Research of the dynamic regulatory mechanism of Compound Danshen Dripping Pills on myocardial infarction based on metabolic trajectory analysis.

BACKGROUND: Myocardial infarction (MI) is a serious cardiovascular disease, which presents different pathophysiological changes with the prolongation of the disease. Compound danshen dripping pills (CDDP) has obvious advantages in MI treatment and widely used in the clinic. However, the current studies were mostly focused on the endpoint of CDDP intervention, lacking the dynamic attention to the disease process. It is of great value to establish a dynamic research strategy focused on the changes in pharmacodynamic substances for guiding clinical medication more precisely. PURPOSE: It is aimed to explore the dynamic regulating pattern of CDDP on MI based on metabolic trajectory analysis, and then clarify the variation characteristic biomarkers and pharmacodynamic substances in the intervention process. METHODS: The MI model was successfully prepared by coronary artery left anterior descending branch ligation, and then CDDP intervention was given for 28 days. Endogenous metabolites and the components of CDDP in serum were measured by LC/MS technique simultaneously to identify dynamic the metabolic trajectory and screen the characteristic pharmacodynamic substances at different points. Finally, network pharmacology and molecular docking techniques were used to simulate the core pharmacodynamic substances and core target binding, then validated at the genetic and protein level by Q-PCR and western blotting technology. RESULTS: CDDP performed typical dynamic regulation features on metabolite distribution, biological processes, and pharmacodynamic substances. During 1-7 days, it mainly regulated lipid metabolism and inflammation, the Phosphatidylcholine (PC(18:1(9Z/18:1(9Z)) and Sphingomyelin (SM(d18:1/23:1(9Z)), SM(d18:1/24:1(15Z)), SM(d18:0/16:1(9Z))) were the main characteristic biomarkers. Lipid metabolism was the mainly regulation pathway during 14-21 days, and the characteristic biomarkers were the Lysophosphatidylethanolamine (LysoPE(0:0/20:0), PE-NMe2(22:1(13Z)/15:0)) and Sphingomyelin (SM(d18:1/23:1(9Z))). At 28 days, in addition to inflammatory response and lipid metabolism, fatty acid metabolism also played the most important role. Correspondingly, Lysophosphatidylcholine (LysoPC(20:0/0:0)), Lysophosphatidylserine (LPS(18:0/0:0)) and Fatty acids (Linoelaidic acid) were the characteristic biomarkers. Based on the results of metabolite distribution and biological process, the characteristic pharmacodynamic substances during the intervention were further identified. The results showed that various kinds of Saponins and Tanshinones as the important active ingredients performed a long-range regulating effect on MI. And the other components, such as Tanshinol and Salvianolic acid B affected Phosphatidylcholine and Sphingomyelin through Relaxin Signaling pathway during the early intervention. Protocatechualdehyde and Rosmarinic acid affected Lysophosphatidylethanolamine and Sphingomyelin through EGFR Tyrosine kinase inhibitor resistance during the late intervention. Tanshinone IIB and Isocryptotanshinone via PPAR signaling pathway affected Lysophosphatidylcholine, Lysophosphatidylserine, and Fatty acids. CONCLUSION: The dynamic regulating pattern was taken as the entry point and constructs the dynamic network based on metabolic trajectory analysis, establishes the dynamic correlation between the drug-derived components and the endogenous metabolites, and elucidates the characteristic biomarkers affecting the changes of the pharmacodynamic indexes, systematically and deeply elucidate the pharmacodynamic substance and mechanism of CDDP on MI. It also enriched the understanding of CDDP and provided a methodological reference for the dynamic analysis of complex systems of TCM.

[Research progress on induced hepatic stellate cell ferroptosis in prevention and treatment of liver fibrosis].

Liver fibrosis is a key pathological stage in the progression of chronic liver disease. If the disease is mistreated, it can further deteriorate into liver failure, which seriously affects the quality of life of patients and brings heavy medical costs. Hepatic stellate cell(HSC) activation triggers extracellular matrix(ECM) deposition, which plays an important driving role in liver fibrosis, and ferroptosis is an effective strategy to clear or reverse the activation of HSCs into a deactivated phenotype. Therefore, inhibiting the activation and proliferation of HSCs by regulating ferroptosis is the key to the treatment of this disease, so as to derive the prospect of inducing ferroptosis of HSCs(including RNA-binding proteins, non-coding RNA, chemicals, and active components of traditional Chinese medicine) to intervene in liver fibrosis. On this basis, this paper started from the activation of HSCs to induce ECM deposition and focused on summarizing the mechanism of inducing HSC ferroptosis in delaying the progression of liver fibrosis, so as to continuously enrich the clinical practice of liver fibrosis and provide a reference for subsequent basic research.

