N-benzyl-N-methyldecan-1-amine and its derivative mitigate 2,4- dinitrobenzenesulfonic acid-induced colitis and collagen-induced rheumatoid arthritis.

As our previous study revealed that N-benzyl-N-methyldecan-1-amine (BMDA), a new molecule originated from Allium sativum, exhibits anti-neoplastic activities, we herein explored other functions of the compound and its derivative [decyl-(4-methoxy-benzyl)-methyl-amine; DMMA] including anti-inflammatory and anti-oxidative activities. Pretreatment of THP-1 cells with BMDA or DMMA inhibited tumor necrosis factor (TNF)-α and interleukin (IL)-1ß production, and blocked c-jun terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), MAPKAP kinase (MK)2 and NF-κΒ inflammatory signaling during LPS stimulation. Rectal treatment with BMDA or DMMA reduced the severity of colitis in 2,4-dinitrobenzenesulfonic acid (DNBS)-treated rat. Consistently, administration of the compounds decreased myeloperoxidase (MPO) activity (representing neutrophil infiltration in colonic mucosa), production of inflammatory mediators such as cytokine-induced neutrophil chemoattractant (CINC)-3 and TNF-α, and activation of JNK and p38 MAPK in the colon tissues. In addition, oral administration of these compounds ameliorated collagen-induced rheumatoid arthritis (RA) in mice. The treatment diminished the levels of inflammatory cytokine transcripts, and protected connective tissues through the expression of anti-oxidation proteins such as nuclear factor erythroid-related factor (Nrf)2 and heme oxygenase (HO)1. Additionally, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels did not differ between the BMDA- or DMMA-treated and control animals, indicating that the compounds do not possess liver toxicity. Taken together, these findings propose that BMDA and DMMA could be used as new drugs for curing inflammatory bowel disease (IBD) and RA.

FAT10 Induces cancer cell migration by stabilizing phosphorylated ABI3/NESH.

The WAVE regulatory complex (WRC) is involved in various cellular processes by regulating actin polymerization. The dysregulation of WRC components is associated with cancer development. ABI family member 3 (ABI3)/new molecule including SH3 (NESH) is one of the WRC components and it has been reported that ABI3 phosphorylation can affect WRC function. Although several residues of ABI3 have been reported to be possible phosphorylation sites, it is still unclear which residues are important for the function of ABI3. Furthermore, it is unclear how the phosphorylated form of ABI3 is regulated. Here, we demonstrate that ABI3 is stabilized by its interaction with human leukocyte antigen-F adjacent transcript 10 (FAT10). Using phospho-dead or phospho-mimetic mutants of ABI3, we showed that serine 213 and 216 are important phosphorylation sites of ABI3. In particular, FAT10 has a higher affinity for the phosphorylated form of ABI3 than the non-phosphorylated form, and it stabilizes the phosphorylated form more than the non-phosphorylated form through this differential affinity. The interaction between FAT10 and the phosphorylated form of ABI3 promoted cancer cell migration. Therefore, our results suggest that FAT10 stabilizes the phosphorylated form of ABI3, which may lead to WRC activation, thereby promoting cancer cell migration.

Myeloid IPMK promotes the resolution of serum transfer-induced arthritis in mice.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by widespread joint inflammation, which leads to joint damage, disability, and mortality. Among the several types of immune cells, myeloid cells such as macrophages are critical for controlling the pathogenesis of RA. Inositol phosphates are water-soluble signaling molecules, which are synthesized by a series of enzymes including inositol phosphate kinases. Previous studies revealed actions of inositol phosphates and their metabolic enzymes in the modulation of inflammation such as Toll-like receptor-triggered innate immunity. However, the physiological roles of inositol polyphosphate (IP) metabolism in the regulation of RA remain largely uncharacterized. Therefore, our study sought to determine the role of inositol polyphosphate multikinase (IPMK), a key enzyme for IP metabolism and various cellular signaling control mechanisms, in mediating RA. Using myeloid cell-specific IPMK knockout (KO) mice, arthritis was induced via intraperitoneal K/BxN serum injection, after which disease severity was evaluated. Both wild-type and IPMK KO mice developed similar RA phenotypes; however, conditional deletion of IPMK in myeloid cells led to elevated arthritis scores during the resolution phase, suggesting that IPMK deficiency in myeloid cells impairs the resolution of inflammation. Bone marrow-derived IPMK KO macrophages exhibited no apparent defects in immunoglobulin Fc receptor (FcR) activation, osteoclast differentiation, or resolvin signaling. Taken together, our findings suggest that myeloid IPMK is a key determinant of RA resolution.

