SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: Biological & pharmaceutical bulletin

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Alzheimer’s disease (AD) is a most serious age-related neurodegenerative disorder accompanied with significant memory impairments in this world. Recently, microRNAs have been reported to be invlolved in the pathophysiology of AD. Previous studies have shown that miR-206 is implicated in the pathogenesis of AD via suppressing the expression of BDNF in the brain. Here, we examined the miR-206-3p and miR-206-5p expression in the hippocampus and cortex of APP/PS1 transgenic mice treated with donepezil, a drug approved for treating AD in clinic. We found that the expression of miR-206-3p was significantly up-regulated in the hippocampus and cortex of APP/PS1 mice, while donepezil administration significantly reversed this dysfunction. In addition, enhancing the miR-206-3p level by the usage of AgomiR-206-3p significantly attenuated the anti-dementia effects of donepezil in APP/PS1 mice. Together, these results suggested that miR-206-3p is involved in the anti-dementia effects of donepezil, and could be a novel pharmacological target for treating AD.

Concepts: Alzheimer's disease, Brain, Neurology, Neurodegenerative disorders, Memory, Hippocampus, Semantic memory, Genetically modified organism

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Chronic Fatigue (CF) is a common reason for consulting a physician due to affecting quality of life, but only a few effective treatments are available. The aim of this study was to examine the effectiveness of subcutaneous injection of the human placental extract (HPE) on medically indescribable cases of CF and safety in a randomized, double-blind, placebo-controlled clinical trial. A total of seventy eight subjects with CF were randomly assigned to either a HPE group or a placebo group. Subjects in the HPE group were treated with HPE three times a week subcutaneously for 6 weeks, whereas those in the placebo group with normal saline. Then, the Fatigue Severity Scale (FSS), Visual Analog Scale (VAS) and Multidimensional Fatigue Inventory (MFI) were measured in both CF group and chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF) subgroup. The FSS, VAS and MFI score at baseline were not different between the HPE and placebo group in total subjects with CF. In CFS group, the FSS (p= 0.0242), VAS (p =0.0009) and MFI (p= 0.0159) scores measured at the end of the study period decreased more in the HPE group than in the placebo group when compared with those at the baseline. There were no significant differences between the HPE group and placebo group in the mean change from baseline in FSS, VAS, and MFI in subjects with ICF during the study period. The subcutaneous injection of HPE was effective in the improvement of CFS.

Concepts: Pharmacology, Medicine, Clinical trial, Effectiveness, Placebo, Group theory, Normal subgroup, Chronic fatigue syndrome

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For screening of skin-whitening ingredients that modulate inhibition of melanogenesis, tyrosinase promoter-based assay using a 3D spheroid culture technique is a beneficial tool to improve the accuracy of raw material screening in cosmetics through mimicking of the in vivo microenvironment. Although the advantages of high-throughput screening (HTS) are widely known, there has been little focus on specific cell-based promoter assays for HTS in identifying skin-whitening ingredients that inhibit accumulation of melanin. The aim of this study was therefore to develop a large-scale compatible assay through pTyr-EGFP, an enhanced green fluorescent protein (EGFP)-based tyrosinase-specific promoter, to seek potential melanogenesis inhibitors for cosmetic use. Herein, a stably transfected human melanoma cell line expressing EGFP under the control of a 2.2-kb fragment derived from the tyrosinase gene was generated. Spontaneous induction of the tyrosinase promoter by 3D spheroid culture resulted in increased expression of EGFP, providing a significant correlation with the tyrosinase mRNA level, and subsequent inhibition of tyrosinase activity. Importantly, the pTyr-EGFP system provided successful tracking of the changes in the live image and real-time monitoring. Thus tyrosinase promoter-based fluorescent assay using a 3D spheroid culture can be useful as a screening system for exploring the efficiency of anti-melanogenesis ingredients.

Concepts: Protein, Green fluorescent protein, Cell culture, Enzyme inhibitor, Inhibitor, Melanin, Melanocyte, Tyrosinase

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Trastuzumab has been administered to patients with HER2-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest P values in GWAS (P = 7.60 x 10-7 - 2.01 x 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 x 10-6, 8.88 x 10-5, 1.07 x 10-4, 1.42 x 10-4, 1.60 x 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥ 5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (P = 7.82 x 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.

