Generation of interleukin-8 by plasmin from AVLPR-interleukin-8, the human fibroblast-derived neutrophil chemotactic factor

AbstractPlasmin mainly cleaved the Arg5-Ser6 bond of Arg-Val-Leu-Pro-Arg-interleukin-8 (AVLPR-IL-8) produced by human dermal fibroblasts, which resulted in the conversion of AVLPR-IL-8 to IL-8 and the inactive pentapeptide, though a minor cleavage of AVLPR-IL-8 by plasmin at Lys8-Glu9 bond occurred

Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia

Propofol-induced vasodilation and aging

Background : Propofol causes vasodilation via endothelium-dependent and -independent mechanisms. Because endothelial function is impaired with aging, the effects of propofol on endothelium-dependent vasodilation might be altered by aging. The aim of this study was thus to determine the effects of aging on vascular responses to propofol. Methods : Young (4-6 weeks old) or adult (16-25 weeks old) rats were anesthetized with sevoflurane. The thoracic aorta was dissected and cut into pieces 3-4mm in length. In some rings, the endothelium was deliberately removed. The ring segment of the aorta was mounted for isometric force recording at a resting tension of 0.5-1.0 g in a 2 ml organ bath, containing Krebs-Ringer bicarbonate buffer. Arteries were precontracted with phenylephrine, and the function of endothelium was confirmed with acetylcholine. Then, we studied the concentration-dependent effects of propofol in endothelium-intact (control group) and -denuded aortic rings (denuded group), as well as those treated with N[ω]-nitro-L-arginine methylester (L-NAME group). Results : Relaxation due to propofol was observed in the control groups of both young and adult rats in a concentration-dependent manner, but the magnitude of relaxation was significantly greater in young rats. In addition, in young rats, relaxation due to propofol was significantly and equally reduced in both L-NAME and denuded groups at all propofol concentrations that we studied (10[-6]-10[-3] M). In adult rats, relaxation due to propofol was quite similar between control and L-NAME groups at all propofol concentrations, whereas it was significantly reduced in the denuded group. Conclusion : These results suggest that endothelium-derived nitric oxide plays an important role in propofol-induced vasodilation in young rats, but not in adult rats

Individual hematopoietic stem cells in human bone marrow of patients with aplastic anemia or myelodysplastic syndrome stably give rise to limited cell lineages

Mutation of the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIG-A) gene in hematopoietic stem cells (HSCs) results in the loss of glycosylphosphatidylinositol- anchored proteins (GPI-APs) on HSCs, but minimally affects their development, and thus can be used as a clonal maker of HSCs. We analyzed GPI-APs expression on six major lineage cells in a total of 574 patients with bone marrow (BM) failure in which microenvironment itself is thought to be unaffected, including aplastic anemia (AA) or myelodysplastic syndrome (MDS). GPI-APs-deficient (GPIAPs-) cells were detected in 250 patients. Whereas the GPIAPs- cells were seen in all six lineages in a majority of patients who had higher proportion ([dbmtequ]3%) of GPIAPs- cells, they were detected in only limited lineages in 92.9% of cases in the lower proportion (<3%) group. In all 250 cases, the same lineages of GPI-APs- cells were detected even after 6-18-month intervals, indicating that the GPIAPs- cells reflect hematopoiesis maintained by a self-renewing HSC in most of cases. The frequency of clones with limited lineages seen in mild cases of AA was similar to that in severe cases, and clones with limited lineages were seen even in two health volunteer cases. These results strongly suggest most individual HSCs produce only restricted lineages even in a steady state. While this restriction could reflect heterogeneity in the developmental potential of HSCs, we propose an alternative model in which the BM microenvironment is mosaic in supporting commitment of progenitors toward distinct lineages. Our computer simulation based on this model successfully recapitulated the observed clinical data. © AlphaMed Press

Periostin Promotes Tumor Lymphangiogenesis

Background: Metastasis to regional lymph nodes via lymphatic vessels plays a key role in cancer progression. Tumor lymphangiogenesis is known to promote lymphatic metastasis, and vascular endothelial growth factor C (VEGF-C) is a critical activator of tumor lymphangiogenesis during the process of metastasis. We previously identified periostin as an invasion- and angiogenesis-promoting factor in head and neck squamous cell carcinoma (HNSCC). In this study, we discovered a novel role for periostin in tumor lymphangiogenesis. Methods and Findings: Periostin overexpression upregulated VEGF-C mRNA expression in HNSCC cells. By using conditioned media from periostin-overexpressing HNSCC cells, we examined tube formation of lymphatic endothelial cells. Conditioned media from periostin-overexpressing cells promoted tube formation. To know the correlation between periostin and VEGF-C, we compared Periostin expression with VEGF-C expression in 54 HNSCC cases by immunohistochemistry. Periostin expression was correlated well with VEGF-C expression in HNSCC cases. Moreover, correlation between periostin and VEGF-C secretion was observed in serum from HNSCC patients. Interestingly, periostin itself promoted tube formation of lymphatic endothelial cells independently of VEGF-C. Periostin-promoted lymphangiogenesis was mediated by Src and Akt activity. Indeed possible correlation between periostin and lymphatic status in periostin-overexpressing xenograft tumors and HNSCC cases was observed. Conclusions: Our findings suggest that periostin itself as well as periostin-induced upregulation of VEGF-C may promote lymphangiogenesis. We suggest that periostin may be a marker for prediction of malignant behaviors in HNSCC and a potential target for future therapeutic intervention to obstruct tumoral lymphatic invasion and lymphangiogenesis in HNSCC patients

Development of a Multifunctional Lightweight Membrane with a High Specific Power Generation Capacity

As a lighter power generation system, Japan Aerospace Exploration Agency (JAXA) and Sakase Adtech Corp. are developing a demonstrator component named “Harvesting Energy with Lightweight Integrated Origami Structure” (HELIOS), which is a deployable lightweight membrane structure. HELIOS has solar arrays on its surface and demonstrates the technology which enables higher specific power generation capacity compared to the conventional solar array panels. The membrane also has communication antennas, showing the potency of lightweight membrane’s multifunctionality such as large data transmitting by 5G antennas and high-resolution observation by interferometer antennas. This paper presents the component’s concept and design, and the expected achievements

Pharmacological characterization of a novel 5-hydroxybenzothiazolone-derived b2-adrenoceptor agonist with functional selectivity for anabolic effects on skeletal muscle resulting in a wider cardiovascular safety window in preclinical studies

Copyright ª 2019 by The Author(s) The anabolic effects of b2-adrenoceptor (b2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of b2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived b2-AR agonist in comparison with formoterol as a representative b2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human b2-AR and selectivity over the b1-AR and b3-AR. 5-HOB also shows potent agonistic activity at the b2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue–derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional b2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects