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Objective: To identify specific Chinese medicines (CM) that may benefit patients with primary liver cancer (PLC), and to explore the mechanism of action of these medicines. Methods: In this retrospective, singlecenter study, prescription information from PLC patients was used in combination with Traditional Chinese Medicine Inheritance Supports System to identify the specific core drugs. A system pharmacology approach was employed to explore the mechanism of action of these medicines. Results: Taking CM more than 6 months was significantly associated with improved survival outcomes. In total, 77 putative targets and 116 bioactive ingredients of the core drugs were identified and included in the analysis (P<0.05). A total of 1,036 gene ontology terms were found to be enriched in PLC. A total of 75 pathways identified from Kyoto Encyclopedia of Genes and Genomes were also enriched in this disease, including fluid shear stress, interleukin-17 signaling, signaling between advanced glycan end products and their receptors, cellular senescence, tumor necrosis factor signaling, p53 signaling, cell cycle signaling, steroid hormone biosynthesis, T-helper 17 cell differentiation, and metabolism of xenobiotics by cytochrome. Docking studies suggested that the ingredients in the core drugs exert therapeutic effects in PLC by modulating c-Jun and interleukin-6. Conclusions: Receiving CM for 6 months or more improves survival for the patients with PLC. The core drugs that really benefit for PLC patients likely regulates the tumor microenvironment and tumor itself. [ABSTRACT FROM AUTHOR]

Aims : Cardiac lipotoxicity is the common consequence of lipid metabolism disorders in cardiomyocytes during development of heart failure (HF). Adenosine 5′monophosphate-activated protein kinase (AMPK) acts as an energy sensor and has a beneficial effect in reducing lipotoxicity. Notoginsenoside R1 (NGR1) is extracted from the traditional Chinese medicine Panax notoginseng (Burkill) F.H.Chen (P. notoginseng) and has definite cardioprotective effects. However, whether NGR1 can attenuate HF by mitigating lipotoxicity has not been elucidated yet. This study aimed to explore whether NGR1 plays a protective role against HF by ameliorating cardiac lipotoxicity via the AMPK pathway. Methods : In this study, HF mice model was established by left anterior descending (LAD) ligation. palmitic acid (PA) stimulated H9C2 cell model was applied to clarify the effects and potential mechanism of NGR1 on lipotoxicity. In vivo , NGR1 (7.14 mg/kg/days) and positive drug (simvastatin: 2.9 mg/kg/days) were orally administered for 14 days. Echocardiography was applied to assess heart functions. Lipid levels were measured by Enzyme-linked immunosorbent assay (ELISA) and key proteins in the AMPK pathway were detected by western blots. In vitro , NGR1 (40 μmol/L) or Compound C (an inhibitor of AMPK, 10 μmol/L) was co-cultured with PA stimulation for 24 h in H9C2 cells. CCK-8 assay was used to detect cell viability. Key lipotoxicity-related proteins were detected by western blots and the LipidTOX™ neutral lipid stains were used to assess lipid accumulation. In addition, Apoptosis was assessed by Hoechst/PI staining. Results : NGR1 could significantly improve the cardiac function and myocardial injury in mice with HF and up-regulate the expression of p-AMPK. Impressively, NGR1 inhibited the synthesis of diacylglycerol (DAG) and ceramide and promoted fatty acid oxidation (FAO) in vivo. Moreover, NGR1 significantly promoted expression of CPT-1A, the key enzyme in FAO pathway, and down-regulated the expression of GPAT and SPT, which were the key enzymes catalyzing production of DAG and ceramide. In vitro experiments showed that NGR1 could significantly attenuate lipid accumulation in PA-induced H9C2 cells and the Hoechst/PI staining results showed that NGR1 ameliorated lipotoxicity-induced apoptosis in PA-stimulated H9C2 cell model. Furthermore, co-treatment with inhibitor of AMPK abrogated the protective effects of NGR1. The regulative effects of NGR1 on lipid metabolism were also reversed by AMPK inhibitor. Conclusion : NGR1 could significantly improve the heart function of mice with HF and reduce cardiac lipotoxicity. The cardio-protective effects of NGR1 are mediated by the activation of AMPK pathway. [ABSTRACT FROM AUTHOR]

