Systems Pharmacology Approach and Experiment Evaluation Reveal Multidimensional Treatment Strategy of LiangXueJieDu Formula for Psoriasis

Clinical studies have demonstrated the anti-psoriatic effect of the LiangXueJieDu (LXJD) herbal formula. However, the systemic mechanism and the targets of the LXJD formula have not yet been elucidated. In the present study, a systems pharmacology approach, metabolomics, and experimental evaluation were employed. First, by systematic absorption-distribution-metabolism-excretion (ADME) analysis, 144 active compounds with satisfactory pharmacokinetic properties were identified from 12 herbs of LXJD formula using the TCMSP database. These active compounds could be linked to 125 target proteins involved in the pathological processes underlying psoriasis. Then, the networks constituting the active compounds, targets, and diseases were constructed to decipher the pharmacological actions of this formula, indicating its curative effects in psoriasis treatment and related complications. The psoriasis-related pathway comprising several regulatory modules demonstrated the synergistic mechanisms of LXJD formula. Furthermore, the therapeutic effect of LXJD formula was validated in a psoriasis-like mouse model. Consistent with the systems pharmacology analysis, LXJD formula ameliorated IMQ-induced psoriasis-like lesions in mice, inhibited keratinocyte proliferation, improved keratinocyte differentiation, and suppressed the infiltration of CD3+ T cells. Compared to the model group, LXJD formula treatment remarkably reduced the expression of inflammatory cytokines and factors, such as IL-1β, IL-6, TNF-α, Cox2, and inhibited the phosphorylation of p-P65, p-IқB, p-ERK, p-P38, p-PI3K, p-AKT, indicating that LXJD formula exerts its therapeutic effect by inhibiting the MAPK, PI3K/AKT, and NF-қB signaling pathways. The metabolic changes in the serum of psoriasis patients were evaluated by liquid chromatography coupled with orbitrap mass spectrometry (LC-MS). The LXJD formula improved two perturbed metabolic pathways of glycerophospholipid metabolism and steroid hormone biosynthesis. Overall, this study revealed the complicated anti-psoriatic mechanism of LXJD formula and also offered a reliable strategy to elucidate the complex therapeutic mechanism of this Chinese herbal formula in psoriasis from a holistic perspective.

A Network Pharmacological Approach to Reveal the Pharmacological Targets and Its Associated Biological Mechanisms of Prunetin-5-O-Glucoside against Gastric Cancer

Gastric cancer (GC) is an aggressive malignancy with increased mortality rate and low treatment options. Increasing evidence suggests that network pharmacology will be a novel method for identifying the systemic mechanism of therapeutic compounds in diseases like cancer. The current study aimed to use a network pharmacology approach to establish the predictive targets of prunetin-5-O-glucoside (PG) against gastric cancer and elucidate its biological mechanisms. Primarily, genes associated with the pathogenesis of GC was identified from the DiGeNET database and targets of PG was obtained from the Swiss target prediction database. In total, 65 correlative hits were identified as anti-gastric cancer targets of PG. Functional enrichment and pathway analysis revealed significant biological mechanisms of the targets. Interaction of protein network and cluster analysis using STRING resulted in three crucial interacting hub targets namely, HSP90AA1, CDK2, and MMP1. Additionally, the in vitro cytotoxic potential of PG was assessed on three gastric cancer cells (AGS, MKN-28, and SNU-484). Furthermore, the crucial targets were validated using molecular docking, followed by their expressions being evaluated by western blot and Human Protein Atlas. The findings indicate that the pharmacological action of PG against GC might be associated with the regulation of three core targets: HSP90AA1, CDK2, and MMP1. Thus, the network pharmacology undertaken in the current study established the core active targets of PG, which may be extensively applied with further validations for treatment in GC.

Quality Development Model of Management Islamic Religious Higher Education of Nahdltul Ulama

Quality management was a systemic mechanism in ensuring the sustainability of University. This lack of quality Islamic Religious Higher Education / Perguruan Tinggi Keagamaan Islam (PTKI) including Islamic Religious Higher Education NU / Perguruan Tinggi Keagamaan Islam Nahdlatul Ulama (PTKI NU) resulted less productive and competitive. The aim of this research was to describe the implementation of the development of high-quality management education in the Islamic Religious Higher Education of Nahdlatul Ulama or Perguruan Tinggi Keagamaan Islam Nahdlatul Ulama (PTKI NU). The method was qualitative based on multisitus through inductive analysis. The result showed that in planning of quality management education which was done by three PTKI NU was systemic and structured, where each University was oriented to improve the quality academic, with varying strategies through a needs analysis process. Next, the implementation of quality management aspects of higher education of three PTKI NU varied and has the same quality management aspects, namely carry out the procedure, preparation of human resources through training, financial support, and focus on in integration of two areas of quality : quality of students and Tri Darma Peguruan Tinggi. Furthermore, the evaluation aspects of quality management implemented mechanisms of self-evaluation, internal academic quality audit. Keywords: Quality Education Management, Quality Development Model Education Management