[UPLC-QE-Orbitrap-MS combined with network pharmacology to explore differential components and mechanisms of raw and scorched rhubarb for treatment of ulcerative colitis].

This study compared the therapeutic difference effects of the raw and scorched rhubarb for the treatment of ulcerative colitis(UC) and explored their difference in chemical components and mechanisms by using ultra-high performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry(UPLC-QE-Orbitrap-MS) and network pharmacology. The UC therapeutic effects of Shaoyao Decoction with the raw rhubarb or the scorched rhubarb were evaluated by dextran sulfate sodium(DSS)-induced mouse model. The results showed that Shaoyao Decoction with either the raw rhubarb or the scorched rhubarb could relieve the UC symptoms of mice to different extents, while the scorched rhubarb-based formula showed advantages in reducing hemorrhagic diarrhea and inflammation levels. UPLC-QE-Orbitrap-MS was used to identify a total of 78 small molecules in the water decoction of the raw and scorched rhubarb. Multivariate statistical methods were used to screen components increasing significantly after the scorching process. The seven compounds included five free anthraquinones, gallic acid, and 5-hydroxymethylfurfural(HMF). Meanwhile, the nine compounds decreasing scorching were mainly combined anthraquinones and catechins-related compounds. Network pharmacology and molecular docking suggested that free anthraquinones, gallic acid, and 5-HMF may act on core targets such as B-cell lymphoma-2(BCL2), epidermal growth factor receptor(EGFR), tumor necrosis factor(TNF), and caspase-3(CASP3) and influence the signaling pathways such as phosphoinositide-3-kinase/protein kinase B(PI3K/Akt), hypoxia inducible factor-1(HIF-1), TNF, and mitogen-activated protein kinase(MAPK), so as to regulate the inflammation response, oxidative stress, and cell apoptosis to relieve UC symptoms. This study compared the therapeutic effects and chemical components of the raw and scorched rhubarb, providing the clinical reference for using rhubarb to treat UC.

Pulmonary scedosporiosis in an intractable immunocompetent host: A case report and literature review.

Pulmonary scedosporiosis is a rare pulmonary infection that often presents with nonspecific symptoms and radiological findings. In this report, we present a case of localized pulmonary scedosporiosis in an immunocompetent patient and analyze a total of 25 immunocompetent patients with pulmonary scedosporiosis. Through this case and the literature, we highlight the importance of considering pulmonary scedosporiosis in patients with nonspecific clinical symptoms and radiological findings resembling aspergilloma. This case and the literature further emphasize the significance of surgical intervention. Regardless of the use of antifungal drugs, surgery should be conducted as soon as possible.

Evolutionary dynamics in financial markets with heterogeneities in investment strategies and reference points.

In nature and human societies, the effects of homogeneous and heterogeneous characteristics on the evolution of collective behaviors are quite different from each other. By incorporating pair pattern strategies and reference point strategies into an agent-based model, we have investigated the effects of homogeneous and heterogeneous investment strategies and reference points on price movement. In the market flooded with the investors with homogeneous investment strategies or homogeneous reference points, large price fluctuations occur. In the market flooded with the investors with heterogeneous investment strategies or heterogeneous reference points, moderate price fluctuations occur. The coexistence of different kinds of investment strategies can not only refrain from the occurrence of large price fluctuations but also the occurrence of no-trading states. The present model reveals that the coexistence of heterogeneous populations, whether they are the individuals with heterogeneous investment strategies or heterogeneous reference points of stock prices, is an important factor for the stability of the stock market.

Identification of triple-negative breast cancer and androgen receptor expression based on histogram and texture analysis of dynamic contrast-enhanced MRI.

BACKGROUND: Triple-negative breast cancer (TNBC) is highly malignant and has a poor prognosis due to the lack of effective therapeutic targets. Androgen receptor (AR) has been investigated as a possible therapeutic target. This study quantitatively assessed intratumor heterogeneity by histogram analysis of pharmacokinetic parameters and texture analysis on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to discriminate TNBC from non-triple-negative breast cancer (non-TNBC) and to identify AR expression in TNBC. METHODS: This retrospective study included 99 patients with histopathologically proven breast cancer (TNBC: 36, non-TNBC: 63) who underwent breast DCE-MRI before surgery. The pharmacokinetic parameters of DCE-MRI (Ktrans, Kep and Ve) and their corresponding texture parameters were calculated. The independent t-test, or Mann-Whitney U-test was used to compare quantitative parameters between TNBC and non-TNBC groups, and AR-positive (AR+) and AR-negative (AR-) TNBC groups. The parameters with significant difference between two groups were further involved in logistic regression analysis to build a prediction model for TNBC. The ROC analysis was conducted on each independent parameter and the TNBC predicting model for evaluating the discrimination performance. The area under the ROC curve (AUC), sensitivity and specificity were derived. RESULTS: The binary logistic regression analysis revealed that Kep_Range (p = 0.032) and Ve_SumVariance (p = 0.005) were significantly higher in TNBC than in non-TNBC. The AUC of the combined model for identifying TNBC was 0.735 (p < 0.001) with a cut-off value of 0.268, and its sensitivity and specificity were 88.89% and 52.38%, respectively. The value of Kep_Compactness2 (p = 0.049), Kep_SphericalDisproportion (p = 0.049), and Ve_GlcmEntropy (p = 0.008) were higher in AR + TNBC group than in AR-TNBC group. CONCLUSION: Histogram and texture analysis of breast lesions on DCE-MRI showed potential to identify TNBC, and the specific features can be possible predictors of AR expression, enhancing the ability to individualize the treatment of patients with TNBC.

Exploring the common pathogenesis of Alzheimer's disease and type 2 diabetes mellitus via microarray data analysis.

Background: Alzheimer's Disease (AD) and Type 2 Diabetes Mellitus (DM) have an increased incidence in modern society. Although more and more evidence has supported that DM is prone to AD, the interrelational mechanisms remain fully elucidated. Purpose: The primary purpose of this study is to explore the shared pathophysiological mechanisms of AD and DM. Methods: Download the expression matrix of AD and DM from the Gene Expression Omnibus (GEO) database with sequence numbers GSE97760 and GSE95849, respectively. The common differentially expressed genes (DEGs) were identified by limma package analysis. Then we analyzed the six kinds of module analysis: gene functional annotation, protein-protein interaction (PPI) network, potential drug screening, immune cell infiltration, hub genes identification and validation, and prediction of transcription factors (TFs). Results: The subsequent analyses included 339 common DEGs, and the importance of immunity, hormone, cytokines, neurotransmitters, and insulin in these diseases was underscored by functional analysis. In addition, serotonergic synapse, ovarian steroidogenesis, estrogen signaling pathway, and regulation of lipolysis are closely related to both. DEGs were input into the CMap database to screen small molecule compounds with the potential to reverse AD and DM pathological functions. L-690488, exemestane, and BMS-345541 ranked top three among the screened small molecule compounds. Finally, 10 essential hub genes were identified using cytoHubba, including PTGS2, RAB10, LRRK2, SOS1, EEA1, NF1, RAB14, ADCY5, RAPGEF3, and PRKACG. For the characteristic Aß and Tau pathology of AD, RAPGEF3 was associated significantly positively with AD and NF1 significantly negatively with AD. In addition, we also found ADCY5 and NF1 significant correlations with DM phenotypes. Other datasets verified that NF1, RAB14, ADCY5, and RAPGEF3 could be used as key markers of DM complicated with AD. Meanwhile, the immune cell infiltration score reflects the different cellular immune microenvironments of the two diseases. Conclusion: The common pathogenesis of AD and DM was revealed in our research. These common pathways and hub genes directions for further exploration of the pathogenesis or treatment of these two diseases.

[Quality evaluation of commercial Ginseng Radix et Rhizoma Rubra based on multi-component quantitative analysis].

