Search

Neuropathic pain is caused by injury or disease of the somatosensory system, and its course is usually chronic. Several studies have been dedicated to investigating neuropathic pain-related targets; however, little attention has been paid to the persistent alterations that these targets, some of which may be crucial to the pathophysiology of neuropathic pain. The present study aimed to identify potential targets that may play a crucial role in neuropathic pain and validate their long-term impact. Through bioinformatics analysis of RNA sequencing results, we identified Slc9a1 and validated the reduced expression of sodium-hydrogen exchanger 1 (NHE1), the protein that Slc9a1 encodes, in the spinal nerve ligation (SNL) model. Colocalization analysis revealed that NHE1 is primarily co-localized with vesicular glutamate transporter 2-positive neurons. In vitro experiments confirmed that poly(lactic-co-glycolic acid) nanoparticles loaded with siRNA successfully inhibited NHE1 in SH-SY5Y cells, lowered intracellular pH, and increased intracellular calcium concentrations. In vivo experiments showed that sustained suppression of spinal NHE1 expression by siRNA-loaded nanoparticles resulted in delayed hyperalgesia in naïve and SNL model rats, whereas amiloride-induced transient suppression of NHE1 expression yielded no significant changes in pain sensitivity. We identified Slc9a1 , which encodes NHE1, as a key gene in neuropathic pain. Utilizing the sustained release properties of nanoparticles enabled us to elucidate the chronic role of decreased NHE1 expression, establishing its significance in the mechanisms of neuropathic pain. [ABSTRACT FROM AUTHOR]

Arthroscopic visualization and access of the posterior knee are limited when using standard anterior and posterior portals. The creation of a trans-septal portal allows for complete access to the posterior compartment as arthroscopic instruments are able to be passed back and forth between the posteromedial and posterolateral compartments. Due to the close proximity of the popliteal artery and its branches, precise portal placement and safe orientation of arthroscopic instruments are critical to avoid iatrogenic injury. The conventional technique of trans-septal portal creation, involving a posterolateral portal, can be difficult in some cases. To overcome these obstacles, a posteromedial technique of trans-septal portal creation is presented. By using the medial parapatellar portal as the viewing portal, our technique allows for direct visualization of the posterior septum on each step of creation of the trans-septal portal, eliminating the need for "blind" maneuvers. What is more, no posterolateral portal is needed, decreasing the risk of potential complications. Using the posterior cruciate ligament fibers as a main landmark for trans-septal portal placement, preservation of the posterior part of the septum is achieved. This ensures optimal safe-margin distance away from the popliteal neurovascular bundle and making the technique safe and reproducible. [Display omitted] [ABSTRACT FROM AUTHOR]

Knee extension contracture is a common postinjury and postsurgical complication, which decreases knee joint flexion. Many techniques have been described in the literature to restore knee flexion, with the most common one being an arthroscopic lysis of adhesions. However, in severe cases, additional intra- and extra-articular procedures are needed to restore full knee flexion. Manipulation under anesthesia (MUA) is one of them. Unfortunately, it may lead to devastating complications, such as iatrogenic rupture of the patellar tendon or fractures of the patella or tibial tuberosity. Therefore, the purpose of this report is to present a safer modification of MUA for knee extension contracture in cases in which excessive force is demanded to achieve flexion. The key aim of the "patellar base support" technique (PBS technique) is to stretch the contracted quadriceps muscle with controlled and decreased tension on the patella, patellar tendon, and tibial tuberosity. [Display omitted] [ABSTRACT FROM AUTHOR]

