農業用殺菌剤、植物病原菌の有害代謝産物によるファイトアレキシンの生産

The endocarp of the fresh pea pod incubated with solution or suspension of agricultural fungicides, phytotoxic metabolites of plant pathogenic fungi formed the pea phytoalexin, pisatin. Among the compounds tested, cycloheximide, triazine, dichlone, phenyimercury acetate, UV degradation product of phenylmercury acetate, triphenyltin fungicides, and 3-hydroxy-5-methylisoxazole induced pisatin. Ophiobolin, a toxin from Cochliobolus mtyabeanus, and ascochitine, a toxic metabolite from Ascochyta fabae, also induced pisatin. The possibilities of the development of harmless plant disease control agents was discussed in relation- to the induced synthesis of phytoalexins

Naturally Occurring 3RS, 7R, 11R-Phytanic Acid Suppresses In Vitro T-Cell Production of Interferon-Gamma

Background: Among the eight stereoisomers of phytanic acid (PA), the 3RS, 7R, 11R-isomer is naturally occurring and is present in foods and the human body. PA is considered to have possible health benefits in the immune system. However, it remains undetermined whether these effects are elicited by the 3RS, 7R, 11R-PA isomer, because previous studies used a commercially available PA whose isomer configuration is unknown. In this study, we synthesized a preparation of 3RS, 7R, 11R-PA, and investigated its in vitro immunomodulatory effects, especially the T-cell production of interferon (IFN)-γ, which is associated with various autoimmune diseases. This study also investigated the effects of 3RS, 7R, 11R-PA on NF-κB activity in order to address the mechanism of its immunomodulatory effects. Methods: Mouse splenocytes and purified T-cells were stimulated with T-cell mitogens and incubated with 3RS, 7R, 11R-PA, followed by evaluation of IFN-γ production. The effect of 3RS, 7R, 11R-PA on NF-κB activity was also investigated using an A549 cell line with stable expression of an NF-κB-dependent luciferase reporter gene. Results: 3RS, 7R, 11R-PA significantly reduced in vitro IFN-γ production at both the protein and mRNA levels, and was accompanied by decreased expression of T-bet, a key regulator of Th1 cell differentiation. The results indicated that NFκB-mediated transcriptional activity was significantly decreased by 3RS, 7R, 11R-PA and that GW6471, an antagonist of peroxisome proliferator activated receptor α (PPARα), abrogated the inhibitory effect of 3RS, 7R, 11R-PA on NF-κB activity. Conclusions: The present study suggests that 3RS, 7R, 11R-PA is a functional and bioactive fatty acid, and has a potentially beneficial effect for amelioration of T-cell mediated autoimmune diseases. This study also indicates that interference in the NF-κB pathway via PPARα activation is a potential mechanism of the immunomodulatory effects of 3RS, 7R, 11R-PA

Changes in Expression of the Autophagy-Related Genes Microtubule-Associated Protein 1 Light Chain 3β and Autophagy Related 7 in Skeletal Muscle of Fattening Japanese Black Cattle: A Pilot Study

Objective Autophagy is a bulk degradation system for intracellular proteins which contributes to skeletal muscle homeostasis, according to previous studies in humans and rodents. However, there is a lack of information on the physiological role of autophagy in the skeletal muscle of meat animals. This study was planned as a pilot study to investigate changes in expression of two major autophagy-related genes, microtubule-associated protein 1 light chain 3β (MAP1LC3B) and autophagy related 7 (ATG7) in fattening beef cattle, and to compare them with skeletal muscle growth. Methods Six castrated Japanese Black cattle (initial body weight: 503±20 kg) were enrolled in this study and fattened for 7 months. Three skeletal muscles, M. longissimus, M. gluteus medius, and M. semimembranosus, were collected by needle biopsy three times during the observation period, and mRNA levels of MAP1LC3B and ATG7 were determined by quantitative reverse-transcription polymerase chain reaction. The expression levels of genes associated with the ubiquitin-proteasome system, another proteolytic mechanism, were also analyzed for comparison with autophagy-related genes. In addition, ultrasonic scanning was repeatedly performed to measure M. longissimus area as an index of muscle growth. Results Our results showed that both MAP1LC3B and ATG7 expression increased over the observation period in all three skeletal muscles. Interestingly, the increase in expression of these two genes in M. longissimus was highly correlated with ultrasonic M. longissimus area and body weight. On the other hand, the expression of genes associated with the ubiquitin-proteasome system was unchanged during the same period. Conclusion These findings suggest that autophagy plays an important role in the growth of skeletal muscle of fattening beef cattle and imply that autophagic activity affects meat productivity