Silicosis is a lung fibrotic disease caused by chronic silica exposure. Aberrations in long non-coding RNA (lncRNA) expression are associated with fibrotic diseases, but the role of lncRNAs in silicosis pathogenesis remains unclear. Here, we investigated the expression of lncRNAs during silicosis and the role of MRAK050699 in epithelial–mesenchymal transition (EMT). Differentially expressed lncRNAs in the lung tissues of normal and silicosis rats were compared, and their biological effects were determined using the Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. There were 1077 differentially expressed lncRNAs (378 upregulated and 699 downregulated). MRAK052509, MRAK139674, AY539881, MRAK050699, XR_6113, and BC167061 were selected to verify expression in silicosis rats using quantitative reverse transcription polymerase chain reaction. MRAK050699 was knocked down in rat alveolar type II epithelial cells, and the molecular mechanism of transforming growth factor-β (TGF-β)-induced EMT in these cells was studied. All selected lncRNAs were upregulated in the silicosis rats, consistent with the sequencing results. MRAK050699 knockdown inhibited EMT of RLE-6TN cells by regulating the TGF-β/Smad3 signaling pathway. Thus, the differential expression of lncRNAs is related to silicosis development, and MRAK050699 plays an important role in EMT, suggesting a potential therapeutic target for silicosis. [ABSTRACT FROM AUTHOR]

Summary: Aim: Multifactors contribute to the development of postoperative cognitive dysfunction (POCD), of which the most important mechanism is neuroinflammation. Prostaglandin E2 (PGE2) is a key neuroinflammatory molecule and could modulate hippocampal synaptic transmission and plasticity. This study was designed to investigate whether PGE2 and its receptors signaling pathway were involved in the pathophysiology of POCD. Methods: Sixteen‐month old male C57BL/6J mice were exposed to laparotomy. Cognitive function was evaluated by fear conditioning test. The levels of PGE2 and its 4 distinct receptors (EP1‐4) were assessed by biochemical analysis. Pharmacological or genetic methods were further applied to investigate the role of the specific PGE2 receptors. Results: Here, we found that the transcription and translation level of the EP3 receptor in hippocampus increased remarkably, but not EP1, EP2, or EP4. Immunofluorescence results showed EP3 positive cells in the hippocampal CA1 region were mainly neurons. Furthermore, pharmacological blocking or genetic suppression of EP3 could alleviate surgery‐induced hippocampus‐dependent memory deficits and rescued the expression of plasticity‐related proteins, including cAMP response element‐binding protein (CREB), activity‐regulated cytoskeletal‐associated protein (Arc), and brain‐derived neurotrophic factor (BDNF) in hippocampus. Conclusion: This study showed that PGE2‐EP3 signaling pathway was involved in the progression of POCD and identified EP3 receptor as a promising treatment target. [ABSTRACT FROM AUTHOR]

As a traditional Chinese medicine formula, Jingxin Zhidong Formula (JXZDF) based on ancient amber powder has been prescribed to alleviate tic disorders (TD) according to our clinical practice for many years. However, the underlying molecular mechanisms remain largely unknown. To explore the potential mechanism of JXZDF in the treatment of TD by using network pharmacology and experimental validation. The chemical components of JXZDF were detected and the potential pathway enrichment analyses were conducted based on network pharmacology. Finally, we performed cell viability assays and Western blotting on LPS-induced BV-2 cells, and subsequently performed behavioral tests and Western blotting in SD rats model for TD to explore the mechanism of JXZDF on TD. By LC-ESI-MS/MS system and searching the databases, we identified 5 key compounds and 29 hub targets of JXZDF on TD. KEGG enrichment analysis showed that PI3K/AKT signaling pathway may be the key pathway for JXZDF on TD. The vitro experimental results proved that JXZDF can inhibit the phosphorylation of PI3K and AKT proteins on LPS-induced BV-2 cells. The animal experimental results indicated that JXZDF can effectively alleviate the stereotypic behavior and hyperactivity of the TD rats, and downregulated PI3K/AKT pathway to inhibit microglia activation in the hippocampus tissue. This study indicated that JXZDF can change microglial activation and expression of proinflammatory mediators through the inactivation of PI3K/AKT signaling pathway, which may be one of the mechanisms of JXZDF in treating TD. [Display omitted] [ABSTRACT FROM AUTHOR]

