ATXN3 promotes proliferation, stemness and motility of clear cell renal cell carcinoma cells by regulating S100A8 ubiquitination.

Background: Clear cell renal cell carcinoma (ccRCC) is a dominant subtype of kidney cancer with a dismal outcome at advanced stages. Ataxin 3 (ATXN3) has been proven to play a cancer-promoting role in several tumors and is upregulated in the patients with renal cell carcinoma. Thus, the objective of this research is to examine the biological roles and underlying mechanisms of ATXN3 in ccRCC. Methods: Bioinformatics analysis was carried out to analyze ATXN3 expression in ccRCC tissues and patient survival. Gain- and loss-of-function assays were applied to explore the effect of ATXN3 on ccRCC cell malignant behavior in vitro. The effect of ATXN3 on the NF-κB pathway was assessed by Western blot and immunofluorescence staining. The binding between ATXN3 and S100A8 and the effect of ATXN3 on S100A8 ubiquitination were verified using coimmunoprecipitation. Results: ATXN3 was upregulated in ccRCC tissues and correlated with adverse patient outcome. ATXN3 overexpression facilitated the proliferation, stemness, invasion and migratory capacity of ccRCC cells, whereas silencing had the opposite effect. ATXN3 enhanced the activity of the NF-κB pathway. Silencing ATXN3 facilitated S100A8 ubiquitination. Rescue experiments demonstrated that S100A8 downregulation reversed the promoting effect of ATXN3 on malignant behavior and NF-κB pathway activation in ccRCC cells. Conclusion: ATXN3 exerts a cancer-promoting effect in ccRCC by regulating S100A8 ubiquitination. Therefore, targeting the ATXN3/S100A8/NF-κB axis may provide a novel underlying therapeutic strategy for ccRCC.

S100 Calcium-Binding Protein A8 Functions as a Tumor-Promoting Factor in Renal Cell Carcinoma via Activating NF-κB Signaling Pathway.

BACKGROUND: Renal cell carcinoma (RCC), arising from the renal tubular epithelium, is one of the most common types of genitourinary malignancies. Based on the Gene Expression Omnibus (GEO) database (GSE100666), S100 calcium-binding protein A8 (S100A8) was highly expressed in RCC tissues. S100A8, an inflammatory regulatory factor, has emerged as an important mediator associated with the occurrence and development of cancer. MATERIALS AND METHODS: The Gene Expression Omnibus (GEO) database was used to identify the key genes and investigate the main signaling pathways in RCC. Human RCC samples and corresponding adjacent normal tissues were collected in our hospital. The expression of S100A8 in human RCC samples was detected using western blotting and immunohistochemical analysis. S100A8 overexpression or knockdown was mediated by using Lipofectamine 3000 in human renal cell carcinoma cell line 786-O and ACHN cells. Basic experiments, including MTT and cell apoptosis assays, were utilized for investigating the function of S100A8 in RCC. Furthermore, the levels of inflammation were also evaluated in 786-O and ACHN cells. RESULTS: In the current study, we found that downregulation of S100A8 inhibited proliferation and promoted apoptosis in 786-O and ACHN RCC cells. Of note, S100A8 silencing downregulated the phosphorylation of NF-κB p65, thereby decreasing the levels of TNF-α, cleaved caspase1, and MMP9. By contrast, S100A8 upregulation could increase these expressions. CONCLUSION: Overall, S100A8 knockdown restrained RCC malignant biological properties, which was associated with the deactivation of the NF-κB signaling pathway. This present study demonstrates new insights that S100A8 may be a potential therapeutic target in RCC.

An improved group teaching optimization algorithm for global function optimization.

This paper proposes an improved group teaching optimization algorithm (IGTOA) to improve the convergence speed and accuracy of the group teaching optimization algorithm. It assigns teachers independently for each individual, replacing the original way of sharing the same teacher, increasing the evolutionary direction and expanding the diversity of the population; it dynamically divides the students of the good group and the students of the average group to meet the different needs of convergence speed and population diversity in different evolutionary stages; in the student learning stage, the weak self-learning part is canceled, the mutual learning part is increased, and the population diversity is supplemented; for the average group students, a new sub-space search mode is proposed, and the teacher's teaching method is improved to reduce the diversity in the population evolution process. and propose a population reconstruction mechanism to expand the search range of the current population and ensure population diversity. Finally, the experimental results on the CEC2013 test suite show that IGTOA has clear advantages in convergence speed and accuracy over the other five excellent algorithms.

