Pierisin, Cytotoxic and Apoptosis-Inducing DNA ADP-Ribosylating Protein in Cabbage Butterfly.

Pierisin-1 was serendipitously discovered as a strong cytotoxic and apoptosis-inducing protein from pupae of the cabbage butterfly Pieris rapae against cancer cell lines. This 98-kDa protein consists of the N-terminal region (27 kDa) and C-terminal region (71 kDa), and analysis of their biological function revealed that pierisin-1 binds to cell surface glycosphingolipids on the C-terminal side, is taken up into the cell, and is cleaved to N- and C-terminal portions, where the N-terminal portion mono-ADP-ribosylates the guanine base of DNA in the presence of NAD to induce cellular genetic mutation and apoptosis. Unlike other ADP-ribosyltransferases, pieisin-1 was first found to exhibit DNA mono-ADP-ribosylating activity and show anti-cancer activity in vitro and in vivo against various cancer cell lines. Pierisin-1 was most abundantly produced during the transition from the final larval stage to the pupal stage of the cabbage butterfly, and this production was regulated by ecdysteroid hormones. This suggests that pierisn-1 might play a pivotal role in the process of metamorphosis. Moreover, pierisin-1 could contribute as a defense factor against parasitization and microbial infections in the cabbage butterfly. Pierisin-like proteins in butterflies were shown to be present not only among the subtribe Pierina but also among the subtribes Aporiina and Appiadina, and pierisin-2, -3, and -4 were identified in these butterflies. Furthermore, DNA ADP-ribosylating activities were found in six different edible clams. Understanding of the biological nature of pierisin-1 with DNA mono-ADP-ribosylating activity could open up exciting avenues for research and potential therapeutic applications, making it a subject of great interest in the field of molecular biology and biotechnology.

Neurosurgical Treatment of Patients with Posterior Fossa Acute Subdural Hematoma Right after Cardiac Surgery.

As posterior fossa acute subdural hematoma (ASDH) right after cardiac surgery is extremely rare, the clinical course and optimal treatment strategy remain undetermined. We performed a retrospective analysis of patients with posterior fossa ASDH right after cardiac surgery requiring neurosurgical treatment at our institution over a 7-year period and, in this study, discussed the neurosurgical strategy and clinical course. Collected data included clinical history, laboratory results, time course, symptoms, neurosurgical treatment, outcome at discharge, and imaging studies. All six patients were women who had no history of head trauma and had received antithrombotic therapy during the perioperative period of cardiac surgery. All patients showed lower platelets count and were diagnosed with ASDH within 3 days (longest time 64 h) right after cardiac surgery. After discontinuation of anticoagulation therapy and administration of reversal agents, they underwent emergency hematoma evacuation craniotomy (n = 5) or burr hole drainage surgery (n = 1), which were performed in the prone (n = 4) or lateral (n = 2) positions. Four of these patients showed favorable outcomes, and two showed poor outcomes. One of the poor-outcome patients received three antithrombotic therapies, and another developed rapidly progressive ASDH. Posterior fossa ASDH associated with antithrombotic therapy right after cardiac surgery is frequently found in women, and emergent neurosurgical treatment with anticoagulation discontinuation and reversal agent administration can be performed safely. Burr hole drainage surgery might be acceptable in nonsevere cases. By contrast, we must pay attention to cases receiving both anticoagulant and antiplatelet drugs and rapid progression cases.

Interstitial pneumonia in immunocompetent laboratory rats caused by natural infection with Pneumocystis carinii.

Pneumocystis (P.) carinii is known to cause fatal pneumonia in immunocompromised rats. Cases of P. carinii interstitial pneumonia in immunocompetent rats have been shown histologically to present with perivascular lymphoid cuffs, which have previously been attributed to rat respiratory virus. This study aims to determine the prevalence and pathological characteristics of P. carinii in immunocompetent laboratory rats in experimental facilities in Japan. An epidemiological survey for this agent was performed using PCR to assess 1,981 immunocompetent rats from 594 facilities in Japan. We observed that 6 of the 1,981 rats (0.30%) from 4 out of 594 facilities (0.67%) were positive for P. carinii without infection of other known pathogens. Gross pulmonary lesions were found in 4 of the 6 affected rats. The lungs of these rats contained scattered dark red/gray foci. Histopathologically, the lungs exhibited interstitial pneumonia with lymphoid perivascular cuffs: Pneumocystis cysts were observed using Grocott's methenamine silver stain. To our knowledge, this report is the first to reveal the prevalence of natural P. carinii infection in immunocompetent laboratory rats in Japan.

