Pharmacokinetic characterization of dehydroevodiamine in the rat brain

The objective of this study was to examine the kinetics of the distribution of dehydroevodiamine (DHED) in the rat brain. After an intravenous infusion of 15 min (dose of 1-10 mg/kg), the temporal profiles of the plasma levels of DHED declined in a multiexponential manner. Moment analysis indicated that the clearance and steady-state volume of distribution for DHED were not statistically different with the dose, indicating that the pharmacokinetics for DHED is linear in the range examined. Nonlinear regression analysis of DHED concentrations in the plasma and the brain revealed that the linear kinetics into and out from the brain reasonably described the data and that the clearances for influx into and efflux from the brain were comparable. Transport clearances for DHED across MBEC4 monolayers, an in vitro model of the blood-brain barrier, were also comparable for influx and efflux, and were independent of the medium concentration. The concentration of DHED in cerebrospinal fluid was negligible compared with that found in plasma, indicating that the drug is not primarily distributed to the brain via the blood-cerebrospinal fluid barrier. These observations indicate that DHED is transported from the systemic circulation to the brain via the blood-brain barrier by linear kinetics.     

Shikonin induces cell cycle arrest in human gastric cancer (AGS) by early growth response 1 (Egr1)-mediated p21 gene expression

Ethnopharmacological relevance

Lithospermum erythrorhizon, a naphthoquinone compound derived from a shikonin, has long been used as traditional Chinese medicine for treatment of various diseases, including cancer. To evaluate the cytotoxic effects of shikonin on AGS gastric cancer cells via induction of cell cycle arrest.

Materials and methods

We observed the effects of 12.5–100 ng/mL dosage of shikonin treatment on AGS cancer cell line with the incubation time of 6 h. Cytotoxic effects were assessed by measuring the changes in the intracellular ROS, appearance of senescence phenotype, cell cycle progression, CDK and cyclins expression levels upon shikonin treatment. We also examined upon the activation of Egr1-mediated p21 expression, by siRNA transfection, Luciferase assay, and ChIP assay.

Results

In this study, we found that shikonin inhibits cell proliferation by arresting cell cycle progression at the G2/M phase via modulation of p21 in AGS cells. Also, our results revealed that the p21 gene was transactivated by early growth response1 (Egr1) in response to the shikonin treatment. Transient Egr1 expression enhanced shikonin-induced p21 promoter activity, whereas the suppression of Egr1 expression by small interfering RNA attenuated the ability of shikonin to induce p21 promoter activity.

Conclusion

Our results suggested that the anti-proliferative activity of shikonin was due to its ability to induce cell cycle arrest via Egr1–p21 signaling pathway. Thus, the work stated here validates the traditional use of shikonin in the treatment of cancer.     

Sociodemographic and lifestyle factors affecting the self‐perception period of lower urinary tract symptoms of international prostate symptom score items

Aims: This study investigated the influence of sociodemographic and lifestyle factors on the lower urinary tract symptom (LUTS) self‐perception period and International Prostate Symptom Score. Method: This cross‐sectional study examined 209 men aged ≥ 40 years with non‐treated LUTS who participated in a prostate examination survey. Questions included International Prostate Symptom Score (IPSS) items with self‐perception periods for each item. Sociodemographic and lifestyle factors were also assessed. Participants were divided by mild LUTS (IPSS less than 8) and moderate‐to‐severe LUTS (IPSS 8 or higher). Results: Self‐perception period of the moderate‐to‐severe LUTS (n = 110) was affected by BMI; the self‐perception period of the mild LUTS (n = 90) was affected by age, income, occupation and concomitant disease. Moderate‐to‐severe LUTS were affected by self‐perception period (p = 0.03). Self‐perception period was affected by concern for health (p = 0.005) by multivariate analysis, and self‐perception period of mild LUTS was affected by BMI (p = 0.012). Moderate‐to‐severe LUTS were affected by age, number of family members, concern for health and drinking (p < 0.05, respectively) by multivariate analysis. Conclusion: Lower urinary tract symptom was affected by self‐perception period. In moderate‐to‐severe LUTS, age, concern for health and drinking were affecting factors of self‐perception period.     

