An account on the history of pharmacology in Spain.

Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of particular relevance was the appointment in 1872 of Osswald Shmiedeberg as chairman of an Institute of Pharmacology at the University of Strassbourg, Germany. Teófilo Hernando pioneered in Spain the new emerging pharmacology at the beginning of the XX Century. He made a posdoctoral stay in the laboratory of Schmiedeberg, working on digitalis. In 1912 he won the chair of "Materia Médica y Arte de Recetar" at "Universidad Central of Madrid" (today, "Universidad Complutense de Madrid", UCM). He soon decided to transform such subject to the emerging modern pharmacology, with the teaching of experimental pharmacology in the third course of medical studies and clinical therapeutics (today clinical pharmacology) in the sixth course. This was the status of pharmacology in 1920, supporting the view that Hernando was a pioneer of clinical pharmacology. However, the Spanish Civil War and the II Word War interropted this division of preclinical and clinical pharmacology; only in the 1980's was clinical pharmacolgy partially developed in Spain. From a scientific point of view, Hernando directly trained various young pharmacologists that extended the new science to various Spanish universities. Some of his direct disciples were Benigno Lorenzo Velázquez, Francisco García Valdecasas, Rafael Méndez, Tomás Alday, Gabriel Sánchez de la Cuesta, Dámaso Gutiérrez or Ramón P é rez-Cirera. One of the central research subject was the analysis of the effects of digitalis on the cat and frog heart. In the initiation of the 1970 s pharmacologists trained by those Hernando's students grew throughout various universities and the "Consejo Superior de Investigaciones Científicas" (CSIC). And hence, in 1972 the "Sociedad Española de Farmacología" (SEF) emerged. Later on, in the 1990's the "Sociedad Española de Farmacología Clínica (SEFC) also emerged. The relationship between the two societies is still weak. Out of the vast scope of the pharmacological sciences, Spanish pharmacologists have made relevant contributions in two areas namely, neuropsychopharmacology and cardiovacular pharmacology. Nonetheless, in other areas such as smooth muscle, gastroenterology, pharmacogenetics and hepatic toxicity, Spanish pharmacologists have also made relevant contributions. A succint description of such contributions is made. Finally, some hints on perspectives for the further development of preclinical and clinical pharmacology in Spain, are offered.

Safety pharmacology 2023 and implementation of the ICH E14/S7B Q&A guidance document.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). We highlight here the content derived from the recent 2022 Safety Pharmacology Society (SPS) and Canadian Society of Pharmacology and Therapeutics (CSPT) joint meeting held in Montreal, Quebec, Canada. The meeting also generated 179 abstracts (reproduced in the current volume of JPTM). As in previous years the manuscripts reflect various areas of innovation in SP including a comparison of the sensitivity of cross-over and parallel study designs for QTc assessment, use of human-induced pluripotent stem cell (hi-PSC) neuronal cell preparations for use in neuropharmacological safety screening, and hiPSC derived cardiac myocytes in assessing inotropic adversity. With respect to the latter, we anticipate the emergence of a large data set of positive and negative controls that will test whether the imperative to miniaturize, humanize and create a high throughput process is offset by any loss of precision and accuracy.

"Appraisal of state-of-the-art" The 2021 Distinguished Service Award of the Safety Pharmacology Society: Reflecting on the past to tackle challenges ahead.

This appraisal of state-of-the-art manuscript highlights and expands upon the thoughts conveyed in the lecture of Dr. Jean-Pierre Valentin, recipient of the 2021 Distinguished Service Award of the Safety Pharmacology Society, given on the 2nd December 2021. The article reflects on the strengths, weaknesses, opportunities, and threats that surrounded the evolution of safety and secondary pharmacology over the last 3 decades with a particular emphasis on pharmaceutical drug development delivery, scientific and technological innovation, complexities of regulatory framework and people leadership and development. The article further built on learnings from past experiences to tackle constantly emerging issues and evolving landscape whilst being cognizant of the challenges facing these disciplines in the broader drug development and societal context.