Establishing an induced pluripotent stem cell line from neonatal common marmoset fibroblasts by an all-in-one episomal vector approach.

Epstein-Barr virus (EBV)-based episomal vector system enables persistent transgene expression, which is advantageous for efficient derivation of transgene-free induced pluripotent stem cells (iPSCs) without viral transduction. Here, we report establishment of an iPSC line from somatic fibroblasts of a neonatal common marmoset monkey (marmoset; Callithrix jacchus) using an all-in-one episomal vector that we newly developed. The established iPSC line, named NM-iPS, showed standard characteristics of pluripotency such as pluripotency-related marker expression, three germ layer differentiation, and normal karyotype (2n = 46). The novel iPSC line would be a useful resource for stem cell research using non-human primates.

Leakage sign for acute subdural hematoma in clinical treatment.

BACKGROUND: Acute subdural hematoma (ASDH) is a serious traumatic disease, and predictive methods for hematoma growth are necessary to decide whether emergent operation is necessary. This study aimed to evaluate the incidence of "leakage" using computed tomography angiography (CTA) in patients with ASDH and to identify its prognostic value. METHODS: Sixty-seven patients with ASDH were examined using CTA (mean age 64.1 ± 20.6 years; 24 men) by analyzing two serial scans (CTA phase and delayed phase). We defined a positive leakage sign as a > 10% increase in Hounsfield units (HU) in the region of interest. Hematoma expansion was determined using plain CT after 24 h in patients who did not undergo emergent surgery. RESULTS: Of the 67 patients, conservative therapy was administered to 35 patients; of these patients, 9 showed hematoma expansion, and 8 of these 9 patients (88.9%) showed positive leakage signs. The sensitivity and specificity of leakage signs to hematoma expansion in the no-surgery group were 88.8% and 76.1%, respectively. All positive leakage signs were found within 4.5 h of injury; patients showing negative leakage signs showed a decreased tendency towards hematoma 24 h after injury. Patients presenting with positive leakage signs had poor outcomes. CONCLUSIONS: The results indicated that the leakage sign is a sensitive predictor of hematoma expansion and poor outcomes in ASDH. If the hematoma is small but leakage sign-positive, strict observation is necessary and aggressive surgery may improve outcomes.

[Head Injuries due to Ladder-related Falls].

We examined the clinical characteristics and outcomes of patients who had fallen from ladders and statistically analyzed the prognostic factors, highlighting the impact of the coexistence of head injuries on their prognoses. The clinical records of patients who had experienced ladder-related falls who were admitted to the Advanced Emergency Medical Service Center at Kurume University Hospital between April 2013 and August 2015 were retrospectively reviewed. A total of 86 patients were enrolled. The mean patient age was 69.2 years, and 82 patients were male. The median fall height was 2.55 m. Sixty patients fell during non-professional use of the ladder. Forty-four patients experienced some type of head injury. Although the older patients had more frequent complications with head injuries, the height of the fall was not related statistically. The group of patients with head injuries exhibited trends of older age, lower Glasgow Coma Scale scores, higher Injury Severity Score, and poorer outcomes than those of the group of patients without head injuries. Multivariate analysis showed that head injury and non-professional use were independent risk factors for poor outcomes. Our results revealed that ladder-related falls with head injury can occur when older people are working at home, even if they have fallen from a low height. Especially when older men work with the ladder at home, local community-based education and guidance for the prevention of ladder-related fall injuries are needed.

Adiponectin deficiency-induced diabetes increases TNFα and FFA via downregulation of PPARα.

Expression of peroxisome proliferator-activated receptor (PPAR) α was investigated in adiponectin knockout mice to elucidate the relationship between PPARα and adiponectin deficiency-induced diabetes. Adiponectin knockout (Adp-/-) mice were generated by gene targeting. Glucose tolerance test (GTT), insulin tolerance test (ITT), and organ sampling were performed in Adp-/- mice at the age of 10 weeks. PPARα, insulin, triglyceride, free fatty acid (FFA), and tumor necrosis factor α (TNFα) were analyzed from the sampled organs. Adp-/- mice showed impaired glucose tolerance and insulin resistance. Additionally, PPARα levels were decreased and plasma concentration of triglyceride, FFA and TNFα were increased. These data may indicate that insulin resistance in Adp-/- mice is likely caused by an increase in concentrations of TNFα and FFA via downregulation of PPARα.