Microglia play a critical role in neuropathic pain. Since upregulated Foxp3 in microglia enhances tissue repair by resolving neuroinflammation in excitotoxin-induced neuronal death, it may attenuate neuropathic pain in a similar manner. Therefore, this study tests whether Foxp3 introduced with poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (Foxp3 NPs) can alleviate neuropathic pain by inhibiting microglia activity. The prepared Foxp3 NPs had an anti-inflammatory effect on lipopolysaccharide-stimulated BV2 cells in vitro , and localized to spinal microglia in vivo. Further, the Foxp3 NPs significantly attenuated pain behavior induced by spinal nerve ligation in rats for 7 days by suppressing microglial activity, followed by the downregulation of pro-nociceptive genes and the upregulation of anti-nociceptive genes in the spinal dorsal horn. Collectively, these data suggest that Foxp3 NPs effectively relieve neuropathic pain in animals by reducing microglia activity and subsequent modulation of neuroinflammation, and may be of therapeutic value in the treatment of neuropathic pain. Neuropathic pain was induced by lumbar 5 spinal nerve ligation in rats. NC or Foxp3 plasmids-encapsulated PLGA nanoparticles (NC NPs or Foxp3 NPs) were then administered intrathecally into the spinal subarachnoid space of rats with neuropathic pain. Pain behavior in von Frey filaments tests was significantly attenuated in rats with the Foxp3 NPs compared with the NC NPs. Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] • The red stem of Pohang spinach (RS) has higher flavonoids than the white stem of general spinach (GS). • The high flavonoid content may help prevent chronic disease by reducing inflammation. • RS has preventive effects on arthritis pain and cartilage damage. • RS inhibits ROS generation in inflammatory macrophages and has a strong antioxidant effect. The levels of major and minor compounds in vegetables, including spinach (Spinacia oleracea L.), depend on various factors, including variety, agronomic management, and environmental conditions, which are responsible for taste, shape, and quality. Pohang Province spinach is from the same seeds as general spinach, but has a red stem and tastes different. The effects of the meteorological conditions and soil characteristics of the cultivation area on nutrient composition are unclear, as are the effects of this spinach on osteoarthritis (Damasio et al.). The nutrient composition of red-stem Pohang spinach (Ween et al.) was compared to that of general spinach (GS). The anti-inflammatory and antioxidant effects of RS, GS, and quercetin were examined in a mono-iodoacetate -induced OA rat model and in murine macrophages. The cation and anion chromatograms showed that the chemical composition of RS differed from that of GS, such as levels of flavonoids, including apigenin (19.57-fold) and limocitrin 3-glucoside (26.40-fold). Both RS and GS reduced cartilage degradation and had analgesic effects in the OA model, but in early OA, RS had a greater analgesic effect than GS. GS and RS enhanced collagen type II and thymocyte differentiation antigen 1 (Thy1) expression but inhibited matrix metalloproteinase 13 (MMP13) expression in the knee joints of rats. RS suppressed ROS production in macrophages and had a strong antioxidant effect. Both GS and RS have therapeutic potential for OA, but RS has greater anti-inflammatory and antioxidant effects. The chemical composition of spinach is affected by its growth environment and RS is particularly effective for medical applications such as OA. [ABSTRACT FROM AUTHOR]

Chromanone-2-carboxylates and chroman-2-carboxylates are useful building blocks for the synthesis of a variety of bioactive compounds, such as repinotan, fidarestat, and nebivolol. An efficient and practical enantiospecific synthesis of chromanone-2-carboxylates and chroman-2-carboxylates has been accomplished using intramolecular Mitsunobu etherification of methyl ( S )-2-hydroxy-4-oxo-4-(2′-hydroxy)phenylbutanoates derived from l -malic acid. [ABSTRACT FROM AUTHOR]

Targeting microglial activation is emerging as a clinically promising drug target for neuropathic pain treatment. Fexofenadine, a histamine receptor 1 antagonist, is a clinical drug for the management of allergic reactions as well as pain and inflammation. However, the effect of fexofenadine on microglial activation and pain behaviors remains elucidated. Here, we investigated nanomedicinal approach that targets more preferentially microglia and long-term analgesics. Fexofenadine significantly abolished histamine-induced microglial activation. The fexofenadine-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Fexo NPs) injection reduced the pain sensitivity of spinal nerve ligation rats in a dose-dependent manner. This alleviation was sustained for 4 days, whereas the effective period by direct fexofenadine injection was 3 h. Moreover, Fexo NPs inhibited microglial activation, inflammatory signaling, cytokine release, and a macrophage phenotype shift towards the alternative activated state in the spinal cord. These results show that Fexo NPs exhibit drug repositioning promise as a long-term treatment modality for neuropathic pain. Fexofenadine-encapsulated PLGA nanoparticles (Fexo NPs) and negative control nanoparticles (NC NPs) were generated by sonication with the typical double emulsion (W/O/W) method. As a neuropathic pain model, lumbar 5 spinal nerve ligated rats were administered intrathecally into the spinal subarachnoid space with/without fexofenadine alone, NC NPs, and Fexo NPs. Then, the thermal hyperalgesia was assessed as paw withdrawal latency (PWL) by using Hargreaves Apparatus. The results highlighted that fexofenadine-loaded nanoparticles prolong pain relief in SNL rats. Fexo NPs also reduced M1/M2 macrophage ratio and inhibited cytokine release. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Endosomal escape is one of the important processes for efficient non-viral gene delivery. In this study, we synthesized a novel non-viral vector called polyxylitol-based gene carrier (XGC) through a Miachael addition reaction between xylitol diacrylate as a crosslinking agent and low molecular weight polyethylenimine (PEI 1.2kDa). The small amount of xylitol integrated into XGC (3.9% w/w) contributed 50% of the osmotic pressure of XGC, and enhaned the osmolysis of endosome cooperatively with the proton sponge effect, thus improving endosomal escape. Furthermore, XGC showed higher transfection efficiency in vivo in muscle tissue than pDNA alone or PEI 25kDa. In conclusion, our results show that XGC enhanced transfection efficiency compared with PEI 25kDa, the golden standard non-viral gene carrier, by enhancing endosomal escape without increasing the number of transfected cells. From the Clinical Editor: Enhanced gene delivery methods would greatly facilitate the development of gene therapies. These authors demonstrate that a polyxylitol-based gene carrier enhanced the transfection efficiency compared with the gold standard non-viral gene carrier, as a result of enhancing endosomal escape without increasing the number of transfected cells, warranting further studies of this method. [Copyright &y& Elsevier]

We report a 57-year-old man who was found to have a left ventricular apical mass during a routine check-up. He previously had neither any subjective symptom nor hemodynamic problem. The mass was located deeply in the left ventricular cavity. With exploration using a mediastinoscope, we successfully resected the tumor, which was a yellowish lipoid mass that adhered to the trabeculae near the apex. Histopathologic examination of the tumor was consistent with a lipoma, a very rare benign primary cardiac tumor. The mediastinoscope can be useful for surgical resection of tumors located deeply in the left ventricle. [ABSTRACT FROM AUTHOR]

The X-ray imaging performance of a phosphor-coupled photodiode array detector was assessed for use in a cone-beam computed tomography (CBCT) system for printed-circuit board inspection. The radiographic image quality of a detector is mainly responsible for the tomographic image quality. The radiographic image quality can be improved by increasing the X-ray exposure level, but CT scans at higher exposure can impose an enormous heat load on the X-ray tube. In this study, the detective quantum efficiency (DQE) was used to describe the image quality per air kerma as a metric to assess the detector performance. Measurement results were obtained for 40-kVp and 50-kVp tungsten-target X-ray beams, which show that the DQE of the detector is tolerant of air kerma levels as low as 0.8 μ Gy. Below this level, the electronic noise of the detector system could degrade the DQE performance. The concept of DQE and the measurement procedure are described, including the modulation-transfer function and the noise-power spectrum. [ABSTRACT FROM AUTHOR]

Background/objectives The effect of aspirin and clopidogrel in a fixed-dose combination (FDC) on platelet function was compared with separate formulations in patients that had undergone percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Methods This was a phase IV, prospective, multicenter, single-arm, non-inferiority study. Patients that had taken aspirin 100 mg and clopidogrel 75 mg once daily as separate formulations for > 6 months after PCI with DES were enrolled, and then switched to an aspirin/clopidogrel FDC once-daily for 4 weeks. Platelet reactivity was determined using the VerifyNow® P2Y12 assay at baseline (immediately prior to switching) and 4 weeks later. Results A total of 648 patients (the full-analysis population; age, 63.6 ± 9.0 years; male, 76.5%) finished the study, and 565 (the per-protocol population) completed without protocol violations. In the per-protocol population, the % inhibitions of P2Y12 and ARU were not significantly different between baseline and after 4 weeks of FDC treatment (29.2 ± 20.0% to 29.0 ± 19.9%, P = 0.708; 445.1 ± 69.2 to 446.2 ± 63.0, P = 0.799, respectively) and the difference in P2Y12 inhibition observed did not exceed the predetermined limit of non-inferiority (95% CI, − 0.9 to 1.3). In the full-analysis population, the % inhibitions of P2Y12, PRU, and ARU were not significantly changed after 4 weeks of FDC treatment. Conclusions This study demonstrates that the efficacy of platelet inhibition by an aspirin/clopidogrel FDC was not inferior to that of separate aspirin and clopidogrel formulations in patients that had undergone PCI with DES. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Obovatol is isolated from Magnolia obovata leaves and this active component has various pharmacological properties such as anti-oxidant, anti-platelet, anti-fungal and anti-inflammatory activities. In the present study, we investigated the inhibitory effects of obovatol on in vitro vascular smooth muscle cell (VSMC) proliferation and in vivo neointimal formation in a rat carotid artery injury model. Methods and results: Obovatol (1–5μM) exerted concentration-dependent inhibition on platelet-derived growth factor (PDGF)-BB-induced rat VSMC proliferation, without exhibiting any cellular toxicity or apoptosis, as determined by cell count, [3H]thymidine incorporation and Annexin-V-binding analyses. Treatment with obovatol blocked the cell cycle in G1 phase by down-regulating the expression of cyclins and CDKs, and selectively up-regulating the expression of p21Cip1, a well-known CDK inhibitor. Effects of perivascular delivery of obovatol were assessed 14 days after injury. The angiographic mean luminal diameters of the obovatol-treated groups (100μg and 1mg: 0.78±0.06 and 0.77±0.07AU, respectively) were significantly larger than that of the control group (0.58±0.07AU). The obovatol-treated groups (100μg and 1mg: 0.14±0.04 and 0.09±0.03mm2, respectively) showed significant reduction in neointimal formation versus the control group (0.17±0.02mm2). Immunohistochemical staining demonstrated strong expression of p21Cip1 in the neointima of the obovatol-treated groups. Conclusions: These data suggest that obovatol inhibits VSMC proliferation by perturbing cell cycle progression, possibly due to activation of p21Cip1 pathway. These results also show that obovatol may have potential as an anti-proliferative agent for the treatment of restenosis and atherosclerosis. [Copyright &y& Elsevier]

