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Zhang et al. design ginsenoside structural analogues and demonstrate that their combination shows more potent immunomodulatory activities than individual ginsenosides used alone at the same dosages. They predict that these analogues act on the joint target NLRP3 and consequently suggest that structural analogues hit a shared target to achieve cumulative bioactivity.

ABSTRACT Our previous study found that Qiong-Yu-Gao (QYG), a traditional Chinese medicine formula derived from Rehmanniae Radix, Poria, and Ginseng Radix, has protective effects against cisplatin-induced acute kidney injury (AKI), but the underlying mechanisms remain unknown. In the present study, the potential role of gut microbiota in the nephroprotective effects of QYG was investigated. We found that QYG treatment significantly attenuated cisplatin-induced AKI and gut dysbiosis, altered the levels of bacterial metabolites, with short-chain fatty acids (SCFAs) such as acetic acid and butyric acid increasing and uremic toxins such as indoxyl sulfate and p-cresyl sulfate reducing, and suppressed histone deacetylase expression and activity. Spearman’s correlation analysis found that QYG-enriched fecal bacterial genera Akkermansia, Faecalibaculum, Bifidobacterium, and Lachnospiraceae_NK4A136_group were correlated with the altered metabolites, and these metabolites were also correlated with the biomarkers of AKI, as well as the indicators of fibrosis and inflammation. The essential role of gut microbiota was further verified by both the diminished protective effects with antibiotics-induced gut microbiota depletion and the transferable renal protection with fecal microbiota transplantation. All these results suggested that gut microbiota mediates the nephroprotective effects of QYG against cisplatin-induced AKI, potentially via increasing the production of SCFAs, thus suppressing histone deacetylase expression and activity, and reducing the accumulation of uremic toxins, thereby alleviating fibrosis, inflammation, and apoptosis in renal tissue. IMPORTANCE Cisplatin-induced acute kidney injury is the main limiting factor restricting cisplatin’s clinical application. Accumulating evidence indicated the important role of gut microbiota in pathogenesis of acute kidney injury. In the present study, we have demonstrated that gut microbiota mediates the protective effects of traditional Chinese medicine formula Qiong-Yu-Gao against cisplatin-induced acute kidney injury. The outputs of this study would provide scientific basis for future clinical applications of QYG as prebiotics to treat cisplatin-induced acute kidney injury, and gut microbiota may be a promising therapeutic target for chemotherapy-induced nephrotoxicity.

Background: A digital text abstract presents the essential information of an article, and we can find the trend and value of the research by analyzing it rigorously and digging up knowledge. Therefore, this study focuses on the abstracts of index journals in China and Taiwan from July 2010 to June 2020 (a total of 3283 abstracts). Methods: Through the concepts of text mining and natural language processing (NLP), it constructs processes such as text retrieval, text segmentation and word cloud analysis, TF-IDF weight analysis, co-word analysis, network analysis, and trend analysis, and analyses a large amount of text data. Results: The results show that the scope of research in China covers the fields of social sports and sports science, and research in Taiwan covers both natural and social sciences. The network diagram highlights the richness of sports-related research fields in the two regions, but research on sports philosophy is relatively rare. Conclusions: It is suggested that all disciplines/departments should re-allocate the same resources, so as to show a balanced development trend and help expand a new chapter in the sports academic field.

Interleukin (IL)-20 is a proinflammatory cytokine in the IL-10 family. IL-20 is associated with tumor promotion in the pathogenesis of oral, bladder, and breast cancer. However, little is known about the role of IL-20 in prostate cancer. We hypothesize that IL-20 promotes the growth of prostate cancer cells. Immunohistochemical staining showed that IL-20 and its receptors were expressed in human PC-3 and LNCaP prostate cancer cell lines and in prostate tumor tissue from 40 patients. In vitro, IL-20 upregulated N-cadherin, STAT3, vimentin, fibronectin, RANKL, cathepsin G, and cathepsin K, and increased the migration and colony formation of prostate cancer cells via activated p38, ERK1/2, AKT, and NF-κB signals in PC-3 cells. We investigated the effects of anti-IL-20 monoclonal antibody 7E on prostate tumor growth in vivo using SCID mouse subcutaneous and intratibial xenograft tumor models. In vivo, 7E reduced tumor growth, suppressed tumor-mediated osteolysis, and protected bone mineral density after intratibial injection of prostate cancer cells. We conclude that IL-20 is involved in the cell migration, colony formation, and tumor-induced osteolysis of prostate cancer. Therefore, IL-20 might be a novel target for treating prostate cancer.

Variegated expression of killer Ig-like receptors (KIR) in human NK cells is a stochastic process exclusive to subsets of mature NK cells and CD8+ T cells. Allele-specific KIR expression is maintained by DNA methylation within the proximal promoter regions. Because KIR genes are densely methylated in NK cell progenitors, there is an implied stage of human NK cell development in which DNA demethylation takes place to allow for active transcription. When and how this process occurs is unknown. In this study, we show that KIR proximal promoters are densely methylated in less mature CD56bright NK cells and are progressively demethylated in CD56dim NK cells as they mature and acquire KIR. We hypothesized that ten-eleven translocation (TET) enzymes, which oxidize 5mC on DNA could mediate KIR promoter demethylation. The catalytic efficiency of TET enzymes is known to be enhanced by ascorbic acid. We found that the addition of ascorbic acid to ex vivo culture of sorted CD56bright NK cells increased the frequency of KIR expression in a dose-dependent manner and facilitated demethylation of proximal promoters. A marked enrichment of the transcription factor Runx3 as well as TET2 and TET3 was observed within proximal KIR promoters in CD56bright NK cells cultured with ascorbic acid. Additionally, overexpression of TET3 and Runx3 promoted KIR expression in CD56bright NK cells and NK-92 cells. Our results show that KIR promoter demethylation can be induced in CD56bright, and this process is facilitated by ascorbic acid. [ABSTRACT FROM AUTHOR]

Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001). Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2), up-regulation of Bcl-2 homologous antagonist/killer (Bak), and nuclear translocation of apoptosis-inducing factor (AIF) in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (Erk1/2), MAPK/Erk kinase (MEK), and proline-rich Akt substrate of 40-kDa (PRAS40), which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies. [ABSTRACT FROM AUTHOR]

A low-cost transistor outline-CAN (TO-CAN) package, which is combined with flexible printed circuit board (PCB) and hard PCB, has been developed for a 25-Gb/s optical subassembly module. On the flexible PCB, the transmission line structure used top ground microstrip line, and the wider transmission bandwidth can be obtained. Using ground pads and ground notch technologies, the impedance of connection between flexible PCB and hard PCB was designed to match with the impedances of signal traces of the flexible and hard PCBs. In the TO-CAN package, a TO-46 header was used, and the header needs to closely connect with the flexible PCB. The bandwidth of TO-46 package combined with flexible and hard PCBs can achieve above 23 GHz. The clear 25-Gb/s transmission eye diagram was also measured, and the rise time, fall time, and Q-factor of the eye diagram are 13.78, 13.56 ps, and 8.76, respectively. The TO-46 package combined with flexible and hard PCBs has been verified to be suitable for application in 25-Gb/s optical subassembly modules. [ABSTRACT FROM AUTHOR]

Earnings management is popular in the banking industry. Earnings can be manipulated by discretionary loan loss provisions (DLLP). Analysing the trajectories of banks' DLLP (i.e. their change in DLLP over time) is an effective way to assess the performance in earnings management for the banking industry, but seems not to have been addressed in the earnings management literature. In this study, we analyse the trajectories of DLLP with the yearly data from 2007 through 2012 for four types of banks in China. The results have indicated that state-owned banks, policy banks and city commercial banks seem to manage earnings well. Cautionary notes about bank risks are provided. [ABSTRACT FROM AUTHOR]