To comprehensively evaluate the quality of commercial Ginseng Radix et Rhizoma Rubra, 43 batches of commercial Ginseng Radix et Rhizoma Rubra were collected to determine the content of nine ginsenosides Rg_1, Re, Rb_1, Rk_3, Rh_4, 20(S)-Rg_3, 20(R)-Rg_3, Rk_1, and Rg_5 by high performance liquid chromatography(HPLC). The quality of the commercial Ginseng Radix et Rhizoma Rubra was evaluated by correlation analysis, principal component analysis, factor analysis, analysis of variance(ANOVA), and cluster heatmap analysis. The content determination indicated that the content of common ginsenosides in commercial Ginseng Radix et Rhizoma Rubra were higher while that of rare ginsenosides were lower. Multivariate statistical analysis revealed that ginsenosides Rg_1 and Rb_1 were significantly positively correlated with rare ginsenosides, and Rg_1, Rb_1 and rare ginsenosides played an important role in evaluating the quality of commercial Ginseng Radix et Rhizoma Rubra. In combination with the processing principle and current quality situation of Ginseng Radix et Rhizoma Rubra, it is recommended to improve the content limit of Rb_1 in the existing quality standards.

SmDXS5, acting as a molecular valve, plays a key regulatory role in the primary and secondary metabolism of tanshinones in Salvia miltiorrhiza.

Red sage, the dry root and rhizome of the herbaceous plant Salvia miltiorrhiza Bunge, is widely used for treating various diseases. The low content of tanshinones (terpenoids) has always restricted development of the S. miltiorrhiza industry. Here, we found that SmDXS5, a rate-limiting enzyme-coding gene located at the intersection of primary and secondary metabolism, can effectively change the transcription level and secondary metabolome profile of hairy roots of S. miltiorrhiza, and significantly increase the content of tanshinones. Agrobacterium rhizogenes was used to infuse S. miltiorrhiza explants, and hairy roots of S. miltiorrhiza expressing the SmDXS5 gene were obtained successfully. We identified 39 differentially accumulated metabolites (DAMs) by metabolomics based on ultra-high performance liquid chromatography quadrupole exactive mass spectrometry and multivariate statistics. These DAMs might be key metabolites of SmDXS5 gene regulation. RNA sequencing was used to compare gene expression between the hairy roots of the SmDXS5 overexpressing group and the blank control (BC) group. Compared with the BC group, 18,646 differentially expressed genes were obtained: 8994 were upregulated and 9,652 downregulated. The combined transcriptome and metabolome analyses revealed that the mevalonate and methylerythritol phosphate pathways and synthase gene expression levels in the SmDXS5 overexpressing group were upregulated significantly, and the accumulation of tanshinone components was increased significantly, which promoted the process of glycolysis and promoted the transformation of carbohydrates to secondary metabolism. Moreover, the expression of SmPAL, the first rate-limiting enzyme gene of the phenylpropane pathway, decreased, reducing the accumulation of phenolic acid, another secondary metabolite. Therefore, SmDXS5 can be defined as a 'valve' gene, mainly responsible for regulating the distribution of primary and secondary metabolic flow of tanshinones in S. miltiorrhiza, and for other secondary metabolic pathways. The discovery of SmDXS5 and its molecular valve function in regulating primary and secondary metabolism will provide a basis for the industrial production of tanshinone components, and cultivation of high quality S. miltiorrhiza.

IL-13 Regulates Orai1 Expression in Human Bronchial Smooth Muscle Cells and Airway Remodeling in Asthma Mice Model via LncRNA H19.

Background: Increased proliferation and hypertrophy of airway smooth muscle cells (ASMCs) contribute substantially to airway remodeling in asthma. Interleukin (IL)-13 regulates ASMC proliferation by increasing Orai1 expression, the pore-forming subunit of store-operated Ca2+ entry (SOCE). The underlying mechanisms of this effect are not fully understood. Methods: Bioinformatic analysis identified an interaction between microRNA 93-5p (miR-93-5p) and long non-coding RNA (lncRNA) H19, and between miR-93-5p and Orai1. RNA interference was used to investigate H19 knockdown on IL-13-induced proliferation and migration of in vitro cultured human bronchial smooth muscle cells (hBSMCs). Functional relevance of H19 in airway inflammation and airway remodeling was investigated in murine models of acute and chronic asthma. Results: IL-13 concentration-dependently increased the expression of H19 and Orai1 and decreased the expression of miR-93-5p in hBSMCs. H19 knockdown partly reversed the effects of IL-13 on the expression of miR-93-5p and Orai1 and attenuated the proliferation and migration of hBSMCs promoted by IL-13. IL-13-promoted expression of Orai1 was attenuated by miR-93-5p mimic and increased by miR-93-5p inhibitor. IL-13-promoted proliferation of hBSMCs was increased by miR-93-5p inhibitor but not affected by miR-93-5p mimic, whereas IL-13-promoted migration of hBSMCs was increased by miR-93-5p inhibitor and attenuated by miR-93-5p mimic. The inhibiting effect of H19 knockdown on IL-13-induced Orai1 expression and the proliferation and migration of hBSMCs was counteracted by miR-93-5p inhibitor but only marginally or not impacted by miR-93-5p mimic. The expression of H19 and Orai1 was higher in the lungs of asthmatic mice than in control mice. In asthmatic mice, H19 siRNA reduced Orai1 expression, inflammatory cell infiltration, goblet cell hyperplasia, collagen deposition and smooth muscle mass in the lungs. Conclusion: H19 may mediate the effects of IL-13 on Orai1 expression by inhibition of miR-93-5p in hBSMCs. H19 may be a therapeutic target for airway inflammation and airway remodeling.

