Resveratrol alleviates MSU-induced gouty arthritis in rats through inhibition of HIF-1α- and NLRP3-derived IL-1ß secretion in macrophages.

Gouty arthritis is an acute and chronic joint inflammatory joint disease characterized by the deposition of monosodium urate (MSU) crystals in joints and periarticular tissues. Resveratrol (3, 5, 4-trihydroxy-trans-stilbene, RV), a natural polyphenolic compound, has anti-inflammatory and antioxidant properties. The purpose of this study was to investigate the effect of resveratrol on rats with gouty arthritis and its molecular mechanism. THP-1-derived macrophages were induced by lipopolysaccharide (LPS) and MSU to create an in vitro gout cell inflammation model, and rats were injected with MSU crystals into the right ankle joint for an in vivo acute gouty arthritis model. We investigated the anti-inflammatory properties of resveratrol using these in vitro and in vitro models. Our findings suggested that resveratrol effectively reduced ankle swelling and synovial inflammation in a dose-dependent manner in rats with acute gouty arthritis, with almost the same effect as colchicine treatment. In MSU-treated THP-1-derived macrophages, resveratrol inhibited NLRP3 inflammasome activation and IL-1ß secretion. Furthermore, resveratrol and the HIF-1α inhibitor PX478 both inhibited the expression of the NLRP3 inflammasome, IL-1ß, and HIF-1α. This study demonstrated that resveratrol significantly improved the symptoms of acute gouty arthritis and its potential mechanism may be IL-1ß reduction via HIF-1α modulation and inhibition of NLRP3 inflammasome activation. Our study might offer a novel sight for the treatment of gouty arthritis.

The prognostic signature based on glycolysis-immune related genes for acute myeloid leukemia patients.

Acute myeloid leukemia (AML) is widely considered an immunoresponsive malignancy. However, potential association between glycolysis-immune related genes and AML patients' prognosis has been seldom studied. AML-related data was downloaded from TCGA and GEO databases. We grouped patients according to Glycolysis status, Immune Score and combination analysis, basing on which overlapped differentially expressed genes (DEGs) were identified. The Risk Score model was then established. The results showed that totally 142 overlapped genes were probably correlated with glycolysis-immunity in AML patients, among which 6 optimal genes were screened to construct Risk Score. High Risk Score was an independent poor prognostic factor for AML. In conclusion, we established a relatively reliable prognostic signature of AML based on glycolysis-immunity related genes, including METTL7B, HTR7, ITGAX, TNNI2, SIX3 and PURG.

Synthesis of the Key Intermediate of SM-406 (Xevinapant) and Its Analogues.

Efficient methods for the synthesis of three dipeptide mimetics with diazabicycloalkanone amino acid scaffolds were developed. Among them, compound 3, which contains a 1,5-diazabicyclo[6,3,0]dodecanone amino acid core structure, was used as the key intermediate of a clinical staged IAP inhibitor SM-406 (Xevinapant). Compared with the reported methods for the synthesis of compound 3 and its derivatives, our method is more efficient and more suitable for large scale preparation.

FASN Targeted by miR-497-5p Regulates Cell Behaviors in Cervical Cancer.

Cervical cancer (CC) is a severe malignant tumor. Recently, more and more evidence has shown that abnormal expression of fatty acid synthase (FASN) occurs in varying tumors. Therefore, this investigation devoted to FASN in CC along with its upstream regulatory miRNA. Their expression levels were tested by qRT-PCR. Cell function experiments were undertaken to test tumor-related cell behaviors. Identification of their interplay was conducted by western blot and dual-luciferase methods. As analyzed, miR-497-5p was at low level in human CC cell lines, while FASN was overexpressed and demonstrated as a target of miR-497-5p. Cell function experiments demonstrated the targeting of miR-497-5p to FASN 3'-UTR, thus restraining CC development. To sum up, this investigation primarily revealed miR-497-5p/FASN axis in CC, by which potential CC biomarkers, could be developed. However, the mechanism of the axis was not determined in vivo, as one of the study limitations.

LncSNHG3 promotes hepatocellular carcinoma epithelial mesenchymal transition progression through the miR-152-3p/JAK1 pathway.

BACKGROUND: The dysregulation of LncRNAs is related to the malignant progression of many cancers. OBJECTIVE: The study aimed to investigate the expression and the biological role of LncSNHG3 in hepatocellular carcinoma (HCC). METHODS: The TCGA data of the LncSNHG3 in HCC were analyzed. The expression in HCC cell lines was detected by qRT-PCR. Proliferation, migration, and invasion of HepG2 and Huh7 were examined by cell counting kit-8, colony formation, transwell assays, and wound healing assays. At the same time, the interactions among LncSNHG3, miR-152-3p, and JAK1 were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation, subcellular distribution. Xenograft tumor-bearing mice models were used to measure the effect of LncSNHG3 on the growth of HCC in vivo. The apoptosis and epithelial mesenchymal transition (EMT)-associated proteins were checked by WB and IHC. RESULTS: LncSNHG3 was overexpressed in HCC tissues and cell lines. In addition, it is correlated with the tumor stage and survival time of HCC patients. Down-regulated LncSNHG3 could significantly suppress the EMT progression of HCC in vivo and in vitro. LncSNHG3 could promote the JAK1 expression by sponging miR-152-3p. CONCLUSIONS: LncSNHG3 acted as an oncogene and promoted the EMT procession in HCC by binding miR-152-3p and promoting JAK1 expression. Predictably, LncSNHG3 was used as a potential marker and will be used as a novel therapy target for HCC in the future.

