Efficient protective activity of a planar catechin analogue against radiation-induced apoptosis in rat thymocytes

About two thirds of biological damage due to low linear energy transfer (LET) radiation, such as X-rays and the plateau region of heavy-ion beams, is known to be caused by the hydroxyl radical (˙OH), the most powerful reactive oxygen species (ROS), generated via ionisation and excitation of water molecules. Thus, compounds having an efficient scavenging activity against ROS are expected to exhibit a radioprotective activity. A planar catechin analogue, where an isopropyl fragment was introduced into the catechol ring of (+)-catechin, showed an efficient protective effect against X-ray induced apoptosis in rat thymocytes compared to (+)-catechin. The planar catechin scavenged 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH˙) solubilised in water by β-cyclodextrin about 10-fold faster than (+)-catechin in phosphate buffer (0.1 M, pH 7.4) at 298 K. Furthermore, the experimental log P value of the planar catechin (1.22) is reported to be significantly larger than that of (+)-catechin (0.44). The higher radical-scavenging activity and lipophilicity of the planar catechin than those of (+)-catechin may contribute in part to the higher protective activity against X-ray-induced apoptosis in rat thymocytes.

A planar catechin analogue showed a significant higher protective activity against X-ray induced apoptosis in rat thymocytes than (+)-catechin.     

Evaluation of the cell survival curve under radiation exposure based on the kinetics of lesions in relation to dose-delivery time

We have investigated the dose rate effects on cell damage caused by photon-beam irradiation. During a relatively long dose-delivery time with a low dose rate, lesions created in cells may undergo some reactions, such as DNA repair. In order to investigate these reactions quantitatively, we adopted the microdosimetric–kinetic (MK) model and deduced a cell surviving fraction (SF) formula for continuous irradiation. This model enabled us to estimate the SF from dose and dose rate. The parameters in the MK model were determined so as to generate the SF, and we attempted to evaluate the dose rate effects on the SF. To deduce the cell-specific parameters in the SF formula, including the dose rate, we performed a split-dose experiment and a single-dose experiment with a constant dose-delivery time (10 min) (to retain the condition for equivalent behavior of cell lesions) by means of a clonogenic assay. Then, using the MK model parameters, the SFs were reproduced for a variety of dose rates (1.0, 0.31, 0.18, 0.025 and 0.0031 Gy/min) and were compared with reported experimental data. The SF curves predicted by the MK model agreed well with the experimental data, suggesting that the dose rate effects appear in the kinetics of cell lesions during the dose-delivery time. From fitting the analysis of the model formula to the experimental data, it was shown that the MK model could illustrate the characteristics of log-SF in a rectilinear form at a high dose range with a relatively low dose rate.     

κ Opioid receptor ligands regulate angiogenesis in development and in tumours

Opioid systems mainly regulate physiological functions such as pain, emotional tone and reward circuitry in neural tissues (brain and spinal cord). These systems are also found in extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood and blood vessels), and recent studies have elucidated their roles in various organs. The current review focuses on the roles of opioid systems in blood vessels, especially angiogenesis, during development and tumour malignancy. The balance between endogenous activators and inhibitors of angiogenesis delicately maintains a normally quiescent vasculature to sustain homeostasis. Disturbance of this balance causes pathogenic angiogenesis and, especially in tumours, several activators such as VEGF are highly expressed in the tumour microenvironment and strongly induce tumour angiogenesis, the so-called angiogenic switch. Recently, we demonstrated that κ opioid receptor agonists function as anti-angiogenic factors, which impede the angiogenic switch, in vascular development and tumour angiogenesis by inhibiting the expression of receptors for VEGF. In clinical medicine, angiogenesis inhibitors that target VEGF signalling such as bevacizumab are used as anti-cancer drugs. Although therapies that inhibit tumour angiogenesis have been highly successful for tumour therapy, most patients eventually develop resistance to this anti-angiogenic therapy. Thus, we must identify novel targets for anti-angiogenic agents to sustain inhibition of angiogenesis for tumour therapy. The regulation of responses to κ opioid receptor ligands could be useful for controlling vascular formation under physiological conditions and in cancers, and thus could offer therapeutic benefits beyond the relief of pain.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Imido-substituted triazines as dehydrative condensing reagents for the chemoselective formation of amides in the presence of free hydroxy groups

In this paper, we discuss the synthesis of imido-substituted chlorotriazines and demonstrate their use in dehydrative condensation reactions. Chemoselective amide-forming reactions of amino alcohols using succinimido-substituted chlorotriazine (2A) proceeded smoothly. Occasionally, nonselectivity was problematic during the synthesis of hydroxy-substituted amides. Moreover, it was noteworthy that this method was applicable to hydroxy-substituted carboxylic acids that could have formed a lactone or an ester during the carboxylic acid activation step. The imido-substituted chlorotriazine (2A) was superior to the amido-substituted chlorotriazine and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in terms of reaction rates and yields.

