Reniformin A suppresses non-small cell lung cancer progression by inducing TLR4/NLRP3/caspase-1/GSDMD-dependent pyroptosis.

Pyroptosis is an inflammatory form of programmed cell death that plays an important role in regulating tumor progression. Reniformin A (RA) is a natural compound isolated from the medicinal herb Isodon excisoides that has been applied as folk medicine in the treatment of esophageal cancer. However, whether RA has an individual function in cancer and the molecular mechanisms remain unclear. Here, we show that in non-small-cell lung cancer (NSCLC), RA inhibits tumor growth by functioning as a pyroptosis inducer to promote TLR4/NLRP3/caspase-1/GSDMD axis. Specially, RA treatment increased Toll-like receptor 4 (TLR4) protein expression level by enhancing the TLR4 stability. Based on the molecular docking, we identified that RA directly bound to TLR4 to activate the NLRP3 inflammasome and promote pyroptosis in A549 cells. Moreover, TLR4 is essential for RA-induced pyroptosis, and loss of TLR4 abolished RA-induced pyroptosis and further reduced the inhibitory effect of RA on NSCLC. In vivo experiments confirmed that RA inhibited the growth of lung tumors in mice by affecting pyroptosis in a dose-dependent manner. Furthermore, TLR4 knockdown abolished RA-induced pyroptosis and inhibited the effect of RA chemotherapy in vivo. In conclusion, we propose that RA has a significant anticancer effect in NSCLC by inducing TLR4/NLRP3/caspase-1/GSDMD-mediated pyroptosis, which may provide a potential strategy for the treatment of NSCLC.

Decreased acetylation of HDGF improves oviduct production in Rana dybowskii, Rana amurensis, and Rana huanrenensis.

The oviduct of female Rana dybowskii is a functional food and can be used as a component of Traditional Chinese medicine. The differentially expressed genes enriched was screened in cell growth of three Rana species. We quantitatively analyzed 4549 proteins using proteomic techniques, enriching the differentially expressed proteins of Rana for growth and signal transduction. The results showed that log2 expression of hepatoma-derived growth factor (HDGF) was increased. We further verified 5 specific differential genes (EIF4a, EIF4g, HDGF1, HDGF2 and SF1) and found that HDGF expression was increased in Rana dybowskii. Through acetylation modification analysis, we identified 1534 acetylation modification sites in 603 proteins, including HDGF, and found that HDGF acetylation expression was significantly reduced in Rana dybowskii. Our results suggest that HDGF is involved in the development of oviductus ranae, which is regulated by acetylation modification.

QTL mapping and candidate gene analysis for yield and grain weight/size in Tartary buckwheat.

BACKGROUND: Grain weight/size influences not only grain yield (GY) but also nutritional and appearance quality and consumer preference in Tartary buckwheat. The identification of quantitative trait loci (QTLs)/genes for grain weight/size is an important objective of Tartary buckwheat genetic research and breeding programs. RESULTS: Herein, we mapped the QTLs for GY, 1000-grain weight (TGW), grain length (GL), grain width (GW) and grain length-width ratio (L/W) in four environments using 221 recombinant inbred lines (XJ-RILs) derived from a cross of 'Xiaomiqiao × Jinqiaomai 2'. In total, 32 QTLs, including 7 for GY, 5 for TGW, 6 for GL, 11 for GW and 3 for L/W, were detected and distributed in 24 genomic regions. Two QTL clusters, qClu-1-3 and qClu-1-5, located on chromosome Ft1, were revealed to harbour 7 stable major QTLs for GY (qGY1.2), TGW (qTGW1.2), GL (qGL1.1 and qGL1.4), GW (qGW1.7 and qGW1.10) and L/W (qL/W1.2) repeatedly detected in three and above environments. A total of 59 homologues of 27 known plant grain weight/size genes were found within the physical intervals of qClu-1-3 and qClu-1-5. Six homologues, FtBRI1, FtAGB1, FtTGW6, FtMADS1, FtMKK4 and FtANT, were identified with both non-synonymous SNP/InDel variations and significantly differential expression levels between the two parents, which may play important roles in Tatary buckwheat grain weight/size control and were chosen as core candidate genes for further investigation. CONCLUSIONS: Two stable major QTL clusters related to grain weight/size and six potential key candidate genes were identified by homology comparison, SNP/InDel variations and qRT‒qPCR analysis between the two parents. Our research provides valuable information for improving grain weight/size and yield in Tartary buckwheat breeding.