Multidisciplinary treatment system for bone metastases for early diagnosis, treatment and prevention of malignant spinal cord compression

Malignant spinal cord compression (MSCC) is a serious complication of cancers. The present study aimed to establish a multidisciplinary treatment system for urgent magnetic resonance imaging (MRI) and referral to orthopedists in order to prevent neurological deficits caused by MSCC. In the present study, the extent to which this system achieved early diagnosis and treatment and prevented MSCC‑caused neurological deficits was examined. The records from patients with neurological deficits caused by MSCC before (between April 2007 and March 2012; group A) and after (between April 2012 and March 2017; group B) the establishment of the multidisciplinary system at the Shikoku Cancer Center (Ehime, Japan) were retrospectively evaluated. The numbers of patients with neurological deficits were 38 and 7 in groups A and B, respectively. All patients received radiotherapy. The incidence of neurological deficits was 13.2 and 3.4% in groups A and B, respectively (P<0.001). The proportion of patients with improvement in the severity of neurological deficits was 5.3 and 28.6% in groups A and B, respectively (P<0.001). The interval between physicians' recognition of a neurological deficit and MRI and the start of treatment, the number of cases, and the severity of neurological deficits were evaluated in groups A and B. The median interval between recognition of a neurological deficit by physicians and MRI was 3 and 0 days in groups A and B, respectively (P<0.001). The median interval between physicians' recognition of a neurological deficit and the start of treatment was 3 and 0 days in groups A and B, respectively (P<0.001). By using a multidisciplinary treatment system, the incidence and severity of neurological deficits following treatment were significantly improved. Therefore, the multidisciplinary treatment system used in the present study may be useful for early diagnosis, treatment and prevention of MSCC in patients with bone metastases

Small airway disease associated with Sjögren’s syndrome: Clinico-pathological correlations

SummaryBackgroundRelationships among clinical, physiological, imaging and pathological findings of small airway disease associated with Sjögren’s syndrome have remained unclear.Subjects and methods: We retrospectively studied 14 patients who underwent surgical lung biopsy and who were diagnosed with small airway disease associated with primary or secondary Sjögren’s syndrome. We compared clinical, bronchoalveolar lavage, physiological, imaging and pathological findings between primary and secondary Sjögren’s syndrome. We scored HRCT and pathological abnormalities and investigated correlations among physiological, HRCT and pathological data, changes in physiological parameters and in HRCT scores after two years of treatment, as well as correlations between these values and pathological scores.ResultsBronchoalveolar lavage fluid, physiological, imaging and pathological findings of the airways did not significantly differ between primary and secondary Sjögren’s syndrome. Air trapping on HRCT negatively correlated with MEF50 and MEF25. Although lymphoid cell infiltration and peribronchiolar fibrosis were the most common pathologies, constrictive change scores correlated negatively with MEF50 and MEF25, positively with air trapping scores and negatively with improvements after therapy in MEF50, MEF25 and air trapping.ConclusionsConstrictive change was the most significant determinant of physiological and imaging presentations and of changes in these factors after therapy for small airway disease associated with Sjögren’s syndrome

Changes in expression of the autophagy-related genes microtubule-associated protein 1 light chain 3β and autophagy related 7 in skeletal muscle of fattening Japanese Black cattle: a pilot study