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Assays using lysate reagents prepared from horseshoe crab hemocyte extract (limulus amoebocyte lysate, LAL) are commonly and widely used to detect and measure endotoxin in parenteral drugs and medical devices. However, lysate reagents suffer from lot-to-lot variations leading to possible fluctuations in testing. Also, this continued usage of lysate reagents leads to the possible decline of the horseshoe crab population. Recently, a new recombinant chromogenic reagent, PyroSmart, consisting of three recombinant factors was introduced to the market. There are now three recombinant products; two with recombinant factor C reagents and PyroSmart with the complete recombinant LAL system. We evaluated the applicability of the reagent to the harmonized bacterial endotoxins test in the United States, European and Japanese pharmacopeias. The recombinant product showed equivalent potency of thirteen endotoxins from different bacterial strains to conventional chromogenic lysate reagents as long as their assay modes are identical. All analytical characteristics or assay parameters of the reagent satisfied the acceptance criteria which are set for the use for the bacterial endotoxins test filed in the pharmacopeias. All of 109 parenteral drugs tested can be measured with PyroSmart within respective maximum allowable dilutions. The lot-to-lot variation in recovery of endotoxin added in the parenteral drugs for PyroSmart was equal to or less than those of six limulus lysate reagents. In conclusion, the present study suggests that the recombinant reagent, PyroSmart, provide a good alternative to the LAL reagents with better lot-to-lot variation.

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In this study, we have prepared perfluorohexane (PFH)-based acoustic nanodroplets (PFH-NDs) and evaluated their theranostic characteristics. Nile Red (NR) was incorporated into PFH-NDs as a model of hydrophilic drugs (NR-PFH-NDs). The mean particle diameters of PFH-NDs and NR-PFH-NDs were 205±1.8 nm and 346.3±6, respectively. There was no significant PFH leakage from PFH-NDs during 90 min incubation at 37ºC in the presence of 10% rat serum. The in vitro ultrasonography showed that the phase transition of PFH-NDs from liquid droplets to gassed bubbles could be induced by therapeutic low-intensity ultrasound with a frequency of 1 MHz and an intensity of 5 W/cm2. Irradiation of ultrasound in combination with NR-PFH-NDs enhanced uptake of NR in murine adenocarcinoma cells (C26). After intravenous injection of PFH-NDs to mice, PFH gradually disappeared from blood circulation with an elimination half-life of 43.3 min. Intravenous injection of PFH-NDs also resulted in significant contrast enhancement in the mouse carotid artery upon therapeutic low-intensity ultrasound irradiation. These results suggest the potential of PFH-NDs as a novel contrast agent for further theranostic applications.

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The pharmacokinetics of vancomycin (VAN) was retrospectively examined based on trough concentrations at large scale to identify pharmacokinetic differences between Japanese hematologic malignancy and non-malignancy patients. Data from 261 hematologic malignancy patients and 261 non-malignancy patients, including the patient’s background, VAN dose, and pharmacokinetics of VAN estimated by an empirical Bayesian method, were collected and analyzed. Our results showed significantly higher values for VAN clearance and shorter elimination half-lives in patients with hematologic malignancies than non-malignancy patients. In addition, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to hematologic malignancies. In conclusion, since in hematologic cancer patients VAN clearance is increased, the blood concentration of VAN becomes lower than expected and this may contribute to the survival of resistant bacteria when VAN is administered at low doses. These results suggest that early monitoring of VAN levels in hematologic cancer patients might be recommended to maintain desired effects without side-effects.

