Recent reports suggested that phosphatase of regenerating liver (PRL)-3 might be involved in colorectal carcinoma metastasis with an unknown mechanism.Here we demonstrated that PRL-3 expression was upregulated in human liver carcinoma compared with normal liver. PRL-3 was also highly expressed in metastatic melanoma B16-BL6 cells but not in its lowly metastatic parental cell line, B16 cells. B16 cells transfected with PRL-3 cDNA displayed morphological transformation from epithelial-like shape to fibroblast-like shape. PRL-3-overexpressed cells showed much higher migratory ability, which could be reversed by specific anti-sense oligodeoxynucleotide and the phosphatase inhibitors sodium orthovanadate or potassium bisperoxo oxovanadate V. Meanwhile, the expression of the catalytically inactive PRL-3 mutations (D72A or C104S) significantly reduced the cell migratory capability. In addition, PRL-3 transfectants demonstrated altered extracellular matrix adhesive property and up-regulated integrin-mediated cell spreading efficiency. Furthermore, we confirmed that PRL-3 could facilitate lung and liver metastasis of B16 cells in an experimental metastasis model in mice, consistent with accelerated proliferation and growth rate both in vitro and in vivo. Together, these observations provide convincing evidence that PRL-3 truly plays a causal role in tumor metastasis. Metastasis is the leading cause of death in cancer patients and involves a complex, multistep process including detachment of tumor cells from a primary cancer, invasion of surrounding tissue, entry into the circulatory system, reinvasion, and proliferation at a distant secondary site. 1,2 A wide variety of stimuli have been associated with the spread of tumor cells, including cytokines, hormones, growth factors, cell adhesion molecules, and extracellular components. Many of these stimuli transmit signals via a tyrosyl phosphorylation pathways that dictate whether a tumor cell will grow and divide, change shape, migrate, differentiate, or die. Protein tyrosine phosphorylation is a major posttranslational modification that cells use to regulate signal transduction. The homeostasis of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKases) that catalyze tyrosine phosphorylation, and protein tyrosine phosphatase (PTPases) that are responsible for dephosphorylation. PTKases, PTPases, and their corresponding substrates are integrated into elaborate signaltransducing networks. Deregulation of phosphorylation is known to result in neoplastic or nonneoplastic disease. 4Phosphatases are as important as the well-studied PTKases because phosphorylation is a dynamic and reversible process. 5 The PTPase superfamily can be divided into three major classes: tyrosine-specific and low-molecular weight phosphatases, which strictly dephosphorylate phosphotyrosine residues, and dual-specific phosphatases, which use protein substrates that contain phosphotyrosine, phosphoserine, and phosphothreonine. Tyrosine-specific PTPases can be further divided into two ...
(2014) Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitisassociated cancer, Autophagy, 10:6,[972][973][974][975][976][977][978][979][980][981][982][983][984][985]
Polyketides with unknown architectures are highly desired for the discovery of new drugs and agrochemicals. Here, the mantis-associated Daldinia eschscholzii, a fungus known to produce immunosuppressants dalesconols A and B, was found to simultaneously generate four novel skeletons capable of shaping the unusual chemistry of the fungal polyketides, of which seven were structurally unique and substantially immunosuppressive. In particular, the scaled-up fermentation of the microbe enabled the structural characterization of minor or "transitional" intermediate polyketides that allowed the reasonable recognition of the four biosynthetic pathways initiated by condensations of four, five, six and eight acetate units, respectively. Furthermore, the decarbonylation reaction of triketone, as in the case of daeschol A, was described for the first time, in addition to the structural correction of sporothrin C and nodulone. The work provided a set of novel immunosuppressive molecules that are of significance to drug discovery.
Background Western-style diets arouse neuroinflammation and impair emotional and cognitive behavior in humans and animals. Our previous study showed that a high-fructose diet caused the hippocampal neuroinflammatory response and neuronal loss in animals, but the underlying mechanisms remained elusive. Here, alterations in the gut microbiota and intestinal epithelial barrier were investigated as the causes of hippocampal neuroinflammation induced by high-fructose diet. Results A high-fructose diet caused the hippocampal neuroinflammatory response, reactive gliosis, and neuronal loss in C57BL/6N mice. Depletion of the gut microbiota using broad-spectrum antibiotics suppressed the hippocampal neuroinflammatory response in fructose-fed mice, but these animals still exhibited neuronal loss. Gut microbiota compositional alteration, short-chain fatty acids (SCFAs) reduction, intestinal epithelial barrier impairment, NOD-like receptor family pyrin domain-containing 6 (NLRP6) inflammasome dysfunction, high levels of serum endotoxin, and FITC-dextran were observed in fructose-fed mice. Of note, SCFAs, as well as pioglitazone (a selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist), shaped the gut microbiota and ameliorated intestinal epithelial barrier impairment and NLRP6 inflammasome dysfunction in fructose-fed mice. Moreover, SCFAs-mediated NLRP6 inflammasome activation was inhibited by histamine (a bacterial metabolite) in ex vivo colonic explants and suppressed in murine CT26 colon carcinoma cells transfected with NLRP6 siRNA . However, pioglitazone and GW9662 (a PPAR-γ antagonist) exerted no impact on SCFAs-mediated NLRP6 inflammasome activation in ex vivo colonic explants, suggesting that SCFAs may stimulate NLRP6 inflammasome independently of PPAR-γ activation. SCFAs and pioglitazone prevented fructose-induced hippocampal neuroinflammatory response and neuronal loss in mice. Additionally, SCFAs activated colonic NLRP6 inflammasome and increased DCX + newborn neurons in the hippocampal DG of control mice. Conclusions Our findings reveal that gut dysbiosis is a critical factor for a high-fructose diet-induced hippocampal neuroinflammation in C57BL/6N mice possibly mediated by impairing intestinal epithelial barrier. Mechanistically, the defective colonic NLRP6 inflammasome is responsible for intestinal epithelial barrier impairment. SCFAs can stimulate NLRP6 inflammasome and ameliorate the impairment of intestinal epithelial barrier, resulting in the protection against a high-fructose diet-induced hippocampal neuroinflammation and neuronal loss. This study addresses a gap in the understanding of neuronal injury associated with Western-style diets. A new intervention strategy for reducing the risk of neurodegenerative diseases through SCFAs supplementation or dietary fiber consumption is emphasized. ...
Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo . However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8 + IFN- γ + T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin , which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.
Going with a gut reaction: Dalesconols A (structure shown) and B were discovered in the title fungus (middle picture) derived from the mantis gut. The novel architecture and biological profiles of these natural products make the dalesconols attractive lead compounds for the development of immunosuppressive agents.
Two homologous meroterpenoid gene clusters consisting of contiguous genes encoding polyketide synthase (PKS), prenyltransferase (PT), terpenoid cyclase (TC) and other tailoring enzymes were identified from two phylogenetically distinct fungi through computational analysis. Media optimization guided by reverse-transcription PCR (RT-PCR) enabled two strains to produce eight new and two known meroterpenoids (1-10). Using gene inactivation, heterologous expression, and biochemical analyses, we revealed a new polyketide-terpenoid assembly line that utilizes a pair of PKSs to synthesize 2,4-dihydroxy-6-alkylbenzoic acid, followed by oxidative decarboxylation, farnesyl transfer, and terpene cyclization to construct the meroterpenoid scaffold. In addition, two of the isolated meroterpenoids (3 and 17 d) showed immunosuppressive bioactivity. Our work reveals a new strategy for meroterpenoid natural products discovery, and reveals the biosynthetic pathway for compounds 1-10.
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