In this paper, a smaller and cheaper novel Subminiature Modular Plug-in Mini (SMPM) connector has been used to replace a K-type connector. The SMPM connector is installed on the top of printed circuit board (PCB) and soldering with an electrode to reduce the trace of a microstrip and to maintain the high frequency performance. Three designs of the PCB electrode have been simulated and verified experimentally. The optimized impedance mismatch of the soldering point between a SMPM connector and the PCB electrode is controlled within a range of ±2-Ohm. The 3-dB bandwidth of the whole setup including two SMPM connectors and a 2.5-cm long microstrip is above 25-GHz. This optimization can be used in designing high-speed PCB for the application of 100GBASE Ethernet. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 1133–1149. The bioactivity of endothelin-1 (ET-1) has been suggested in the development of CNS diseases, including disturbance of water homeostasis and blood-brain barrier integrity. Recent studies suggest that hypoxic/ischemic injury of the brain induces release of ET-1, behaving through a G-protein coupled ET receptor family. The deleterious effects of ET-1 on astrocytes may aggravate brain inflammation. Increased plasma levels of matrix metalloproteinases (MMPs), in particular MMP-9, have been observed in patients with neuroinflammatory disorders. However, the detailed mechanisms underlying ET-1-induced MMP-9 expression remain unknown. In this study, the data obtained with zymographic, western blotting, real-time PCR, and immunofluorescent staining analyses showed that ET-1-induced MMP-9 expression was mediated through an ETB-dependent transcriptional activation. Engagement of Gi/o- and Gq-coupled ETB receptor by ET-1 led to activation of p42/p44 MAPK and then activated transcription factors including Ets-like kinase, nuclear factor-kappa B, and activator protein-1 (c- Jun/c- Fos). These activated transcription factors translocated into nucleus and bound to their corresponding binding sites in MMP-9 promoter, thereby turning on MMP-9 gene transcription. Eventually, up-regulation of MMP-9 by ET-1 enhanced the migration of astrocytes. Taken together, these results suggested that in astrocytes, activation of Ets-like kinase, nuclear factor-kappa B, and activator protein-1 by ETB-dependent p42/p44 MAPK signaling is necessary for ET-1-induced MMP-9 gene up-regulation. Understanding the mechanisms of MMP-9 expression and functional changes regulated by ET-1/ETB system on astrocytes may provide rational therapeutic interventions for brain injury associated with increased MMP-9 expression. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4)-mediated signaling pathways have caught the attention of strategies designed for rheumatoid arthritis (RA). In this study, we identified that cPLA2α acted as a modulator of LPS-induced VCAM-1 expression and THP-1 (human acute monocytic leukemia cell line) adherence. Treatment of RA synovial fibroblasts (RASFs) with LPS, a TLR4 agonist, promoted the VCAM-1 expression and THP-1 adherence which were decreased by pretreatment with a selective cytosolic phospholipase A2 (cPLA2) inhibitor (AACOCF3), implying the involvement of cPLA2α in these responses. This notion was further confirmed by knockdown of cPLA2α expression by transfection with cPLA2α small interfering RNA (siRNA) leading to a decrease in VCAM-1 expression and THP-1 adherence induced by LPS. Subsequently, the LPS-stimulated cPLA2α phosphorylation was attenuated by pretreatment with a MEK1/2 inhibitor (U0126), suggesting that LPS-stimulated cPLA2α phosphorylation and activity are mediated through an ERK-dependent mechanism. Moreover, COX-2-derived PGE2 production appeared to involve in LPS-induced VCAM-1 expression which was attenuated by pretreatment with selective COX-2 inhibitors (NS-398 and celecoxib), transfection with COX-2 siRNA, or PGE2 receptor antagonists. In addition, pretreatment with ecosapentaenoic acid (EPA), a substrate competitor of arachidonic acid (AA), also blocked LPS-induced VCAM-1 mRNA and protein expression, and THP-1 adherence. Collectively, these results suggest that LPS-induced VCAM-1 expression and adhesion of THP-1 cells are mediated through the TLR4/ERK/cPLA2α phosphorylation and COX-2 expression/PGE2 synthesis in RASFs. J. Cell. Physiol. 223: 480–491, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Bacterial infections have been shown to be involved in several inflammatory diseases such as brain inflammation. A major factor for these findings is due to the secretion of pro-inflammatory mediators by host cells triggered by the components released from the bacteria. Among these components, lipoteichoic acid (LTA), a component of Gram-positive bacterial cell wall, has been found to be elevated in cerebrospinal fluid of patients suffering from meningitis. Moreover, increased plasma levels of matrix metalloproteinases (MMPs), in particular MMP-9, have been observed in patients with brain inflammatory diseases and may contribute to disease pathology. However, the molecular mechanisms underlying LTA-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells) remain poorly defined. Here, the data with zymographic, Western blotting, RT-PCR, and immunofluorescent staining analyses showed that LTA induced MMP-9 expression and activation via a TLR2-activated c-Src-dependent transactivation of PDGFR pathway. Transactivation of PDGFR led to activation of PI3K/Akt and p42/p44 MAPK and then activated the IKK/NF-κB cascade. The activated-NF-κB translocated into nucleus which bound to κB-binding site of MMP-9 promoter, and thereby turned on transcription of MMP-9. Eventually, upregulation of MMP-9 by LTA enhanced cell migration of astrocytes. Taken together, these results suggested that in RBA-1 cells, activation of NF-κB by a c-Src-dependent PI3K/Akt-p42/p44 MAPK activation mediated through transactivation of PDGFR is essential for MMP-9 gene upregulation induced by LTA. Understanding the regulation of MMP-9 expression and functional changes by LTA/TLR system on astrocytes may provide potential therapeutic targets of Gram-positive bacterial infection in brain disorders. [ABSTRACT FROM AUTHOR]