In this paper, we discuss the synthesis of imido-substituted chlorotriazines and demonstrate their use in dehydrative condensation reactions.     

A case of eosinophilic fasciitis without skin manifestations: a case report in a patient with lupus and literature review

Clinical Rheumatology - Eosinophilic fasciitis (EF) is a rare connective tissue disease that causes inflammation and fibrosis of the fascia, inducing pain and motor dysfunction. Characteristic skin...     

Type 1 Autoimmune Pancreatitis Extending along the Main Pancreatic Duct: IgG4-related Pancreatic Periductitis

We herein report a unique form of autoimmune pancreatitis (AIP) spreading along the main pancreatic duct (MPD). A 70-year-old man was referred for a small lesion at the pancreatic neck, accompanying an adjacent cyst and dilated upstream MPD. Four years earlier, health checkup images had shown a pancreatic cyst but no mass lesion. Endoscopic ultrasonography showed a contrast-enhanced, tumorous lesion, mainly occupying the MPD. With a preoperative diagnosis of ductal neoplasms mainly spreading in the MPD, Whipple''s resection was performed. The resected specimens showed MPD periductitis with IgG4-related pathology, indicating type 1 AIP. Clinicians should practice caution concerning the various AIP forms.     

Ventilatory efficiency during ramp exercise in relation to age and sex in a healthy Japanese population

BackgroundThe current understanding of ventilator efficiency variables during ramp exercise testing in the normal Japanese population is insufficient, and the responses of tidal volume (VT) and minute ventilation (V?E) to the ramp exercise test in the normal Japanese population are not known.MethodsA total of 529 healthy Japanese subjects aged 20–78 years underwent cardiopulmonary exercise testing using a cycle ergometer with ramp protocols. VT and V?E at rest, at anaerobic threshold, and at peak exercise were determined. The slope of V?E versus carbon dioxide (V?CO₂) (V?E vs. V?CO₂ slope), minimum V?E/V?CO₂, and oxygen uptake efficiency slope (OUES) were determined.ResultsFor males and females in their 20 s, peak VT (VTpeak) was 2192 ± 376 and 1509 ± 260 mL (p < 0.001), peak V?E (V?Epeak) was 80.6 ± 18.7 and 57.7 ± 13.9 L/min (sex differences p < 0.001), the V?E vs. V?CO₂ slope was 24.4 ± 3.2 and 25.7 ± 3.2 (p = 0.035), the minimum V?E/V?CO₂ was 24.2 ± 2.3 and 27.0 ± 2.8 (p < 0.001), and the OUES was 2452 ± 519 and 1991 ± 315 (p < 0.001), respectively. VTpeak and V?Epeak decreased with age and increased with weight and height. The V?E vs. V?CO₂ slope and minimum V?E/V?CO₂ increased with age, while conversely, the OUES decreased with age.ConclusionsWe have established the normal range of VT and V?E responses, the V?E vs. V?CO₂ slope, the minimum V?E/V?CO₂, and the OUES for a healthy Japanese population. Some of these parameters were influenced by weight, height, sex, and age. These results provide useful reference values for interpreting the results of cardiopulmonary exercise testing in cardiac patients.     

Increase of angiotensin converting enzyme gene expression in the hypertensive aorta.

To investigate the possible role of vascular angiotensin converting enzyme (ACE) in the development and maintenance of hypertension, we examined aortic ACE messenger RNA (mRNA) levels in two-kidney, one clip (2K1C) hypertensive rats. The blood pressure was increased remarkably at 4 weeks (early stage) after clipping and remained elevated at 12 weeks (chronic stage). The aorta ACE mRNA levels were significantly elevated in both early and chronic stages concurrently with the increases in aortic ACE activity and blood pressure. The plasma renin activity rose markedly at 4 weeks, but returned to the normal level at 12 weeks. Neither ACE activity in the lung and plasma, nor ACE mRNA level in the lung was altered at either stage. The aorta and liver angiotensinogen mRNA levels and renal renin mRNA level were increased at 4 weeks but decreased at 12 weeks. These results indicate that the acceleration of all components in the renin-angiotensin system may contribute to the development of 2K1C hypertension in the early stage. In the chronic stage, the increased vascular ACE induced by the elevated ACE mRNA levels in the aorta may play the primary role in the acceleration of local angiotensin II formation and thus may sustain the hypertension.