Dilp8 controls a time window for tissue size adjustment in Drosophila

ABSTRACTThe control of organ size mainly relies on precise autonomous growth programs. However, organ development is subject to random variations, called developmental noise, best revealed by the fluctuating asymmetry observed between bilateral organs. The developmental mechanisms ensuring bilateral symmetry in organ size are mostly unknown. In Drosophila, null mutations for the relaxin-like hormone Dilp8 increase wing fluctuating asymmetry, suggesting that Dilp8 plays a role in buffering developmental noise. Here we show that size adjustment of the wing primordia involves a peak of Dilp8 expression that takes place sharply at the end of juvenile growth. Wing size adjustment relies on a crossorgan communication involving the epidermis as the source of Dilp8. We identify ecdysone signaling as both the trigger for epidermal dilp8 expression and its downstream target in the wing primordia, thereby establishing reciprocal feedback between the two hormones as a systemic mechanism controlling organ size precision. Our results reveal a hormone-based time window ensuring fine-tuning of organ size and bilateral symmetry.

Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates

In Parkinson’s disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via the vagus nerve, to the CNS. Here, we compare, in baboon monkeys, the pathological consequences of either intrastriatal or enteric injection of α-synuclein-containing Lewy body extracts from patients with Parkinson’s disease. This study shows that patient-derived α-synuclein aggregates are able to induce nigrostriatal lesions and enteric nervous system pathology after either enteric or striatal injection in a non-human primate model. This finding suggests that the progression of α-synuclein pathology might be either caudo-rostral or rostro-caudal, varying between patients and disease subtypes. In addition, we report that α-synuclein pathological lesions were not found in the vagal nerve in our experimental setting. This study does not support the hypothesis of a transmission of α-synuclein pathology through the vagus nerve and the dorsal motor nucleus of the vagus. Instead, our results suggest a possible systemic mechanism in which the general circulation would act as a route for long-distance bidirectional transmission of endogenous α-synuclein between the enteric and the central nervous systems. Taken together, our study provides invaluable primate data exploring the role of the gut-brain axis in the initiation and propagation of Parkinson’s disease pathology and should open the door to the development and testing of new therapeutic approaches aimed at interfering with the development of sporadic Parkinson’s disease.

A systems pharmacology approach to determine the mechanisms of action of pleiotropic natural products in breast cancer from transcriptome data

Plant-derived compounds as natural products have attracted a lot of attention in the treatment of complex diseases, especially cancers, primarily due to their poly-pharmacologic mechanisms of action. However, methodological limitations have impeded gaining complete knowledge of their molecular targets. While most of the current understanding of these compounds is based on reductive methods, it is increasingly becoming clear that holistic techniques, leveraging current improvements in omic data collection and bioinformatics methods, are better suited for elucidating their systemic effects. Here, to provide an explanation to the mechanisms of action of plant-derived natural products in breast cancer, we applied a data integration approach to comprehensively study oncogenic signaling pathways targeted by withaferin A, actein, compound kushen injection and indole-3-carbinol. Specifically, we mapped the transcriptome-level response of cancer cell lines to these molecules on a human protein-protein interaction network and constructed the underlying active subnetworks. We used these subnetworks to define the perturbed signaling pathways and validated their relevance in carcinogenesis. The similarity of each identified oncogenic signaling pathway in terms of overlapping genes was subsequently used to construct pathway-pathway interaction networks, which were used to reduce pathway redundancy and to identify pathway crosstalk. Filtered pathways were then mapped on three major carcinogenesis processes. The results showed that the pleiotropic effects of plant-derived drugs at the gene expression level can be used to predict targeted pathways. Thus, from such pathways, it is possible to infer a systemic mechanism of action of such natural products.