Atractylenolide III Improves Mitochondrial Function and Protects Against Ulcerative Colitis by Activating AMPK/SIRT1/PGC-1α.

Ulcerative colitis (UC) is a complex inflammatory bowel disease (IBD) associated with mitochondrial function. Atractylenolide III (AT III) is a natural product with anti-inflammatory effects. The aim of this work is to investigate the protective effect of AT III on UC and its underlying mechanisms. Herein, dextran sulfate sodium- (DSS-) induced mice and lipopolysaccharide- (LPS-) stimulated intestinal epithelial cells (IEC-6) were employed to mimic UC pathologies in vivo and in vitro. The results showed that in DSS-induced mice, AT III significantly reversed the body weight loss, colon length reduction, disease activity index (DAI) increase, and histological damage. The production of proinflammatory factors and reduction of antioxidants in colitis were suppressed by AT III. In addition, we demonstrated that AT III attenuated the intestinal epithelial barrier destruction and mitochondrial dysfunction induced by DSS, which was similar to the in vitro results in LPS-treated IEC-6 cells. The protein levels of p-AMPK, SIRT1, and PGC-1α along with acetylated PGC-1α were also upregulated by AT III in vivo and in vitro. In conclusion, these findings support that AT III may protect against mitochondrial dysfunction by the activation of the AMPK/SIRT1/PGC-1α signaling pathway during UC development.

Trojan-Like Peptide Drug Conjugate Design and Construction for Application in Treatment of Triple-Negative Breast Cancer.

Clinical treatment of triple negative breast cancer (TNBC) is very poor for lack of effective treatment combination selection. Protein C receptor (PROCR) is a novel cancer stem marker in TNBC patients tumor tissues. Developed based on peptide BP10 with affinity to PROCR as a targeting element, constructing a peptide drug conjugate of BP10 covalently coupling doxorubicin with disulfide bonds. This study demonstrated that the constructed BP10-DOX can selectively target Triplenegative breast cancer cells expressing PROCR and controlled release of DOX in response to the GSH environment. Moreover, BP10-DOX improves the therapeutic efficiency on MDA-MB-231 cells in vitro. Further evidence obtained from in vivo xenograft experiments revealed that administration of BP10-DOX enhanced the antitumor efficacy. This study developed a promising chemotherapy strategy for TNBC.

Shenlijia Attenuates Doxorubicin-Induced Chronic Heart Failure by Inhibiting Cardiac Fibrosis.

Application of the anticancer drug doxorubicin (DOX) is restricted due to its adverse, cardiotoxic side effects, which ultimately result in heart failure. Moreover, there are a limited number of chemical agents for the clinical prevention of DOX-induced cardiotoxicity. Based on the theories of traditional Chinese medicine (TCM) on chronic heart failure (CHF), Shenlijia (SLJ), a new TCM compound, has been developed to fulfill multiple functions, including improving cardiac function and inhibiting cardiac fibrosis. In the present study, the protective effects and molecular mechanisms of SLJ on DOX-induced CHF rats were investigated. The CHF rat model was induced by intraperitoneal injection of DOX for six weeks with the cumulative dose of 15 mg/kg. All rats were then randomly divided into the control, CHF, CHF + SLJ (3.0 g/kg per day), and CHF + captopril (3.8 mg/kg per day) groups and treated for further four weeks. Echocardiography and the assessment of hemodynamic parameters were performed to evaluate heart function. A protein chip was applied to identify proteins with diagnostic values that were differentially expressed following SLJ treatment. The data from these investigations showed that SLJ treatment significantly improved cardiac function by increasing the left ventricular ejection fraction, improving the hemodynamic index, and inhibiting interstitial fibrosis. Protein chip analysis revealed that SLJ upregulated MCP-1, MDC, neuropilin-2, TGF-ß3, thrombospondin, TIE-2, EG-VEGF/PK1, and TIMP-1/2/3 expressions and downregulated that of MMP-13. In addition, immunohistochemistry and western blot results further confirmed that SLJ promoted TIMP-1/2/3 and inhibited MMP-13 expression. The results of the present study suggest that SLJ was effective against DOX-induced CHF rats and is related to the improvement of heart function and ultrastructure and the inhibition of myocardial fibrosis.

