Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

Macrolactins from Marine-Derived Bacillus subtilis B5 Bacteria as Inhibitors of Inducible Nitric Oxide and Cytokines Expression.

In order to find new natural products with anti-inflammatory activity, chemical investigation of a 3000-meter deep-sea sediment derived bacteria Bacillus subtilis B5 was carried out. A new macrolactin derivative was isolated and identified as 7,13-epoxyl-macrolactin A (1). Owing to the existence of the epoxy ring, 1 exhibited a significant inhibitory effect on the expression of inducible nitric oxide and cytokines, compared with previously isolated known macrolactins (2-5). Real-time Polymerase Chain Reaction (PCR) analysis showed that the new compound significantly inhibited the mRNA expressions of inducible nitric oxide synthase (iNOS), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Reverse transcription-PCR analysis demonstrated that the new compound reduced the mRNA expression level of IL-1ß in a concentration-dependent manner.

NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR-IL-1R signalling axis.

Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-κB activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD.

[Effect of Negative Emotions on Serum Levels of Adrenocorticotropic Hormones and Neuropeptide Y in Hepatitis B Liver Cirrhosis Patients].

OBJECTIVE: To explore the effect of negative emotions on serum levels of adrenocorticotropic hormone (ACTH) and neuropeptide Y (NYP) in hepatitis B liver cirrhosis (HBLC) patients. METHODS: Totally 617 HBLC patients were assigned to the negative emotion group (415 cases) and the non-negative emotion group (202 cases) judged by negative emotions. Case numbers of various grading Child-Pugh were recorded in the two groups. Their liver functions were compared between the two groups. Serum levels of ACTH and NPY were detected using double antibody sandwich enzyme-linked immunosorbent assay (ELISA) in the two groups. RESULTS: There was no statistical difference in Child-Pugh grading between the two groups (χ2 = 0.65, P = 0.72). Compared with the non-negative emotional group, serum ACTH levels decreased significantly in the negative emotion group with statistical difference (P < 0.05). There was no statistical difference in serum ACTH levels between the two groups (P > 0.05). CONCLUSION: The negative emotion of HBLC patients was not related to the serum ACTH level, but to relatively lower-concentration serum NPY levels.

Laparoscopy-assisted versus open gastrectomy with D2 lymph node dissection for advanced gastric cancer: a meta-analysis.

A raising number of surgeons have chosen laparoscopy-assisted gastrectomy (LAG) as an alternative to open gastrectomy (OG) with D2 lymph node dissection for treatment of advanced gastric cancer (ADG). But no meta-analysis has been performed to evaluate the value of LAG versus OG with regard to safety and efficacy for treatment of ADG. A comprehensive literature research was performed in PubMed, Web of Science and Embase to identify studies that compared LAG and OG with D2 lymph node dissection for treatment of ADG. Data of interest were checked and subjected to meta-analysis with RevMan 5.1 software. 11 studies with 1904 patients (982 in LAG and 922 in OG) were enrolled. Pooled risk ratios (RR) and weighted mean difference (WMD) with 95% confidence intervals (CI) were appropriately derived from random-effects models or fixed-effects models. Compared with OG, LAG was associated with less blood loss (WMD = -144.47; P < 0.05), shorter time of first flatus time (WMD = -0.91; P < 0.05) and postoperative hospital stay (WMD = -3.27; P < 0.05), and lower morbidity (RR = 0.70; P < 0.05), but longer operation time (WMD = 41.78; P < 0.05). No significant differences were noted in terms of harvested lymph nodes (WMD = 1.85; P = 0.09), pathological N stage (χ(2) 3.97; P = 0.26), tumor size (WMD = -0.05; P = 0.81), mortality (RR 0.82; P = 0.76), cancer recurrence rate (RR 0.77; P = 0.18) and 3-year overall survival rate (RR 1.09; P = 0.18). Compared with OG, LAG with D2 lymph node dissection for ADG had the advantages of minimal invasion, faster recovery, and fewer complications, and it could achieve the same degree of radicality, harvested lymph nodes, short-term and long-term prognosis as OG, though the operation time was slightly longer.

Targeting truncated retinoid X receptor-α by CF31 induces TNF-α-dependent apoptosis.

A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α-mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α-mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNF-α activation of AKT by inhibiting TNF-α-induced tRXR-α interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α-dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells.