the most comprehensive web-based resources for the study of drug sensitivities for multiple diseases.

DrugComb: an integrative cancer drug combination data portal.

Drug combination therapy has the potential to enhance efficacy, reduce dose-dependent toxicity and prevent the emergence of drug resistance. However, discovery of synergistic and effective drug combinations has been a laborious and often serendipitous process. In recent years, identification of combination therapies has been accelerated due to the advances in high-throughput drug screening, but informatics approaches for systems-level data management and analysis are needed. To contribute toward this goal, we created an open-access data portal called DrugComb (https://drugcomb.fimm.fi) where the results of drug combination screening studies are accumulated, standardized and harmonized. Through the data portal, we provided a web server to analyze and visualize users' own drug combination screening data. The users can also effectively participate a crowdsourcing data curation effect by depositing their data at DrugComb. To initiate the data repository, we collected 437 932 drug combinations tested on a variety of cancer cell lines. We showed that linear regression approaches, when considering chemical fingerprints as predictors, have the potential to achieve high accuracy of predicting the sensitivity of drug combinations. All the data and informatics tools are freely available in DrugComb to enable a more efficient utilization of data resources for future drug combination discovery.

Drug combination sensitivity scoring facilitates the discovery of synergistic and efficacious drug combinations in cancer.

High-throughput drug screening has facilitated the discovery of drug combinations in cancer. Many existing studies adopted a full matrix design, aiming for the characterization of drug pair effects for cancer cells. However, the full matrix design may be suboptimal as it requires a drug pair to be combined at multiple concentrations in a full factorial manner. Furthermore, many of the computational tools assess only the synergy but not the sensitivity of drug combinations, which might lead to false positive discoveries. We proposed a novel cross design to enable a more cost-effective and simultaneous testing of drug combination sensitivity and synergy. We developed a drug combination sensitivity score (CSS) to determine the sensitivity of a drug pair, and showed that the CSS is highly reproducible between the replicates and thus supported its usage as a robust metric. We further showed that CSS can be predicted using machine learning approaches which determined the top pharmaco-features to cluster cancer cell lines based on their drug combination sensitivity profiles. To assess the degree of drug interactions using the cross design, we developed an S synergy score based on the difference between the drug combination and the single drug dose-response curves. We showed that the S score is able to detect true synergistic and antagonistic drug combinations at an accuracy level comparable to that using the full matrix design. Taken together, we showed that the cross design coupled with the CSS sensitivity and S synergy scoring methods may provide a robust and accurate characterization of both drug combination sensitivity and synergy levels, with minimal experimental materials required. Our experimental-computational approach could be utilized as an efficient pipeline for improving the discovery rate in high-throughput drug combination screening, particularly for primary patient samples which are difficult to obtain.

Ultrahigh-performance liquid chromatography with tandem mass spectrometry for the determination of 10 alkaloids in beagle plasma after the oral administration of the three Coptidis rhizoma extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Coptidis rhizoma (CR) is the dried rhizome of the ranunculaceous plant CR. For decades in China, this plant has been used to treat hypertension, hyperlipidemia, and chronic diarrhea and has been officially included in the Chinese Pharmacopoeia. The present paper presents a review of the pharmacokinetics of CR. AIM OF THE STUDY: The pharmacokinetic studies and differences of 10 alkaloids among Coptis deltoidea C. Y. cheng et Hsiao, Coptis chinensis Franch and Coptis teeta Wall. Are seldom reported. This study is the first to determine corydaline, dehydrocorydaline, tetrahydropalmatine, palmatine, magnoflorine, jatrorrhizine, berberine, worenine, berberrubine, and coptisine, which adopted an ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry, simultaneously. MATERIALS AND METHODS: Chromatographic separation was performed within 8 min by using an Agilent SB-C18 column (150 mm × 2.1 mm, 1.8 µm) with gradient mobile phase consisting of 0.3% acetic acid water (v/v) and acetonitrile at a flow rate of 0.3 mL/min. Multiple reaction monitoring mode was used to detect the tandem mass spectrum in the positive ionization mode by electrospray ionization source. RESULTS: The method was fully validated to be linear over a wide concentration (r > 0.9916), and the linear concentration range was 0.195-2260 ng/mL. Intra- and interday precisions were below 14.19% and 18.56% for the 10 analytes, respectively. The accuracy ranged from -9.30% to 6.31%. The extraction recovery of the 10 alkaloids and internal standard ranged from 79.76% to 95.37%. Pharmacokinetic comparative study showed that the Cmax and AUC0-∞ values of dehydrocorydaline, tetrahydropalmatine, palmatine, magnoflorine, jatrorrhizine, berberine, worenine, berberrubine, and coptisine increased significantly (p < 0.05), which was different for beagles after oral administration. The results can help determine the mechanism of action and guide clinical application of these three extracts. CONCLUSION: This validated method was successfully applied for the pharmacokinetics study of beagle plasma after oral administration of three CR extract types.