After ischemic injury to brain, disruption of the blood–brain barrier (BBB) raises the possibility of exposing the central nervous system (CNS) to oxidized low-density lipoprotein (oxLDL), a risk factor implicated in neurodegenerative diseases. Matrix metalloproteinases (MMPs), especially MMP-9, contribute to extracellular matrix (ECM) remodeling during the CNS diseases. However, the molecular mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes remained unclear. Here, we reported that oxLDL induced MMP-9 expression via a PKC-δ/p42/p44 MAPK-dependent Elk-1 activation in rat brain astrocyte (RBA)-1 cells, revealed by gelatin zymography, RT-PCR, and Western blotting analyses. These responses were attenuated by pretreatment with pharmacological inhibitors and transfection with dominant negative mutants. Moreover, Elk-1-mediated MMP-9 gene transcription was confirmed by transfection with an Elk-1 binding site -mutated MMP-9 promoter construct (mt-Ets-MMP9), which blocked oxLDL-stimulated MMP-9 luciferase activity. Understanding the regulatory mechanisms by which oxLDL induced MMP-9 expression in astrocytes might provide a new therapeutic strategy of brain diseases. [ABSTRACT FROM AUTHOR]

In a previous study, interleukin-1β (IL-1β) has been shown to induce matrix metalloproteinases (MMPs) expression through mitogen-activated protein kinases and nuclear factor-κB pathways in rat brain astrocytes. Moreover, transactivation of growth factor receptors and phosphatidylinositol 3-kinase (PI3K)/Akt cascade has been mentioned in the expression of several inflammatory genes. Here, we first report that IL-1β-induced up-regulation of proMMP-9 was inhibited by genistein. IL-1β also stimulated phosphorylation of several protein tyrosine kinases such as c-Src and platelet-derived growth factor receptor (PDGFR), which was further confirmed by western blotting using an anti-phospho-c-Src or anti-phospho-PDGFR antibody, respectively. IL-1β-stimulated c-Src, PDGFR, and Akt phosphorylation and proMMP-9 expression were attenuated by the inhibitors of c-Src (PP1), PDGFR (AG1296), and PI3K (LY294002), respectively, or transfection with dominant negative plasmid of c-Src or short hairpin RNAs of PDGFR and Akt. Moreover, IL-1β-induced proMMP-9 expression was blocked by pre-treatment with curcumin (a p300 inhibitor). We further confirmed that IL-1β stimulated p300 recruitment to MMP-9 promoter, and then acetylated histone H4 by immunoprecipitation and chromatin immunoprecipitation–PCR assays. The recruitment and activation of p300 in MMP-9 promoter were inhibited by pre-treatment with PP1, AG1296, and LY294002, respectively. Moreover, IL-1β stimulated the c-Src-dependent transactivation of PDGFR/PI3K/Akt cascade is independent of nuclear factor-κB pathway. These results indicated that in rat brain astrocytes cells, PI3K/Akt activation was mediated through c-Src-dependent transactivation of PDGFR promoted transcriptional co-factor p300 recruitment and activation and eventually led to increased proMMP-9 expression by IL-1β. [ABSTRACT FROM AUTHOR]