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The aim of the study was to investigate the changes in the reactive oxygen species (ROS), Sirt1, p53 and acetylated p53 in brain tissue of newborn rats exposed to hyperoxia to clarify the role of Sirt1 signaling pathway in brain injury. Neonate rats were randomly divided into normoxic group and hyperoxic group. Rats in the normoxic group were exposed to room air while the rats in the hyperoxic group were put in a hyperoxic chamber (80%±5% oxygen) for 1 to 14 days. Data, including weight growth, the water content of brain tissue, HE and Tunel stain, ROS expression, the relative expression of Sirt1 mRNA and p53 mRNA, and the protein relative expression of Sirt1, p53 and acetylated p53 were analyzed at 1, 7 and 14 days after exposure. A reduced body weight and increased water content were observed in the brain tissue of hyperoxic group compared to normoxic group. HE staining and Tunel staining of brain tissue suggested that cell damaged after hyperoxic exposure. RT-PCR and western blot results showed that the expression of Sirt1 in the hyperoxic group was lower than that in the normoxic group while the expression of p53 was higher than that in the normoxic group. In addition, western blot data indicated acetylated p53 expression was higher in the hyperoxic group. Hyperoxic exposure can lead to brain injury in newborn SD rats. These events might be regulated by the Sirt1 pathway, which downregulated the deacetylation of p53.

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Vitamin D has an immune-modulating effect, related to the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD). However, few studies have focused on the difference between patients with asthma and COPD in the association of circulating vitamin D levels with clinical outcomes. We sought to investigate the associations of circulating vitamin D levels with health-related quality of life (HR-QOL), severity, and exacerbations. Subjects included 152 asthma patients and 50 COPD patients. We measured plasma concentrations of 25-hydroxyvitamin D3 [25(OH)D3]. HR-QOL was assessed using the EuroQoL 5-Dimension (EQ-5D) and the 12-item Short Form Health Survey (SF-12) scales. Exacerbations were recorded during a one-year follow-up. Associations between plasma 25 (OH)D3 concentrations and outcome variables were evaluated using linear regression. Plasma concentrations of 25(OH)D3 were positively associated with the EQ-5D index value and the SF-12 physical component score in patients with asthma; however, such associations were not observed in patients with COPD. A significant association between severity and plasma concentrations of 25(OH)D3 was found only in patients with COPD. The hazard ratios (95% confidence interval) of plasma 25(OH)D3 concentrations (per 1 ng/mL decrease) for time to first exacerbation was 1.38 (1.10-1.75; p = 0.006) and 0.95 (0.87-1.03; p = 0.179) in patients with COPD and asthma, respectively. Lower concentrations of plasma 25(OH)D3 contributed to lower HR-QOL in patients with asthma, and were associated with severity and risk of future exacerbations in patients with COPD.

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Anandamide (AEA) played potent neuroprotective activities via cannabinoid type 1 (CB1) and 2 (CB2) receptor. N-linoleyltyrosine (NITyr), as an AEA analogue, was synthesized in our laboratory and evaluated the neuroprotective effects and mechanisms for the first time. NITyr was synthesized via substitution reaction. The neuroprotective effects of NITyr were evaluated in a gerbil model of transient cerebral ischemia. Each gerbil was subjected to open field test (OFT), Rotard rod test (RRT), Morris water maze (MWM) successively and executed after animal behaviors. Part of the brain was stained with hematoxylin and eosin (HE) and Nissl staining, and the rest for biochemical analysis. NITyr could not increase spontaneous locomotor activity and ameliorate the anxiety behavior in the OFT but could improve the motor coordination in the RRT and the spatial memory impairment in the MWM. Immunohistochemically, NITyr could attenuate the ischemia-induced neural loss in the hippocampus. The Enzyme-linked immunosorbent assay (ELISA) suggested that NITyr ameliorated the inflammation and oxidative stress. Consistently, NITyr could up-regulate the expressions of p-phosphadylinositol 3-kinase (PI3K) and p-Akt but not PI3K and Akt in the hippocampus. In addition to oxidative stress, CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251 could reverse the above phenomena. However, CB1 receptor antagonist AM251 could reverse oxidative stress. Accordingly, NITyr could up-regulate the expressions of CB2 but not CB1. NITyr could improve the motor coordination, learning and memory impairments, neural loss in the hippocampus and the inflammation of the mice via CB2 receptor involvement of PI3K/Akt signaling pathway.