Objective Autophagy is a bulk degradation system for intracellular proteins which contributes to skeletal muscle homeostasis, according to previous studies in humans and rodents. However, there is a lack of information on the physiological role of autophagy in the skeletal muscle of meat animals. This study was planned as a pilot study to investigate changes in expression of two major autophagy-related genes, microtubule-associated protein 1 light chain 3β (MAP1LC3B) and autophagy related 7 (ATG7) in fattening beef cattle, and to compare them with skeletal muscle growth. Methods Six castrated Japanese Black cattle (initial body weight: 503±20 kg) were enrolled in this study and fattened for 7 months. Three skeletal muscles, M. longissimus, M. gluteus medius, and M. semimembranosus, were collected by needle biopsy three times during the observation period, and mRNA levels of MAP1LC3B and ATG7 were determined by quantitative reverse-transcription polymerase chain reaction. The expression levels of genes associated with the ubiquitin-proteasome system, another proteolytic mechanism, were also analyzed for comparison with autophagy-related genes. In addition, ultrasonic scanning was repeatedly performed to measure M. longissimus area as an index of muscle growth. Results Our results showed that both MAP1LC3B and ATG7 expression increased over the observation period in all three skeletal muscles. Interestingly, the increase in expression of these two genes in M. longissimus was highly correlated with ultrasonic M. longissimus area and body weight. On the other hand, the expression of genes associated with the ubiquitin-proteasome system was unchanged during the same period. Conclusion These findings suggest that autophagy plays an important role in the growth of skeletal muscle of fattening beef cattle and imply that autophagic activity affects meat productivity

Epithelial EP4 plays an essential role in maintaining homeostasis in colon

Colonic epithelial cells comprise the mucosal barrier, and their dysfunction promotes microbial invasion from the gut lumen and induces the development of intestinal inflammation. The EP4 receptor is known to mediate the protective effect of prostaglandin (PG) E2 in the gastrointestinal tract; however, the exact role of epithelial EP4 in intestinal pathophysiology remains unknown. In the present study, we aimed to investigate the role of epithelial EP4 in maintaining colonic homeostasis by characterizing the intestinal epithelial cell-specific EP4 knockout (EP4 cKO) mice. Mice harboring the epithelial EP4 deletion showed significantly lower colonic crypt depth and lower numbers of secretory cell lineages, as well as impaired epithelial cells in the colon. Interestingly, EP4-deficient colon epithelia showed a higher number of apoptotic cells. Consistent with the defect in mucosal barrier function of colonic epithelia and secretory cell lineages, EP4 cKO colon stroma showed enhanced immune cell infiltration, which was accompanied by increased production of inflammatory cytokines. Furthermore, EP4-deficient colons were susceptible to dextran sulfate sodium (DSS)-induced colitis. Our study is the first to demonstrate that epithelial EP4 loss resulted in potential "inflammatory" status under physiological conditions. These findings provided insights into the crucial role of epithelial PGE2/EP4 axis in maintaining intestinal homeostasis

JNK pathway plays a critical role for expansion of human colorectal cancer in the context of BRG1 suppression

Tumor stem cells (TSCs), capable of self-renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c-JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c-JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC

Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis

膵癌悪性化の分子機構解明 --RECK発現の低下が膵癌の浸潤・転移を引き起こす--. 京都大学プレスリリース. 2023-09-19.RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast–like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC

Increased fatty acyl saturation of phosphatidylinositol phosphates in prostate cancer progression

Phosphoinositides (PIPs) participate in many cellular processes, including cancer progression; however, the metabolic features of PIPs associated with prostate cancer (PCa) are unknown. We investigated PIPs profiles in PTEN-deficient prostate cancer cell lines, human prostate tissues obtained from patients with PCa and benign prostate hyperplasia (BPH) specimens using mass spectrometry. In immortalized normal human prostate PNT1B cells, PTEN deficiency increased phosphatidylinositol tris-phosphate (PIP3) and decreased phosphatidylinositol mono- and bis-phosphate (PIP1 and PIN2 consistent with PTEN\u27s functional role as a PI(3,4,5)P-3 3-phosphatase. In human prostate tissues, levels of total (sum of all acyl variants) phosphatidylinositol (PI) and PIP1 in PCa were significantly higher than in BPH, whereas PIP2 and PIP3 contents were significantly lower than in BPH. PCa patients had significantly higher proportion of PI, PIP1, and PIP2 with 0-2 double bonds in acyl chains than BPH patients. In subgroup analyses based on PCa aggressiveness, mean total levels of PI with 0-2 double bonds in acyl chains were significantly higher in patients with pathological stage T3 than in those with pathological stage T2. These data indicate that alteration of PIPs level and the saturation of acyl chains may be associated with the development and aggressiveness of prostate cancer, although it is unknown whether this alteration is causative