The goal of this study was to investigate whether circulating C1q/TNF-α-related protein 1 (CTRP1) levels are associated with diabetes. In addition, relationships between CTRP1 and other diabetes-related cytokines were elucidated, including adiponectin and fibroblast growth factor 21 (FGF21). A total of 178 subjects (78 men and 100 women) aged 29-70 years (mean age, 46.1 years) were randomly selected. The sera from a normal glucose tolerance group (n = 68) and a prediabetes/type 2 diabetes group (n = 110) were collected; then, circulating levels of CTRP1, adiponectin, and FGF21 were determined via enzyme-linked immunosorbent assay in all sera. Subjects with either prediabetes or diabetes exhibited higher circulating CTRP1 levels than healthy subjects. Sera analysis revealed that CTRP1 was positively correlated with age, body mass index, fasting blood glucose, and circulating FGF21 levels. However, CTRP1 was negatively correlated with total cholesterol and total circulating adiponectin levels in univariate analysis. In addition, multivariate analysis found that CTRP1 was independently associated with age, fasting blood glucose, and circulating FGF21 levels. CTRP1 was correlated with homeostasis model assessment-β (HOMA-β), but no correlation was observed with HOMA-insulin resistance. In conclusion, circulating CTRP1 levels are increased in subjects with type 2 diabetes and are positively associated with circulating FGF21 levels.
Abstract Previously, we found that adiponectin (APN) suppresses IL-2–induced NK cell activation by downregulating the expression of the IFN-γ–inducible TNF-related apoptosis-inducing ligand and Fas ligand. Although the antitumor function of APN has been reported in several types of solid tumors, with few controversial results, no lymphoma studies have been conducted. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. We observed attenuated EL4 growth in the APNKO mice. Increased numbers of splenic NK cells and splenic CTLs were identified under naive conditions and EL4-challenged conditions, respectively. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation. Additionally, there were decreased levels of myeloid-derived suppressor cell accumulation in the EL4-bearing APNKO mice. Enforced MHC class I expression on B16F10 cells led to attenuated growth of these tumors in APNKO mice. Thus, our results suggest that EL4 regression in APNKO mice is not only due to an enhanced antitumor immune response but also to a high level of MHC class I expression.
Abstract IK depletion leads to an aberrant mitotic entry because of chromosomal misalignment through the enhancement of Aurora B activity at the interphase. Here, we demonstrate that IK, a spliceosomal component, plays a crucial role in the proper splicing of the ATM pre-mRNA among other genes related with the DNA Damage Response (DDR). Intron 1 in the ATM pre-mRNA, having lengths <200 bp, was not spliced in the IK-depleted cells and led to a deficiency of the ATM protein. Subsequently, the IK depletion-induced ATM protein deficiency impaired the ability to repair the damaged DNA. Because the absence of SMU1 results in IK degradation, the mechanism underlying IK degradation was exploited. IK was ubiquitinated in the absence of SMU1 and then subjected to proteolysis through the 26S proteasome. To prevent the proteolytic degradation of IK, a deubiquitinating enzyme, USP47, directly interacted with IK and stabilized it through deubiquitination. Collectively, our results suggest that IK is required for proper splicing of the ATM pre-mRNA and USP47 contributes toward the stabilization of IK.