[Pharmacokinetics of Achyranthes bidentata on adjuvant arthritis rats by microdialysis and UHPLC-MS/MS].

To investigate the " drug-guide" effect of Achyranthes bidentata saponins( ABS) and geniposide( GE) in the treatment on adjuvant arthritis( AA) rats. A UHPLC-MS/MS method for the quantitative determination of GE,zingibroside R1,ginsenoside Ro and chikusetsu saponin Ⅳa in rat blood and joint dialysate was established. After single or combined administration with ABS and GE was given to AA rat model,a microdialysis sampling method for rat joint cavity and jugular vein blood vessels was established to collect microdialysis samples. Waters Acquity HSS C_(18) column was used to separate the above four components,with mobile phase as acetonitrile-0. 1% formic acid water as mobile phase for gradient elution. ESI source was adopted for mass spectra in a negative ion scanning mode. Multiple reaction monitoring( MRM) mode was applied to detect the above four components. The methodological results showed that GE,zingibroside R1,ginsenoside Ro and chikusetsu saponin Ⅳa demonstrated a good linear relationship within the concentration ranges of 2-4 000,16-4 096,14-3 584,23-5 888 µg·L-1 respectively. The precision,accuracy,stability and matrix effect of these four ingredients reached the requirements of quantitative analysis of biological samples. The pharmacokinetic results demonstrated that the combined administration of ABS and GE( 60 mg·kg~(-1)+60 mg·kg~(-1)) can increase the degree of GE in joint cavity distribution,and the AUCjoint/AUCplasmwere twice of that of single administration of GE( 60 mg·kg~(-1)),which indicated that ABS might played a vital role in GE's distribution to joint cavity. Moreover,there was no significant difference between the distribution trend of total three ABS and GE in rats. The pharmacodynamics results showed that the combined administration of ABS and GE has stronger effects on paw swelling,arthritis index and synovial pathomorphology of AA rats than single administration of GE,which suggested that ABS might improve GE's anti-inflammatory effect in AA rats. Based on the above results,ABS has a targeting effect in increasing GE's concentration in joint cavity,with a synergy in efficacy.

Quantitative Analysis of Multi-components by Single Marker and Fingerprint Analysis of Achyranthes bidentata Blume.

A simple and effective method of high performance liquid chromatography (HPLC) with diode array detection was established to identify the origin of Achyranthes bidentata Blume and evaluate its quality, based on chromatographic fingerprint combined with the similarity analysis, hierarchical cluster analysis and the quantitative analysis of multi-components by single marker (QAMS). In the chromatographic fingerprint, 16 peaks were selected as the common model to evaluate the similarities among 18 batches (S1-S18) of A. bidentata Blume samples collected from different origins in China. The similarities values for 18 batches of samples were more than 0.75, which compared with control fingerprint. Furthermore, 18 batches of A. bidentata Blume samples were categorized into two groups for quantitative analysis, the quantification of three bioactive constituents (ß-ecdysterone, cyasterone and 5-hydroxymethyl furfural) between QAMS and external standard method proved the consistency of the two methods, the three constituents showed good regression (R > 0.9995) within linear ranges, and their recoveries were within the range of 97.6-101.5%. This study demonstrated that the quality of A. bidentata Blume can be successfully evaluated by means of a combination of HPLC chromatographic fingerprint and QAMS approach.