Outcomes and prognostic factors for patients with cervical esophageal cancer undergoing definitive radiotherapy or chemoradiotherapy.

Cervical esophageal cancer (CEC) is uncommon, accounting for less than 5% of all esophageal cancers. The management of CEC is controversial. This study investigated treatment outcomes and prognostic factors of survival in CEC patients undergoing definitive radiotherapy or concurrent chemoradiotherapy (CCRT). Ninety-one CEC patients were treated by intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DCRT) between July 2007 and September 2017. The mean prescription dose was 64 Gy (range 54-70 Gy) delivered as 1.8-2.2 Gy per fraction per day, 5 days a week. Out of 91 patients, 34 received concurrent cisplatin-based chemotherapy (CT) including 18 patients who also received neoadjuvant CT. Overall survival (OS), locoregional failure-free survival (LRFFS), and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Prognostic factors of survival were determined in univariate (log-rank test) and multivariate (Cox proportional hazard model) analysis. Treatment-related toxicity was also assessed. Median follow-up time for all patients was 19 months. Two-year OS, LRFFS and PFS of all patients were 58.2%, 52.5% and 48.1%, respectively. Clinical stage was an independent prognostic factor for OS (HR = 2.35, 95% CI: 1.03-5.37, p = 0.042), LRFFS (HR = 3.84, 95% CI: 1.38-10.69, p = 0.011), and PFS (HR = 2.68, 95% CI: 1.11-6.45, p = 0.028). Hoarseness was an independent prognostic factor for OS (HR = 2.10, 95% CI: 1.05-4.19, p = 0.036). CCRT was independently associated with better LRFFS (HR = 0.33, 95% CI: 0.14-0.79, p = 0.012). 3DCRT and IMRT with concurrent CT is well-tolerated and may improve local tumor control in CEC patients. Advanced clinical stage and hoarseness are adverse prognostic factors for OS, LRFFS, and PFS in CEC.

Genome-Wide Characterization of Heat-Shock Protein 70s from Chenopodium quinoa and Expression Analyses of Cqhsp70s in Response to Drought Stress.

Heat-shock proteins (HSPs) are ubiquitous proteins with important roles in response to biotic and abiotic stress. The 70-kDa heat-shock genes (Hsp70s) encode a group of conserved chaperone proteins that play central roles in cellular networks of molecular chaperones and folding catalysts across all the studied organisms including bacteria, plants and animals. Several Hsp70s involved in drought tolerance have been well characterized in various plants, whereas no research on Chenopodium quinoa HSPs has been completed. Here, we analyzed the genome of C. quinoa and identified sixteen Hsp70 members in quinoa genome. Phylogenetic analysis revealed the independent origination of those Hsp70 members, with eight paralogous pairs comprising the Hsp70 family in quinoa. While the gene structure and motif analysis showed high conservation of those paralogous pairs, the synteny analysis of those paralogous pairs provided evidence for expansion coming from the polyploidy event. With several subcellular localization signals detected in CqHSP70 protein paralogous pairs, some of the paralogous proteins lost the localization information, indicating the diversity of both subcellular localizations and potential functionalities of those HSP70s. Further gene expression analyses revealed by quantitative polymerase chain reaction (qPCR) analysis illustrated the significant variations of Cqhsp70s in response to drought stress. In conclusion, the sixteen Cqhsp70s undergo lineage-specific expansions and might play important and varied roles in response to drought stress.

Reversal of Chemoresistance in Human Lung Cancer Cell Line A549/Taxol by Synthetic Second Mitochondria-Derived Activator of Caspase Peptide.

BACKGROUND: Chemoresistance is a leading cause of treatment failure in advanced lung cancer, including that with the extensively prescribed taxol. Recently, a series of structurally unique second mitochondria-derived activators of caspase (Smac) that act as antagonists of inhibitor of apoptosis proteins (IAPs) have been discovered, exhibiting the ability of inducing enhanced apoptosis of various cancer cell types when combined with chemotherapy. In the present study, we synthesized the second mitochondria-derived activator of caspase peptide (Smac-N7 for short) and explored its capacity in combination with taxol in vitro. METHODS: The sensitivity assay and reversal ability of Smac-N7 were tested by MTT. Flow cytometry was used to analyze apoptosis of cells with Annexin V/PI double staining technique. Cell cloning ability was performed to reflect its biological behavior in each group. RESULTS: Concentrations with inhibitory rates < 10% were selected as the reversal value of Smac-N7 peptide using MTT. The reversal folds were 2.52, 3.26, 3.67, and 5.4 in taxol + Smac-N7 (0.0390625, 0.078125, 0.15625, 0.3125 µg/mL, respectively), and concentrations of Smac-N7 and reversal folds appeared in an obvious positive correlation (r(s) = 1, p = 0.000). Apoptosis analyzed at 48 hours by flow cytometry showed the apoptotic rates in taxol and 0.0390625, 0.078125, 0.15625, and 0.3125 µg/mL Smac-N7 + taxol groups were 15.4 ± 1.09%, 20.8% ± 2.18%, 28.4% ± 4.17%, 37.64% ± 6.41%, and 46.6% ± 7.76%, respectively. Concentrations of Smac-N7 appeared to have negative correlations with PE and SF (r(s) = -1, p < 0.05), which showed that the cells' cloning ability in 0.3125 µg/mL Smac-N7 + taxol group was worse than that of other groups. CONCLUSIONS: When combined with taxol, 0.3125 µg/mL Smac-N7 peptide may significantly increase taxol-induced apoptosis in chemoresistant A549/taxol lung cells at 48 hours, and is potentially useful as a reversal agent in lung cancer therapy.