Biological & pharmaceutical bulletin最新文献

Commercially available so-called sanitizers in Japan are often touted as having remarkable "sanitizing (jokin)" effect, "virus-removal" capabilities, and "99.99%" removal rate of microbes and pathogens. In this study, we investigated the bactericidal efficacy of these so-called sanitizers for environmental surfaces against Enterococcus faecalis and Pseudomonas aeruginosa. Of note, out of 43 products, 24 (55.8%) did not exhibit bactericidal effects on either Enterococcus or Pseudomonas. Among these 43 products, there were no bactericidal effects in 9 (47.4%) of 19 products that stated as containing "alcohol" as the formula; as well as 4 (80%) of 5 products stating only "benzalkonium chloride"; similarly no effect in 5 (83.3%) of 6 stating only"chlorine chemicals." Furthermore, 6 (46.2%) of 13 products that stated components other than alcohol, benzalkonium chloride, and chlorine chemicals on the product container or with no description of constituent components failed to show any bactericidal effects. Four disinfectants (alcohol for disinfection, 0.1% benzalkonium chloride, 0.05% (500 ppm) hypochlorite, 0.1% (1000 ppm) hypochlorite) as control showed bactericidal effect. The lack of bactericidal activity in nearly half of sanitizers may be explained by the low concentration of the effective ingredient such as alcohol, benzalkonium chloride, and hypochlorite. In sanitizers containing hypochlorite, degradation of hypochlorite with prolongation of time after manufacturing may be another reason.

Rho kinase inhibitor fasudil exerts therapeutic effects against vasospasms. In this study, we aimed to compare its suppressive effects on serotonin (5-HT)- and noradrenaline (NAd)-induced contractions of human endothelium-denuded internal thoracic arteries (ITAs) and saphenous veins (SVs). NAd and 5-HT induced concentration-dependent contractions in both ITAs and SVs. However, fasudil (3 µmol/L) pretreatment decreased these constrictor-induced contractions in both ITAs and SVs. Fasudil exerted similar inhibitory effects on 5-HT and NAd in ITAs. However, in SVs, fasudil exerted stronger inhibitory effects on NAd-induced contractions than on 5-HT-induced contractions. Therefore, inhibitory effects of fasudil on 5-HT-induced contractions were stronger in ITAs than in SVs. Overall, these results suggest that Rho kinases exert different effects on the two vasoconstrictors in SVs, but not in ITAs, thus explaining their different graft patencies.

Mesoridazine and metoclopramide are cationic drugs that are distributed in the human brain despite being substrates of multidrug resistance protein 1 (MDR1), an efflux transporter expressed at the blood-brain barrier (BBB). We investigated their transport mechanisms at the BBB using hCMEC/D3, a human cerebral microvascular endothelial cell line often used as an in vitro BBB model. The cells exhibited time- and concentration-dependent uptake of mesoridazine and metoclopramide, with K_m values of 34 and 277 µM, respectively. The uptake of both drugs significantly decreased in the presence of typical inhibitors and/or substrates of the H⁺-coupled organic cation (H⁺/OC) antiporter but not in the presence of inhibitors or substrates of organic cation transporters (OCTs), OCTN2, OATPs, SLC35F2, or the plasma membrane monoamine transporter (PMAT). Furthermore, metoclopramide uptake by hCMEC/D3 cells was pH- and energy-dependent, whereas mesoridazine uptake was unaffected by intracellular acidification and treatment with metabolic inhibitors. These results suggest that the H⁺/OC antiporter is involved in the influx of mesoridazine and metoclopramide into the brain across the BBB.

Energy metabolism is crucial for cell polarity and pathogenesis. Mitochondria, which are essential for maintaining energy homeostasis within cells, can be targeted by drug delivery to regulate energy metabolism. However, there is a lack of research comparing how mitochondria control energy metabolism in different cell types derived from the neural crest. Understanding the effects of berberine (BBR), a compound that acts on mitochondria, on energy metabolism in neural crest-derived cells is important. This study reports how MITO-Porter, a mitochondria-targeted liposome, affects neuroblasts (Neuro2a cells) and normal human epidermal melanocytes (NHEMs) when loaded with BBR. We found that treatment with MITO-Porter containing BBR reduced mitochondrial respiration in Neuro2a cells, while it caused a slight increase in NHEMs. Additionally, the treatment shifted the ATP production pathway in Neuro2a cells to rely more on glycolysis, while in NHEMs, there was a slight decrease in the reliance on glycolysis. We also observed a significant decrease in ATP production in Neuro2a cells, while NHEMs showed a tendency to increase ATP production. Importantly, on the basis of the results of the Premix WST-1 assay, the study found that BBR treatment was not toxic to either cell type. It is important to take note of the varied effects of BBR treatment on different cell types derived from the neural crest. These findings necessitate attention when utilizing NHEMs as a cell model in the development of therapeutic strategies for neurodegenerative diseases, including the use of BBR for metabolic control.

Cloperastine (CLP) is a drug with a central antitussive effect that is used to treat bronchitis. Therefore, we have attempted to examine the anti-inflammatory effects of CLP. CLP reduced the secretion of interleukin (IL)-6, a pro-inflammatory cytokine, from RAW264.7 monocyte/macrophage-linage cells treated with lipopolysaccharide (LPS). IL-6 is a biomarker of sepsis and has been suggested to exacerbate its symptoms. We found that the intraperitoneal administration of CLP reduced IL-6 levels in the lungs and also improved hypothermia in mice with LPS-induced sepsis. CLP ameliorated kidney pathologies such as congestion and increased the survival rate of mice administered with a lethal dose of LPS. To reveal the mechanisms underlying the anti-inflammatory function of CLP, we analysed the intracellular signaling in LPS-treated RAW264.7 cells. CLP induced the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3 (GSK3) and also increased the amount of nuclear factor erythroid-2-related factor 2 (Nrf2) in RAW264.7 cells with/without LPS. Wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), reduced the upregulated phosphorylation levels of Akt and GSK3 and the increased amount of Nrf2. It also halted the reduction of IL-6 secretion caused by CLP. These results suggest that CLP has an anti-inflammatory function via Akt/GSK3/Nrf2 signaling and could be a candidate drug for the treatment of inflammatory diseases, including sepsis.

The treatment of patients with cancer in an outpatient setting is important for maintaining patients' QOL and reducing the social burden of therapy, thus requiring extensive intervention by pharmacists in the outpatient setting. Japan has a system to certify pharmacists with specialized knowledge and skills in palliative care. However, few studies have investigated the impact of certified pharmacists' activities and of pharmacists' interventions on hospitalization and outpatient visits. Therefore, in this study, we retrospectively investigated the effects of interventions by certified pharmacists during the period from the introduction of opioid analgesics to hospitalization for pain management and the duration of outpatient visits at a single acute care hospital. Analysis using the Cox proportional hazards model showed that interventions by certified pharmacists significantly reduced hospitalizations for pain management (p = 0.014). Further, the results of the log-rank test showed that interventions by certified pharmacists significantly prolonged the period from the introduction of opioid analgesics to hospitalization compared with the absence of such interventions (p = 0.013). Additionally, interventions by certified pharmacists significantly increased the duration of outpatient visits compared with the absence of such interventions (p < 0.001). These results suggest that active and careful interventions by pharmacists, including certified pharmacists, contribute to the maintenance of the patients' QOL and healthcare economics by extending the period from the introduction of opioid analgesics to hospitalization for pain management and the duration of outpatient visits.

