Diffusion-Dominated Luminescence Dynamics of CsPbBr3 Studied Using Cathodoluminescence and Microphotoluminescence Spectroscopy.

Time-resolved or time-correlation measurements using cathodoluminescence (CL) reveal the electronic and optical properties of semiconductors, such as their carrier lifetimes, at the nanoscale. However, halide perovskites, which are promising optoelectronic materials, exhibit significantly different decay dynamics in their CL and photoluminescence (PL). We conducted time-correlation CL measurements of CsPbBr3 using Hanbury Brown-Twiss interferometry and compared them with time-resolved PL. The measured CL decay time was on the order of subnanoseconds and was faster than PL decay at an excited carrier density of 2.1 × 1018 cm-3. Our experiment and analytical model revealed the CL dynamics induced by individual electron incidences, which are characterized by highly localized carrier generation followed by a rapid decrease in carrier density due to diffusion. This carrier diffusion can play a dominant role in the CL decay time for undoped semiconductors, in general, when the diffusion dynamics are faster than the carrier recombination.

Hepatoprotective effects of baicalein against liver ischemia-reperfusion injury and partial hepatectomy in a rat model.

BACKGROUND: Baicalein is the main active flavonoid in Scutellariae Radix and is included in shosaikoto, a Kampo formula used for treating hepatitis and jaundice. However, little is known about its hepatoprotective effects against hepatic ischemia-reperfusion injury (HIRI), a severe clinical condition directly caused by interventional procedures. We aimed to investigate the hepatoprotective effects of baicalein against HIRI and partial hepatectomy (HIRI + PH) and its potential underlying mechanisms. METHODS AND RESULTS: Male Sprague-Dawley rats received either baicalein (5 mg/kg) or saline intraperitoneally and underwent a 70% hepatectomy 15 min after hepatic ischemia. After reperfusion, liver and blood samples were collected. Survival was monitored 30 min after hepatic ischemia and hepatectomy. In interleukin 1ß (IL-1ß)-treated primary cultured rat hepatocytes, the influence of baicalein on inflammatory mediator production and the associated signaling pathway was analyzed. Baicalein suppressed apoptosis and neutrophil infiltration, which are the features of HIRI + PH treatment-induced histological injury. Baicalein also reduced the mRNA expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α). In addition, HIRI + PH treatment induced liver enzyme deviations in the serum and hypertrophy of the remnant liver, which were suppressed by baicalein. In the lethal HIRI + PH treatment group, baicalein significantly reduced mortality. In IL-1ß-treated rat hepatocytes, baicalein suppressed TNF-α and chemokine mRNA expression as well as the activation of nuclear factor-kappa B (NF-κB) and Akt. CONCLUSIONS: Baicalein treatment attenuates HIRI + PH-induced liver injury and may promote survival. This potential hepatoprotection may be partly related to suppressing inflammatory gene induction through the inhibition of NF-κB activity and Akt signaling in hepatocytes.

Olprinone, a Selective Phosphodiesterase III Inhibitor, Has Protective Effects in a Septic Rat Model after Partial Hepatectomy and Primary Rat Hepatocyte.

Olprinone (OLP) is a selective inhibitor of phosphodiesterase III and is used clinically in patients with heart failure and those undergoing cardiac surgery; however, little is known about the effects of OLP on hepatoprotection. The purpose of this study aimed to determine whether OLP has protective effects in in vivo and in vitro rat models of endotoxin-induced liver injury after hepatectomy and to clarify the mechanisms of action of OLP. In the in vivo model, rats underwent 70% partial hepatectomy and lipopolysaccharide treatment (PH/LPS). OLP administration increased survival by 85.7% and decreased tumor necrosis factor-α, C-X-C motif chemokine ligand 1, and inducible nitric oxide synthase (iNOS) mRNA expression in the livers of rats treated with PH/LPS. OLP also suppressed nuclear translocation and/or DNA binding ability of nuclear factor kappa B (NF-κB). Pathological liver damage induced by PH/LPS was alleviated and neutrophil infiltration was reduced by OLP. Primary cultured rat hepatocytes treated with the pro-inflammatory cytokine interleukin-1ß (IL-1ß) were used as a model of in vitro liver injury. Co-treatment with OLP inhibited dose-dependently IL-1ß-stimulated iNOS induction and NF-κB activation. Our results demonstrate that OLP may partially inhibit the induction of several inflammatory mediators through the suppression of NF-κB and thus prevent liver injury induced by endotoxin after liver resection.