[Compatibility mechanism of Gegen Qinlian Decoction in treatment of ulcerative colitis based on network pharmacology].

Gegen Qinlian Decoction(GQD) is commonly used for the clinical treatment of ulcerative colitis(UC) and other diseases, but its compatibility mechanism has not been elucidated systematically. In this study, the compatibility mechanism of GQD against UC was revealed based on the blood components in the mouse model of UC by network pharmacology. The targets of blood components of GQD were collected to construct a protein-protein interaction(PPI) network. The key targets were screened out according to the topological parameters of the network, and 16 core components were identified, such as puerarin, chrysin, berberine, and liquiritigenin, based on the key targets in the blood components. Functional enrichment analysis was performed on the key targets, and the regulatory network of the prescription was constructed, which elucidated the compatibility mechanism of the Chinese herbal drugs in the prescription at both target and pathway levels. The results showed that all the Chinese herbal drugs in GQD had heat-clearing and toxin-removing effects, and the four Chinese herbal drugs synergistically exerted their effects by co-regulating protooncogenes, such as FOS and JUN, and characteristically regulating signal transducer and activator of transcription 3(STAT3) and interleukin-6(IL-6). The pathway analysis revealed that GQD exerted heat-clearing and toxin-removing effects mainly by regulating the inflammatory response-related signaling pathways, such as Toll-like receptor, tumor necrosis factor(TNF), and mitogen-activated protein kinase(MAPK). Furthermore, the study revealed the synergistic effects of Chinese herbal drugs in GQD based on the TNF signaling pathway. The results showed that the sovereign drug Puerariae Lobatae Radix played a primary role in the regulation of targets in the TNF signaling pathway, the minister drugs Scutellariae Radix and Coptidis Rhizoma showed the synergistic effects with Puerariae Lobatae Radix, and the assistant and guiding drug Glycyrrhizae Radix et Rhizoma supported Puerariae Lobatae Radix in the key target NF-κB and the process of cell adhesion. The drugs in GQD showed good characteristics of compatibility in the TNF signaling pathway. This study is expected to provide the basis for the further exploration of the compatibility mechanism of GQD.

[Study on serum pharmacodynamic material basis of Gegen Qinlian Decoction in treatment of ulcerative colitis based on UHPLC-Q-Orbitrap-MS].

This study established a mouse model of ulcerative colitis and explored the serum transitional components of Gegen Qinlian Decoction by UHPLC-Q-Orbitrap-MS. Based on the exact relative molecular weight and MS/MS spectrum, 55 prototype components and 59 metabolites were identified from the model group, while 18 prototype components and 35 metabolites from the control group. The prototype components in serum were mainly flavonoids and the characteristic components of the model group were alkaloids. Glucuronidation, sulfonation, and glycosylation have been confirmed to be the main metabolic types in vivo. The results of comparative analysis of differences indicated that puerarin, baicalin, wogonoside, wogonin, chrysin, oroxylin A, berberine, berberrubine, and palmatine were the characteristic components in model state, which at the same time, were confirmed by pharmacological studies to be the serum pharmacodynamic material basis of Gegen Qinlian Decoction in the treatment of ulcerative colitis. This study has provided reference for explaining the metabolic transformation pattern and mechanism of action of Gegen Qinlian Decoction in vivo.

Market impact shapes competitive advantage of investment strategies in financial markets.