Immune Tolerance Effect in Mesenteric Lymph Node Lymphocytes of Geniposide on Adjuvant Arthritis Rats.

Rheumatoid arthritis (RA) is a systemic, Th1 cytokine-predominant autoimmune disease result in a chronic and inflammatory disorder. Geniposide (GE), an iridoid glycoside compound that is purified from Gardenia jasminoides Ellis, has antiinflammatory and other immunoregulatory effects, but its exact mechanism of actions on RA is unknown. The aim of this study was to elucidate antiinflammation effects of GE on adjuvant arthritis (AA) rats and its possible immune tolerance mechanisms. Male Sprague-Dawley rats were administered with GE (30, 60, and 120 mg/kg) orally from day 17 to 24 after immunization. Lymphocyte proliferation was assessed by MTT. Levels of interleukin-2 (IL-2), IL-4, and transforming growth factor-ß1 were tested by ELISA. The expression of ß2-AR, GRK2, and ß-arrestin-1 and ß-arrestin-2 was detected by western blot. Geniposide was found to relieve the secondary hind paw swelling and arthritis scores, along with attenuating histopathologic changes and decreasing IL-2 and increasing IL-4, transforming growth factor-ß1 in mesenteric lymph node (MLN) lymphocytes of AA rats. In addition, GE in vivo increased the expression of ß2-AR and decreased the expression of GRK2, ß-arrestin-1 and ß-arrestin-2, and level of cyclic adenosine monophosphate of MLN lymphocytes in AA rats. From these results, we can infer that GE on immune tolerance effects, ß2-AR desensitization, and ß2-AR-AC-cyclic adenosine monophosphate transmembrane signal transduction of MLN lymphocytes plays crucial roles in antiinflammatory and immunoregulatory pathogeneses of RA. Copyright © 2017 John Wiley & Sons, Ltd.

Antiinflammation Effects and Mechanisms Study of Geniposide on Rats with Collagen-Induced Arthritis.

Geniposide (GE), an iridoid glycoside compound purified from Gardenia jasminoides Ellis, has antiinflammatory and other pharmacological effects, but its mechanism of actions on rheumatoid arthritis (RA) have not been clarified. The purpose of this article was to investigate the pharmacological effects of GE on collagen-induced arthritis (CIA) rats and its feasible mechanisms. Collagen-induced arthritis was induced by injection of chicken type II collagen emulsion. The rats were orally administered with GE (33, 66, and 132 mg/kg) from days 14 to 30 after immunization. The histological examination showed that GE could attenuate histopathologic changes of mesenteric lymph node (MLN) in CIA rats. Geniposide inhibited the production of Interleukin 6 (IL-6) and IL-17, while promoting the production of IL-4 and transforming growth factor-beta 1 in MLN lymphocytes (MLNLs). Moreover, the proliferation capability of MLNLs was increased after the administration of GE. In addition, the treatment with GE in vivo decreased the expressions of P-Raf, P-MEK, and P-Erk1/2 in MLNLs. These results may highlight the antiinflammatory effects and possible mechanisms of GE in MLNLs of RA. Copyright © 2017 John Wiley & Sons, Ltd.

Tissue-specific pathway association analysis using genome-wide association study summaries.