Hyperuricemia is caused by an imbalance of uric acid and is associated with many diseases. Although gout which is one of hyperuricemia-related diseases is curable with anti-hyperuricemic drugs some medications have side effects, such as hypersensitivity in patients with circulatory system disorders, flare reoccurrences, and increased cardiac risk. This study consisted of test tube (xanthine oxidase's inhibition) and animal study. Animal study using with ICR mice was composed of control, potassium oxonate-induced hyperuricemia, allopurinol, and 3 Korean red ginseng water extract (KRGWE) treatment groups (62.5; 125, and 500 mg/kg). We orally administered KRGWE once a day for 7 d to induce hyperuricemia and injected PO 2 h before the final KRGWE administration. We measured serum uric acid, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen, and creatinine and analyzed the genes such as organic anion transport (OAT)-1, OAT-3, and urate transport (URAT)-1. KRGWE dose-dependently controlled xanthine oxidase activity in the serum and completely inhibited serum uric acid. KRGWE affected both uric acid excretion-related and uric acid reabsorption-related gene expression. KRGWE stimulated uric acid excretion-related gene expressions, such as OAT-1 and OAT-3, but inhibited uric acid reabsorption-related gene expression, such as URAT-1. KRGWE improved liver and kidney functioning. KRGWE improved liver/kidney functioning and is promising anti-hyperuricemic agent which can control serum uric acid via downregulating URAT1 and upregulating OAT1 and OAT3.

Host immunity and autophagy of cancer cells markedly impact the development of gastric cancer. Hua-Zhuo-Jie-Du decoction (TDP) has been used in gastritis clinically. This study aimed to evaluate the effects of TDP combined with cisplatin (DDP) on gastric cancer and explore the molecular mechanism. A total of 16 BALB/c nude mice were used to model the SGC7901 cells xenograft and treated with TDP and DDP or both, with the model group as the control. Hematoxylin-Eosin (H&E) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining were performed, and the expression levels of CD31 and Ki-67 were quantified by immunohistochemistry staining. Additionally, cyclooxygenase (COX)-2, matrix metalloproteinas (MMP)-2, and MMP-9 expression levels were quantified using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). WB was used to determine Cleaved-caspase3, Beclin-1, LC3B, and p-p62 levels. Lastly, flow cytometry was employed to evaluate immune responses in mice. TDP and DDP significantly decreased tumor weight and nuclear division, resulting in loosely distributed cells. Besides, TDP and DDP down-regulated the protein expression levels of Ki-67, CD31, COX-2, MMP-2, and MMP-9, as well as decreased the number of CD4+ IL-17+ cells. Conversely, TDP and DDP up-regulated Cleaved-caspase3 expression and the proportion of CD3+/CD4+ and CD8+/CD3+ cells. Notably, optimal effects were achieved using the combination of DDP and TDP. Furthermore, DDP increased the LCII/LCI ratio and the Beclin-1 levels while down-regulating p62 levels. However, TDP alleviated these effects. These results collectively indicated that the combination of TDP with DDP can inhibit the development of gastric cancer cells by mediating the immune and autophagy signaling pathways.

Residual cancer cells after radiation therapy may acquire malignant phenotypes such as enhanced motility and migration ability, and therefore it is important to identify targets for preventing radiation-induced malignancy in order to increase the effectiveness of radiotherapy. G-Protein-coupled receptors (GPCRs) such as adenosine A2B receptor and cannabinoid receptors (CB1, CB2, and GPR55) may be involved, as they are known to have roles in proliferation, invasion, migration and tumor growth. In this study, we investigated the involvement of A2B and cannabinoid receptors in γ-radiation-induced enhancement of cell migration and actin remodeling, as well as the involvement of cannabinoid receptors in cell migration enhancement via activation of A2B receptor in human lung cancer A549 cells. Antagonists or knockdown of A2B, CB1, CB2, or GPR55 receptor suppressed γ-radiation-induced cell migration and actin remodeling. Furthermore, BAY60-6583 (an A2B receptor-specific agonist) enhanced cell migration and actin remodeling in A549 cells, and this enhancement was suppressed by antagonists or knockdown of CB2 or GPR55, though not CB1 receptor. Our results indicate that A2B receptors and cannabinoid CB1, CB2, and GPR55 receptors all contribute to γ-radiation-induced acquisition of malignant phenotypes, and in particular that interactions of A2B receptor and cannabinoid CB2 and GPR55 receptors play a role in promoting cell migration and actin remodeling. A2B receptor-cannabinoid receptor pathways may be promising targets for blocking the appearance of malignant phenotypes during radiotherapy of lung cancer.