Superación profesional sobre uso racional de medicamentos dirigida a los médicos generales integrales / Professional improvement on the rational use of medications intended comprehensive general practitioners

RESUMEN Fundamento: el vertiginoso avance de la industria farmacéutica exige al médico general integral un proceso de superación continuo que favorezca el uso racional de los medicamentos. Objetivo: caracterizar la superación de estos profesionales relacionada con el uso racional de medicamentos en la Facultad de Medicina 1 de Santiago de Cuba. Métodos: se realizó un estudio descriptivo transversal en el que se analizaron las actividades de superación profesional de cinco cursos académicos desde el 2014 al 2019 a través de la revisión documental de los planes de superación profesional, así como los programas correspondientes. Resultados: las actividades relacionadas con el uso racional de medicamentos eran insuficientes y con tendencia a la disminución de un curso a otro; la forma de organización del posgrado más empleada fueron los cursos, seguidas de los talleres. Para incorporar los contenidos de uso racional de medicamentos se utilizaron, con más frecuencia, elementos de terapéutica de una enfermedad o grupo de estas así como la introducción de la medicina natural y tradicional. En las actividades se abordaron aspectos novedosos, pero no se hizo referencia a la terapéutica razonada. Conclusiones: se caracterizó la superación profesional para los médicos generales integrales relacionada con el uso racional de medicamentos la cual fue valorada como insuficiente por lo que urge retomar los aspectos que resultaron deficitarios en esta caracterización.

ABSTRACT Background: the vertiginous advance of the pharmaceutical industry demands from the comprehensive general practitioner a continuous improvement process that favors the rational use of medications. Objective: to characterize the improvement of these professionals related to the rational use of medications in the Faculty of Medicine 1 of Santiago de Cuba. Methods: a cross-sectional descriptive study was carried out in which the professional improvement activities of five academic courses from 2014 to 2019 were analyzed through the documentary review of the professional improvement plans, as well as the corresponding programs. Results: the activities related to the rational use of medications were insufficient and tended to decrease from one course to another; the most used form of postgraduate organization were courses, followed by workshops. To incorporate the contents of rational use of medications, therapeutic elements of a disease or group of diseases were used, as well as the introduction of Herbal and Folk medicine. In the activities, novel aspects were addressed, but no reference was made to reasoned therapy. Conclusions: professional improvement for comprehensive general practitioners related to the rational use of medications was characterized, which was assessed as insufficient, so it is urgent to retake the aspects that were deficient in this characterization.

Effectiveness of hypnotherapeutic and pharmacological treatment in primary monosymptomatic enuresis / Efectividad del tratamiento hipnoterapéutico y farmacológico en la enuresis primaria monosintomática

Abstract: Background: In primary monosymptomatic enuresis, it is not clear what dynamic changes occur in the efficacy of hypnotherapeutic versus pharmacological treatment plan. Objective: Determine the changes over time in the effectiveness of hypnotherapy and a pharmacological treatment plan in primary monosymptomatic enuresis. Method: A prospective, longitudinal and analytical study (time series) was performed on a universe of 119 patients between 7 and 16 years old, with primary monosymptomatic enuresis. 40 patients treated with imipramine and 79 patients with 1 session/1 hour /week of hypnotherapy were evaluated on the frequency of temporal changes of enuretic episodes during 14 weeks of treatments at the Hypnosis Clinic. Results: A logarithmic scale of the distributions of temporal changes in the frequencies of enuretic episodes in hypnotherapeutic and pharmacological treatments is presented, with an enuretic plateau from week 3 to week 6 in hypnotherapy. Conclusions: The hypnotherapeutic treatment was more favorable, as it had an early and efficient response compared to treatment with imipramine.