Predictive Value of Leakage Signs for Pure Brain Contusional Hematoma Expansion.

Hematoma expansion is an important consideration in patients with traumatic brain injury (TBI). No precise methods are available, however, for predicting the expansion of TBI-related hematoma. We aimed to establish a more sensitive predictor for contusional hematoma expansion based on the presence of leakage signs on computed tomography angiography (CTA). Thirty-three patients with pure contusion were included in the analysis (age: 64.1 ± 20.6 years; 24 men and 7 women). We compared Hounsfield unit (HU) values within set regions of interest (diameter, 10 mm) between serial CTA phase and delayed-phase CT images (5 min after CTA phase). Positive leakage signs were defined as >10% increases in HU value. Hematoma expansion was determined using plain CT at 24 h in patients who did not undergo emergent surgery. Glasgow Coma Scale (GCS) scores measured at admission and 24 h after admission were also compared. Leakage signs predicted hematoma expansion with high specificity (100%) and sensitivity (92.8%). Patients with positive leakage signs had significant decreases in GCS scores 24 h after the scan (GCS change: positive group, -0.92 ± 0.59; negative group, 1.14 ± 0.82). Positive leakage signs were clearly associated with surgical hematoma removal. Five patients without hematoma who had positive leakage signs at admission exhibited significant expansion of hematomas 24 h later. Our results indicate that leakage signs had high sensitivity in the prediction of contusional hematoma expansion and were significantly associated with delayed neurological deterioration and the necessity of surgical removal.

Structural basis of autoinhibition and activation of the DNA-targeting ADP-ribosyltransferase pierisin-1.

ADP-ribosyltransferases transfer the ADP-ribose moiety of ßNAD+ to an acceptor molecule, usually a protein that modulates the function of the acceptor. Pierisin-1 is an ADP-ribosyltransferase from the cabbage butterfly Pieris rapae and is composed of N-terminal catalytic and C-terminal ricin B-like domains. Curiously, it ADP-ribosylates the DNA duplex, resulting in apoptosis of various cancer cells, which has raised interest in pierisin-1 as an anti-cancer agent. However, both the structure and the mechanism of DNA ADP-ribosylation are unclear. Here, we report the crystal structures of the N-terminal catalytic domain of pierisin-1, its complex with ßNAD+, and the catalytic domain with the linker connecting it to the ricin B-like domains. We found that the catalytic domain possesses a defined, positively charged region on the molecular surface but that its overall structure is otherwise similar to those of protein-targeting ADP-ribosyltransferases. Electrophoretic mobility shift assays and site-directed mutagenesis indicated that pierisin-1 binds double-stranded but not single-stranded DNA and that Lys122, Lys123, and Lys124, which are found in a loop, and Arg181 and Arg187, located in a basic cleft near the loop, are required for DNA binding. Furthermore, the structure of the catalytic domain with the linker revealed an autoinhibitory mechanism in which the linker occupies and blocks both the ßNAD+- and DNA-binding sites, suggesting that proteolytic cleavage to remove the linker is necessary for enzyme catalysis. Our study provides a structural basis for the DNA-acceptor specificity of pierisin-1 and reveals that a self-regulatory mechanism is required for its activity.

Metachronous serous endometrial intraepithelial carcinoma and serous peritoneal carcinoma: analysis of probable independent lesions.

BACKGROUND: Uterine serous endometrial intraepithelial carcinoma (SEIC) is an immediate precursor of invasive carcinoma. The majority of stage IA SEICs are curable, but those with latent peritoneal metastasis and/or capillary lymphatics invasion may have poor prognoses Careful pathologic staging is thus needed to predict the risk of recurrence and to determine postoperative therapeutic strategies. CASE PRESENTATION: A 71-year-old woman was hospitalized for the treatment of peritoneal carcinoma. She had undergone total hysterectomy and bilateral salpingo-oophorectomy due to SEIC (stage IA) at age 63 years, and had received medical check-ups every year since. Elevated serum CA125 (184 U/mL) was detected for the first time 8 years after surgery. A thorough workup revealed no potential primary lesion other than that in the peritoneum. Tumor reduction surgery was performed. Histologic analysis of the peritoneal lesion was high-grade serous carcinoma. The peritoneal carcinoma was diffusely immunostained for p53; thus, possible recurrence of SEIC was suspected. Tumor DNAs were microdissected from the uterine and peritoneal lesions and p53 mutation analysis was done. SEIC and peritoneal carcinomas had distinct p53 mutations that were mutually exclusive. CONCLUSIONS: The present case raised a concern about the difficulty of histologic staging for SEICs. Although SEICs confined to the uterine endometrium in most cases predict a good prognosis, microscopic metastasis to the peritoneum may not be detectable at hysterectomy. If secondary malignancies of a serous phenotype develop years later, comprehensive reexamination of SEIC is mandated, with the help of DNA analysis.