Zisheng Shenqi Decoction Ameliorates Monosodium Urate-Mediated Gouty Arthritis in Rats via Promotion of Autophagy through the AMPK/mTOR Signaling Pathway.

Gouty arthritis (GA) is an inflammatory disease owing to the accumulation of monosodium urate (MSU) in joints, leading to redness and burning pain. In this study, the effect of Zisheng Shenqi Decoction (ZSD) on a rat model of MSU-induced GA was investigated. ZSD obviously diminished the right paw thickness, the degree of the swelling of the paw, and the infiltration of the inflammatory cell, as well as cartilage erosion, and widened the joint space in MSU-treated rats. Besides, MSU remarkably elevated the release of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and IL-18; however, ZSD treatment dose dependently lowered these levels and resulted in a significant decrease in articular elastase activity. Also, ZSD administration increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) but declined malondialdehyde (MDA) and nitrogen monoxide (NO) contents. Importantly, western blotting analysis revealed that NOD-like receptor protein 3 (NLRP3), cleaved caspase-1, IL-1ß, nuclear factor-E2-related factor 2 (Nrf2) in the cytoplasm, phosphorylated mammalian target of rapamyclin (p-mTOR), and p62 expressions were downregulated, whereas the levels of nuclear Nrf2, phosphorylated AMP-activated protein kinase (p-AMPK), Beclin-1, and LC3II/I were upregulated by ZSD. Immunofluorescence assay indicated that ZSD evidently promoted nuclear translocation of LC3. Taken together, ZSD inhibited inflammation and oxidative stress and facilitated autophagy through the activation of the AMPK pathway and suppression of the mTOR signaling pathway, demonstrating its potential for preventing and curing GA.

Exploration of the mechanism of Zisheng Shenqi decoction against gout arthritis using network pharmacology.

BACKGROUND: In this study, the network pharmacological methods were used to predict the target of effective components of compounds in Zisheng Shenqi Decoction (ZSD, or Nourishing Kidney Qi Decoction) in the treatment of gouty arthritis (GA). METHOD: The main effective components and corresponding key targets of herbs in the ZSD were discerned through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis (TCMSP), Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine (BATMAN-TCM) database. UniProt database and Swiss Target Prediction (STP) database was used to rectify and unify the target names and supply the target information. The targets related to GA were obtained by using GeneCards database. After we discovered the potential common targets between ZSD and GA, the interaction network diagram of "ZSD-component-GA-target" was constructed by Cytoscape software (Version 3.7.1). Subsequently, the Protein-protein interaction (PPI) network of ZSD effective components-targets and GA-related targets was constructed by Search Tool for the Retrieval of Interacting Genes Database (STRING). Bioconductor package "org.Hs.eg.db" and "cluster profiler" package were installed in R software (Version 3.6.0) which used for Gene Ontology analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis. RESULTS: 146 components and 613 targets of 11 herbal medicines in the ZSD were got from TCMSP database and BATMAN-TCM database. 987 targets of GA were obtained from GeneCards database. After intersected and removed duplications, 132 common targets between ZSD and GA were screened out by Cytoscape software (Version 3.7.1). These common targets derived from 81 effective components of 146 components, such as quercetin, stigmasterol and kaempferol. They were closely related to anti-inflammatory, analgesic and anti oxidative stress and the principal targets comprised of Purinergic receptor P2X, ligand-gated ion channel 7 (P2x7R), Nod-like receptor protein 3 (NLRP3) and IL-1ß. GO enrichment analysis and KEGG pathway enrichment analysis by R software (Version 3.6.0) showed that the key target genes had close relationship with oxidative stress, reactive oxygen species (ROS) metabolic process and leukocyte migration in aspects of biological process, cell components and molecular function. It also indicated that ZSD could decrease inflammatory reaction, alleviate ROS accumulation and attenuate pain by regulating P2 × 7R and NOD like receptor signaling pathway of inflammatory reaction. CONCLUSION: A total of 81 effective components and 132 common target genes between ZSD and GA were screened by network pharmacology. The PPI network, GO enrichment analysis and KEGG pathway enrichment analysis suggested that ZSD can exerte anti-inflammatory and analgesic effects on the treatment of GA by reducing decreasing inflammatory reaction, alleviating ROS accumulation, and attenuating pain. The possible molecular mechanism of it mainly involved multiple components, multiple targets and multiple signaling pathways, which provided a comprehensive understanding for further study. In general, the network pharmacological method applied in this study provides an alternative strategy for the mechanism of ZSD in the treatment of GA.

