The Role of PPARs in Cancer

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARα is mainly expressed in the liver, where it activates fatty acid catabolism. PPARα activators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high-density lipoprotein cholesterol. PPARδ is expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte differentiation. PPARδ activators have been proposed for the treatment of metabolic disease. PPARγ2 is expressed exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation. PPARγ is involved in glucose metabolism through the improvement of insulin sensitivity and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor growth

Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases

Tanaka M., Shirakura K., Takayama Y., et al. Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases. Communications Biology 7, 599 (2024); https://doi.org/10.1038/s42003-024-06317-z .Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein, Roundabout4 (ROBO4). ROBO4 has been shown to ameliorate multiple diseases in mice, including infectious diseases and sepsis. However, its mechanisms are not fully understood. In this study, using RNA-seq analysis, we found that ROBO4 downregulates prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2. Mechanistic analysis reveals that ROBO4 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) and TNF receptor-associated factor 7 (TRAF7), a ubiquitin E3 ligase. In this complex, ROBO4 enhances IQGAP1 ubiquitination through TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2 expression in inflammatory endothelial cells. In addition, Robo4-deficiency in mice exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain. Thus, we reveal the molecular mechanism by which ROBO4 suppresses the inflammatory response and vascular hyperpermeability, highlighting its potential as a promising therapeutic target for inflammatory diseases

Molecular Characterization of the Tumor Suppressor Candidate 5 Gene: Regulation by PPARγ and Identification of TUSC5 Coding Variants in Lean and Obese Humans

Tumor suppressor candidate 5 (TUSC5) is a gene expressed abundantly in white adipose tissue (WAT), brown adipose tissue (BAT), and peripheral afferent neurons. Strong adipocyte expression and increased expression following peroxisome proliferator activated receptor γ (PPARγ) agonist treatment of 3T3-L1 adipocytes suggested a role for Tusc5 in fat cell proliferation and/or metabolism. However, the regulation of Tusc5 in WAT and its potential association with obesity phenotypes remain unclear. We tested the hypothesis that the TUSC5 gene is a bona fide PPARγ target and evaluated whether its WAT expression or single-nucleotide polymorphisms (SNPs) in the TUSC5 coding region are associated with human obesity. Induction of Tusc5 mRNA levels in 3T3-L1 adipocytes by troglitazone and GW1929 followed a dose-response consistent with these agents' binding affinities for PPARγ. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPARγ protein binds a ∼ −1.1 kb promotor sequence of murine TUSC5 transiently during 3T3-L1 adipogenesis, concurrent with histone H3 acetylation. No change in Tusc5 mRNA or protein levels was evident in type 2 diabetic patients treated with pioglitazone. Tusc5 expression was not induced appreciably in liver preparations overexpressing PPARs, suggesting that tissue-specific factors regulate PPARγ responsiveness of the TUSC5 gene. Finally, we observed no differences in Tusc5 WAT expression or prevalence of coding region SNPs in lean versus obese human subjects. These studies firmly establish the murine TUSC5 gene locus as a PPARγ target, but the significance of Tusc5 in obesity phenotypes or in the pharmacologic actions of PPARγ agonists in humans remains equivocal

Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K‐RAS status for unresectable colorectal liver metastasis (BECK study): Long‐term results of survival

[Background/Purpose]To investigate the long‐term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy. [Methods]Recurrence and survival data with long‐term follow‐up were analyzed in the cohort of a multi‐institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study). [Results]A total of 22/12 patients with K‐RAS wild‐type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left‐sided primary tumors than in right‐sided tumors (75.0% vs 30.0%, P = .022). The median follow‐up was 72.6 months. The 5‐year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5‐year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow‐up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5‐year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1‐4). [Conclusions]Conversion hepatectomy achieved a similar long‐term survival to the results of previous studies in initially resectable patients, although many of them experienced several post‐hepatectomy recurrences. Left‐sided primary was found to be the predictor for conversion hepatectomy

Alternative Stable States Generated by Ontogenetic Niche Shift in the Presence of Multiple Resource Use

It has been suggested that when juveniles and adults use different resources or habitats, alternative stable states (ASS) may exist in systems coupled by an ontogenetic niche shift. However, mainly the simplest system, i.e., the one-consumer–two-resource system, has been studied previously, and little is known about the development of ASS existing in more complex systems. Here, I theoretically investigated the development of ASS caused by an ontogenetic niche shift in the presence of multiple resource use. I considered three independent scenarios; (i) additional resources, (ii) multiple habitats, and (iii) interstage resource sharing. The model analyses illustrate that relative balance between the total resource availability in the juvenile and adult habitats is crucial for the development of ASS. This balance is determined by factors such as local habitat productivity, subsidy inputs, colonization area, and foraging mobility. Furthermore, it is also shown that interstage resource sharing generally suppresses ASS. These results suggest that the anthropogenic impacts of habitat modifications (e.g., fragmentation and destruction) or interaction modifications (e.g., changes in ontogeny and foraging behavior) propagate through space and may cause or prevent regime shifts in the regional community structure