Resumen: Antecedentes: En la enuresis monosintomática primaria, no está claro qué cambios dinámicos ocurren en la eficacia del plan de tratamiento hipnoterapéutico versus farmacológico. Objetivo: Determinar los cambios dinámicos a lo largo del tiempo en la efectividad de la hipnoterapia y un plan de tratamiento farmacológico en la enuresis infantil no orgánica. Método: Se realizó un estudio prospectivo, longitudinal y analítico (serie temporal) en un universo de 119 pacientes entre 7 y 16 años, con enuresis nocturna no orgánica. 40 pacientes tratados con imipramina y 79 pacientes con 1 sesión / 1 hora / semana de hipnoterapia fueron evaluados en la frecuencia de cambios temporales de episodios enuréticos durante 14 semanas de tratamientos en la Clínica de Hipnosis. Resultados: Se presenta un modelo logarítmico de las distribuciones de cambios temporales en las frecuencias de episodios enuréticos en tratamientos hipnoterapéuticos y farmacológicos, con una meseta enurética desde la semana 3 a la semana 6 en hipnoterapia. Conclusiones: El tratamiento hipnoterapéutico fue más favorable, ya que tuvo una respuesta temprana y eficaz en comparación con el tratamiento con imipramina.

[Technology and evaluation best practices for in vivo cardiovascular safety pharmacology studies].

In vivo cardiovascular experiments as part of safety pharmacology studies have been developed for small molecule drug candidates to maximize detection power for potential undesirable pharmacodynamic effects of a drug candidate on physiological functions, and have been established with appropriate expertise. Conscious freely-moving telemeterized non-rodents are generally used for the in vivo cardiovascular experiments. The technology and evaluation best practices for the experiments have been optimized by multiple researchers and as a result, the experiments considerably contribute to the estimation of cardiovascular risks for humans. In addition, as described in ICH E14&S7B Q&A draft, non-clinical studies are gaining importance in the integrated risk assessment for QT prolongation in humans, and high quality data obtained in non-clinical studies are being required. This manuscript introduces actual technology and evaluation for in vivo cardiovascular safety pharmacology studies based on Japan activity for Improvement of Cardiovascular Evaluation by Telemetry system (J-ICET), which is one of the working groups hosted by Japanese Safety Pharmacology Society.

Investigation on the mechanisms of guiqi huoxue capsule for treating cervical spondylosis based on network pharmacology and molecular docking.

BACKGROUND: Guiqi huoxue capsule (GQHXC) is a patented Chinese medicine used for treating a liver and kidney deficiency and blood stasis syndrome due to qi deficiency. It is caused by cervical spondylosis (cervical spondylotic radiculopathy (CSR), mixed cervical spondylosis mainly composed of nerve root type). Its underlying mechanisms need, however, to be further clarified. METHODS: In this study, collecting compounds, predicting therapeutic targets, constructing networks, and analyzing biological functions and pathways were based on network pharmacology analysis. In addition, molecular docking verification was engaged to assess the binding potential of selected target-compound pairs. RESULTS: We established 5 networks: compound-putative target network of GQHXC, protein-protein interaction (PPI) network related to CSR, compound-CSR target network, potential therapeutic targets PPI network, and herb-compound-target-pathway network. Network analysis indicated that 7 targets (tumor necrosis factor [TNF], interleukin 6 [IL6], nitric oxide synthase 3 [NOS3], Interleukin-8 [CXCL8], prostaglandin-endoperoxide synthase 2 [PTGS2], vascular endothelial growth factor A [VEGFA], and AP-1 transcription factor subunit [JUN]) might be the therapeutic targets of GQHXC in CSR. Moreover, molecular docking verification showed that TNF, IL6, NOS3, CXCL8, PTGS2, VEGFA, and JUN had a good is interaction with the corresponding compounds. Furthermore, enrichment analysis indicated that GQHXC might exert a curative role in CSR by regulating some important pathways, such as TNF signaling pathway, NF-kappa B signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and so on. CONCLUSION: Our study preliminarily explained the underlying mechanisms of GQHXC for treating CSR, and molecular docking verification was adopted as an additional verification. These findings laid a valuable foundation for experimental research and further application of GQHXC in the clinical treatment of CSR.

Mechanisms and molecular targets of the Yu-Ping-Feng powder for allergic rhinitis, based on network pharmacology.

ABSTRACT: In traditional Chinese medicine (TCM), Yu-Ping-Feng powder (YPFP) has been used to treat allergic rhinitis (AR) for centuries. However, the mechanisms underlying its effects or its molecular targets in AR treatment are yet to be elucidated. Therefore, the active compounds of YPFP and their targets were collected and identified from the Traditional Chinese Medicine Systems Pharmacology database. Moreover, AR-associated targets were acquired from the GeneCards and Online Mendelian Inheritance in Man database. Proteins interactions network of YPFP presumed targets and AR-associated targets were examined and merged to reveal the candidate YPFP targets against AR.Cytoscape software and BisoGenet Database were employed to perform the Visualization and Integrated Discovery (Cluster Profiler R package, version: 3.8.1). Kyoto Encyclopedia of Genes and Genomes and genome pathway analyses. To identify the key target genes, a gene-pathway network has been constructed.We identified 44 effective active compounds and 622 YPFP targets. Also 1324 target genes related to AR were identified. Twenty pathways, including those of AGE-RAGE signaling, fluid shear stress, atherosclerosis, PI3K-Akt signaling, and tumor necrosis factor signaling was enriched significantly. MAPK1 was identified as the core gene, while others including RELA, AKT1, NFKBIA, IL6, and JUN, were also important in the gene-pathway network. Clearly, network pharmacology can be applied in revealing the molecular targets and mechanisms of action of complex herbal preparations.These findings suggested that YPFP could treat AR by regulating immunological functions, diminishing inflammation, and improving immunity through different pathways.

Chrono-Drug Discovery and Development Based on Circadian Rhythm of Molecular, Cellular and Organ Level.

The paired suprachiasmatic nuclei (SCN) is the circadian pacemaker in mammals. Clock genes ultimately regulates a vast array of circadian rhythms involved in biological, physiological and behavioral process. The clock genes are closely related to sleep disorders, metabolic syndromes, and cancer diseases. Monitoring rhythm, overcoming rhythm disruption, and manipulating rhythm from the perspective of the clock genes play an important role to improve chronopharmacotherapy. Such an approach should be achieved by overcoming the new challenges in drug delivery systems that match the circadian rhythm (Chrono-DDS). Gene and antibody delivery, targeting specific molecules for certain diseases have been focused in recent studies on pharmacotherapy. One of important candidates should also be clock genes. New drugs targeting the molecular clock are being developed to manage diseases in humans. The circadian dynamics of cancer stem cells are controlled by the tumor microenvironment and provide proof for its implication in chronotherapy against triple-negative breast cancer. To examine the relationship between the circadian clock and chronic kidney disease (CKD) exacervation leads to clarify the novel molecular mechanisms causing renal malfunction in mice with CKD. A novel inhibitor of cell cycle regulatory factors has been identified and the inhibitor repressed renal inflammation in a CKD mouse model. Therefore, this review aims to introduce the role of the molecular clock in the time-dependent dosing changes in the therapeutic effect and safety of a drug and the possibility of drug discovery and development based on the molecular clock.

[Current state of and challenges in in vivo central nervous system evaluation in safety pharmacology studies-Topic overview and initiatives of the Japanese Safety Pharmacology Society].

The modified Irwin's method and functional observational battery (FOB）used in non-clinical studies for predicting side effects that may appear in the central nervous system (CNS）in clinical studies consist of mainly macroscopic observation and largely depend on the observer's ability. Therefore, appropriate training for the observer and consistency of findings are extremely important, making it necessary for methods and judgment criteria to be standardized. In addition, because of concern for animal welfare as well as an increase in biopharmaceutical and anticancer drug development, there is increasing opportunity to incorporate safety pharmacological evaluation into general toxicity studies. While CNS evaluation can be incorporated into general toxicity studies relatively easily, studies need to be designed in such a way that reliable data can be obtained without reducing the ability to detect neurobehavioral abnormalities. It is therefore important to improve CNS evaluation techniques and to share these techniques with new observers in order to reliably detect the effects on the CNS during drug development.

Study on Mechanism of Ginkgo biloba L. Leaves for the Treatment of Neurodegenerative Diseases Based on Network Pharmacology.