Following the publication of the above article, an interested reader drew to the authors' attention that they had mentioned that activated PKCδ phosphorylates IKKβ in order that IKKβ is relocated to the plasma membrane, resulting in the induction of mast cell degranulation; however, four references the authors had included did not seem to support this statement. The authors have re-examined their paper, and realized that the four references the reader mentioned were indeed cited incorrectly, and wish to rectify this error through revising the third paragraph in the Discussion section, the References section, and an associated figure (Fig. 6C) in order to avoid any further misunderstandings on the part of the readership. First, the authors wish to revise the wording of the third and fourth paragraphs of the Discussion, as featured on pp. 1101-1102, to the following (changed text is indicated in bold): 'We showed that CRT exerts anti-AD effect through inhibition of the mast cell degranulation in mast cells. Upon IgE/antigen stimulation, the immunoreceptor tyrosine-based activation motif (ITAM) region of FcεRI receptor which is on the mast cell surface is phosphorylated and the initial signalling protein kinases Lyn and Syk are recruited to the ITAM (28,29). Then, the activated Lyn and Syk leads to phosphorylation of the transmembrane adaptor linker for activation of T cells (LAT). Phosphorylated LAT which is a scaffold for multimolecular signalling complexes and activates PLCγ through phosphorylation. The activated PLCγ hydrolyses phosphatidylinositol biphosphate (PIP2) to generate second signalling molecules IP3 and DAG, which activate PKCs including PKCδ to induce the mast cell degranulation (30,31). On the other hand, cross-linking of FcεRI also activates IKKβ, which moves to the lipid raft fractions and phosphorylates synaptosomal-associated protein 23 (SNAP-23) leading to degranulation (7). Since PKCδ phosphorylates IKKα, but not IKKβ (32), it is not likely that two signalling pathways are directly connected. In this study, novel function of CRT on phosphorylations of Lyn/Syk kinases in mast cells is elucidated for the first time. Furthermore, it is likely that this inhibitory effect of CRT on Lyn/Syk kinases negatively affected activities of their downstream signalling molecules including PLCγ, PKCδ, and IKKβ, which leads to decrease in mast cell degranulation by CRT treatment. Besides the inhibitory effect of CRT on mast cell degranulation, here we provide additional evidence that CRT exerts anti-AD effects through inactivation of MAPK and NF‑κB. It has been reported that CRT regulates the activities of MAPK and NF‑κB in various cell types. In rhabdomyosarcoma, hepatoma, and breast carcinoma, CRT activates MAPK p38/JNK and suppresses ERK1/2, followed by caspase-independent apoptosis (10,33,34). In chronic myeloid leukaemia cells, CRT enhances TNF‑α-induced apoptosis through the activation of MAPK p38 (35). In smooth muscle cells, CRT exerts anti-migration/invasion effect as it inhibits TNF‑α/NF‑κB signalling pathway (36).' Secondly, the authors wish to make the following changes to the Reference list: New references 30-32 have been inserted to the list, as follows: 30. Ozawa K, Szallasi Z, Kazanietz MG, Blumberg PM, Mischak H, Mushinski JF and Beaven MA: Ca2+-dependent and Ca2+-independent isozymes of protein kinase C mediate exocytosis in antigen-stimulated rat basophilic RBL-2H3 cell. J Biol Chem 268: 1749-1756, 1993. 31. Cho SH, Woo CH, Yoon SB and Kim JH: Protein kinase Cδ functions downstream of Ca2+ mobilization in FcεRI signaling to degranulation in mast cells. J Allergy Clin Immunol 114: 1085-1092, 2004. 32. Yamaguchi T, Miki Y and Yoshida K: Protein kinase Cδ activates IκB-kinase α to induce the p53 tumor suppressor in response to oxidative stress. Cell Signal 19: 2088-2097, 2007. The addition of these new references means that the former references 30-33 have been accordingly renumbered to references 33-36. Finally, the authors have revised Fig. 6C, as it appeared on p. 1102, in order to assist the understanding of the readers, and the corrected version of Fig. 6 appears on the next page. All these corrections have been approved by all the authors, with the exception of the first author, Sumiyasuren Buyanravjikh, who is no longer uncontactable. The authors regret that these errors were included in the paper, even though they did not substantially alter any of the major conclusions reported in the study, are grateful to the Editor for allowing them this opportunity to publish a Corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 18: 1095‑1193, 2018; DOI: 10.3892/mmr.2018.9042]
Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation.To investigate the physiological/pathophysiological role of CTRP1 in BP regulation.CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ΔCAG). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice.For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.
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