Glioblastoma multiforme is one of the most serious malignant brain tumors and is characterized by resistance to chemotherapy and radiation therapy. Recent studies suggest that autophagy may play an important role not only in the regulation of cancer development and progression but also in determining the response of cancer cells to anticancer therapy. The purpose of the present study was to assess the relationship between protein expressions of two autophagy markers, LC3B and Beclin-1, with clinical parameters in astrocytoma patients. Furthermore, the expression of CD133, a marker of the cancer stem-like cells, in astrocytoma patients was also investigated. A total of 106 thin-section slides were retrospectively collected from astrocytoma patients. LC3B, but not Beclin-1, protein expression was found to significantly correlate with resistance to radiation- or chemotherapy. In addition, high intensity of LC3B staining was predictive of poor prognosis. Furthermore, survival time of patients with high-level expression in both CD133 and LC3B was significantly shorter than those with weak expression in both CD133 and LC3B. These results suggest that astrocytoma cancer stem-like cells together with enhanced autophagy may cause resistance to radiation therapy/chemotherapy and that targeting the cancer stem-like cell in astrocytoma may offer a viable therapeutic approach.
Increasing evidence has implicated endothelin-1 (ET-1), a potent vasoconstrictive peptide, in the pathophysiology of cerebral vasospasm after subarachnoid haemorrhage (SAH). Endothelin-converting enzyme-1 (ECE-1), the protease involved in the final step of post-translational processing of ET-1, cleaves the inactive precursor big ET-1 at the Trp(21)-Val (22) peptide bond. In our previous study, we found that an inhibitor of ECE-1, CGS 26303, could prevent and reverse the arterial narrowing after SAH in rabbits. CGS 26393, a prodrug of CGS 26303, is an orally active, long-acting inhibitor of ECE-1. The present study examined the effects of CGS 26393 on the prevention and reversal of cerebral vasospasm after SAH. New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. In the prevention study, the drug was given orally 1 h before the induction of SAH. All drug treatments in the reversal study were initiated at 23 h after induction of SAH. One of three dosages (3, 10 or 30 mg/kg) of CGS 26393 or vehicle was administrated orally twice daily, and all animals were sacrificed by perfusion and fixation 48 h after SAH. Basilar arteries were removed and sectioned, and cross-sectional areas were measured. Cerebrospinal fluid (CSF) was collected prior to perfusion. Oral administration of CGS 26393 attenuated SAH-induced cerebral vasospasm in a dose-dependent manner in both the prevention and reversal groups. These effects achieved statistical significance at all dosages when compared with the SAH-only or SAH plus vehicle groups. Moreover, the attenuation of vasospasm following oral administration of CGS 26393 was more efficacious than that obtained with bolus injections of CGS 26303. The levels of free CGS 26303 in the CSF were increased in a dose-dependent manner in all three CGS 26393-treated groups. This study provides the first evidence that oral administration of an inhibitor of ECE-1, CGS 26393, is capable of preventing and reversing cerebral vasospasm following SAH. These findings also reinforce evidence demonstrating that treatment with an ECE-1 inhibitor is a potentially viable therapeutic approach for reducing cerebral vasospasm after SAH.
Traditional Chinese medicine (TCM) has been proposed to prevent urolithiasis. In China, Flos carthami (FC, also known as Carthamus tinctorius) (Safflower; Chinese name: Hong Hua/紅花) has been used to treat urological diseases for centuries. We previously performed a screening and confirmed the in vivo antilithic effect of FC extract. Here, ex vivo organ bath experiment was further performed to study the effect of FC extract on the inhibition of phenylepinephrine (PE) (10−4 and 10−3 M) ureteral peristalsis of porcine ureters with several α 1-adrenergic antagonists (doxazosin, tamsulosin, and terazosin) as experimental controls. The results showed that doxazosin, tamsulosin, and terazosin dose (approximately 4.5 × 10−6 − 4.5 × 10−1 μg/mL) dependently inhibited both 10−4 and 10−3 M PE-induced ureteral peristalsis. FC extract achieved 6.2% ± 10.1%, 21.8% ± 6.8%, and 24.0% ± 5.6% inhibitions of 10−4 M PE-induced peristalsis at doses of 5 × 103, 1 × 104, and 2 × 104 μg/mL, respectively, since FC extract was unable to completely inhibit PE-induced ureteral peristalsis, suggesting the antilithic effect of FC extract is related to mechanisms other than modulation of ureteral peristalsis.
The mechanisms by which mexiletine exerts its effects in increasing myocardial circulation, and smooth muscle perfusion and alleviating diabetic neuropathic pain have been widely discussed. The purpose of this study was to examine the protective effect of this compound in ischemia/reperfusion-induced cerebral injury following middle cerebral artery occlusion in Sprague-Dawley rats. Blood flow to the left cerebral hemisphere of the animals was interrupted by occluding the left cerebral artery and both carotid arteries simultaneously for 3 hrs. These animals were assigned to one of ten groups and divided into treatment group and pretreatment group; 1) control treatment group (n=8); 2) vehicle treatment group (n=8); 3) lower dose mexiletine (400 microg/kg) treatment group (n=8); 4) medium dose mexiletine (800 microg/kg) treatment group (n=8); 5) high dose mexiletine (2 mg/kg) treatment group (n=8); 6) control pretreatment group (n=8); 7) vehicle pretreatment group (n=8); 8) lower dose mexiletine (400 microg/kg) pretreatment group (n=8); 9) medium dose mexiletine (800 microg/kg) pretreatment group (n=8); and 10) high dose mexiletine (2 mg/kg) pretreatment group (n=8). The volume of cerebral infarction was measured in serial brain sections stained with triphenyltetrazolium chloride (TTC). Tissue infarction volume and tissue edema were estimated for each animal. The volume of cerebral infarction was significantly decreased in rats pretreated with mexiletine, and the ratio of tissue edema was also decreased as the dose of mexiletine increased. These results demonstrate that mexiletine, an anti-arrhythmic and use-dependent Na+ channel blocker, has protective effects in stroke at concentrations sufficient to confer significant protection, as measured by the volume of infarction and brain edema index in a model of focal, neocortical ischemia in Sprague-Dawley rats.
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