Abstract: Epothilone D (Epo-D) is a paclitaxel-like microtubule-stabilizing agent that was isolated from the myxobacterium Sorangium cellulosum. Although Epo-D can inhibit proliferation in multiple tumor cell lines, the effect of Epo-D on neointimal hyperplasia after angioplasty has not been reported. The aim of the present study was to investigate the effects of Epo-D on neointimal hyperplasia using an in vivo rat carotid artery injury model. We demonstrated that local Epo-D treatment significantly reduced neointimal hyperplasia after in vivo rat carotid artery injury, and Epo-D potently inhibited DNA synthesis, cell cycle progression and cell proliferation after FBS- and PDGF-BB-stimulation; PDGF-BB has been identified as the most potent growth factor for stimulating the proliferation of activated rat aortic smooth muscle cells (RASMCs). To clarify the specific effects of Epo-D on cell cycle machinery, we examined its effects on cyclin-dependent kinase (CDK)2, CDK4, cyclin E, p27, and retinoblastoma (Rb) proteins as cell cycle-related proteins in cellular lysates from PDGF-BB-stimulated RASMCs. Epo-D treatment significantly decreased the level of CDK2 protein, but did not change the levels of CDK4 and cyclin E proteins. Furthermore, Epo-D inhibited the phosphorylation of Rb, a key regulator of the G1 to S phase transition in the cell cycle. These findings suggest that Epo-D may regulate the cell cycle G1-checkpoint proteins as its major molecular mechanism for inhibiting neointimal hyperplasia after in vivo rat carotid artery injury. [Copyright &y& Elsevier]

Vascular endothelial cell senescence is an important cause of cardiac-related diseases. Mitochondrial reactive oxygen species (mtROS) have been implicated in cellular senescence and multiple cardiovascular disorders. CR6 interacting factor 1 (CRIF1) deficiency has been shown to increase mtROS via the inhibition of mitochondrial oxidative phosphorylation; however, the mechanisms by which mtROS regulates vascular endothelial senescence have not been thoroughly explored. The goal of this study was to investigate the effects of CRIF1 deficiency on endothelial senescence and to elucidate the underlying mechanisms. CRIF1 deficiency was shown to increase the activity of senescence-associated β-galactosidase along with increased expression of phosphorylated p53, p21, and p16 proteins. Cell cycle arrested in the G0/G1 phase were identified in CRIF1-deficient cells using the flow cytometry. Furthermore, CRIF1 deficiency was also shown to increase cellular senescence by reducing the expression of Sirtuin 3 (SIRT3) via ubiquitin-mediated degradation of transcription factors PGC1α and NRF2. Downregulation of CRIF1 also attenuated the function of mitochondrial antioxidant enzymes including manganese superoxide dismutase (MnSOD), Foxo3a, nicotinamide-adenine dinucleotide phosphate, and glutathione via the suppression of SIRT3. Interestingly, overexpression of SIRT3 in CRIF1-deficient endothelial cells not only reduced mtROS levels by elevating expression of the antioxidant enzyme MnSOD but also decreased the expression of cell senescence markers. Taken together, these results suggest that CRIF1 deficiency induces vascular endothelial cell senescence via ubiquitin-mediated degradation of the transcription coactivators PGC1α and NRF2, resulting in decreased expression of SIRT3. Image 1 • CRIF1 deficiency induces endothelial senescence by regulating mitochondrial anti-oxidant system. • CRIF1 deficiency inhibits SIRT3 expression via ubiquitination of PGC1α and NRF2. • Overexpression of SIRT3 attenuates CRIF1 deficiency-induced endothelial senescence. [ABSTRACT FROM AUTHOR]