Protein phosphatase magnesium-dependent 1A induces inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly inflammatory autoimmune disease. Although proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-6, play a key role in the pathogenesis of RA, the causes of chronic inflammation are not fully understood. Here, we report that protein phosphatase magnesium-dependent 1A (PPM1A) levels were increased in RA synovial fluid compared with osteoarthritis (OA) synovial fluid and positively correlated with TNF levels. In addition, PPM1A expression was increased in synovial tissue from RA patients and joint tissue from a mouse model of arthritis. Finally, extracellular PPM1A induced inflammation by stimulating macrophages to produce TNF through toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MyD88) signaling pathway. Our findings suggest that extracellular PPM1A may contribute to the pathogenesis of RA by functioning as a damage-associated molecular pattern (DAMP) to induce inflammation.

DYSF expression in clear cell renal cell carcinoma: A retrospective study of 2 independent cohorts.

OBJECTIVE: Renal cell carcinoma (RCC) is the most typical type of kidney cancer in adults. Hypercalcemia is a well known paraneoplastic syndrome associated with RCC and recent studies have reported that hypercalcemia is closely related to the poor prognosis of RCC patients. Clear cell RCC (ccRCC) is the most common and aggressive subtype of RCC. Although the histological classification of RCC is important for determination of appropriate treatment strategies, effective biomarkers for predicting prognosis of ccRCC have not yet been identified. Since calcium levels affect the prognosis of RCC patients, we evaluated whether the calcium-sensing genes on the plasma membrane, including those encoding calcium channels, CaSR, GPRC6a, and DYSF, could be used as biomarkers to predict the prognosis of ccRCC patients. METHODS: Information from 537 patients from The Cancer Genome Atlas (TCGA; n = 446) and International Cancer Genome Consortium (ICGC; n = 91) was used in this study. Among these genes, DYSF was the only gene whose expression correlated with overall survival of both TGCA and ICGC patients. RESULTS: Although DYSF gene expression was higher in ccRCC tissue than in normal kidney tissue, Kaplan-Meier curves showed that the survival rate of ccRCC patients with high DYSF expression was significantly higher than that of patients with low DYSF expression (TCGA, P < 0.0001; ICGC, P = 0.0011). We also validated the potential of DYSF as a prognostic biomarker for ccRCC by conducting a time-dependent area under the curve (AUC) analysis and 5-years receiver operating characteristic curve analysis. Finally, multivariate regression analysis revealed that the expression of DYSF is independent of other prognostic parameters (TCGA, P = 0.017; ICGC, P = 0.006). CONCLUSIONS: These results suggested that DYSF may play a suppressive role in the progression of ccRCC and could act as a promising prognostic biomarker for predicting the survival of ccRCC patients.

VNN3 is a potential novel biomarker for predicting prognosis in clear cell renal cell carcinoma.

Although pathological observations provide approximate prognoses, it is difficult to achieve prognosis in patients with existing prognostic factors. Therefore, it is very important to find appropriate biomarkers to achieve accurate cancer prognosis. Renal cell carcinoma (RCC) has several subtypes, the discrimination of which is crucial for proper treatment. Here, we present a novel biomarker, VNN3, which is used to prognose clear cell renal cell carcinoma (ccRCC), the most common and aggressive subtype of kidney cancer. Patient information analyzed in our study was extracted from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts. VNN3 expression was considerably higher in stages III and IV than in stages I and II. Moreover, Kaplan-Meier curves associated high VNN3 expression with poor prognoses (TCGA, p < .0001; ICGC, p = .00076), confirming that ccRCC prognosis can be predicted via VNN3 expression patterns. Consistent with all patient results, the prognosis of patients with higher VNN3 expression was worse in both low stage (I and II) and high stage (III and IV) (TCGA, p < 0.0001 in stage I and II; ICGC, p = 0.028 in stage I and II; TCGA, p = 0.005 in stage III and IV). Area under the curve and receiver operating characteristic curves supported our results that highlighted VNN3 expression as a suitable ccRCC biomarker. Multivariate analysis also verified the prognostic performance of VNN3 expression (TCGA, p < .001; ICGC, p = .017). Altogether, we suggest that VNN3 is applicable as a new biomarker to establish prognosis in patients with ccRCC.