Bradykinin (BK), an inflammatory mediator, has been shown to induce cytosolic phospholipase A2 (cPLA2) expression implicating in inflammatory responses in various cell types. However, the detailed mechanisms underlying BK-induced cPLA2 expression in astrocytes remain unclear. RT-PCR and Western blotting analysis showed that BK induced the expression of cPLA2 mRNA and protein, which was inhibited by Hoe140, suggesting the involvement of B2 BK receptors, confirmed by immunofluorescence staining using anti-B2 BK receptor antibody. BK-induced cPLA2 expression and phosphorylation of p42/p44 MAPK was attenuated by PD98059, indicating the involvement of MEK1/2-p42/p44 MAPK in these responses. BK-induced cPLA2 expression might be due to the translocation of NF-κB into nucleus which was inhibited by Hoe140, helenalin, and PD98059, implying the involvement of NF-κB. Moreover, BK-induced cPLA2 expression was attenuated by rottlerin, suggesting that PKC-δ might be involved in these responses. This hypothesis was supported by the transfection with a dominant negative plasmid of PKC-δ significantly attenuated BK-induced response. In addition, BK-stimulated translocation of PKC-δ from cytosol to membrane fraction was inhibited by rottlerin but not by PD98059, indicating that PKC-δ might be an upstream component of p42/p44 MAPK. Accordingly, BK-induced phosphorylation of p42/p44 MAPK was attenuated by rottlerin but not by helenalin. These results suggest that in RBA-1 cells, BK-induced cPLA2 expression was sequentially mediated through activation of PKC-δ, p42/p44 MAPK, and NF-κB. Understanding the regulation of cPLA2 expression induced by BK in astrocytes might provide a new therapeutic strategy of brain injury and inflammatory diseases. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase (MMR)-9 expression induced by interleukin-1β (IL-1β) was investigated in rat brain astrocyte-1(RBA-1). Here we report that the mitogen-activated protein kinases (MARKs) and nuclear factor-kappa B (NF-κB) pathways participate in the induction of MMR-9 expression by IL-1β Zymographic, western blotting, and RT-PCR analyses showed that IL-1β increased expression of MMF-9 mRNA and protein, which were inhibited by inhibitors of MEK½ (U0126), p38 (SB202190), and JNK (SF600125). In accordance with these findings, IL-1β stimulated phosphorylation of p42/p44 MARK, p38, and c-Jun N-terminal kinase (JNK), which was attenuated by U0126, SB202190, or SF600125, respectively. Furthermore, this up-regulation of MMR-9 mRNA and protein was blocked by a specific NF-κB inhibitor helenalin. Consistently, IL-1β-stimulated translocation of N F-κB into the nucleus and degradation of inhibitory kappa B-α (IκB-α) was revealed by western blotting and immunofluorescence staining, which was blocked by helenalin, but not by U0126, SB202190, or SF600125. Taken together, these results suggest that in RBA-1 cells, activation of p42/p44 MARK, p38, JNK and NF-κB pathways is essential for IL-1β-induced MMR-9 gene expression via transcription and translation processes. An increased understanding of the signal transduction pathways involved in IL-1β-induced MMR-9 expression on RBA-1 may be of potential therapeutic value in the treatment of inflammatory disease. [ABSTRACT FROM AUTHOR]

Low back pain due to lumbar disc herniation (LDH) is very common in clinic. This randomized controlled trial was designed to investigate the effects of integrative TCM conservative therapy for low back pain due to LDH. A total of 408 patients with low back pain due to LDH were randomly assigned to an experimental group with integrative TCM therapy and a control group with normal conservative treatment by the ratio of 3 : 1. The primary outcome was the pain by the visual analogue scale (VAS). The secondary outcome was the low back functional activities by Chinese Short Form Oswestry Disability Index (C-SFODI). Immediately after treatment, patients in the experimental group experienced significant improvements in VAS and C-SFODI compared with the control group (between-group difference in mean change from baseline, -16.62 points, P < 0.001 in VAS; -15.55 points, P < 0.001 in C-SFODI). The difference remained at one-month followup, but it is only significant in C-SFODI at six-month followup (-7.68 points, P < 0.001). No serious adverse events were observed. These findings suggest that integrative TCM therapy may be a beneficial complementary and alternative therapy for patients with low back pain due to LDH.

Non-specific low back pain (NLBP) is an increasing health problem for athletes. This randomized controlled trial was designed to investigate the effects of Chinese massage combined with herbal ointment for NLBP. 110 athletes with NLBP were randomly assigned to experimental group with Chinese massage combined with herbal ointment or control group with simple massage therapy. The primary outcome was pain by Chinese Short Form McGill Pain Questionnaire (C-SFMPQ). The secondary outcome was local muscle stiffness by Myotonometer. After 4 weeks, the experimental group experienced significant improvements in C-SFMPQ and in local muscle stiffness compared with control group (between-group difference in mean change from baseline, -1.24 points, P = 0.005 in sensory scores; -3.14 points, P < 0.001 in affective scores; -4.39 points, P < 0.001 in total scores; -0.64 points, P = 0.002 in VAS; -1.04 points, P = 0.005 in local muscle stiffness during relaxation state). The difference remained at one month followup, but it was only significant in affective scores (-2.83 points, P < 0.001) at three months followup. No adverse events were observed. These findings suggest that Chinese massage combined with herbal ointment may be a beneficial complementary and alternative therapy for athletes with NLBP.