Cancer Chemoprevention by Citrus Pulp and Juices Containing High Amounts of β-Cryptoxanthin and Hesperidin

β-Cryptoxanthin, a carotenoid, and hesperidin, a flavonoid, possess inhibitory effects on carcinogenesis in several tissues. We recently have prepared a pulp (CHRP) and citrus juices (MJ2 and MJ5) from a satsuma mandarin (Citrus unshiu Mar.) juice (MJ). They contain high amounts of β-cryptoxanthin and hesperidin. We have demonstrated that CHRP and/or MJs inhibit chemically induced rat colon, rat tongue, and mouse lung tumorigenesis. Gavage with CHRP resulted in an increase of activities of detoxifying enzymes in the liver, colon, and tongue rats'. CHRP and MJs were also able to suppress the expression of proinflammatory cytokines and inflammatory enzymes in the target tissues. This paper describes the findings of our in vivo preclinical experiments to develop a strategy for cancer chemoprevention of colon, tongue, and lung neoplasms by use of CHRP and MJs

Pathobiology and Chemoprevention of Bladder Cancer

Our understanding of the pathogenesis of bladder cancer has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies, prevention, or strategies to manage patients who are suspected to have or who have been diagnosed with bladder cancer is the ultimate goal. In particular, the chemoprevention of bladder cancer development is important, since urothelial cancer frequently recurs, even if the primary cancer is completely removed. The numerous alterations of both oncogenes and tumor suppressor genes that have been implicated in bladder carcinogenesis represent novel targets for therapy and prevention. In addition, knowledge about these genetic alterations will help provide a better understanding of the biological significance of preneoplastic lesions of bladder cancer. Animal models for investigating bladder cancer development and prevention can also be developed based on these alterations. This paper summarizes the results of recent preclinical and clinical chemoprevention studies and discusses screening for bladder cancer

Lack of Modifying Effects of Intratracheal Instillation of Quartz or Dextran Sulfate Sodium (DSS) in Drinking Water on Lung Tumor Development Initiated with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Female A/J Mice

The purpose of the present study was to investigate the effects of inflammation, induced by intratracheal instillation (i.t.) of quartz as an environmental factor in the lung or drinking of dextran sulfate sodium (DSS) as an environmental factor in the colon on lung tumors in female A/J mice initiated with NNK. For comparison, colonic preneoplastic lesions, aberrant crypt foci (ACF), were also assessed. A/J mice at 6 weeks of age were divided into 5 groups, and Groups 1, 2 and 3 were pretreated with NNK (2 mg / 0.1 ml saline / mouse, intraperitoneal injection) at week 0. For a week, 2% DSS in drinking water was administered to the mice in Groups 2 and 4 beginning in week 1. In week 2, the mice of Groups 3 and 5 were exposed to intratracheal instillation of quartz (0.1 mg/rat) suspended in 25 μl saline. The experiment was terminated after 16 weeks. The results for the lung tumors and colonic ACFs showed a lack of modifying effects of the inflammation in either site. Hematologically and histopathologically, the inflammation induced by 0.1 mg quartz in the lung and 2% DSS in the colon was lacking or only mild at the end of 16 weeks. These results suggest that there may be differences in sensitivity to inflammation that determine tumor promoting potential

An Intratracheal Instillation Bioassay System for Detection of Lung Toxicity Due to Fine Particles in F344 Rats

It is an urgent priority to establish in vivo bioassays for detection of hazards related to fine particles, which can be inhaled into deep lung tissue by humans. In order to establish an appropriate bioassay for detection of lung damage after particle inhalation, several experiments were performed in rats using quartz as a typical lung toxic particle. The results of pilot experiments suggest that Days 1 and 28 after intratracheal instillation of 2 mg of fine test particles in vehicle are most appropriate for detection of acute and subacute inflammatory changes, respectively. Furthermore, the BrdU incorporation on Day 1 and the iNOS level on Day 28 proved to be suitable end-point markers for this purpose. An examination of the toxicity of a series of particles was performed with the developed bioassay. Although some materials, including nanoparticles, demonstrated toxicity that was too strong for sensitive assessment, a ranking order could be clarified. The bioassay thus appears suitable for rapid hazard identification with a possible ranking of the toxicity of various particles at single concentrations