The role of Anglo-German Naval Agreement in escalation of crisis trends of the Versailles system (based on the materials of new archival documents)

This article reviews the role of Anglo-German Naval Agreement of 1935 in escalation of crisis trends of the Versailles system. Leaning on the British Russian archival documents, which recently became available for the researchers, the author analyzes the reasons and consequences of conclusion of this agreement between the key European democratic power and Nazi Reich. Emphasis is placed on analyzing the moods within the political elite of the United Kingdom. It is proven that the agreement became a significant milestone in escalation of crisis trends in the Versailles model of international relations. It played a substantial role in establishment of the British appeasement policy with regards to revanchist powers in the interbellum; policy that objectively led to disintegration of the created in 1919 systemic mechanism, and thus, the beginning of the World War II. The novelty of this work is substantiated by articulation of the problem. This article is first within the Russian and foreign historiography to analyze execution of the Anglo-German Naval Agreement based on the previously unavailable archival materials. The conclusion is made that this agreement played a crucial role in the process of disintegration of interbellum system of international relations. Having officially sanctioned the violation of the articles of the Versailles Treaty of 1919 by Germany, Great Britain psychologically reconciled to the potential revenge of Germany, which found reflection in the infamous appeasement policy. This launched the mechanism for disruption of status quo that was established after the World War I in Europe. This resulted in collapse of the architecture of international security in the key region of the world, rapid deterioration of relations between the countries, and a new world conflict.

SUBSTANTIATION OF EFFECTIVE INSTRUMENTS OF REGULATION OF FINANCIAL IMBALANCES OF ENDOGENOUS-ORIENTED DEVELOPMENT OF THE REGIONS OF UKRAINE

The article deals with instruments recommended for regulating financial imbalances of endogenous-oriented development of the regions of Ukraine as an integral part of the regional economy management mechanism, and also explored the ways of regulating regional socioeconomic processes in crisis conditions. The basic principles of selection of instruments for the regulation of financial imbalances of endogenous-oriented development of regions are determined. The classification of instruments of regulation of financial imbalances of endogenous-oriented development is considered. The basic tools used to support the development of regions and municipalities are analyzed: legal; related to the development of appropriate strategies and programs; based on the implementation of inter-municipal cooperation; financial. The three main directions of financial imbalance regulation tools for endogenous-oriented development of the regions are investigated, which are used to analyze the impact on the effectiveness of regional development at different stages of the economic cycle. The system of specially organized measures of regulation of financial imbalances of endogenously oriented development of regions is substantiated. In modern conditions, great attention is paid to the problems of regulation of financial imbalances of endogenously oriented development of regions of Ukraine, the implementation of which requires special instruments. A holistic presentation of the systemic mechanism of regulation of financial imbalances of endogenously oriented development of regions is offered. After all, ensuring endogenous-oriented development of regions in the current conditions of functioning of the economy of Ukraine requires the implementation of strategies of socioeconomic transformation, which will be aimed at changing the financial imbalances of development of regions and mechanisms for their implementation. Endogenously oriented regional development means increasing the level of overcoming adverse social, economic and environmental risks and trends, with the ability of regions to provide financial imbalances, self-regulation, self-improvement with maximum use of internal as well as external borrowing resources to meet the needs of the population of the regions. The endogenous-oriented development of the regions is conditioned by the identification of instruments for regulating the financial imbalances of the regions and the identification of conditions for their achievement, which are derivatives for ensuring the endogenously-oriented development of the regions as a whole.

Evaluation of the Impact Induced by High Dietary Sucrose Concentration and Glucocorticoid Medication on Dentin Formation of Young Rats

The impact of sucrose and systemic cortisone treatment on the response of dentin was examined in an experimental rat model. After 2 months of a modified diet and/or medication period, the areas of dentin formation and dentinal caries were quantified in the mandibular molars of growing animals. The 60% sucrose diet significantly reduced dentin formation and increased dentinal caries progression. The presence of glucocorticoid medication alone reduced dentin formation. Cortisone medication in combination with sucrose diet further decreased dentin apposition. Rats receiving the control diet positively responded to the dentinal caries by increasing dentin formation to prevent pulpal exposure. The rate of dentine formation was lower in rats with high sucrose diet and predentin area was wider compared to the control group fed normal diet. The enlargement of the predentin region in sucrose diet rats reflects changes in the functionality of the odontoblasts, such as reduction of matrix synthesis and alteration of the mineralization process. These results indicate that the functional alterations in the pulpo-dentinal complex might contribute to dentinal caries progression through systemic mechanism irrespective of the causative factors.