Sulforaphane Is Protective against Warm Ischemia/Reperfusion Injury and Partial Hepatectomy in Rats.

Sulforaphane (SFN) has various beneficial effects on organ metabolism. However, whether SFN affects inflammatory mediators induced by warm hepatic ischemia/reperfusion injury (HIRI) is unclear. To investigate the hepatoprotective effects of SFN using an in vivo model of HIRI and partial hepatectomy (HIRI + PH), rats were subjected to 15 min of hepatic ischemia with blood inflow occlusion, followed by 70% hepatectomy and release of the inflow occlusion. SFN (5 mg/kg) or saline was randomly injected intraperitoneally 1 and 24 h before ischemia. Alternatively, ischemia was prolonged for 30 min to evaluate the effect on mortality. The influence of SFN on the associated signaling pathways was analyzed using the interleukin 1ß (IL-1ß)-treated primary cultured rat hepatocytes. In the HIRI + PH-treated rats, SFN reduced serum liver enzyme activities and the frequency of pathological liver injury, such as apoptosis and neutrophil infiltration. SFN suppressed tumor necrosis factor-alpha (TNF-α) mRNA expression and inhibited nuclear factor-kappa B (NF-κB) activation by HIRI + PH. Mortality was significantly reduced by SFN. In IL-1ß-treated hepatocytes, SFN suppressed the expression of inflammatory cytokines and NF-κB activation. Taken together, SFN may have hepatoprotective effects in HIRI + PH in part by inhibiting the induction of inflammatory mediators, such as TNF-α, via the suppression of NF-κB in hepatocytes.

Identification of Anti-Inflammatory Compounds from Peucedanum praeruptorum Roots by Using Nitric Oxide-Producing Rat Hepatocytes Stimulated by Interleukin 1ß.

The roots of Peucedanum praeruptorum Dunn and Angelica decursiva Franchet et Savatier are designated Zenko, which is a crude drug defined by the Japanese Pharmacopoeia. This crude drug is used as an antitussive and an expectorant and is included in the Kampo formula Jinsoin, which improves cough, fever, and headache. Although the anti-inflammatory effects of this crude drug have been determined, the constituents responsible for this effect remain unknown. To investigate biologically active compounds, rat hepatocytes were used, which produce proinflammatory mediator nitric oxide (NO) in response to proinflammatory cytokine interleukin 1ß (IL-1ß). A methanol extract of P. praeruptorum roots, which suppressed IL-1ß-induced NO production, was fractionated into three crude fractions (ethyl acetate (EtOAc)-soluble, n-butanol-soluble, and water-soluble fractions) based on hydrophobicity. The EtOAc-soluble fraction markedly inhibited NO production. After this fraction was purified, three biologically active compounds were identified as praeruptorins A, B, and E, the contents of which were high. A comparison of their activities indicated that praeruptorin B exhibited the highest potency to inhibit NO production by decreasing inducible NO synthase expression and suppressed the expression of mRNAs encoding proinflammatory cytokines. Collectively, the three praeruptorins may primarily contribute to the anti-inflammatory effects of P. praeruptorum roots.

Activation of transcription factor HIF inhibits IL-1ß-induced NO production in primary cultured rat hepatocytes.

Roxadustat and other hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have recently been approved for the treatment of chronic renal anemia. In macrophages and monocytes, the activation of HIF-1 by pro-inflammatory cytokines induces iNOS expression and activity through the NF-κB pathway to produce nitric oxide (NO), which causes liver injury when excessively produced. Few studies have reported a relationship between HIF activity and iNOS induction in hepatocytes. We investigated the effect of drug- and hypoxia-induced HIF activations on NO production in primary cultured rat hepatocytes. Roxadustat treatment and hypoxic conditions activated HIF. Contrary to expectations, HIF-PHI treatment and hypoxia inhibited IL-1ß-induced NO production. RNA-Seq analysis of mRNA expression in rat hepatocytes showed that roxadustat treatment decreased the expression of genes related to inflammation, and genes in the NF-κB signaling pathway were induced by IL-1ß. Moreover, roxadustat suppressed IL-1ß-activated signaling pathways in an HIF-dependent manner. GalN/LPS-treated rats were used as in vivo models of hepatic injury, and roxadustat treatment showed a tendency to suppress the death of rats. Therefore, exogenous HIF-1 activation, including HIF-PHI and hypoxia exposures, suppressed IL-1ß-induced iNOS mRNA expression and subsequent NO production in hepatocytes, by suppressing the NF-κB signaling pathway. Roxadustat treatment suppresses the expression of pro-inflammatory genes by activating HIF, and thus may exhibit hepatoprotective effects.