Lian-Qu formula treats metabolic syndrome via reducing fat synthesis, insulin resistance and inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic syndrome (MetS) is a pathological condition characterized by obesity, hyperglycemia, hypertension and hyperlipidemia that increases the risk of cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease. The traditional Chinese medicine Lian-Qu formula (LQF) is modified from Xiaoxianxiong decoction, which has been used for coronary heart disease or metabolic disease in clinical for a long time. However, the pharmacological mechanism of LQF on MetS is unclear. AIM OF THE STUDY: Here, we explored the actions of LQF on MetS via network pharmacology and validated the mechanism in the MetS mice. MATERIALS AND METHODS: The chemical components of LQF were searched in the traditional Chinese medicine systems pharmacology database and the natural product activity & species source database. The related targets of MetS disease were gathered from genes cluster with literature profiles database. The protein-protein interaction network was constructed to obtain the key target genes. The Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment of the key targets were performed to predict the potential mechanisms of LQF action on MetS. And then, the high-fat diet-induced MetS mice were used to validate its therapeutic effect and molecular targets. Insulin tolerance test and oral glucose tolerance test were used to assess insulin sensitivity. Body weight and visceral fat index were measured to assess obesity. Liver metabolism was detected by H&E section, oil red O staining and untargeted lipid metabolomics experiments. Finally, the key targets of LQF action on MetS were verified by PCR and ELISA kits. RESULTS: A total of 466 components in LQF were obtained, among which 71 were active. These components correspond to 74 targets associated with MetS. The predicted targets of LQF worked on MetS were AKT1, INSR, PPARs, FASN, LDLR, TNF, CRP, IL-6, IL-1ß and so on. Furthermore, these targets were related to pathways in cellular response to lipid, inflammatory response, glucose transmembrane transport and insulin resistance. Finally, the animal experiments validated that LQF inhibited lipids accumulation by inhibiting the gene expression of FASN and increasing ADPN, and it relieved insulin resistance by increasing GLUT-4 expression. Moreover, LQF alleviated inflammation by reducing IL-6 and CRP levels. CONCLUSION: LQF exerted anti-MetS effects through improving insulin sensitivity, ameliorating hyperlipidemia and obesity, reducing liver injury, and inhibiting inflammatory response.

Mapping QTLs for 1000-grain weight and genes controlling hull type using SNP marker in Tartary buckwheat (Fagopyrum tataricum).

BACKGROUND: Tartary buckwheat (Fagopyrum tataricum), an important pseudocereal crop, has high economic value due to its nutritional and medicinal properties. However, dehulling of Tartary buckwheat is difficult owing to its thick and tough hull, which has greatly limited the development of the Tartary buckwheat processing industry. The construction of high-resolution genetic maps serves as a basis for identifying quantitative trait loci (QTLs) and qualitative trait genes for agronomic traits. In this study, a recombinant inbred lines (XJ-RILs) population derived from a cross between the easily dehulled Rice-Tartary type and Tartary buckwheat type was genotyped using restriction site-associated DNA (RAD) sequencing to construct a high-density SNP genetic map. Furthermore, QTLs for 1000-grain weight (TGW) and genes controlling hull type were mapped in multiple environments. RESULTS: In total, 4151 bin markers comprising 122,185 SNPs were used to construct the genetic linkage map. The map consisted of 8 linkage groups and covered 1444.15 cM, with an average distance of 0.35 cM between adjacent bin markers. Nine QTLs for TGW were detected and distributed on four loci on chromosome 1 and 4. A major locus detected in all three trials was mapped in 38.2-39.8 cM region on chromosome 1, with an LOD score of 18.1-37.0, and explained for 23.6-47.5% of the phenotypic variation. The genes controlling hull type were mapped to chromosome 1 between marker Block330 and Block331, which was closely followed by the major locus for TGW. The expression levels of the seven candidate genes controlling hull type present in the region between Block330 and Block336 was low during grain development, and no significant difference was observed between the parental lines. Six non-synonymous coding SNPs were found between the two parents in the region. CONCLUSIONS: We constructed a high-density SNP genetic map for the first time in Tartary buckwheat. The mapped major loci controlling TGW and hull type will be valuable for gene cloning and revealing the mechanism underlying grain development and easy dehulling, and marker-assisted selection in Tartary buckwheat.