Ginkgo biloba L. leaves (GBLs), as widely used plant extract sources, significantly improve cognitive, learning and memory function in patients with dementia. However, few studies have been conducted on the specific mechanism of Neurodegenerative diseases (NDs). In this study, network pharmacology was employed to elucidate potential mechanism of GBLs in the treatment of NDs. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to obtain the chemical components in accordance with the screening principles of oral availability and drug-like property. Potential targets of GBLs were integrated with disease targets, and intersection targets were exactly the potential action targets of GBLs for treating NDs; these key targets were enriched and analyzed by the protein protein interaction (PPI) analysis and molecular docking verification. Key genes were ultimately used to find the biological pathway and explain the therapeutic mechanism by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Twenty-seven active components of GBLs may affect biological processes such as oxidative reactions and activate transcription factor activities. These components may also affect 120 metabolic pathways, such as the PI3K/AKT pathway, by regulating 147 targets, including AKT1, ALB, HSP90AA1, PTGS2, MMP9, EGFR and APP. By using the software iGEMDOCK, the main target proteins were found to bind well to the main active components of GBLs. GBLs have the characteristics of multi-component and multi-target synergistic effect on the treatment of NDs, which preliminarily predicted its possible molecular mechanism of action, and provided the basis for the follow-up study.

Network pharmacology integrated with molecular docking reveals the common experiment-validated antipyretic mechanism of bitter-cold herbs.

ETHNOPHARMACOLOGICAL RELEVANCE: Bitter-cold herbs have been used to clearing heat and expelling damp in clinical practice in China for thousands of years. AIM OF THE STUDY: This study aimed to investigate the common molecular mechanism of bitter-cold herbs through network pharmacology analysis, molecular docking and experimental validation in vivo. MATERIALS AND METHODS: Network pharmacological analysis integrated with molecular docking was employed to identify the active compounds and core action targets of the bitter-cold herbs. Then, the yeast-induced pathological model was established, and the antipyretic effect of the herbs was evaluated by checking rectal temperatures of the mice hourly. Lastly, the protein expression of core targets was examined to reveal the antipyretic mechanism. RESULTS: A total of 52 lead compounds from the four bitter-cold herbs, Phellodendri Chinensis Cortex (PCC), Sophorae Flavescentis Radix (SFR), Gentianae Radix Et Rhozima (GRER) and Coptidis Rhizoma (CR), and 248 compounds-related targets were screened out with PTGS2 ranking the first. The results from molecular docking showed that 22 compounds adopted the same orientation as aspirin and had an excellent stability in the active site pocket of PTGS2. Furthermore, these herbs exerted potential therapeutic effects through 38 related pathways. On the other hand, the outcome of animal experiments showed that they could significantly attenuate the yeast-induced mice fever with dose-dependent relationship. Further experimental results demonstrated that administration of yeast suspension raised protein expression of PTGS2 significantly, which was evidently inhibited in the high or low-dose groups of GRER as well as in the low-dose group of SFR (P < 0.01) though a higher expression of PTGS2 was shown in the low-dose group of CR compared with FM group (P < 0.01). CONCLUSIONS: The bitter-cold herbs can alleviate fever response and their antipyretic effect may mainly be attributed to regulating the expression of PTGS2 after the formation of ligand-receptor/PTGS2 complexes, and their active compounds might be nominated as antipyretic lead-ligand candidates.

