Gastroparesis might not be uncommon in patients with diabetes mellitus in a real-world clinical setting: a cohort study.

BACKGROUND: This study investigated the frequency of diabetic gastroparesis and associated risk factors in a real-world clinical setting. METHODS: This retrospective cross-sectional study included patients who underwent assessments of solid gastric emptying time (GET) by technetium-99 m scintigraphy between May 2019 and December 2020. We categorized patients into three groups according to gastric retention of technetium-99 m: rapid (< 65% at 1 h or < 20% at 2 h), normal (≤60% at 2 h and/or ≤ 10% at 4 h), and delayed (> 60% at 2 h and/or > 10% at 4 h). RESULTS: Patients with diabetes mellitus (DM) were more likely to show abnormal GET than those without DM (119 [70.8%] vs. 16 [44.4%]). The mean glycated A1c was 10.3% in DM patients. DM patients with normal GET were significantly younger (57.2 years, P = 0.044) than those with delayed (65.0 years) or rapid GET (60.2 years). Fasting glucose levels were the lowest in the normal GET group and the highest in the rapid GET group (delayed: 176.3 mg/dL, normal: 151.2 mg/dL, rapid: 181.0 mg/dL, P = 0.030). However, glycated A1c was not significantly different among the delayed, normal, and rapid GET groups in patients with DM. Patients with delayed and rapid GET showed a higher frequency of retinopathy (6.0 vs. 15.5%, P = 0.001) and peripheral neuropathy (11.3 vs. 24.4%, P = 0.001) than those with normal GET. In the multinomial logistic regression analysis, retinopathy demonstrated a positive association with delayed GET, while nephropathy showed a significant negative correlation. CONCLUSION: DM gastroparesis in the clinical setting was not uncommon. Abnormal GET, including delayed and rapid GET, was associated with DM retinopathy or peripheral neuropathy.

Interoperable Nanoparticle Sensor Capable of Strain and Vibration Measurement for Rotor Blade Monitoring.

Recent advances in nanomaterials technology create the new possibility to fabricate high performance sensors. However, there has been limitations in terms of multivariate measurable and interoperable sensors. In this study, we fabricated an interoperable silver nanoparticle sensor fabricated by an aerodynamically focused nanomaterial (AFN) printing system which is a direct printing technique for inorganic nanomaterials onto a flexible substrate. The printed sensor exhibited the maximum measurable frequency of 850 Hz, and a gauge factor of 290.62. Using a fabricated sensor, we evaluated the sensing performance and demonstrated the measurement independency of strain and vibration sensing. Furthermore, using the proposed signal separation algorithm based on the Kalman filter, strain and vibration were each measured in real time. Finally, we applied the printed sensor to quadrotor condition monitoring to predict the motion of a quadrotor.

The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells.

BACKGROUND: Chemotherapeutic drug resistance remains a clinical obstacle in cancer management. Drug-resistant cancer cells usually exhibit cross-resistance to ionizing radiation, which has devastating consequences for patients. With a better understanding of the molecular mechanisms, it will be possible to develop strategies to overcome this cross-resistance and to increase therapeutic sensitivity. METHODS: Natural and synthetic flavonoid compounds including xanthohumol, the principal flavonoid in hops, were investigated for its radio-sensitizing activity on human breast cancer MCF-7 and adriamycin-resistant MCF-7 (MCF-7/ADR) cells. Chemo-sensitizing or radio-sensitizing effect was analyzed by tetrazolium-based colorimetric assay and flow cytometry. Western blot analysis, confocal microscopy, gene silencing with siRNA transfection and luciferase reporter gene assay were performed to examine signaling molecule activation. RESULTS: Among the tested flavonoid compounds, pretreatment of the cells with xanthohumol significantly sensitized MCF-7/ADR cells to the radiation treatment by inducing apoptosis. In MCF-7/ADR cells, treatment with xanthohumol alone or with gamma-rays significantly decreased levels of anti-apoptotic proteins. Multi-drug resistance 1 (MDR1), epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) expression levels in MCF-7/ADR cells were suppressed by xanthohumol treatment. In addition, xanthohumol treatment increased death receptor (DR)-4 and DR5 expression. The xanthohumol-induced changes of these resistance-related molecules in MCF-7/ADR cells were synergistically increased by gamma-ray treatment. CONCLUSIONS: Xanthohumol restored sensitivity of MCF-7/ADR cells to doxorubicin and radiation therapies. GENERAL SIGNIFICANCE: Our results suggest that xanthohumol may be a potent chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition.