Bitter melon fruit extract enhances intracellular ATP production and insulin secretion from rat pancreatic ß-cells.

Bitter melon (Momordica charantia L.) has been shown to have various health-promoting activities, including antidiabetic and hypoglycaemic effects. Improvement in insulin sensitivity and increase in glucose utilisation in peripheral tissues have been reported, but the effect on insulin secretion from pancreatic ß-cells remains unclear. In this study, we investigated the effect of bitter melon fruit on insulin secretion from ß-cells and the underlying mechanism. The green fruit of bitter melon was freeze-dried and extracted with methanol. The bitter melon fruit extract (BMFE) was fractionated using ethyl acetate (fraction A), n-butanol (fraction B) and water (fraction C). Insulin secretory capacity from INS-1 rat insulinoma cell line and rat pancreatic islets, as well as glucose tolerance in rats by oral glucose tolerance test (OGTT), was measured using BMFE and fractions. ATP production in ß-cells was also examined. BMFE augmented insulin secretion from INS-1 cells in a dose-dependent manner. The significant augmentation of insulin secretion was independent of the glucose dose. Fraction A (i.e. hydrophobic fraction), but not fractions B and C, augmented insulin secretion significantly at the same level as that by BMFE. This finding was also observed in pancreatic islets. In OGTT, BMFE and fraction A decreased blood glucose levels and increased serum insulin levels after glucose loading. The decrease in blood glucose levels was also observed in streptozotocin-induced diabetic rats. In addition, BMFE and fraction A increased the ATP content in ß-cells. We concluded that hydrophobic components of BMFE increase ATP production and augment insulin secretion from ß-cells, consequently decreasing blood glucose levels.

Comparative Analysis of Anti-inflammatory Activity of the Constituents of the Rhizome of Cnidium officinale Using Rat Hepatocytes.

The rhizome of Cnidium officinale (Umbelliferae) (known as Senkyu in Japan; COR) has been used as a crude drug in Japanese Kampo formulas, such as Jumihaidokuto (to treat eczema and urticaria) and Kakkontokasenkyushin'i (to treat rhinitis). COR contains phthalides, which are thought to be potent principal constituents. Few studies have been reported about the comparison of anti-inflammatory activity of COR constituents. We aimed to identify the constituents in COR and compare their anti-inflammatory activity. COR was extracted with methanol and fractionated into ethyl acetate (EtOAc)-soluble, n-butanol-soluble, and water-soluble fractions. Primary cultured rat hepatocytes were used to assess anti-inflammatory activity by monitoring the interleukin (IL)-1ß-induced production of nitric oxide (NO), an inflammatory mediator. The EtOAc-soluble fraction significantly suppressed NO production without showing cytotoxicity in IL-1ß-treated hepatocytes, whereas the n-butanol-soluble fraction showed less potency, and the water-soluble fraction did not significantly affect the NO levels. Four constituents were isolated from the EtOAc-soluble fraction and identified as senkyunolide A, (3S)-butylphthalide, neocnidilide, and cnidilide. Among these phthalides and (Z)-ligustilide, senkyunolide A and (Z)-ligustilide efficiently suppressed NO production in hepatocytes, whereas the others showed less potency in the suppression of NO production. Furthermore, senkyunolide A decreased the levels of the inducible nitric oxide synthase (iNOS) protein and mRNA, as well as the levels of mRNAs encoding proinflammatory cytokines (e.g., tumor necrosis factor α) and chemokine C-C motif ligand 20. These results suggest that senkyunolide A may cause the anti-inflammatory and hepatoprotective effects of COR by suppressing the genes involved in inflammation.

Bitter melon fruit extract has a hypoglycemic effect and reduces hepatic lipid accumulation in ob/ob mice.