Purpose A fixed-dose combination of a stain and an antihypertensive drug may be useful for the treatment of patients with hypertension and hyperlipidemia. It may also improve patient drug compliance to help control risk factors of cardiovascular disease. This study was designed to evaluate the blood pressure–lowering and cholesterol-lowering effect of a fixed-dose combination of irbesartan-atorvastatin compared with monotherapy by either agent over an 8-week treatment period. Methods Patients with comorbid hypertension and hypercholesterolemia were screened for this randomized, double-blind, Phase III study. Eligible study patients were randomly assigned to test groups receiving a combination of irbesartan 300 mg and atorvastatin 40 mg or 80 mg (IRB300 + ATO40 and IRB300 + ATO80). Comparator groups comprised monotherapy groups with irbesartan 300 mg (IRB300) or atorvastatin 40 mg (ATO40) or atorvastatin 80 mg (ATO80), or placebo. Patients who were eligible at screening were subjected to a 4- to 6-week washout period before commencing 8 weeks of therapy per their assigned group. The primary efficacy end points were percent change in LDL-C and sitting diastolic blood pressure (DBP) levels from baseline to end of therapy. Tolerability profiles of combination therapy were compared with other groups. Findings A total of 733 patients with comorbid hypertension and hypercholesterolemia were screened for this study; 230 eligible patients were randomized to treatment. The mean age of patients was 58.9 (8.5) years, and their mean body mass index was 25.8 (3.2) kg/m 2 . More than two thirds (70.9%) of the study patients were male. Mean LDL-C and sitting DBP levels at baseline were 149.54 (29.19) mg/dL and 92.32 (6.03) mm Hg, respectively. Percent reductions in LDL-C after 8 weeks were 46.74% (2.06%) in the IRB300 + ATO40 group and 48.98% (2.12%) in the IRB300 + ATO80 group; these values were 47.13% (3.21%) and 48.30% (2.98%) in the ATO40 and ATO80 comparator groups. Similarly, a reduction in sitting DBP after 8 weeks was –8.50 (1.06) mm Hg in the IRB300 + ATO40 group and 10.66 (1.08) mm Hg in the IRB300 + ATO80 group compared with 8.40 (1.65) mm Hg in the IRB300 group. The incidence rate for treatment-emergent adverse events was 22.27% and was similar between the monotherapy and combination groups. Implications A once-daily combination product of irbesartan and atorvastatin provided an effective, safe, and more compliable treatment for patients with coexisting hypertension and hyperlipidemia. ClinicalTrials.gov identifier: NCT01442987. [ABSTRACT FROM AUTHOR]

Long-term stress during pregnancy causes neurologic deficits to offspring with altered gamma-aminobutyric acid (GABA) system in the brain. However, it is not clear how prenatal stress affects the maturing GABAergic interneurons and the resulting abnormalities in infantile seizures. Here, we showed that prenatal stress alters the maturation of GABA inhibitory system using a seizure model induced by prenatal stress. Prenatal stress with betamethasone or acute immobilization stress (AIS) on gestational day 15 increased the seizure susceptibility to N -methyl- d -aspartate-triggered spasms on postnatal day 15. The expression of GABA was lower in the prenatally stressed group, which compromise the decrease of glutamate decarboxylase 67-immunopositive cells. Prenatal stress markedly decreased the expression of K + /Cl − co-transporter (KCC2) in the cortex. GABA induced membrane depolarization demonstrated prenatal stress models had significant higher membrane depolarization compared to control. GABA increased KCC2 expression in cultured cortex-containing slices. Taken together, our results showed that prenatal stress with betamethasone or AIS altered the maturation of GABAergic progenitors and resulted in the lack of GABA input, which in turn, decreased KCC2 expression and lowered seizure threshold. We conclude that delayed GABA excitatory/inhibitory shift would render the cortical neuronal circuit more susceptible to excitatory input in prenatal stress induced seizure. [ABSTRACT FROM AUTHOR]