Molecular mechanism of Fufang Zhenzhu Tiaozhi capsule in the treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease based on network pharmacology and validation in minipigs.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Zhenzhu Tiaozhi formula (FTZ) of which a patented preparation of Chinese herbal medicine has been well documented with significant clinical curative effect for hyperglycemia and hyperlipidemia. Because of the complexity of the chemical constituents of Chinese herbal formulas, the holistic pharmacological mechanism of FTZ acting on type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) remains unclear. AIM OF THE STUDY: To investigate the pharmacological efficacy and mechanism of FTZ in the treatment of T2DM accompanied by NAFLD. MATERIALS AND METHODS: Network pharmacology and validation in minipigs were used in this study. First, potential bioactive compounds of FTZ were identified by the traditional Chinese medicine system pharmacology technology platform (TCMSP). Then, targets of compounds were gathered using DrugBank, SwissTargetPrediction and TCMSP, while targets for T2DM and NAFLD were collected from CTD (compounds-targets-diseases network) and GeneCards. Common targets were defined as direct therapeutic targets acting on T2DM with NAFLD. In addition, crucial targets were chosen by the protein-protein interaction (PPI) network and contribution to compound-therapeutic targets in T2DM with the NAFLD network. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the metabolism-related signaling pathways affected by FTZ. Candidate patterns selected by network pharmacology were tested in the minipigs model of T2DM with NAFLD. Measurements of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting insulin (FINS) and fasting blood glucose (FBG) in the blood and the expression levels of proteins, including PI3K-AKT and HIF-1α, in the livers of the minipigs were followed by the administration of FTZ. RESULTS: A total of 116 active compounds and 82 potential targets related to T2DM and NAFLD were found. Pathway and functional enrichment analysis showed that FTZ mainly regulates metabolism-related pathways, including PI3K-AKT, HIF-1α, TNFα and MAPK. Animal experiments showed that FTZ treatment significantly reduced the serum levels of TG, TC, LDL-C and FBG, increased serum levels of HDL-C, ameliorated systemic insulin resistance (IR), and attenuated liver damage in minipigs with T2DM and NAFLD. FTZ treatment has an obviously favorable influence on hepatic steatosis and liver lipid accumulation in the histopathologic features of HE, Oil red O staining, and electron microscopy. Mechanistically, FTZ improved liver metabolism by increasing the phosphorylation of PI3K-AKT and decreasing the expression of HIF-1α. CONCLUSION: Network pharmacology was supported by experimental studies, which indicated that FTZ has demonstrated therapeutic benefits in T2DM and NAFLD by regulating the PI3K-AKT and HIF-1α signaling pathways.

Deciphering the metabolic profile and pharmacological mechanisms of Achyranthes bidentata blume saponins using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry coupled with network pharmacology-based investigation.

ETHNOPHARMACOLOGICAL RELEVANCE: Achyranthes bidentata Blume (AB) is a traditional Chinese medicine (TCM) widely used as a dietary supplement and anti-arthritis drug. Pharmacological studies have shown that Achyranthes bidentata Blume saponins (ABS) are the main bioactive ingredient. However, the metabolic profile and mechanisms of action of ABS against rheumatic arthritis (RA) remain to be established. AIM OF THE STUDY: Our main objective was to investigate the metabolic profile and pharmacological activities of ABS against RA. MATERIALS AND METHODS: In this study, an analytical method based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) coupled with a metabolism platform was developed for metabolic profiling of ABS in rat liver microsomes and plasma. Then, the in vivo metabolites of ABS and their targets associated with RA were used to construct the network pharmacological analysis. Gene ontology (GO) enrichment, KEGG signaling pathway analyses and pathway network analyses were performed. The therapeutic effect of ABS on RA was further evaluated using an adjuvant arthritis (AA) model and network pharmacology results validated via Western blot. RESULTS: Overall, 26 and 21 metabolites of ABS were tentatively characterized in rat liver microsomes and plasma, respectively. The metabolic pathways of ABS mainly included M+O, M+O-H2, M+O2, and M+O2-H2. Data form network pharmacology analysis suggested that MAPK, apoptosis, PI3K-AKT and p53 signaling pathways contribute significantly to the therapeutic effects of ABS on RA. In pharmacodynamics experiments, ABS ameliorated the symptoms in AA rats in a dose-dependent manner and restored the homeostasis of pro/anti-inflammatory factors. Western blot results further demonstrated a significant ABS-induced decrease in phosphorylation of ERK in the MAPK pathway (P < 0.01). CONCLUSION: Application of an analytical method based on UPLC-QTOF/MS, network pharmacology and validation experiments offers novel insights into the components and mechanisms of ABS that contribute to its therapeutic effects against RA, providing useful directions for further research.