Bitter melon (Momordica charantia L.) is a vegetable and has been used as traditional medicine. Recently, we reported that bitter melon fruit extracts and its ethyl acetate (EtOAc)-soluble fraction markedly suppressed the expression of proinflammatory genes, including the inducible nitric oxide synthase gene. However, it is unclear whether bitter melon exhibits antidiabetic effects. In this study, we showed that cucurbitacin B, a cucurbitane-type triterpenoid, was present in an EtOAc-soluble fraction and suppressed nitric oxide production in hepatocytes. When the EtOAc-soluble fraction was administered for 7 days to ob/ob mice, a type 2 diabetes mellitus model, the mice fed with this fraction exhibited a significant decrease in body weight and blood glucose concentrations compared with the mice fed without the fraction. The administration of the fraction resulted in significant increases in serum insulin concentrations and the levels of both insulin receptor mRNA and protein in the ob/ob mouse liver. The EtOAc-soluble fraction decreased the interleukin-1ß mRNA expression, as well as hepatic lipid accumulation in hepatocytes. Taken together, these results indicate that administration of an EtOAc-soluble fraction improved hyperglycemia and hepatic steatosis, suggesting that this fraction may be responsible for both the antidiabetic and anti-inflammatory effects of bitter melon fruit.

A sense oligonucleotide to inducible nitric oxide synthase mRNA increases the survival rate of rats in septic shock.

Natural antisense transcripts (asRNAs) that do not encode proteins are transcribed from rat, mouse, and human genes, encoding inducible nitric oxide synthase (iNOS), which catalyzes the production of the inflammatory mediator nitric oxide (NO). In septic shock, NO is excessively produced in hepatocytes and macrophages. The iNOS asRNA interacts with and stabilizes iNOS mRNA. We found that single-stranded 'sense' oligonucleotides corresponding to the iNOS mRNA sequence reduced iNOS mRNA levels by interfering with the mRNA-asRNA interactions in rat hepatocytes. The iNOS sense oligonucleotides that were substituted with phosphorothioate bonds and locked nucleic acids efficiently decreased the levels of iNOS mRNA and iNOS protein. In this study, the gene expression patterns in the livers of two endotoxemia model rats with acute liver failure were compared. Next, we optimized the sequence and modification of the iNOS sense oligonucleotides in interleukin 1ß-treated rat hepatocytes. When a sense oligonucleotide was simultaneously administered with d-galactosamine and bacterial lipopolysaccharide (LPS) to rats, their survival rate significantly increased compared to the rats administered d-galactosamine and LPS alone. In the livers of the sense oligonucleotide-administered rats, apoptosis in the hepatocytes markedly decreased. These results suggest that natural antisense transcript-targeted regulation technology using iNOS sense oligonucleotides may be used to treat human inflammatory diseases, such as sepsis and septic shock.

Antipyretic analgesic drugs have different mechanisms for regulation of the expression of inducible nitric oxide synthase in hepatocytes and macrophages.

Antipyretic analgesic drugs (including non-steroidal anti-inflammatory drugs) inhibit cyclooxygenase-2 and inducible nitric oxide synthase (iNOS), resulting in decreases of the proinflammatory mediators prostaglandin E2 and nitric oxide (NO), respectively. Both mediators are regulated by nuclear factor-kappa B (NF-κB), a key transcription factor in inflammation. Few reports have compared the efficacy and potency of anti-inflammatory drugs as NO inhibitors. In our study, we examined the effects of four popular antipyretic analgesic drugs on NO production induced in hepatocytes and macrophages. Mouse RAW264.7 macrophages treated with bacterial lipopolysaccharide showed the highest efficacy with regard to NO production; aspirin, loxoprofen, ibuprofen, and acetaminophen dose-dependently suppressed NO induction. Ibuprofen showed the highest potency in suppressing the induced production of NO. In rat hepatocytes, all the drugs inhibited interleukin 1ß-induced NO production and ibuprofen and loxoprofen inhibited NO induction effectively. Unexpectedly, the potency of NO suppression of each drug in hepatocytes did not always correlate with that observed in RAW264.7 cells. Microarray analyses of mRNA expression in hepatocytes revealed that the effects of the four antipyretic analgesic drugs modulated the NF-κB signaling pathway in a similar manner to the regulation of the expression of genes associated with inflammation, including the iNOS gene. However, the affected signal-transducing molecules in the NF-κB pathway were different for each drug. Therefore, antipyretic analgesic drugs may decrease NO production by modulating the NF-κB pathway in different ways, which could confer different efficacies and potencies with regard to their anti-inflammatory effects.

A new flavanone and other flavonoids from green perilla leaf extract inhibit nitric oxide production in interleukin 1ß-treated hepatocytes.

A new flavanone, shisoflavanone A (1), and several flavonoids were purified from the ethyl acetate-soluble fraction of green perilla leaves (Perilla frutescens Britton var. crispa form viridis), and their structures were identified. Shisoflavanone A was elucidated as 8-hydroxy-6,7-dimethoxyflavanone based on its spectral data. Other constituents of the ethyl acetate-soluble fraction, i.e. 5,8-dihydroxy-7-methoxyflavanone (2), negletein (5,6-dihydroxy-7-methoxyflavone) (3), luteolin (4), apigenin (5), esculetin (6), and protocatechuic acid (7), were identified. This is the first time that constituents 2, 3, and 6 have been found in green perilla. Shisoflavanone A and the other constituents (except 7) significantly inhibited nitric oxide production in interleukin 1ß-stimulated rat hepatocytes, which have been used to monitor the anti-inflammatory effects of herbal constituents. The present findings suggest that these constituents, including shisoflavanone A, may be involved in the anti-inflammatory effects of green perilla leaves.

PdRu Bimetallic Nanoparticles/Metal-Organic Framework Composite through Supercritical CO2-Assisted Immobilization.

Metal-nanoparticle (NP)/metal-organic framework (MOF) composites have attracted considerable attention as heterogeneous catalysts. Compared with porous carbon, silica, and alumina, the charge-transfer interaction between the metal NPs and the MOF accelerated the catalytic activity. In this study, PdRu bimetallic NPs were successfully immobilized on MOFs such as MIL-101(Cr) by using supercritical carbon dioxide. The STEM-EDX images show a uniform 3D distribution of the PdRu bimetallic NPs on MIL-101(Cr). The resulting PdRu@MIL-101(Cr) catalyst exhibited higher CO oxidation than monometal/MOF composites such as Pd@MIL-101(Cr) and Ru@MIL-101(Cr). Furthermore, PdRu@MIL-101(Cr) exhibited higher catalytic activity than PdRu@SiO2. This is because the particle size of the PdRu bimetallic NPs in MIL-101(Cr) was within the range of 2-3 nm. The synergistic effects were based on the combination of two metals, Pd and Ru, small bimetal particle formation, and charge-transfer interactions between the bimetal NPs and the MOF. These factors enhance the catalytic activity of the bimetal/MOF composites.

Giant hemorrhagic pancreatic pseudocyst with suspected cystic pancreatic tumor: a case report.

Pancreatic pseudocysts are surrounded by a non-epithelialized wall confined to the pancreas and localized to the pancreatic tissue or adjacent pancreatic cavity. In contrast, pancreatic cystic tumors occur less frequently than solid lesions and are often detected incidentally on imaging. Regarding the qualitative diagnosis of pancreatic pseudocysts, it is important to differentiate them from neoplastic cysts. We report the case of a 74-year-old woman with a giant hemorrhagic pancreatic pseudocyst and a suspected cystic pancreatic tumor, wherein distal pancreatectomy and splenectomy with lymph node dissection were performed. The patient was discharged 11 days postsurgery, with a good postoperative course. There are no reports of giant pancreatic pseudocysts larger than 10 cm with hematoma contents. The presumptive diagnosis of pseudocysts based on imaging alone may be difficult. Surgical resection is considered when it is difficult to distinguish a giant pancreatic pseudocyst from a cystic neoplasm.

Hepatoprotection of a Standardized Extract of Cultured Lentinula edodes Mycelia against Liver Injury Induced by Ischemia-Reperfusion and Partial Hepatectomy.