Simple Summary: Although adipocytes affect the metastatic behavior of cancer cells, the underlying molecular mechanisms remain largely elusive. Thereby, we sought to screen for the signaling pathways responsible for adipocyte-induced motility of breast cancer cells by employing a breast cancer cell/adipocyte coculture system. Our study revealed that adipocyte coculture stimulated PAI-1 expression in breast cancer cells to potentiate cell motility. Furthermore, we obtained evidence that adipocytes secreted leptin to activate OBR in breast cancer cells, which phosphorylated STAT3 to promote the transcription of PAI-1 and repress the expression of miR-34a as the negative regulator of PAI-1. Our study provides new evidence for the involvement of adipocytes in breast cancer evolution, which advances the evolving roles of stromal cells in tumor pathogenesis. The crosstalk between cancer cells and adipocytes is critical for breast cancer progression. However, the molecular mechanisms underlying these interactions have not been fully characterized. In the present study, plasminogen activator inhibitor-1 (PAI-1) was found to be a critical effector of the metastatic behavior of breast cancer cells upon adipocyte coculture. Loss-of-function studies indicated that silencing PAI-1 suppressed cancer cell migration. Furthermore, we found that PAI-1 was closely related to the epithelial-mesenchymal transition (EMT) process in breast cancer patients. A loss-of-function study and a mammary orthotopic implantation metastasis model showed that PAI-1 promoted breast cancer metastasis by affecting the EMT process. In addition, we revealed that leptin/OBR mediated the regulation of PAI-1 through the interactions between adipocytes and breast cancer cells. Mechanistically, we elucidated that leptin/OBR further activated STAT3 to promote PAI-1 expression via miR-34a–dependent and miR-34a–independent mechanisms in breast cancer cells. In conclusion, our study suggests that targeting PAI-1 and interfering with its upstream regulators may benefit breast cancer patients. [ABSTRACT FROM AUTHOR]

The BDNF-TrkB signaling pathway and its downstream cascade disorders participate in learning and memory impairments. The BDNF - TrkB signaling pathway and its downstream cascades are involved in the generation of synapses which then regulate learning and memory. Intraperitoneal injection of LPS damages the BDNF - TrkB signaling pathway and its downstream cascade, leading to cognitive dysfunction. 7,8-DHF can penetrate the blood–brain barrier and activate TrkB receptors, alleviating learning and memory deficits. [Display omitted] • The BDNF-TrkB pathway and downstream cascades are involved in cognitive deficits. • 7,8-DHF could alleviate cognitive deficits via acting on the TrkB in LPS mice. • The mPFC, hippocampus and EC regions are associated with learning and memory. • 7,8-DHF might serve as a potential treating target in neurodegenerative diseases. Accumulating evidence suggests that neuroinflammation is the main mechanism in cognitive dysfunction and that brain-derived neurotrophic factor (BDNF) is involved in learning and memory by binding to tyrosine kinase B (TrkB) receptors. Herein, we tested the roles of the BDNF - TrkB signaling pathway and its downstream cascade in lipopolysaccharide (LPS) induced cognitive dysfunction in mice. Mice were treated with LPS (0.25 mg/kg) for 7 days, and learning and memory function was evaluated by the novel object recognition test (NORT). Western blotting was performed to elucidate roles of the BDNF - TrkB signaling pathway and its downstream cascades in LPS mice. The NORT showed that LPS induced learning and memory deficits in mice. The levels of IL-1β, IL-6, and TNF-α in the serum and central nervous system decreased in LPS mice. In addition, LPS reduced the protein levels of BDNF, p-TrkB, Bcl-2, p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 and increased the expression of Bax in the hippocampus and medial prefrontal cortex regions. In the entorhinal cortex, the protein levels of BDNF, p-TrkB, Bcl-2, p-CaMK2 and p-CREB were decreased, and the protein level of Bax was increased in LPS mice. Interestingly, 7,8-DHF alleviated these disorders in LPS mice and improved learning and memory function; however, the TrkB antagonist ANA12 effectively reversed effects of 7,8-DHF. Therefore, we conclude that the BDNF - TrkB signaling pathway and its downstream cascades disorders in different regions are main mechanisms of cognitive dysfunction, and 7,8-DHF maybe useful as a new treatment for preventing or treating cognitive dysfunction induced by neuroinflammation in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Depression is a common psychopathological disorders. Studies of depression have indicated that zinc play a role in the depression pathophysiology and treatment. In present study, we examined the effects of zinc and imipramine supplement alone or combination of zinc and imipramine in mice induced by chronic restraint stress (CRS). Moreover, the possible roles of zinc receptor (G protein-coupled receptor 39, GPR39)-related pathway was investigated. Decreased weight and increased corticosterone (CORT) were observed after 3 weeks CRS exposure. It was shown that CRS induced lower serum zinc, higher hippocampal zinc, increased immobility time in tail suspension test and decreased movement distance in spontaneous activity test, which could be normalized by zinc (30 mg/kg) and imipramine (20 mg/kg) supplement alone and combination of zinc (15 mg/kg) and imipramine (5 mg/kg) for 3 weeks after CRS exposure. Moreover, the changes in mRNA expressions of GPR39, cAMP-response element binding protein (CREB), brain-derived neurotropic factor (BDNF) and n-methytl-d-aspartate receptors (NMDAR) could be reversed by the same treatment mentioned above. These results suggested that zinc dyshomeostasis in serum and hippocampus and depression-like behavior in CRS exposure animals observed in present study could be normalized by zinc and imipramine. The combination of zinc and imipramine in low dose has synergetic effects. The possible mechanism might be correlated to GPR39 receptor-related pathway. [ABSTRACT FROM AUTHOR]