Cisplatin sensitizes human hepatocellular carcinoma cells, but not hepatocytes and mesenchymal stem cells, to TRAIL within a therapeutic window partially depending on the upregulation of DR5.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines and has been shown to induce cell apoptosis in many types of tumors, but not in normal cells. This tumor-selective property has made TRAIL a promising approach for the development of cancer therapy. However, hepatocellular carcinoma (HCC) cells display a striking resistance to TRAIL. Although some chemotherapeutic agents can overcome this resistance, safety issues remain a concern because the combination of these agents and TRAIL has been reported to induce toxicity in normal hepatocytes. In this study, we examined whether cisplatin could reverse TRAIL resistance in HCC cells with different p53 status and evaluated the toxicity of combination TRAIL and cisplatin to normal hepatocytes and mesenchymal stem cells (MSCs). We observed that cisplatin could efficiently sensitize HCC cells, but not hepatocytes and MSCs to TRAIL-induced apoptosis within a wide therapeutic window. The apoptosis of HCC cells only partially depended on the upregulation of DR5 and the status of p53. In addition, we provide favorable evidence supporting the feasibility of the combination of chemotherapy and MSCs transduced with TRAIL.

[Changes of proteomic spectra of total flavones of Hippophae rhamnoides on myocardial protection].

OBJECTIVE: To study the mechanisms of the anti-myocardial ischemia of total flavones of Hippophae rhamnoides (TFH) at the level of proteome. METHOD: Surface enhanced laser desorption/ionization (SELDI) mass spectrometry with protein chip IMAC3, SAX2 and NP20 was performed to compare the differentially expressed protein in myocardial ischemia in the TFH-treated groups with the 0.9% sodium chloride groups. Protein chips were examined in PBS II - C protein chip reader (ciphergen ciosystem inc) and the protein profiling was analyzed by Proteinchip Software 3. 0. 2. RESULT: The revealed six peaks had significant difference between the TFH-treated groups and the control groups, one of which were up-regulated in the TFH-treated groups, and the other were down-regulated. And in these six distinct proteins, there were four proteins on the IMAC3 chips and one protein on the SAX2 chips. CONCLUSION: The TFH could prevent the myocardium from ischemia via regulating expression of different proteins.

Changes of proteomic spectra of total flavones of Hippophae rhamnoides on myocardial protection / 中国中药杂志

<p><b>OBJECTIVE</b>To study the mechanisms of the anti-myocardial ischemia of total flavones of Hippophae rhamnoides (TFH) at the level of proteome.</p><p><b>METHOD</b>Surface enhanced laser desorption/ionization (SELDI) mass spectrometry with protein chip IMAC3, SAX2 and NP20 was performed to compare the differentially expressed protein in myocardial ischemia in the TFH-treated groups with the 0.9% sodium chloride groups. Protein chips were examined in PBS II - C protein chip reader (ciphergen ciosystem inc) and the protein profiling was analyzed by Proteinchip Software 3. 0. 2.</p><p><b>RESULT</b>The revealed six peaks had significant difference between the TFH-treated groups and the control groups, one of which were up-regulated in the TFH-treated groups, and the other were down-regulated. And in these six distinct proteins, there were four proteins on the IMAC3 chips and one protein on the SAX2 chips.</p><p><b>CONCLUSION</b>The TFH could prevent the myocardium from ischemia via regulating expression of different proteins.</p>

Role of interventional therapy in hepatic artery stenosis and non-anastomosis bile duct stricture after orthotopic liver transplantation.