A standardized extract of cultured Lentinula edodes mycelia (ECLM, AHCC®) has been shown to have beneficial effects on organ metabolism. ECLM has been indicated to have liver protective properties by suppressing inflammatory responses. The pathogenesis of hepatic ischemia-reperfusion injury is thought to involve the induction of inflammatory mediators. However, whether ECLM affects inflammatory mediators caused by warm hepatic ischemia-reperfusion injury and partial hepatectomy (HIRI+PH) has not been clarified. In this study, we evaluated the protective effects of ECLM against liver damage caused by HIRI+PH. Rats were fed a normal diet (HIRI+PH) or a normal diet with 2% ECLM (HIRI+PH and ECLM) for ten days, then the liver and duodenal ligament were clamped and subjected to 15 min of hepatic ischemia. After 70% hepatectomy, the inflow occlusion was released, and liver and blood samples were collected at 3, 6, and 24 h. The effect of ECLM on mortality induced by 30 min of ischemia and hepatectomy was evaluated. The results showed that ECLM attenuated pathological liver damage, including apoptosis, in the rats treated with HIRI+PH, and decreased serum aminotransferase activity; ECLM decreased mRNA levels of the inflammation-related genes inducible nitric oxide synthase and C-X-C motif chemokine ligand 1, and increased mRNA levels of interleukin 10, an anti-inflammatory cytokine; ECLM increased hepatocyte growth factor mRNA levels and Ki-67 labeled nuclei in the liver at 24 h; ECLM significantly reduced HIRI+PH-induced mortality. In conclusion, ECLM may prevent HIRI+PH-induced liver injury in part by suppressing various inflammatory responses and promoting liver regeneration.

Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1ß-treated hepatocytes.

BACKGROUND: Nobiletin is a polymethoxylated flavone that is abundant in the peels of citrus fruits, such as Citrus unshiu (Satsuma mandarin) and Citrus sinensis. The dried peels of C. unshiu (chinpi) have been included in several formulae of Japanese Kampo medicines. Nobiletin may suppress the induction of inducible nitric oxide synthase (iNOS), which synthesizes the inflammatory mediator nitric oxide (NO) in hepatocytes. METHODS: A C. unshiu peel (CUP) extract was prepared. Primary cultured rat hepatocytes were treated with the CUP extract or nobiletin in the presence of interleukin 1ß (IL-1ß), which induces iNOS expression. NO production and iNOS gene expression were analyzed. RESULTS: High-performance liquid chromatography analyses revealed that the nobiletin content in the CUP extract was 0.14%. Nobiletin dose-dependently reduced the NO levels and decreased iNOS expression at the protein, mRNA and antisense transcript levels. Flavone, which does not contain any methoxy groups, also suppressed iNOS induction. Nobiletin reduced the transcriptional activity of iNOS promoter-luciferase constructs and the DNA-binding activity of nuclear factor κB (NF-κB) in the nuclei. CONCLUSIONS: The suppression of iNOS induction by nobiletin suggests that nobiletin may be responsible for the anti-inflammatory effects of citrus peels and have a therapeutic potential for liver diseases.

Two new monoterpene esters from the pericarps of Alpinia zerumbet.

Two new monoterpene esters (1 and 2) and four known compounds (3-6) were isolated from the pericarps of Alpinia zerumbet. Their structures were elucidated by extensive spectroscopic analyses and their anti-inflammatory activity was evaluated by monitoring their inhibitory effects on the interleukin-1ß-induced production of nitric oxide in primary cultured rat hepatocytes. The new compound 1 and cardamonin 3 showed inhibitory activities with IC50 values of 17.6 ± 1.1 and 10.2 ± 1.3 µM, respectively, which are comparable to that of the positive control NG-methyl-L-arginine acetate salt.

Hydrophobic constituents of Polygonum multiflorum roots promote renal erythropoietin expression in healthy mice.

The roots of Polygonum multiflorum Thunberg (Polygonaceae) are used as a crude drug Kashu that is considered to improve blood deficiency based on a Kampo concept. Kashu has been included in Kampo formulas, such as Tokiinshi, which is used to treat eczema and dermatitis with itchiness by inhibiting inflammation and facilitating blood circulation in the skin. However, the effects of P. multiflorum roots on erythropoiesis are unclear. Previously, we isolated six phenolic constituents from an ethyl acetate (EtOAc)-soluble fraction of P. multiflorum root extract and identified them as (E)-2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside [(E)-THSG], emodin, emodin-8-O-ß-D-glucopyranoside, physcion, physcion-8-O-ß-D-glucopyranoside, and catechin. To examine whether P. multiflorum roots facilitate erythropoiesis, the EtOAc-soluble fraction was orally administered to healthy ICR mice. When compared with mice fed a standard diet alone (Controls), the mice fed a diet including the EtOAc-soluble fraction exhibited significantly higher serum erythropoietin (Epo) levels. The renal Epo mRNA levels in EtOAc-soluble fraction-administered mice were significantly higher than those in the control mice. Then, we administered roxadustat, which is a drug to treat the patient suffering with renal anemia by specifically inhibiting hypoxia-inducible factor prolyl hydroxylases. Roxadustat slightly increased renal Epo mRNA levels in healthy mice. Administration of (E)-THSG, a major constituent, significantly increased serum Epo levels. It is likely that (E)-THSG may facilitate the process to convert inactive renal Epo-producing cells to active Epo-producing cells. Collectively, it is implied that (E)-THSG in the EtOAc-soluble fraction of P. multiflorum roots may primarily improve blood deficiency of Kampo concept by promoting erythropoiesis.