MOTIVATION: Pathway association analysis has made great achievements in elucidating the genetic basis of human complex diseases. However, current pathway association analysis approaches fail to consider tissue-specificity. RESULTS: We developed a tissue-specific pathway interaction enrichment analysis algorithm (TPIEA). TPIEA was applied to two large Caucasian and Chinese genome-wide association study summary datasets of bone mineral density (BMD). TPIEA identified several significant pathways for BMD [false discovery rate (FDR) < 0.05], such as KEGG FOCAL ADHESION and KEGG AXON GUIDANCE, which had been demonstrated to be involved in the development of osteoporosis. We also compared the performance of TPIEA and classical pathway enrichment analysis, and TPIEA presented improved performance in recognizing disease relevant pathways. TPIEA may help to fill the gap of classic pathway association analysis approaches by considering tissue specificity. AVAILABILITY AND IMPLEMENTATION: The online web tool of TPIEA is available at https://sourceforge.net/projects/tpieav1/files CONTACT: fzhxjtu@mail.xjtu.edu.cnSupplementary information: Supplementary data are available at Bioinformatics online.

Effect of Xinjiang Uyghur Vernonia anthelmintica Willd Injection Treatment with Silicosis Fibrosis.

Objective. To observe the curative effect of VAWI on Xinjiang Uygur patients with silicosis fibrosis. Methods. After we diagnosed the 40 patients with the first phase of silicosis, we randomly divided them into two groups: the basic treatment group (group A, n = 20) and the VAWI group (group B, n = 20). At the same time, we selected the age-matched healthy patients (n = 20). We applied the combined protein chip with SELDI-TOF-MS to carry out the serum analysis. The data were analyzed throughout data preprocessing, difference in PEAK screening, hierarchical cluster analysis, and Principal Component Analysis (PCA). We built decision tree model and predict the difference between the PEAK corresponding proteins. Results. The proteins peaks corresponding to name, predicted protein, and gene name were as follows: M2001_69, amyloid beta a4 protein, APP, and M2017_02, amyloid beta a4 protein, APP. The different expression of proteins in patients with silicosis was found before and after with VAWI treatment. The predicted proteins were as follows: M1982_50, amyloid beta a4 protein, APP; M3164_50, fibrinogen alpha chain frag, FGA; M3379_28, fibrinogen alpha chain frag, FGA; and so on. Conclusion. VAWI presented curative effect on patients with silicosis fibrosis via the alternation of proteins expression in serum.

Metabolomics study of renal fibrosis and intervention effects of total aglycone extracts of Scutellaria baicalensis in unilateral ureteral obstruction rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellariae Radix (Scutellaria baicalensis Georgi) is a well-known Traditional Chinese Medicine (TCM) which mainly contains flavonoids. Our previous studies have demonstrated that total aglycone extracts of Scutellaria baicalensis (TAES) can improve kidney disease in rats. AIM OF THE STUDY: To investigate the renal fibrosis (RF) pathogenesis and TAES treatment mechanism in unilateral ureteral obstruction (UUO) rats, using a metabolomics approach based on gas chromatography-mass spectrometry (GC/MS). METHODS: Rats with RF were divided into 6 groups with rats subjected to sham operation as normal control. The effects of TAES on some RF closely related parameters in UUO rats were investigated. A metabolomics method, based on GC/MS, was developed to monitor metabolic alterations in urine. Multivariate data analysis was utilized to identify biomarkers potentially associated with RF and the anti-RF activity of TAES. Ontology-based enrichment analysis by BiNChE and pathway analysis by MetPA aid in the interpretation of difference metabolites. RESULTS: After 10 days of treatment, the parameters of renal function begin returning to normal, and the abnormal high expressions of genes associated with extracellular matrix (ECM) were relived. In the metabolomics study, metabolic perturbations induced by UUO were reversed after treatment and TAES showed a dose-dependent therapy effect on RF, meanwhile, 18 potential biomarkers associated with RF were identified. Enrichment analysis of metabolites shows an over representation of mostly alkane-alpha, omega-diamine and alpha, omega-dicarboxylic acid, and these biomarkers are primarily involved in Glycine, serine and threonine metabolism, Retinol metabolism, Arginine and proline metabolism and Fructose and mannose metabolism. CONCLUSIONS: Our findings indicate that TAES have positive effects on UUO-induced RF in rats, meanwhile, metabolomics method coupled with metabolites enrichment analysis is a useful tool for revealing the pathogenesis of diseases and action mechanism of TCM on the whole body.