Purpose Doubling the dose of antihypertensive drugs is necessary to manage hypertension in patients whose disease is uncontrolled. However, this strategy can result in safety issues. This study compared the safety and efficacy of up-titration of the nifedipine gastrointestinal therapeutic system (GITS) with up-titration of valsartan monotherapy; these were also compared with low-dose combinations of the two therapies. Methods This prospective, open-label, randomized, active-controlled, multicenter study lasted 8 weeks. If patients did not meet the target blood pressure (BP) after 4 weeks of treatment with low-dose monotherapy, they were randomized to up-titration of the nifedipine GITS dose from 30 mg (N30) to 60 mg or valsartan from 80 mg to 160 mg or they were randomized to receive a low-dose combination of N30 and valsartan 80 mg for another 4 weeks. BP variability was assessed by using the SD or the %CV of the short-term BP measured at clinic. Findings Of the 391 patients (20~70 years with stage II or higher hypertension) screened for study inclusion, 362 patients who had 3 BP measurements were enrolled. The reduction in the mean systolic/diastolic BP from baseline to week 4 was similar in both low-dose monotherapy groups with either N30 or valsartan 80 mg. BP variability (SD) was unchanged with either therapy, but the %CV was slightly increased in the N30 group. There was no significant difference in BP variability either in SD or %CV between responders and nonresponders to each monotherapy despite the significant difference in the mean BP changes. The up-titration effect of nifedipine GTS from 30 to 60 mg exhibited an additional BP reduction, but this effect was not shown in the up-titration of valsartan from 80 to 160 mg. Although the difference in BP was obvious between high-dose nifedipine GTS and valsartan, the BP variability was unchanged between the 2 drugs and was similar to the low-dose combinations. There was a low rate of adverse events in all treatment groups. In addition, escalating the dose of either nifedipine GITS or valsartan revealed a similar occurrence of adverse effects with low-dose monotherapy or the low-dose combination. Implications Compared with up-titration of the angiotensin receptor blocker valsartan, up-titration of the calcium channel blocker nifedipine GITS provided no additional increased safety concerns and revealed better mean reductions in BP without affecting short-term BP variability. ClinicalTrials.gov identifier: NCT01071122. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Myelophil, a combination of extracts taken from Astragali Radix and Salviae Miltiorrhizae Radix, is a traditional Chinese medicine used for the treatment of chronic fatigue-associated disorders. Here we examined the ability of Myelophil to alleviate memory impairment in a mouse model. We aimed to investigate whether Myelophil has the pharmacological effects on memory deficits associated with brain dysfunctions using an animal model. Materials and methods: Ten week-old male C57BL/6N mice were pretreated with Myelophil (50, 100, or 200mg/kg), or tacrine (10mg/kg) for 7 days, and then intraperitoneally injected with scopolamine (1mg/kg). Memory-related behaviors were evaluated using the Morris water maze for 5 days. Levels of biomarkers of oxidative stress, antioxidant activity, acetylcholinesterase (AChE) activity, and extracellular signal-regulated kinase (ERK) were measured in brain tissues. Results: Scopolamine treatment increased the escape latency time and shortened time spent in the target quadrant; these effects were ameliorated by pretreatment with Myelophil. Scopolamine-induced changes in reactive oxygen species (ROS), malondialehyde (MDA), and AChE activity were significantly attenuated in mice pretreated with Myelophil. Recovery of antioxidant capacities, including total glutathione (GSH) content, and the activities of GSH-reductase, GSH-S-transferase, and catalase was also evident in Myelophil-treated mice. The strongest effects were seen for ERK and muscarinic acetylcholine receptor 1 (mAChR1) at both the protein and gene expression levels, with significant amelioration of expression levels in the Myelophil pretreatment group. Conclusions: These results suggest that Myelophil confers anti-amnesic properties in a mouse model of memory impairment, driven in part by the modulation of cholinergic activity. [Copyright &y& Elsevier]

Abstract: Iron is an essential, but potentially harmful, metal in the brain. In normal brain, iron has been reported to accumulate mainly in glial cells and occasionally in neurons in some particular nuclei. However, the majority of investigations have targeted the adult brain. Here, we investigated spatiotemporal localization of iron in developing and adult chicken cerebellum using iron histochemistry. Iron reactivity was not detected in the chick cerebellum until embryonic day 12. Iron accumulation was first found in mature myelinating oligodendrocytes located in the inner part of the cerebellar folium at embryonic day 14. From embryonic day 20, iron-positive mature myelinating oligodendrocytes were localized in the white matter and the granular layer. From post-hatching day 2, iron accumulation was observed in Bergmann glia in the Purkinje cell layer as well as in mature myelinating oligodendrocytes. Iron accumulation in microglia was observed in the granular and molecular layers at post-hatching month 12. Our data indicate that during cerebellar development iron is accumulated in a unique sequence according to individual requirements or microenvironmental demands. [Copyright &y& Elsevier]

Abstract: Based on the previous result, several naringenin derivatives modified at position 7 with bulky substituents were designed and synthesized, and their inhibitory effects on HCT116 human colon cancer cells were tested using a clonogenic assay. The half maximal inhibitory concentrations (IC50) of five naringenin derivatives ranged between 1.20μM and 20.01μM which are much better than naringenin used as a control. In addition, new structural modification at C-4 of flavanone results in improving both the anti-cancer effect and anti-oxidative effect. In vitro cyclin dependent kinase 2 (CDK2) binding assay was carried out based on the previous results. To elucidate the possible interaction between naringenin derivatives and CDK2, in silico docking study was performed. This result demonstrates the rationale for the different inhibitory activities of the naringenin derivatives. These findings could be used for designing cancer therapeutic or preventive flavanone-derived agents. [Copyright &y& Elsevier]

Abstract: We have previously reported that fenofibrate displayed a potent antithrombotic effect by the inhibition of platelet aggregation. The present study was designed to investigate the effects of fenofibrate on the neointimal hyperplasia and its possible molecular mechanism. Neointimal hyperplasia was measured in balloon-inflated–induced vascular injury model of male Sprague–Dawley rats and cell proliferation was measured in primary cultured rat aortic vascular smooth muscle cells (VSMCs). Fenofibrate-treated group showed a significant reduction in neointimal formation (0.07±0.04mm2) from the control (0.13±0.04mm2). Fenofibrate significantly inhibited platelet-derived growth factor (PDGF)-BB-induced cell counting and [3H]-thymidine incorporation into DNA. Fenofibrate suppressed the PDGF-BB-inducible progression through G0/G1 to S phase of cell cycle. Moreover, fenofibrate inhibited not only phosphorylation of retinoblastoma (Rb) protein and expression of cyclin D/E, CDK 2/4 and proliferating cell nuclear antigen (PCNA) proteins but also mitogen-activated protein kinase (MAPK) signaling pathways such as ERK 1/2, p38 and JNK phosphorylation. In conclusion, the present study demonstrates that fenofibrate significantly inhibits neointimal formation via G0/G1 arrest of PDGF-BB-induced cell proliferation in association with the inhibition of MAPK, which resulted in the downregulation of expressions of cyclin D/E, CDK 2/4 and PCNA proteins, suggesting that fenofibrate may be useful for individuals with a high risk of thrombotic or cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Abstract: Background: The reduction in plasma LDL-C concentrations with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has been reported to reduce cardiovascular risk and mortality in individuals with or without preexisting coronary artery disease and elevated LDL-C concentrations. Atorvastatin is a statin used for lowering LDL-C concentrations. A generic formulation of atorvastatin is being developed in Korea. This study was undertaken for the purposes of marketing the generic formulation. Objective: This study was designed to compare the efficacy and tolerability of a generic formulation of atorvastatin 20 mg/d versus a branded formulation at the same dosage in hypercholesterolemic Korean adults at high risk for cardiovascular events. Methods: This 8-week, multicenter, randomized, double-blind, double-dummy study was conducted at 10 clinical centers in Korea between September 2008 and May 2009. Male and female patients aged 20 to 85 years at high risk for cardiovascular events (defined as an elevated LDL-C concentration [≥100 mg/dL]) were enrolled. Eligible patients were randomly assigned to receive generic or branded atorvastatin 20 mg once daily for 8 weeks. The primary end point was the percentage change from baseline to 8 weeks in LDL-C concentration. Secondary end points were the percentage changes from baseline in total cholesterol (TC), triglycerides (TG), HDL-C, apolipoprotein (apo) A1 and B, and high-sensitivity C-reactive protein concentrations; small, dense LDL (sdLDL) fraction; and tolerability. Tolerability was assessed using physical examination, laboratory testing, and by recording adverse events (AEs) at each visit. An additional secondary end point was the proportion of patients who achieved an LDL-C goal of <100 mg/dL. Results: A total of 244 patients were randomized to treatment, and 33 patients were withdrawn from the study (9 patients did not receive the study medication, 11 patients due to AEs, and 13 patients due to withdrawal of consent). A total of 211 patients completed the study (50.7% male; 100% Asian; mean [SD] age, 61.7 [9.2] years) (106 patients in the group that received Accepted for publication October 5, 2010. the generic formulation and 105 patients in the group that received the branded formulation). LDL-C concentrations were reduced from the baseline by 44% and 46% after 8 weeks of treatment with the generic and branded formulations, respectively (P = NS). The percentage changes from baseline to study end in HDL-C, TC, TG, apo A1, apo B, and hsCRP concentrations and sdLDL fraction the proportions of patients who achieved the LDL-C goal between the 2 groups did not reach statistical significance. The most commonly reported events were hepatobiliary laboratory abnormality (1.7%), general somatic discomfort (1.7%), and epigastric pain (0.8%) in the group that received the generic formulation, and myalgia (1.7%), epigastric pain (0.9%), and elevation of creatinine phosphokinase (0.9%) in the group that received the branded formulation. No serious AEs were reported in either group. Conclusions: After 8 weeks of treatment, the differences in the LDL-C-lowering effects between the generic and branded formulations of atorvastatin 20 mg/d did not reach statistical significance in these Korean patients at high risk for cardiovascular events. Both formulations were generally well tolerated. [Copyright &y& Elsevier]