The formation of an efficient market depends on the competition between different investment strategies, which accelerates all available information into asset prices. By incorporating market impact and two kinds of investment strategies into an agent-based model, we have investigated the coevolutionary mechanism of different investment strategies and the role of market impact in shaping a competitive advantage in financial markets. The coevolution of history-dependent strategies and reference point strategies depends on the levels of market impact and risk tolerance. For low market impact and low risk tolerance, the majority-win effect makes the trend-following strategies become dominant strategies. For high market impact and low risk tolerance, the minority-win effect makes the trend-rejecting strategies coupled with trend-following strategies become dominant strategies. The coupled effects of price fluctuations and strategy distributions have been investigated in depth. A U-shape distribution of history-dependent strategies is beneficial for a stable price, which is destroyed by the existence of reference point strategies with low risk tolerance. A δ-like distribution of history-dependent strategies leads to a large price fluctuation, which is suppressed by the existence of reference point strategies with high risk tolerance. The strategies that earn more in an inefficient market lose more in an efficient market. Such a result gives us another explanation for the principle of risk-profit equilibrium in financial markets: high return in an inefficient market should be coupled with high risk in an efficient market, low return in an inefficient market should be coupled with low risk in an efficient market.

[Molecular mechanism of Qishen Yiqi Dripping Pills in treating myocardial ischemia:a study based on HIF-1 signaling pathway].

Qishen Yiqi Dripping Pills(QSYQ) are used clinically to treat various myocardial ischemic diseases, such as angina pectoris, myocardial infarction, and heart failure; however, the molecular mechanism of QSYQ remains unclear, and the scientific connotation of traditional Chinese medicine(TCM) compatibility has not been systematically explained. The present study attempted to screen the critical pathway of QSYQ in the treatment of myocardial ischemia by network pharmacology and verify the therapeutic efficacy with the oxygen-glucose deprivation(OGD) model, in order to reveal the molecular mechanism of QSYQ based on the critical pathway. The key targets of QSYQ were determined by active ingredient identification and target prediction, and underwent pathway enrichment analysis and functional annotation with David database to reveal the biological role and the critical pathway of QSYQ. Cell counting Kit-8(CCK-8), lactate dehydrogenase(LDH), and Western blot tests were launched on high-content active ingredients with OGD cell model to reveal the molecular mechanism of QSYQ based on the critical pathway. The results of network pharmacology indicated that QSYQ, containing 18 active ingredients and 82 key targets, could protect cardiomyocytes by regulating biological functions, such as nitric oxide biosynthesis, apoptosis, inflammation, and angiogenesis, through TNF signaling pathway, HIF-1 signaling pathway, PI3 K-Akt signaling pathway, etc. HIF-1 signaling pathway was the critical pathway. As revealed by CCK-8 and LDH tests, astragaloside Ⅳ, salvianic acid A, and ginsenoside Rg_1 in QSYQ could enhance cell viability and reduce LDH in the cell supernatant in a concentration-dependent manner(P<0.05). As demonstrated by the Western blot test, astragaloside Ⅳ significantly down-regulated the protein expression of serine/threonine-protein kinase(Akt1) and hypoxia-inducible factor 1α(HIF-1α) in the HIF-1 signaling pathway, and up-regulated the protein expression of vascular endothelial growth factor A(VEGFA). Salvianic acid A significantly down-regulated the protein expression of upstream phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3 CA) and downstream HIF-1α of Akt1. Ginsenoside Rg_1 significantly down-regulated the expression of HIF-1α protein and up-regulated the expression of VEGFA. The therapeutic efficacy of QSYQ on myocardial ischemia was achieved by multiple targets and multiple pathways, with the HIF-1 signaling pathway serving as the critical one. The active ingredients of QSYQ could protect cardiomyocytes synergistically by regulating the targets in the HIF-1 signaling pathway to inhibit its expression.

Store-operated calcium entry-associated regulatory factor regulates airway inflammation and airway remodeling in asthma mice models.

Store-operated calcium entry (SOCE) is involved in the pathogenesis of airway inflammation and remodeling in asthma. Store-operated calcium entry-associated regulatory factor (SARAF) can downregulate SOCE. We sought to investigate the role of SARAF in the regulation of airway inflammation and remodeling in asthma mice models, as well as in the functional regulation of human airway smooth muscle cells (hASMCs). Balb/c mice were sensitized and challenged with ovalbumin to establish the asthma mice models. Mice were transfected with lentivirus, which expressed the SARAF gene + GFP (green fluorescence protein) or the negative control gene + GFP. Airway resistance was measured with the animal pulmonary function system. Airway inflammation and remodeling were evaluated via histological staining. In vitro cultured hASMCs were transfected with scrambled small interfering RNA (siRNA) or SARAF-specific siRNA, respectively. The proliferation, migration rate, hypertrophy, and SOCE activity of hASMCs were examined with Cell Counting Kit-8, wound healing test, bright field imaging, and Ca2+ fluorescence imaging, respectively. SARAF expression was measured by quantitative real-time PCR. Asthma mice models showed decreased SARAF mRNA expression in the lungs. SARAF overexpression attenuated airway inflammation, resistance, and also remodeling. Downregulation of SARAF expression with siRNA promoted the proliferation, migration, hypertrophy, and SOCE activity in hASMCs. SARAF plays a protective role against airway inflammation and remodeling in asthma mice models by blunting SOCE; SARAF may also be a functional regulating factor of hASMCs.

Exploring the Coordination Modes of a Keggin-Type [ZnW12O40]6- Anionic Cluster: Bonding Patterns, Crystal Structure, and Semiconducting Properties.

Polyoxometalate-based organic-inorganic hybrid compounds (POIHCs) have been greatly developed due to their wide application prospects, but the pursuit of their directed synthesis via molecular design still remains a challenge. Herein, we demonstrate that the coordination modes of the Keggin-type [ZnW12O40]6- anion can be tuned, which leads to different semiconductor characteristics. Using the same building block, ligand, and metal ion (ZnW12, phen, Cu2+), we synthesized three new POIHCs with different bonding patterns by means of different coordination modes of ZnW12. The three POIHCs (H2phen){ZnW12O40[Cu(phen)2]2}·3H2O (1), {ZnW12O40[Cu(phen)(H2O)2]2[Cu(phen)(H2O)]}n·3H2O (2), and (Me4N)2{ZnW12O40[Cu(phen)(H2O)]2}n·5H2O (3) (phen = 1,10-phenanthroline) have been structurally characterized by single-crystal X-ray diffraction. Compound 1 appears as a zero-dimensional coordination complex cluster, while compounds 2 and 3 are both 1D chain structures with different Cu2+ bridge linkages. Although these three POIHCs possess the same chemical components, their semiconductor properties are different, which is demonstrated by measurements of transient photocurrent and band gap (Eg) values. Furthermore, we carried out comparative experiments on the photoconductivity performance of compounds 1-3 and their photocatalytic reduction from O2 to H2O2, indicating the significant influence of the energy level matching on the photocatalytic activity.

Curcumin prevents renal cell apoptosis in acute kidney injury in a rat model of dry-heat environment heatstroke via inhibition of the mitochondrial apoptotic pathway.

Heatstroke is a life-threatening illness that is characterised by a core body temperature >40°C and central nervous system dysfunction. Acute kidney injury (AKI) is a common complication of heatstroke, and the mitochondrial apoptotic pathway has been demonstrated to be one of the leading causes of tissue damage and cell death in AKI. Curcumin is a phenol that is extracted from turmeric and demonstrates anti-apoptotic properties. To test if curcumin can protect the kidney from injury caused by heat stress, the effect of curcumin administration on renal injury and apoptosis of renal tissue was examined in a rat model of dry-heat environment. A total of 50 Sprague-Dawley rats were randomly divided into five groups (n=10): Standard temperature control, dry-heat control and curcumin treatment groups (50, 100 and 200 mg/kg groups). After exposure to a dry-heat environment for 150 min, the rats were anesthetized and euthanized. Blood, urine and renal tissue were collected to quantify the expression of specific mitochondrial apoptosis-related molecules. Curcumin pre-treatment decreased blood urea nitrogen and serum creatinine, urinary kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin levels compared with the dry-heat control group. Curcumin was also revealed to downregulate c-Jun N-terminal kinases (JNK), cytochrome c, caspase-3 and caspase-9 expression upon treatment with 100 and 200 mg/kg curcumin, which may result in inhibition of the mitochondrial apoptotic pathway in renal cells. The current study revealed that Curcumin may to have potential for preventing heatstroke-induced AKI.

Transcriptomic analyses reveal antiinflammatory mechanism of withanolides derived from the fruits of Physalis alkekengi L. var. franchetii.