COMBINATION THERAPY WITH A SENSE OLIGONUCLEOTIDE TO INDUCIBLE NITRIC OXIDE SYNTHASE MRNA AND HUMAN SOLUBLE THROMBOMODULIN IMPROVES SURVIVAL OF SEPSIS MODEL RATS AFTER PARTIAL HEPATECTOMY.

ABSTRACT: Sepsis after a major hepatectomy is a critical problem. In septic shock, the inflammatory mediator, nitric oxide (NO), is overproduced in hepatocytes and macrophages. The natural antisense (AS) transcripts, non-coding RNAs, are transcribed from a gene that encodes inducible nitric oxide synthase (iNOS). iNOS AS transcripts interact with and stabilize iNOS mRNAs. A single-stranded "sense oligonucleotide" (designated as SO1) corresponding to the iNOS mRNA sequence inhibits mRNA-AS transcript interactions and reduces iNOS mRNA levels in rat hepatocytes. In contrast, recombinant human soluble thrombomodulin (rTM) treats disseminated intravascular coagulopathy by suppressing coagulation, inflammation, and apoptosis. In this study, the combination therapy of SO1 and a low dose of rTM was evaluated for hepatoprotection in a rat septic shock model after partial hepatectomy. Rats underwent 70% hepatectomy, followed by intravenous (i.v.) injection of lipopolysaccharide (LPS) after 48 h. SO1 was injected (i.v.) simultaneously with LPS, whereas rTM was injected (i.v.) 1 h before LPS injection. Similarly to our previous report, SO1 increased survival after LPS injection. When rTM, which has different mechanisms of action, was combined with SO1, it did not interfere with the effect of SO1 and showed a significant increase in survival compared with LPS alone treatment. In serum, the combined treatment decreased NO levels. In the liver, the combined treatment inhibited iNOS mRNA and protein expression. A decreased iNOS AS transcript expression by the combined treatment was also observed. The combined treatment decreased mRNA expression of the inflammatory and pro-apoptotic genes while increasing that of the anti-apoptotic gene. Furthermore, the combined treatment reduced the number of myeloperoxidase-positive cells. These results suggested that the combination of SO1 and rTM has therapeutic potential for sepsis.

Omeprazole Increases Survival Through the Inhibition of Inflammatory Mediaters in Two Rat Sepsis Models.

BACKGROUND: Omeprazole (OMZ) is a proton pump inhibitor that is used to reduce gastric acid secretion, but little is known about its possible liver protective effects. This study investigated whether OMZ has beneficial effects in rat septic models of LPS-induced liver injury after D-galactosamine (GalN) treatment and 70% hepatectomy (PH), and to determine the mechanisms of OMZ in an in vitro model of liver injury. METHODS: In the in vivo models, the effects of OMZ were examined 1 h before treatments in both models on survival, nuclear factor (NF)-κB activation, histopathological analysis, and proinflammatory mediator expression in the liver and serum. In the in vitro model, primary cultured rat hepatocytes were treated with IL-1ß in the presence or absence of OMZ. The influence of OMZ on nitric oxide (NO) product and inducible NO synthase (iNOS) induction and on the associated signaling pathway was analyzed. RESULTS: OMZ increased survival and decreased tumor necrosis factor-alpha, iNOS, cytokine-induced neutrophil chemoattractant 1, IL-6, and IL-1ß mRNA expression, and increased IL-10 mRNA expression in the livers of both GaIN/LPS- and PH/LPS-treated rats. Necrosis and apoptosis were inhibited by OMZ in GaIN/LPS rats, but OMZ had no effects on necrosis in PH/LPS rats. OMZ inhibited iNOS induction partially through suppression of NF-κB signaling in hepatocytes. CONCLUSIONS: OMZ inhibited the induction of several inflammatory mediators, resulting in the prevention of LPS-induced liver injury after GalN liver failure and PH, although OMZ showed different doses and mechanisms in the two models.