Preventive effect of dioscin against monosodium urate-mediated gouty arthritis through inhibiting inflammasome NLRP3 and TLR4/NF-κB signaling pathway activation: an in vivo and in vitro study.

Monosodium urate (MSU)-mediated inflammation is closely related to gouty arthritis (GA). Dioscin, an active ingredient, has been reported to possess anti-inflammatory property. Nevertheless, the role of dioscin in GA and the underlying mechanism have not been fully understood. In the present study, we investigated the anti-inflammatory effect of dioscin on MSU-induced GA through in vivo and in vitro experiments. Histopathological analysis showed that dioscin alleviated the severity of GA concomitant with the lowered uric acid and creatinine levels. Moreover, the increasing IL-1ß, IL-6, and TNF-α levels induced by MSU were decreased via administration of dioscin in mice and human synoviocytes. Western blotting results suggested that dioscin inhibited the activation of NLRP3 through down-regulating the protein expressions of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved-caspase-1, as well as IL-1ß. In addition, TLR4, myeloid differentiation primary response gene 88 (MyD88), p-IKKß, p-p65, and NF-κB p65 in nuclei levels were significantly reduced by dioscin. Importantly, dioscin remarkably lowered the NF-κB p65-DNA activity in MSU-treated mice utilizing electrophoretic mobility shift assay (EMSA) analysis. Taken together, dioscin had a protective effect against MSU-initiated inflammatory response via repressing the production of inflammatory cytokines and the activation of inflammasome NLRP3 and TLR4/NF-κB signaling pathway. The above findings revealed that dioscin could be a potential drug for the treatment of GA.

Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats.

Context: Therapeutic doxorubicin administration is restricted as this anticancer drug may be cardiotoxic. The traditional Chinese medicine qiliqiangxin has been approved for clinical treatment of chronic heart failure.Objective: To explore the protective effects and molecular mechanisms of qiliqiangxin on doxorubicin-induced congestive heart failure (CHF) in rats.Materials and methods: A CHF rat model was established via intraperitoneal DOX injections (2.5 mg/kg/week) for 6 weeks. The rats were randomly assigned to control, CHF, CHF + QL (1.0 g/kg/d), or captopril (3.8 mg/kg/d) treatment groups (n = 10) for 4 weeks. MicroRNA sequencing elucidated the molecular mechanisms of qiliqiangxin on doxorubicin-induced CHF in rats.Results: Unlike in the CHF group, QL significantly reduced Bax:Bcl-2 (2.05 ± 0.23 vs. 0.94 ± 0.09, p < 0.05) and the levels of collagen I (0.19 ± 0.02 vs. 0.15 ± 0.01, p < 0.05), collagen III (0.19 ± 0.02 vs. 0.14 ± 0.02, p < 0.05), TGF-ß1 (5.28 ± 0.89 vs. 2.47 ± 0.51, p < 0.05), Smad3 (1.23 ± 0.12 vs. 0.78 ± 0.09, p < 0.05), MMP-2 (0.89 ± 0.01 vs. 0.53 ± 0.05, p < 0.05), and TIMP-2 (0.24 ± 0.03 vs. 0.44 ± 0.03, p < 0.05). QL also upregulated TGF-ß3 (0.65 ± 0.06 vs. 0.96 ± 0.10, p < 0.05) and Smad7 (0.09 ± 0.01 vs. 0.19 ± 0.023, p < 0.05). Moreover, Smad3 was a target of miR-345-3p.Discussion and Conclusions: The beneficial effects of QL on DOX-induced CHF in rats are mediated by reduction in myocardial fibrosis, promotion of TGF-ß3/Smad7, and inhibition of TGF-ß1/Smad3. QL may also modulate specific miRNAs. These results provide evidence that QL might be an effective treatment for DOX-induced CHF.

Zisheng Shenqi decoction ameliorates monosodium urate crystal-induced gouty arthritis in rats through anti-inflammatory and anti-oxidative effects.

Based on traditional Chinese medicinal theories on gouty arthritis, Zisheng Shenqi decoction (ZSD), a novel Chinese medicinal formula, was developed due to its multiple functions, including reinforcing renal function, promoting blood circulation and relieving pain. In the present study, the effect of ZSD on monosodium urate (MSU) crystal-induced gouty arthritis in rats was investigated and the underlying mechanisms were examined. The data from these investigations showed that the injection of MSU crystals into the ankle joint cavity caused significant elevations in ankle swelling and inflammatory cell infiltration into the synovium, whereas these abnormal changes were markedly suppressed by oral administration of ZSD (40 mg/kg) for 7 days. Mechanically, ZSD treatment prevented MSU crystal­induced inflammatory responses, as evidenced by downregulation in the expression levels of NACHT domain, leucine­rich repeat and pyrin domain containing protein (NALP) 1 and NALP6 inflammasomes, decreased serum levels of tumor necrosis factor­α and interleukin­1ß, and inhibited activation of nuclear factor­κB. In addition, ZSD administration markedly enhanced the anti-oxidant status in MSU crystal­induced rats by the increase in the activities of superoxide dismutase and glutathione peroxidase, and the levels of reduced glutathione. These results indicated that ZSD effectively prevented MSU crystal-induced gouty arthritis via modulating multiple anti­oxidative and anti­inflammatory pathways, suggesting a promising herbal formula for the prevention and treatment of gouty arthritis.

Pd/activated carbon sorbents for mid-temperature capture of mercury from coal-derived fuel gas.

Higher concentrations of Hg can be emitted from coal pyrolysis or gasification than from coal combustion, especially elemental Hg. Highly efficient Hg removal technology from coal-derived fuel gas is thus of great importance. Based on the very excellent Hg removal ability of Pd and the high adsorption abilities of activated carbon (AC) for H2S and Hg, a series of Pd/AC sorbents was prepared by using pore volume impregnation, and their performance in capturing Hg and H2S from coal-derived fuel gas was investigated using a laboratory-scale fixed-bed reactor. The effects of loading amount, reaction temperature and reaction atmosphere on Hg removal from coal-derived fuel gas were studied. The sorbents were characterized by N2 adsorption, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The results indicated that the efficiency of Hg removal increased with the increasing of Pd loading amount, but the effective utilization rate of the active component Pd decreased significantly at the same time. High temperature had a negative influence on the Hg removal. The efficiency of Hg removal in the N2-H2S-H2-CO-Hg atmosphere (simulated coal gas) was higher than that in N2-H2S-Hg and N2-Hg atmospheres, which showed that H2 and CO, with their reducing capacity, could benefit promote the removal of Hg. The XPS results suggested that there were two different ways of capturing Hg over sorbents in N2-H2S-Hg and N2-Hg atmospheres.

Preparation, characterization and in vitro evaluation of solid dispersions containing docetaxel.

Solid dispersions using water-soluble carriers were studied for improving the dissolution of docetaxel, a poorly soluble compound. In order to obtain the most optimized formulation, we prepared many solid dispersions with different carriers, different solvents, or at a series of drug-to-carrier ratios, and compared their dissolution. The accumulative dissolution of docetaxel from poloxamer 188 was more excellent than that from PVP(k30) and glyceryl monostearate, and the dissolution of docetaxel from solid dispersion was markedly higher than that of pure docetaxel; meanwhile the increased dissolution was partly dependent on the ratios of docetaxel and poloxamer 188. The ethanol used to prepare solid dispersion is of more significant effect on the dissolution of docetaxel than that of acetone. The docetaxel/poloxamer 188 system was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and environmental scanning electron microscope (ESEM). The results of DSC, XRD, and ESEM analyses of docetaxel/poloxamer 188 system showed that there are intermolecular interactions between docetaxel and poloxamer, and the crystallinity of docetaxel disappeared. These results show that solid dispersion is a promising approach of developing docetaxel drug formulates.