In China, the fruits of Physalis alkekengi L. var. franchetii, which are conventionally utilized as edible berry, have attracted wide attention due to its significant biological activities. In the present study, phytochemical studies on the fruits of Physalis plants afforded six compounds, including two new withanolides (1-2) and four known agnologues (3-6). The inhibitory effects of these compounds on the formation of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in RAW264.7 macrophages were evaluated. Physapubescin M (1), with IC50 value of 1.58 µM, was selected for further study. The protein expression of COX-2 and iNOS, and LPS-induced production of cytokines (IL-6, IL-1ß and TNF-α) were reduced by physapubescin M (1) in a dose-dependent way. In addition, transcriptomic analyses were conducted to profile gene expression alterations in LPS-induced RAW264.7 cells upon treatment of physapubescin M (1) and the potential antiinflammatory mechanism of withnolides was mentioned. These results provide broad view to the underlying antiinflammatory mechanism of withnolides, and give a theoretical basis for the utilization of the fruits of P. alkekengi L. var. franchetii.

The synthesis and cytotoxic activity of derivatives of 4ß-hydroxywithanolide E.

4ß-Hydroxywithanolide E, which can be obtained in large amounts from the Physalis genus, possessed anti-proliferative effects on a variety of human cancer cell lines. For discussing its anti-tumor structure-activity relationship, a series of 4ß-hydroxywithanolide E derivatives (1-17) were synthesized and evaluated for their antitumor activity in vitro towards acute promyelocytic leukemia NB4 cell line by the Alarma blue assay. Cytotoxicity data revealed that the enone structure and C-4 hydroxyl substituents of ring A, together with the side chain (C-20-C-28) play an important effect on the cytotoxicity.

New lathyrane diterpenoids with anti-inflammatory activity isolated from the roots of Jatropha curcas L.

ETHNOPHARMACOLOGICAL RELEVANCE: Jatropha curcas L. (Euphorbiaceae), as a drought resistant shrub mainly cultivated in tropical and subtropical areas worldwide, is widely used as traditional medicine to cure arthritis, dysentery, abscess and pneumonia in Asian, African and South American folklores. The methanolic extracts of the roots have been revealed the anti-inflammatory activity in vivo and vitro. AIM OF STUDY: This research aimed to provide promising anti-inflammatory candidates from the roots of J. curcas. In addition, RNA-Seq was conducted to give targeted genes involved in the anti-inflammatory action. MATERIALS AND METHODS: The diterpenoids were isolated from the CH2Cl2 fraction of the methanolic extract from the roots of J. curcas by column chromatography (CC): silica gel, Sephadex LH-20, ODS, semi-preparative reversed-phase high-performance liquid chromatography (HPLC). The structures were identified based on HR-ESI-MS and 1D, 2D-NMR spectroscopic analysis. Their anti-inflammatory effects were tested on lipopolysaccharide (LPS, 500 ng/mL)-stimulated murine RAW264.7 macrophages. Furthermore, we conducted transcriptome-wide RNA sequencing to profile gene expression alterations in LPS-induced RAW264.7 cells upon treatment with jatrocurcasenone I (4) and analyzed the underlying genes targeted by this compound. RESULTS: Six diterpenoids were obtained from J. curcas, and four of them were identified to be new lathyrane diterpenoids: jatrocurcasenones F-I (1-4). Compounds 3 and 4 exhibited potent inhibitory activities against LPS-induced nitric oxide (NO) production in RAW264.7 cells with IC50 values of 11.28 µM and 7.71 µM, respectively. Western blotting analysis showed that the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were suppressed with the supplementation of 3 and 4. The results of RNA-seq showed that 4 (20 µM) exhibited regulation on the 587 differentially expressed genes (DEGs) induced by LPS (500 ng/mL). Transcriptome-wide RNA sequencing indicated that the protective activity of 4 supplementation was most likely driven by modulating expression levels of IL-1α, IL-1ß, IL-1f6, IL-6, IL-1rn, IL-27, Ccl2, Ccl5, Ccl7, Ccl9, Ccl22, Cxcl10, Tnfsf12, Tnfsf15, Lta, Trim25, Bcl2a1a, Dusp1, Dusp2, Ptgs2, Edn1 and Nr4a1. CONCLUSIONS: This study offered four new lathyrane diterpenoids, of them, jatrocurcasenone I (4) showed significant anti-inflammatory activity. RNA-Seq suggested that jatrocurcasenone I (4) could be a candidate drug for the prevention inflammation-mediated diseases by modulating 24 candidate DEGs.