AIM: To analyze the clinical manifestations and the effectiveness of therapy in patients with orthotopic liver transplantation (OLT)-associated hepatic artery stenosis (HAS) and non-anastomosis bile duct stricture. METHODS: Nine cases were diagnosed as HAS and non-anastomosis bile duct stricture. Percutaneous transluminal angioplasty (PTA) was performed in four HAS cases, and expectant treatment in other five HAS cases; percutaneous transhepatic bile drainage, balloon dilation, stent placement were performed in all nine cases. RESULTS: Diffuse intra- and extra-bile duct stricture was observed in nine cases, which was associated with bile mud siltation and biliary infection. Obstruction of the bile duct was improved obviously or removed. Life span/follow-up period was 13-30 mo after PTA of four HAS cases, 6-23 mo without PTA of other five cases. CONCLUSION: Progressive, non-anastomosis, and diffuse bile duct stricture are the characteristic manifestations of HAS and non-anastomosis bile duct stricture after OLT. These are often associated with bile mud siltation, biliary infection, and ultimate liver failure. Interventional therapy is significantly beneficial.

Superselective uterine arterial embolization with pingyangmycin-lipiodol emulsion for management of symptomatic uterine leiomyoma.

BACKGROUND: Uterine arterial embolization (UAE) is a safe and effective therapy for symptomatic uterine leiomyoma. This study was to assess the effectiveness and the feasibility of pingyangmycin-lipiodol emulsion (PLE) for the management of symptomatic uterine leiomyoma. METHODS: One hundred consecutive patients (aged 21 - 53 years, with 38 in average) with symptomatic uterine leiomyoma underwent superselective UAE with PLE. Clinical symptoms of the patients (including menorrhagia, bulk-related symptoms, and postprocedure-related abdominal pain) and the changes in uterine volume and tumor size after the embolization were analyzed. The patients were followed up for 8 - 21 months (mean, 15 months). RESULTS: Ninety-nine patients (99%, 99/100) were interviewed in their first menses circle after embolization, showing improvements in their abnormal bleeding and bulk-related symptoms to some extent. Imagiological results during follow-up showed a mean of 48% reduction in uterine volume at 6 months and a mean of 75% reduction in tumor size at 9 months. Eighty-three percent of the patients reported complete resolution of postprocedure pain within 7 days. CONCLUSIONS: PLE is effective in the management of uterine leiomyoma, having superiority in alleviating postprocedure-related pain.

Superselective uterine arterial embolization with pingyangmycin-lipiodol emulsion for management of symptomatic uterine leiomyoma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Uterine arterial embolization (UAE) is a safe and effective therapy for symptomatic uterine leiomyoma. This study was to assess the effectiveness and the feasibility of pingyangmycin-lipiodol emulsion (PLE) for the management of symptomatic uterine leiomyoma.</p><p><b>METHODS</b>One hundred consecutive patients (aged 21 - 53 years, with 38 in average) with symptomatic uterine leiomyoma underwent superselective UAE with PLE. Clinical symptoms of the patients (including menorrhagia, bulk-related symptoms, and postprocedure-related abdominal pain) and the changes in uterine volume and tumor size after the embolization were analyzed. The patients were followed up for 8 - 21 months (mean, 15 months).</p><p><b>RESULTS</b>Ninety-nine patients (99%, 99/100) were interviewed in their first menses circle after embolization, showing improvements in their abnormal bleeding and bulk-related symptoms to some extent. Imagiological results during follow-up showed a mean of 48% reduction in uterine volume at 6 months and a mean of 75% reduction in tumor size at 9 months. Eighty-three percent of the patients reported complete resolution of postprocedure pain within 7 days.</p><p><b>CONCLUSIONS</b>PLE is effective in the management of uterine leiomyoma, having superiority in alleviating postprocedure-related pain.</p>