A metabolic data-driven systems pharmacology strategy for decoding and validating the mechanism of Compound Kushen Injection against HCC.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Kushen Injection (CKI) is a widely used TCM formula for treatment of carcinomatous pain and tumors of digestive system including hepatocellular carcinoma (HCC). However, the potential mechanisms of CKI for treatment of HCC have not been systematically and deeply studied. AIM OF STUDY: A metabolic data-driven systems pharmacology approach was utilized to investigate the potential mechanisms of CKI for treatment of HCC. MATERIALS AND METHODS: Based on phenotypic data generated by metabolomics and genotypic data of drug targets, a propagation model based on Dijkstra program was proposed to decode the effective network of key genotype-phenotype of CKI in treating HCC. The pivotal pathway was predicted by target propagation mode of our proposed model, and was validated in SMMC-7721 cells and diethylnitrosamine-induced rats. RESULTS: Metabolomics results indicated that 12 differential metabolites, and 5 metabolic pathways might be involved in the anti-HCC effect of CKI. A total of 86 metabolic related genes that affected by CKI were obtained. The results calculated by propagation model showed that 6475 shortest distance chains might be involved in the anti-HCC effect of CKI. According to the results of propagation mode, EGFR was identified as the core target of CKI for the anti-HCC effect. Finally, EGFR and its related pathway EGFR-STAT3 signaling pathway were validated in vivo and in vitro. CONCLUSION: The proposed method provides a methodological reference for explaining the underlying mechanism of TCM in treating HCC.

Prediction of pharmacological activities from chemical structures with graph convolutional neural networks.

Many therapeutic drugs are compounds that can be represented by simple chemical structures, which contain important determinants of affinity at the site of action. Recently, graph convolutional neural network (GCN) models have exhibited excellent results in classifying the activity of such compounds. For models that make quantitative predictions of activity, more complex information has been utilized, such as the three-dimensional structures of compounds and the amino acid sequences of their respective target proteins. As another approach, we hypothesized that if sufficient experimental data were available and there were enough nodes in hidden layers, a simple compound representation would quantitatively predict activity with satisfactory accuracy. In this study, we report that GCN models constructed solely from the two-dimensional structural information of compounds demonstrated a high degree of activity predictability against 127 diverse targets from the ChEMBL database. Using the information entropy as a metric, we also show that the structural diversity had less effect on the prediction performance. Finally, we report that virtual screening using the constructed model identified a new serotonin transporter inhibitor with activity comparable to that of a marketed drug in vitro and exhibited antidepressant effects in behavioural studies.

Deciphering the correlations between aging and constipation by metabolomics and network pharmacology.

From the points of view of phenomena and experience, aging and constipation are inextricably correlated. However, experimental support and underlying mechanisms are still lacking. The purpose of this study is to explore the relationships between aging and constipation from the perspectives of fecal metabolites and network pharmacology. The behavioral analyses of aging and constipation were carried out on both aging rats and constipation rats. We found that aging rats exhibited not only significant aging behaviors but also significant constipation behaviors, while constipation rats exhibited both significant constipation and aging behaviors. Additionally, fecal metabolomics was carried out and found that 23 metabolites were aging-related and 22 metabolites were constipation-related. Among them, there were 16 differential metabolites in common with 11 metabolic pathways. Network pharmacology was applied to construct the target-pathway network of aging and constipation, revealing that pathway in cancer was the most associated signaling pathway. The current findings will provide not only a novel perspective for understanding aging and constipation, but a theoretical association and understanding the traditional Chinese medicine theory and the Western medicine theory about aging and constipation, as well as support for the clinical research and development of medicine related to constipation in the elderly.

A systems pharmacology approach to identify the autophagy-inducing effects of Traditional Persian medicinal plants.

Aging is correlated with several complex diseases, including type 2 diabetes, neurodegeneration diseases, and cancer. Identifying the nature of this correlation and treatment of age-related diseases has been a major subject of both modern and traditional medicine. Traditional Persian Medicine (TPM) embodies many prescriptions for the treatment of ARDs. Given that autophagy plays a critical role in antiaging processes, the present study aimed to examine whether the documented effect of plants used in TPM might be relevant to the induction of autophagy? To this end, the TPM-based medicinal herbs used in the treatment of the ARDs were identified from modern and traditional references. The known phytochemicals of these plants were then examined against literature for evidence of having autophagy inducing effects. As a result, several plants were identified to have multiple active ingredients, which indeed regulate the autophagy or its upstream pathways. In addition, gene set enrichment analysis of the identified targets confirmed the collective contribution of the identified targets in autophagy regulating processes. Also, the protein-protein interaction (PPI) network of the targets was reconstructed. Network centrality analysis of the PPI network identified mTOR as the key network hub. Given the well-documented role of mTOR in inhibiting autophagy, our results hence support the hypothesis that the antiaging mechanism of TPM-based medicines might involve autophagy induction. Chemoinformatics study of the phytochemicals using docking and molecular dynamics simulation identified, among other compounds, the cyclo-trijuglone of Juglans regia L. as a potential ATP-competitive inhibitor of mTOR. Our results hence, provide a basis for the study of TPM-based prescriptions using modern tools in the quest for developing synergistic therapies for ARDs.

TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches.

Traditional Chinese medicine (TCM) is a precious treasure of the Chinese nation and has unique advantages in the prevention and treatment of diseases. The holistic view of TCM coincides with the new generation of medical research paradigm characterized by network and system. TCM gave birth to a new method featuring holistic and systematic "network target", a core theory and method of network pharmacology. TCM is also an important research object of network pharmacology. TCM network pharmacology, which aims to understand the network-based biological basis of complex diseases, TCM syndromes and herb treatments, plays a critical role in the origin and development process of network pharmacology. This review introduces new progresses of TCM network pharmacology in recent years, including predicting herb targets, understanding biological foundation of diseases and syndromes, network regulation mechanisms of herbal formulae, and identifying disease and syndrome biomarkers based on biological network. These studies show a trend of combining computational, experimental and clinical approaches, which is a promising direction of TCM network pharmacology research in the future. Considering that TCM network pharmacology is still a young research field, it is necessary to further standardize the research process and evaluation indicators to promote its healthy development.

Integrated strategy of LC-MS and network pharmacology for predicting active constituents and pharmacological mechanisms of Ranunculus japonicus Thunb. for treating rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ranunculus japonicus Thunb. (short for R. japonicus) is a topically applied herb with the activities of removing jaundice, nebula and edema, preventing malaria, stopping asthma, promoting diuresis and relieving pain. It was firstly recorded in Zhouhou Beiji Fang and has been used for the treatment of malaria, ulcers, carbuncle, jaundice, migraine, stomachache, toothache and arthritis for over 1800 years. AIM OF THE STUDY: This study aimed to uncover the potentially effective components of R. japonicus and the pharmacological mechanisms against rheumatoid arthritis (RA) by combing LC-MS and network pharmacology. MATERIALS AND METHODS: Firstly, the chemical constituents of R. japonicus were qualitatively identified by UPLC-ESI-LTQ-Orbitrap MS. Then we performed target prediction by PharmMapper, protein-protein interaction (PPI) analysis via String, GO and KEGG pathway enrichment analysis by DAVID and constructed the compound-target-pathway network using Cytoscape. Thirdly, crucial compounds in the network were quantitatively analyzed to achieve quality control of R. japonicus. Finally, the pharmacological activities of R. japonicus and two potentially bioactive ingredients were validated in RA-FLSs (Rheumatoid Arthritis Fibroblast-like Synoviocytes) in vitro. RESULTS: Overall fifty-four ingredients of R. japonicus were identified and forty-five components were firstly discovered in R. japonicus. Among them, twenty-seven validated compounds were predicted to act on twenty-five RA-related targets and they might exhibit therapeutic effects against RA via positive regulation of cell migration, etc. Nine potentially bioactive components of R. japonicus which played important roles in the compound-target-pathway network were simultaneously quantified by an optimized UPLC-ESI-Triple Quad method. In vitro, compared to control group, R. japonicus extract, berberine and yangonin significantly inhibited the migration capacity of RA-FLSs after 24 h treatment. CONCLUSION: This study clarified that R. japonicus and the bioactive ingredients berberine and yangonin might exert therapeutic actions for RA via suppressing the aggressive phenotypes of RA-FLSs through combined LC-MS technology and network pharmacology tools for the first time. The present research provided deeper understanding into the chemical profiling, pharmacological activities and quality control of R. japonicus and offered reference for further scientific research and clinical use of R. japonicus in treating RA.