Abstract: Little is known about the cardioprotective effects against heart failure (HF), the effects on differentiation of bone marrow-derived mononuclear cell (BMMNC), and the biocompatibility of BMMNC-seeded biodegradable poly-glycolide-co-caprolactone (PGCL) scaffolds in a myocardial infarction (MI) animal model. This study hypothesized that implantation of a BMMNC-seeded PGCL scaffold into the epicardial surface in a rat MI model would be biocompatible, induce BMMNC migration into infarcted myocardium, and effectively improve left ventricular (LV) systolic dysfunction. One week after the implantation of a BMMNC-seeded PGCL scaffold, BMMMC showed migration into the epicardial region. Four weeks after implantation, augmented neovascularization was observed in infarcted areas and in infarct border zones. Some BMMNCs exhibited the presence of α-MHC and troponin I, markers of differentiation into cardiomyocytes. In echocardiographic examinations, BMMNC-seeded PGCL scaffold and non-cell-seeded simple PGCL scaffold groups effectively reduced progressive LV dilatation and preserved LV systolic function as compared to control rat MI groups. Thus, BMMNC-seeded PGCL scaffolding influences BMMNC migration, differentiation to cardiomyocytes, and induction of neovascularization, ultimately effectively lessening LV remodeling and progressive LV systolic dysfunction. PGCL scaffolding can be considered as an effective treatment alternative in MI-induced advanced HF. [Copyright &y& Elsevier]

Abstract: The Long–Evans Cinnamon (LEC) rat, which accumulates excess copper (Cu) in its liver, is an animal model of Wilson''s disease. We evaluated and compared the distributions of Cu, ferrous (Fe2+), and ferric (Fe3+) iron in four-brain regions, namely, in the cerebral cortex, cerebellum, substantia nigra (SN), and striatum of LEC and Long–Evans Agouti rats at 30 and 55 weeks. Cu levels were elevated in the striatum of LEC rats, and Fe2+ and Fe3+ were higher in the striatum and SN of LEC rats. Ratios of Fe2+ to Fe3+ were >1 in four regions, and were highest in the striatum and SN of LEC rats. Cu and iron levels were found to be augmented during aging, and we suggest that these accumulations may exert deleterious effects in aged LEC rats. This study is the first report that demonstrates regional differences of Fe2+ and Fe3+ accumulation in the brain of aged LEC rats. Further studies are required to elucidate the mechanisms of Cu and iron accumulations and of their effects. [Copyright &y& Elsevier]

Yuk-Mi-Jihwang-Tang (YJT) has been popularly prescribed to treat aging related disorders over than hundreds of years in East Asia countries. To investigate possible modulatory actions of YJT on chronic restraint stress (CRS)-induced neurodegeneration on hippocampus neuronal injuries. Mice were orally administered with YJT (100, 200, or 400 mg/kg) or ascorbic acid (100 mg/kg) before 4 h of stress for 28 days. Morris water maze task was completed from day 24th to 28th, and stress hormones and biochemical analyzes were measured. Four weeks of the CRS abnormally affected memory impairments by measurement of escape latency and time spent in the target quadrant. Additionally, neurotransmitters were also drastically altered in serum or hippocampus protein levels by CRS. Gene expressions for 5-hydroxytryptamine (5-HT) receptor, 5-HT-transport, and tryptophan hydroxylase were also altered, whereas YJT led to normalize the above alterations. Additionally, YJT also beneficially worked on endogenous redox system as well as inflammatory reactions in the hippocampal neurons. We observed that hippocampal excitotoxicity was induced by CRS which were evidenced by depletion of phosphor-cAMP response element-binding protein, brain-derived neurotrophic factor, nuclear factor erythroid-2-related factor 2, heme oxygenase-1 and abnormally increases of acetylcholine esterase activities in hippocampus protein levels; however, YJT considerably improved the above pathological conditions. Our findings supported YJT enhance memory function via regulation of hippocampal excitotoxicity-derived memory impairment, stress hormone, and endogenous redox, respectively. Image 1 [ABSTRACT FROM AUTHOR]

Microwave dielectric properties of the [(Pb0.2Ca0.8)1−xSrx](Ca1/3Nb2/3)O3 (PCSCN) have been investigated as a function of Sr2+ content (0.05≤x≤0.2). A perovskite single phase with the CaTiO3-type structure was obtained throughout the entire composition range. Dielectric constant (K) increased with increase of Sr2+ content, however, the quality factor (Qf) was decreased. The increase of dielectric constant (K) could be attributed to the increase of ionic polarizability and the decrease of A-site bond valence of the specimens. Temperature coefficient of resonant frequency (TCF) increased with Sr2+ content from −22.26 to −9.15 ppm/°C, which could be explained by the change of bond valence and tolerance factor (t) of the perovskite structure. [Copyright &y& Elsevier]