There are several studies reporting that different plant-based metabolites are potential inhibitors of protein amyloid fibrillation. As chemical features of metabolites can regulate protein aggregation process, in the present in vitro investigation, tau protein was selected as a model of Alzheimer's disease to elaborate the inhibitory effect of syringic acid (SA) on its assembly and associated neurotoxicity in aggregation conditions. Extrinsic fluorescence, Congo red adsorption, and CD spectroscopic studies, TEM, size-exclusion chromatography, and MALDI-TOF mass spectrometry analysis along with MTT and qRT-PCR assays were performed to assess the inhibitory effects of SA against tau aggregation and neurotoxicity. It was shown that SA has the tendency to control the aggregation of the tau proteins through modulating the amyloid kinetic parameters, exposure of hydrophobic residues, and structural changes. Moreover, the structures formed in the presence of SA recovered the viability of neuron-like cells (SH-SY5Y) through regulation of endoplasmic reticulum stress signaling pathway by downregulation of ATF-6, caspase-8 and caspase-3 mRNA. In conclusion, it can be suggested that SA may be used as a potential small molecule in the development of therapeutic platforms against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

In recent years, research on the mechanism of bone destruction in rheumatoid arthritis (RA) has remained in the initial stages, and the mechanism has not been fully elucidated to date. Recent studies have shown that long noncoding RNAs (lncRNAs) participate in RA bone destruction via autophagy, but the specific regulatory mechanism of lncRNA-mediated autophagy is unclear. Therefore, in this article, we review the mechanisms of lncRNA-mediated autophagy in fibroblast-like synoviocytes and chondrocytes in RA bone destruction. We explain that lncRNAs mediate autophagy and participate in many specific pathological processes of RA bone destruction by regulating signalling pathways and the expression of target genes. Specific lncRNAs can be used as markers for molecular diagnosis, mechanistic regulation, treatment and prognosis of RA. [Display omitted] • Autophagy is an important mechanism of bone destruction in RA. • Different lncRNAs have different (promoting or inhibiting) effects on autophagy. • LncRNAs can be used as a marker for molecular diagnosis of RA and a potential target for RA therapy. [ABSTRACT FROM AUTHOR]

Danqi Pill, composed of the root of Salvia miltiorrhiza Bunge and the root of Panax notoginseng , is effective in the clinical treatment of myocardial ischemia in coronary heart diseases. A number of studies have shown that autophagy plays an essential role in cardiac function and energy metabolism, and disordered autophagy is associated with the progression of heart failure. However, the effect and mechanism of Danqi pill on autophagy have not been reported yet. This study aims to elucidate whether Danqi pill restores autophagy to protect against HF and its potential mechanism. Left anterior descending ligation was established to induce an HF rat model, H 2 O 2 -stimulated H9C2 cells model was conducted to clarify the effects and potential mechanism of Danqi pill. In vivo, Danqi pill (1.5 g/kg) were orally administered for four weeks and Fenofibrate (10 mg/kg) was selected as a positive group. In vitro, Danqi pill (10–200 μg/mL) was pre-cultured for 24 h and co-cultured with H 2 O 2 stimulation for 4 h. Importantly, transmission electron microscopy and fluorescence GPF-mRFP-LC3 reporter system were combined to monitor autophagy flux. Furtherly, we utilized Compound C, a specific AMPK inhibitor, to validate whether the autophagy was mediated by AMPK-TSC2-mTOR pathway. Danqi pill significantly improved cardiac function and myocardial injury in HF rats. Intriguingly, Danqi pill potently regulated autophagy mainly by promoting the formation of autophagosomes in vivo. Further results demonstrated that expressions of p-AMPK (P < 0.001) and p-TSC2 (P < 0.001) in cardiac tissue were upregulated by Danqi pill, accompanied with downregulation of p-mTOR (P < 0.01) and p-ULK1(P < 0.01). In parallel with the vivo experiment, in vitro study indicated that Danqi pill dramatically restored autophagy flux and regulated expressions of critical autophagy-related molecules. Finally, utilization of Compound C abrogated the effects of Danqi pill on autophagy flux and the expressions of p-TSC2 (P < 0.05), p-mTOR (P < 0.01) and p-ULK1 (P < 0.05). Danqi pill could improve cardiac function and protect against cardiomyocytes injury by restoring autophagy via regulating the AMPK-TSC2-mTOR signaling pathway. Image 1 [ABSTRACT FROM AUTHOR]