Pierisins and CARP-1: ADP-ribosylation of DNA by ARTCs in butterflies and shellfish.

The cabbage butterfly, Pieris rapae, and related species possess a previously unknown ADP-ribosylating toxin, guanine specific ADP-ribosyltransferase. This enzyme toxin, known as pierisin, consists of enzymatic N-terminal domain and receptor-binding C-terminal domain, or typical AB-toxin structure. Pierisin efficiently transfers an ADP-ribosyl moiety to the N(2) position of the guanine base of dsDNA. Receptors for pierisin are suggested to be the neutral glycosphingolipids, globotriaosylceramide (Gb3), and globotetraosylceramide (Gb4). This DNA-modifying toxin exhibits strong cytotoxicity and induces apoptosis in various human cell lines, which can be blocked by Bcl-2. Pierisin also produces detrimental effects on the eggs and larvae of the non-habitual parasitoids. In contrast, a natural parasitoid of the cabbage butterfly, Cotesia glomerata, was resistant to this toxin. The physiological role of pierisin in the butterfly is suggested to be a defense factor against parasitization by wasps. Other type of DNA ADP-ribosyltransferase is present in certain kinds of edible clams. For example, the CARP-1 protein found in Meretrix lamarckii consists of an enzymatic domain without a possible receptor-binding domain. Pierisin and CARP-1 are almost fully non-homologous at the amino acid sequence level, but other ADP-ribosyltransferases homologous to pierisin are present in different biological species such as eubacterium Streptomyces. Possible diverse physiological roles of the DNA ADP-ribosyltransferases are discussed.

Novel enhanced green fluorescent protein-expressing NOG mouse for analyzing the microenvironment of xenograft tissues.

The interaction between transplanted cells and host tissues is important for the growth and maintenance of transplanted cells. To analyze the mechanisms of these interactions, a systemic fluorescent protein-expressing mouse is a useful recipient. In this study, we generated a novel NOG strain, which strongly expresses enhanced green fluorescent protein (EGFP; PgkEGFP-NOG), especially in the liver, kidney, gastrointestinal tract, and testis. Because the host tissues expressed EGFP, xenotransplanted human cancer cells were clearly identified as EGFP-negative colonies in PgkEGFP-NOG mice. Immunohistochemical analysis revealed that EGFP-expressing stromal tissues formed a complicated tumor microenvironment within xenograft tissues. Moreover, a similar microenvironment was observed in human iPS cell-derived teratomas. Collectively, these results indicated that a suitable microenvironment is essential for the growth and maintenance of xenotransplanted cells and that PgkEGFP-NOG mice represent a useful animal model for analyzing the mechanisms of microenvironment formation.

Nasal immunization with the 40-kDa outer membrane protein of Porphyromonas gingivalis plus cholera toxin induces protective immunity in aged mice.

Previous studies have demonstrated that nasal administration of the outer membrane protein of Porphyromonas gingivalis (40k-OMP) with cholera toxin (CT) as an adjuvant elicits protective immune responses against P. gingivalis in young mice. In the present study, we investigated whether administration of 40k-OMP plus CT would also induce 40k-OMP-specific antibody (Ab) responses to provide protective immunity against P. gingivalis infection in aged mice. Nasal immunization with 40k-OMP plus CT elicited 40k-OMP-specific IgG and IgA Ab responses in serum and a significant anti-40k-OMP IgA Ab response in nasal washes and saliva in 1- and 2-year-old mice. Furthermore, both Th1- and Th2-type cytokine responses were induced by the immunization, and cytokine-associated IgG1, IgG2a, and IgG2b Ab responses were observed in the spleens of aged mice. Although the aged mice showed lower 40k-OMP-specific Ab responses than young mice, their mucosal IgA Ab titers as well as serum IgG Ab responses indicated a retained ability to mediate protective immunity; the only exception was saliva in 2-year-old mice. These findings suggest that nasal immunization with 40k-OMP plus CT can be a potential vaccination strategy for eliciting levels of Abs sufficient to provide protective immunity against P. gingivalis infection in aged mice.