Multi-approach assessment of groundwater biogeochemistry: Implications for the site characterization of prospective spent nuclear fuel repository sites.

The disposal of spent nuclear fuel in deep subsurface repositories using multi-barrier systems is considered to be the most promising method for preventing radionuclide leakage. However, the stability of the barriers can be affected by the activities of diverse microbes in subsurface environments. Therefore, this study investigated groundwater geochemistry and microbial populations, activities, and community structures at three potential spent nuclear fuel repository construction sites. The microbial analysis involved a multi-approach including both culture-dependent, culture-independent, and sequence-based methods for a comprehensive understanding of groundwater biogeochemistry. The results from all three sites showed that geochemical properties were closely related to microbial population and activities. Total number of cells estimates were strongly correlated to high dissolved organic carbon; while the ratio of adenosine-triphosphate:total number of cells indicated substantial activities of sulfate reducing bacteria. The 16S rRNA gene sequencing revealed that the microbial communities differed across the three sites, with each featuring microbes performing distinctive functions. In addition, our multi-approach provided some intriguing findings: a site with a low relative abundance of sulfate reducing bacteria based on the 16S rRNA gene sequencing showed high populations during most probable number incubation, implying that despite their low abundance, sulfate reducing bacteria still played an important role in sulfate reduction within the groundwater. Moreover, a redundancy analysis indicated a significant correlation between uranium concentrations and microbial community compositions, which suggests a potential impact of uranium on microbial community. These findings together highlight the importance of multi-methodological assessments in better characterizing groundwater biogeochemical properties for the selection of potential spent nuclear fuel disposal sites.

A Fatal Case of 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency in a Term Infant with Severe High Anion Gap Acidosis and Review of the Literature.

3-hydroxy isobutyl-CoA hydrolase (HIBCH) deficiency is a recently described, rare inborn error of valine metabolism associated with a Leigh syndrome-like phenotype, neurodegenerative symptoms, and caused by recessive mutations in the HIBCH gene. We report the most severe case to date of an intrauterine growth-restricted term male who presented with severe acidosis and a high anion gap soon after birth. The manifestation was fatal that led to death within 36 hours of life. The diagnosis was made postnatally by Whole Genome Sequencing (WGS). We report a rapid and fatal event of HIBCN in a neonate and review of the literature.

Renal abscess in a Lionhead rabbit due to Encephalitozoon cuniculi and Escherichia coli: A case report.

Background: In rabbits, renal abscesses (pus-filled sores) are rare and diagnosis remains challenging. Therefore, in this study, we aimed to determine the clinical manifestation and diagnostic tests associated with renal abscess identification in rabbits. Case Description: A four-and-a-half-year-old castrated male Lionhead rabbit with a history of poor appetite and abdominal distension was admitted to the animal hospital. Blood analysis, radiography, ultrasonography, and computed tomography scans revealed a kidney abscess found within the renal parenchyma, with severe loss of the cortex and medulla, extending toward the capsule. Consequently, the rabbit underwent nephrectomy. The enlarged right kidney was surgically removed. Histopathological examination of the affected kidney showed severe necrosis and ischemic zones, atrophy of the renal tubules, and prominent heterophils with mixed inflammatory cell infiltrates. Immunohistochemistry and polymerase chain reaction confirmed Encephalitozoon cuniculi and Escherichia coli infections, respectively. Conclusion: This report provides novel insights into the diagnosis of renal abscesses in Lionhead rabbits.

Intravascular papillary endothelial hyperplasia in the lungs of a wild Korean raccoon dog.

A male Korean raccoon dog of unknown age was rescued and placed at the Daejeon Wildlife Rescue Center, Korea. Physical examination revealed severe emaciation and dehydration, as well as thick crusts and alopecia over most of the body. During medical care, the animal died and was submitted for postmortem examination. Firm, brown-red lesions of various sizes were observed on the surface of the lungs. In cross-sections of the lungs, pulmonary vessels were thickened and dilated, with white irregular papillary luminal projections. Histologically, pulmonary blood vessels were severely hyperplastic, characterized by thickened dilated walls and fibrous papillary projections covered with a single layer of endothelial cells (ECs). Hyperplastic fibrous connective tissue was confirmed by Masson trichrome staining. The ECs expressed CD31. We diagnosed the lesion as intravascular papillary endothelial hyperplasia, a unique non-neoplastic reactive process that has not been reported previously in pulmonary vessels of canids, equids, or felids, to our knowledge.