PPAR beta/delta activation of CD300a controls intestinal immunity

Macrophages are important for maintaining intestinal immune homeostasis. Here, we show that PPAR beta/delta (peroxisome proliferator-activated receptor beta/delta) directly regulates CD300a in macrophages that express the immunoreceptor tyrosine based-inhibitory motif (ITIM)-containing receptor. In mice lacking CD300a, high-fat diet (HFD) causes chronic intestinal inflammation with low numbers of intestinal lymph capillaries and dramatically expanded mesenteric lymph nodes. As a result, these mice exhibit triglyceride malabsorption and reduced body weight gain on HFD. Peritoneal macrophages from Cd300a(-/-) mice on HFD are classically M1 activated. Activation of toll-like receptor 4 (TLR4)/MyD88 signaling by lipopolysaccharide (LPS) results in prolonged IL-6 secretion in Cd300a(-/-) macrophages. Bone marrow transplantation confirmed that the phenotype originates from CD300a deficiency in leucocytes. These results identify CD300a-mediated inhibitory signaling in macrophages as a critical regulator of intestinal immune homeostasis

Transcriptional Activation of Low-Density Lipoprotein Receptor Gene by DJ-1 and Effect of DJ-1 on Cholesterol Homeostasis

DJ-1 is a novel oncogene and also causative gene for familial Parkinson’s disease park7. DJ-1 has multiple functions that include transcriptional regulation, anti-oxidative reaction and chaperone and mitochondrial regulation. For transcriptional regulation, DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found the low-density lipoprotein receptor (LDLR) gene is a transcriptional target gene for DJ-1. Reduced expression of LDLR mRNA and protein was observed in DJ-1-knockdown cells and DJ-1-knockout mice and this occurred at the transcription level. Reporter gene assays using various deletion and point mutations of the LDLR promoter showed that DJ-1 stimulated promoter activity by binding to the sterol regulatory element (SRE) with sterol regulatory element binding protein (SREBP) and that stimulating activity of DJ-1 toward LDLR promoter activity was enhanced by oxidation of DJ-1. Chromatin immunoprecipitation, gel-mobility shift and co-immunoprecipitation assays showed that DJ-1 made a complex with SREBP on the SRE. Furthermore, it was found that serum LDL cholesterol level was increased in DJ-1-knockout male, but not female, mice and that the increased serum LDL cholesterol level in DJ-1-knockout male mice was cancelled by administration with estrogen, suggesting that estrogen compensates the increased level of serum LDL cholesterol in DJ-1-knockout female mice. This is the first report that DJ-1 participates in metabolism of fatty acid synthesis through transcriptional regulation of the LDLR gene

How to prevent adverse events of vascular stapling in thoracic surgery: recommendations based on a clinical and experimental study

Background: Advances in the development of staplers for pulmonary vessels have contributed to safe and convenient procedures in thoracic surgery. However, adverse events (AEs) can occur during vascular stapling and cause fatal hemorrhage. We aimed to assess the risk level of using the vessel stapling procedure to reduce such AEs. Methods: First, an animal experiment using pig cardiopulmonary blocks was conducted. Pulmonary arteries were closed with staplers under stressful conditions such as lifting or twisting; vessel stump endurance was analyzed through different methods. Second, AEs associated with clinical stapler use for pulmonary vessels were retrospectively reviewed by studying clinical videos of 263 patients. Results: In the animal experiment, the pressure resistance was significantly lower in the twisted group than in the no strain group (no strain vs. lifting: P=0.2008, no strain vs. twisting: P=0.002, no strain vs. twisting and lifting: P<0.0001). Regarding clinical stapler use, 754 staplers were used against the vessels. AEs occurred in 9 cases, and 7 cases were suspected to be caused by vessel tension. Conclusions: The pulmonary vessel stapling causes stress due to twisting and lifting that decreased stump durability. Avoiding such stress when using stapler for vessels leads to a safer thoracic surgery

Pulmonary syphilis with a cicatricial variant of organizing pneumonia: a case report

Abstract Background Syphilis is a chronic disease that progresses in the primary, secondary, latent, and tertiary stages. Pulmonary manifestations of syphilis are rare, and their histological features have not been well-described. Case presentation A 78-year-old man was referred to our hospital because of a solitary nodular shadow in the right middle lung field on a chest radiograph. Five years prior, a rash appeared on both legs. He was tested for syphilis at a public health center, and the non-treponemal test result was negative. When he was approximately 35 years old, he had unspecified sexual intercourse. Chest computed tomography showed a 13-mm nodule with a cavity in S6 of the right lower lobe of the lung. Robot-assisted resection of the right lower lobe was performed because of suspected localized right lower lobe lung cancer. A cicatricial variant of organizing pneumonia (CiOP) was observed, and immunohistochemistry identified Treponema pallidum inside the macrophages in the nodule cavity. The rapid plasma regain (RPR) value was negative, and the Treponema pallidum hemagglutination assay was positive. The patient was diagnosed as having secondary syphilis with pulmonary involvement. Insidious progression of secondary syphilis may result in CiOP and a negative RPR test result. Conclusions We report the first case of pulmonary syphilis with a histological pattern of CiOP. It may be asymptomatic and difficult to diagnose because the RPR test may be negative for a long period of time. When either non-treponemal or treponemal test results are positive, the possibility of pulmonary syphilis should be considered along with appropriate medical treatment