GPCR-mediated calcium and cAMP signaling determines psychosocial stress susceptibility and resiliency

ストレスに強い脳と弱い脳のメカニズム解明 --うつ病の脳のしくみ解明へ前進--. 京都大学プレスリリース. 2023-04-06.Chronic stress increases the risk of developing psychiatric disorders, including mood and anxiety disorders. Although behavioral responses to repeated stress vary across individuals, the underlying mechanisms remain unclear. Here, we perform a genome-wide transcriptome analysis of an animal model of depression and patients with clinical depression and report that dysfunction of the Fos-mediated transcription network in the anterior cingulate cortex (ACC) confers a stress-induced social interaction deficit. Critically, CRISPR-Cas9–mediated ACC Fos knockdown causes social interaction deficits under stressful situation. Moreover, two classical second messenger pathways, calcium and cyclic AMP, in the ACC during stress differentially modulate Fos expression and regulate stress-induced changes in social behaviors. Our findings highlight a behaviorally relevant mechanism for the regulation of calcium- and cAMP-mediated Fos expression that has potential as a therapeutic target for psychiatric disorders related to stressful environments

Lung Carcinogenic Bioassay of CuO and TiO2 Nanoparticles with Intratracheal Instillation Using F344 Male Rats

Toxicity assessment of nanoparticles, now widespread in our environment, is an important issue. We have focused attention on the carcinogenic potential of copper oxide (CuO) and titanium dioxide (TiO2). In experiment 1, a sequential pilot study, the effectiveness of a carcinogenic bioassay featuring intraperitoneal injection (i.p.) of 20 mg 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) in drinking water for 2 weeks was examined. Based on the results, DHPN, as the lung carcinogen, and evaluation at week 30 were selected as the most appropriate for our purposes in Experiment 1. In experiment 2, the carcinogenic bioassay was used to assess the carcinogenic potentials of instilled nanoparticles of CuO and TiO2. There were no significant intergroup differences in the lung neoplastic lesions induced by DHPN, although the neoplastic lesions induced by the nanoparticles in the CuO or TiO2 intratracheal instillation (i.t.) groups, demonstrated a tendency to increase compared with the microparticles administration. At the very least, the carcinogenic bioassay with DHPN proved useful for assessment of the modifying effects of instilled particles, and further assessment of the carcinogenic potential of nanoparticles appears warranted

Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex

[Background] A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. [Methods] We used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors. [Results] Cartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non–monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. [Conclusions] These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience

C57BL/KsJ-db/db-ApcMin/+ Mice Exhibit an Increased Incidence of Intestinal Neoplasms

The numbers of obese people and diabetic patients are ever increasing. Obesity and diabetes are high-risk conditions for chronic diseases, including certain types of cancer, such as colorectal cancer (CRC). The aim of this study was to develop a novel animal model in order to clarify the pathobiology of CRC development in obese and diabetic patients. We developed an animal model of obesity and colorectal cancer by breeding the C57BL/KsJ-db/db (db/db) mouse, an animal model of obesity and type II diabetes, and the C57BL/6J-ApcMin/+ (Min/+) mouse, a model of familial adenomatous polyposis. At 15 weeks of age, the N9 backcross generation of C57BL/KsJ-db/db-ApcMin/+ (db/db-Min/+) mice developed an increased incidence and multiplicity of adenomas in the intestinal tract when compared to the db/m-Min/+ and m/m-Min/+ mice. Blood biochemical profile showed significant increases in insulin (8.3-fold to 11.7-fold), cholesterol (1.2-fold to 1.7-fold), and triglyceride (1.2-fold to 1.3-fold) in the db/db-Min/+ mice, when compared to those of the db/m-Min/+ and m/m-Min/+ mice. Increases (1.4-fold to 2.6-fold) in RNA levels of insulin-like growth factor (IGF)-1, IRF-1R, and IGF-2 were also observed in the db/db- Min/+ mice. These results suggested that the IGFs, as well as hyperlipidemia and hyperinsulinemia, promoted adenoma formation in the db/db-Min/+ mice. Our results thus suggested that the db/db-Min/+ mice should be invaluable for studies on the pathogenesis of CRC in obese and diabetes patients and the therapy and prevention of CRC in these patients