Cathepsin G Inhibitor Prevents Ultraviolet B- Induced Photoaging in Hairless Mice via Inhibition of Fibronectin Fragmentation

Background: Cathepsin G, a serine protease that is activated by ultraviolet (UV) radiation, increases matrix metalloproteinase-1 (MMP-1) expression in fibroblasts through fibronectin (Fn) fragmentation and promotes the conversion of proMMP-1 to active MMP-1. Objectives: This study investigated whether [2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (KPA), a cathepsin G inhibitor, plays any role in extracellular matrix (ECM) damage in an in vitro 3D dermal equivalent (DE) and an in vivo ultraviolet B (UVB)-irradiated hairless mice. Methods: We examined the potential ECM-protective effects of a cathepsin G inhibitor in an in vitro 3D DE model and an in vivo UVB-irradiated hairless mouse skin model. Results: Among five known serine protease inhibitors, KPA showed the strongest potency and selectivity against cathepsin G. KPA inhibited the cathepsin G-mediated MMP-1 increase and alleviated the downregulation of mRNAs encoding collagen and tissue inhibitor of matrix metalloproteinase-1 in an in vitro 3D DE model. Most importantly, topical application of KPA (0.025%) to the dorsal skin of hairless mice enhanced collagen expression and attenuated UVB-induced Fn fragmentation and upregulation of MMP-2 and MMP-9 activities. Conclusions: Cathepsin G inhibitors may be useful for the prevention of UVB-induced photoaging through amelioration of ECM damage and MMP upregulation.     

Bilateral vertebral artery dissecting aneurysms presenting with subarachnoid hemorrhage treated by staged coil trapping and covered stents graft

The treatment of bilateral vertebral artery dissecting aneurysms (VADAs) presenting with subarachnoid hemorrhage (SAH) is still challenging. The authors report a rare case of bilateral VADA treated with coil trapping of ruptured VADA and covered stents implantation after multiple unsuccessful stent assisted coiling of the contralateral unruptured VADA. A 44-year-old woman was admitted to our hospital because of severe headache and sudden stuporous consciousness. Brain CT showed thick SAH and intraventricular hemorrhage. Cerebral angiography demonstrated bilateral VADA. Based on the SAH pattern and aneurysm configurations, the right VADA was considered ruptured. This was trapped with endovascular coils without difficulty. One month later, the contralateral unruptured VADA was protected using a stent-within-a-stent technique, but marked enlargement of the left VADA was detected by 8-months follow-up angiography. Subsequently two times coil packing for pseudosacs resulted in near complete occlusion of left VADA. However, it continued to grow. Covered stents graft below the posterior inferior cerebellar artery (PICA) origin and a coronary stent implantation across the origin of the PICA resulted in near complete obliteration of the VADA. Covered stent graft can be used as a last therapeutic option for the management of VADA, which requires absolute preservation of VA flow.     

The Surgical Outcome of Endoscopic Dacryocystorhinostomy According to the Obstruction Levels of Lacrimal Drainage System

Objectives

Many factors influence the outcome of endoscopic dacryocystorhinostomy (DCR). One of the most important prognostic factors is the level of obstruction in the lacrimal drainage system. The main objective of this report is to evaluate both the frequency of obstruction by anatomical region of the lacrimal drainage system on dacryocystography (DCG) and the surgical outcome of endoscopic DCR according to the obstruction level.

Methods

A retrospective series of 48 patients (60 eyes) who had undergone endoscopic DCR from January 2005 to November 2007 were enrolled. Preoperative evaluation consisted of a standard examination which included lacrimal irrigation, probing, DCG and osteomeatal unit (OMU) computed tomography. Patients were classified into four groups according to the obstruction level on DCG. Surgical outcome was evaluated postoperatively by subjective improvement of epiphora and patent rhinostomy opening on nasal endoscopic exam.

Results

Of 60 eyes, the levels of obstruction were the common canaliculus in 14 eyes (23.3%), the lacrimal sac in 13 eyes (21.7%), the duct-sac junction in 13 eyes (21.7%) and the nasolacrimal duct (NLD) in 20 eyes (33.3%). The ductsac junction obstruction was treated most successfully (100%), followed by NLD obstruction (90%), common canaliculus obstruction (78.6%) and saccal obstruction (69.2%).

Conclusion

In patients with lacrimal drainage system obstruction, preoperative evaluation of obstruction level using DCG may be helpful for predicting the surgical outcome of endoscopic DCR. The saccal obstruction may have a worse prognosis than the other obstruction levels.