Green tea epigallocatechin-3-gallate attenuates Porphyromonas gingivalis-induced atherosclerosis.

The purpose of this study was to determine whether epigallocatechin-3-gallate (EGCG) ameliorates Porphyromonas gingivalis-induced atherosclerosis. EGCG is a polyphenol extract from green tea with health benefits and P. gingivalis is shown here to accelerate atheroma formation in a murine model. Apolipoprotein E knockout mice were administered EGCG or vehicle in drinking water; they were then fed high-fat diets and injected with P. gingivalis three times a week for 3 weeks. Mice were then killed at 15 weeks. Atherosclerotic plaques in the proximal aorta were determined by Oil Red O staining. Atherosclerosis risk factors in serum, liver or aorta were analysed using cytokine antibody arrays, enzyme-linked immunosorbent assay and real-time PCR. Atherosclerotic lesion areas of the aortic sinus caused by P. gingivalis infection decreased in EGCG-treated groups, wherein EGCG reduced the production of C-reactive protein, monocyte chemoattractant protein-1, and oxidized low-density lipoprotein (LDL), and slightly lowered LDL/very LDL cholesterol in P. gingivalis-challenged mice serum. Furthermore, the increase in CCL2, MMP-9, ICAM-1, HSP60, CD44, LOX-1, NOX-4, p22phox and iNOS gene expression levels in the aorta of P. gingivalis-challenged mice were reduced in EGCG-treated mice. However, HO-1 mRNA levels were elevated by EGCG treatment, suggesting that EGCG, as a natural substance, inhibits P. gingivalis-induced atherosclerosis through anti-inflammatory and antioxidative effects.

Suppressive effect of pioglitazone, a PPAR gamma ligand, on azoxymethane-induced colon aberrant crypt foci in KK-Ay mice.

Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferator- activated receptor γ(PPARγ) agonist that induces differentiation in adipocytes and induces growth arrest and/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-Ay obesity and diabetes model mice, and tried to clarify mechanisms by which the PPARγ ligand inhibits ACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF / mouse to 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-Ay mice with significant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines, such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceral fat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cell proliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggest that pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulated adipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNA levels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potential chemopreventive agent against obesity-associated colorectal cancer.

Novel compound SK-1009 suppresses interleukin-6 expression through modulation of activation of nuclear factor-kappaB pathway.

Although interleukin-6 (IL-6) is an important biological mediator playing an indispensable role in inflammation and cancer, few inhibitors and suppressors are known. In the present study, the underlying mechanisms of a novel chemically synthesized compound SK-1009, which has suppressive properties on IL-6 production in human macrophage cells, were examined. SK-1009 suppressed IL-6 mRNA levels in human colon cancer cells. Thus, the influence of SK-1009 on transcription factor, nuclear factor-kappaB (NF-κB), which is involved in expression of the IL-6 gene was assessed. SK-1009 was found to suppress degradation of I-κB, an NF-κB inhibitory factor, and consequently inhibited the NF-κB activation pathway. The inhibitory property was almost the same as other NF-κB inhibitors, such as 5HPP-33. Thus, SK-1009 exerts a potent inhibitory effect on IL-6 expression, apparently mediated by modulation of activation of NF-κB transcription factor.

Ruptured de novo aneurysm arising at a site remote from the anastomosis 14 years after superficial temporal artery-middle cerebral artery bypass: a case report.

BACKGROUND AND IMPORTANCE: The long-term outcome of superficial temporal artery (STA)-middle cerebral artery (MCA) bypass is unclear. We report a very rare case of a de novo aneurysm after bypass surgery. CLINICAL PRESENTATION: A 57-year-old woman who underwent STA-MCA bypass and internal carotid artery aneurysm treatment 14 years earlier developed a subarachnoid hemorrhage and a temporal lobe hematoma on the same side as the anastomosis. Angiography showed excellent patency of the STA bypass and a ruptured de novo saccular aneurysm at a site remote from the anastomosis. Neck clipping and hematoma evacuation were performed on the second day, and postoperative angiography showed complete aneurysmal clipping. The aneurysm was considered to be caused by hemodynamic stress because it was remote from the anastomosis and had developed after a prolonged interval of 14 years; furthermore, the aneurysm projected because of the hemodynamic force of the STA perfusion. CONCLUSION: This is the first reported case of a de novo MCA aneurysm that developed at a site remote from STA-MCA anastomosis because of hemodynamic force. Therefore, long-term control of blood pressure and repeated imaging examination should be performed to confirm patency and to identify aneurysm formation after STA-MCA bypass.

Discussions about safety criteria and guidelines for radioactive waste management.

In Japan, the clearance levels for uranium-bearing waste have been established by the Nuclear Safety Commission (NSC). The criteria for uranium-bearing waste disposal are also necessary; however, the NSC has not concluded the discussion on this subject. Meanwhile, the General Administrative Group of the Radiation Council has concluded the revision of its former recommendation 'Regulatory exemption dose for radioactive solid waste disposal', the dose criteria after the institutional control period for a repository. The Standardization Committee on Radiation Protection in the Japan Health Physics Society (The Committee) also has developed the relevant safety criteria and guidelines for existing exposure situations, which are potentially applicable to uranium-bearing waste disposal. A new working group established by The Committee was initially aimed at developing criteria and guidelines specifically for uranium-bearing waste disposal; however, the aim has been shifted to broader criteria applicable to any radioactive wastes.

Porphyromonas gingivalis stimulates monocyte adhesion to human umbilical vein endothelial cells.

Monocyte recruitment to the endothelium is a crucial step in the inflammatory response that precedes the development of atherosclerosis. We assessed the effect of Porphyromonas gingivalis on monocyte adhesion to endothelial cells, cytokine production during monocyte/endothelial cell co-culture, and the expression of cell adhesion molecules on human umbilical vein endothelial cells (HUVEC) and their ligands on monocytes. Porphyromonas gingivalis challenge significantly increased the adhesion of THP-1 monocytes to HUVEC, the production of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein 1 (MCP-1) in co-cultures of HUVEC and THP-1 cells, and the transcription and translation of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HUVEC. The transcription of tumor necrosis factor receptor-associated factor 1 was also increased in HUVEC and THP-1 cells by P. gingivalis infection. Moreover, the stimulation of monocyte adhesion to HUVEC by P. gingivalis infection was partially inhibited by pretreatment with a mixture of anti-ICAM-1, -VCAM, and -E-selectin monoclonal antibodies. These data suggest that adherence between HUVEC and THP-1 cells, followed by the production of cytokines and chemokines, was enhanced by increased expression of cell adhesion molecules on P. gingivalis-sensitized HUVEC, which in turn led to inflammatory atherogenesis.

Loss of adiponectin promotes intestinal carcinogenesis in Min and wild-type mice.

BACKGROUND & AIMS: Metabolic syndrome- and obesity-associated cancers, including colon cancer, are common in Western countries. Visceral fat accumulation and decreased levels of plasma adiponectin (APN) have been associated with development of human colorectal adenoma. We investigated the function of APN in intestinal carcinogenesis. METHODS: APN+/+, APN+/-, or APN-/- mice (C57BL/6J) were given injections of azoxymethane (AOM), which led to development of intestinal tumors; these strains of mice were also crossed with Min mice to assess polyp formation. Adipocytokine levels and phosphorylation/activation of AMP-activated protein kinase (AMPK) were evaluated to investigate the mechanisms of APN in tumor growth. RESULTS: The total number of polyps in the intestines of male APN+/-Min and APN-/-Min mice increased 2.4- and 3.2-fold, respectively, by the age of 9 weeks and 3.2- and 3.4-fold, respectively, by 12 weeks, compared with those of APN+/+Min mice. Similar results were obtained from female mice. AOM induced colon tumor formation in 40% of APN+/+, 50% of APN+/-, and 71% of APN-/- (P<.05) mice, respectively; mean values for tumor multiplicity of each genotype were 0.5, 0.6, and 1.1 (P<.05), respectively. Phosphorylation of AMPK decreased in intestinal epithelial cells of APN-/- mice compared with APN+/+ mice. Among serum adipocytokines, plasminogen activator inhibitor-1 levels increased in APN-/-Min mice and APN-/- mice that received injections of AOM. Activation of AMPK suppressed expression of plasminogen activator inhibitor-1 in Min mice. CONCLUSIONS: Mice with disruptions in APN develop more intestinal tumors and have decreased activation (phosphorylation) of AMPK and increased levels of plasminogen activator inhibitor-1, compared with wild-type mice. APN and its receptor might be developed as targets for cancer chemopreventive agents.