Temperature-dependent microbial reactions by indigenous microbes in bentonite under Fe(III)- and sulfate-reducing conditions.

Bentonite is a promising buffer material for constructing spent nuclear fuel (SNF) repositories. However, indigenous microbes in bentonite can be introduced to the repository and subsequent sealing of the repository develops anoxic conditions over time which may stimulate fermentation and anaerobic respiration, possibly affecting bentonite structure and SNF repository stability. Moreover, the microbial activity in the bentonite can be impacted by the heat generated from radionuclides decay. Therefore, to investigate the temperature effect on microbial activities in bentonite, we created microcosms with WRK bentonil (a commercial bentonite) using lactate as the electron donor, and sulfate and/or ferrihydrite (Fe(III)) as electron acceptors with incubation at 18 â„ƒ and 50 â„ƒ. Indigenous WRK microbes reduced sulfate and Fe(III) at both temperatures but with different rates and extents. Lactate was metabolized to acetate at both temperatures, but only to propionate at 18 â„ƒ during early-stage microbial fermentation. More Fe(III)-reduction at 18 â„ƒ but more sulfate-reduction at 50 â„ƒ was observed. Thermophilic and/or metabolically flexible microbes were involved in both fermentation and Fe(III)/sulfate reduction. Our findings illustrate the necessity of considering the influence of temperature on microbial activities when employing bentonite as an engineered buffer material in construction of SNF repository barriers.

Effects of Fe(III) (hydr)oxide mineralogy on the development of microbial communities originating from soil, surface water, groundwater, and aerosols.

Microbial Fe(III) reduction is a key component of the iron cycle in natural environments. However, the susceptibility of Fe(III) (hydr)oxides to microbial reduction varies depending on the mineral's crystallinity, and the type of Fe(III) (hydr)oxide in turn will affect the composition of the microbial community. We created microcosm reactors with microbial communities from four different sources (soil, surface water, groundwater, and aerosols), three Fe(III) (hydr)oxides (lepidocrocite, goethite, and hematite) as electron acceptors, and acetate as an electron donor to investigate the shaping effect of Fe(III) mineral type on the development of microbial communities. During a 10-month incubation, changes in microbial community composition, Fe(III) reduction, and acetate utilization were monitored. Overall, there was greater reduction of lepidocrocite than of goethite and hematite, and the development of microbial communities originating from the same source diverged when supplied with different Fe(III) (hydr)oxides. Furthermore, each Fe(III) mineral was associated with unique taxa that emerged from different sources. This study illustrates the taxonomic diversity of Fe(III)-reducing microbes from a broad range of natural environments.

Activity-Stability Trends of the Sb-SnO2@RuOx Heterostructure toward Acidic Water Oxidation.

Accomplishments of enhanced activity and durability are a major concern in the design of catalysts for acidic water oxidation. To date, most studied supported metal catalysts undergo fast degradation in strongly acidic and oxidative environments due to improper controlling of the interface stability caused by their lattice mismatches. Here, we evaluate the activity-stability trends of in situ crystallized antimony-doped tin oxide (Sb-SnO2)@RuOx (Sb-SnO2@RuOx) heterostructure nanosheets (NSs) for acidic water oxidation. The catalyst prepared by atomic layer deposition of a conformal Ru film on antimony-doped tin sulfide (Sb-SnS2) NSs followed by heat treatment highlights comparable activity but longer stability than that of the ex situ catalyst (where Ru was deposited on Sb-SnO2 followed by heating). Air calcination for in situ crystallization allows the formation of hierarchical mesoporous Sb-SnO2 NSs from as-prepared Sb-SnS2 NSs and parallel in situ transformation from Ru to RuOx, resulting in a compact heterostructure. The significance of this approach significantly resists corrosive dissolution, which is justified by the enhanced oxygen evolution reaction (OER) stability of the catalyst compared to most of the state-of-the-art ruthenium-based catalysts including Carbon@RuOx (which shows ∼10 times higher dissolution) as well as Sb-SnO2@Com. RuOx and Com. RuO2. This study demonstrates the controlled interface stability of heterostructure catalysts toward enhancing OER activity and stability.

Geranyl derivative of phloroacetophenone induces cancer cell-specific apoptosis through Bax-mediated mitochondrial pathway in MCF-7 human breast cancer cells.

Plant-derived polyhenols inhibit cancer cell proliferation and induce apoptosis. Recently, prenylflavonoids and alkyl-phloroacetophenones have been reported for their in vitro antitumor activity. In the present study, we examined the cytotoxic activity of prenyl (3-PAP) and geranyl (3-GAP) derivatives of phloroacetophenone, and xanthohumol (XN), a prenyl-chalcone, in human breast cancer (MCF-7) and human sarcoma (HT1080) cell lines in vitro. 3-GAP showed the strongest cytotoxicity in these cell lines with IC(50) values of less than 10 µM. In addition, we report that 3-GAP is a more potent anti-cancer agent for breast cancer than XN which is a well-known anticancer flavonoid. Moreover, 3-GAP did not induce cytotoxicity in the normal cell line, TCMK-1, whereas 3-PAP and XN significantly reduced TCMK-1 cell viability. In 3-GAP-treated MCF-7 cells, nuclear accumulation and transcriptional activity of p53 were increased. In addition, pro-apoptotic Bax but not B-cell lymphoma 2 (Bcl-2) expression was increased by 3-GAP. In accordance with the Bax increase, 3-GAP induced mitochondrial cytochrome c release and activated caspase-9, an initiator of the caspase cascade. In the MCF-7 cell line which does not express caspase-3, activation of caspase-7, a member of the caspase-3 subfamily, was increased by 3-GAP. The present results indicate that synthetic 3-GAP is a safe and effective anti-cancer agent, and the Bax-mediated mitochondrial pathway is the main apoptosis signaling pathway of 3-GAP in MCF-7 cells.

HMC05, Herbal Formula, Inhibits TNF-α-Induced Inflammatory Response in Human Umbilical Vein Endothelial Cells.

Vascular inflammation has been implicated in the progression of cardiovascular diseases such as atherosclerosis. In the present study, we found that HMC05, an extract from eight different herbal mixtures, dose-dependently inhibited tumor necrosis factor-α (TNF-α)-induced adhesion of monocytes to endothelial cells. Such inhibitory effect of HMC05 correlated with suppressed expression of monocyte chemoattractant protein-1, CC chemokine receptor 2, vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1. In addition, HMC05 significantly inhibited production of reactive oxygen species (ROS) and nuclear factor (NF)-κB activation by TNF-α. Those inhibitory effects of HMC05 (1-10 µg mL(-1)) on the TNF-α-induced inflammatory event was similar to those of berberine (1-10 µM), which is a major component of HMC05 and one of herbal compounds known to have vasorelaxing and lipid-lowering activities. However, berberine significantly reduced the viability of HUVECs in a time- and concentration-dependent manner. In contrast, HMC05 (1-10 µg ml(-1)) did not affect the cell viability for up to 48 h treatment. In conclusion, we propose that HMC05 may be a safe and potent herbal formula against vascular inflammation, and its action may be attributable to the inhibition of ROS- and NF-κB-dependent expression of adhesion molecules and chemokines.

Gukulenins A and B, cytotoxic tetraterpenoids from the marine sponge Phorbas gukulensis.

Gukulenins A (1) and B (2), both having an unprecedented skeleton with a bis-tropolone moiety, were isolated from the Korean marine sponge Phorbas gukulensis. They exhibited significant cytotoxicity against human pharynx, stomach, colon, and renal cancer cell lines in the range 0.05-0.80 microM.

Bub2 regulation of cytokinesis and septation in budding yeast.

BACKGROUND: The mitotic exit network (MEN) is required for events at the end of mitosis such as degradation of mitotic cyclins and cytokinesis. Bub2 and its binding partner Bfa1 act as a GTPase activating protein (GAP) to negatively regulate the MEN GTPase Tem1. The Bub2/Bfa1 checkpoint pathway is required to delay the cell cycle in response to mispositioned spindles. In addition to its role in mitotic exit, Tem1 is required for actomyosin ring contraction. RESULTS: To test the hypothesis that the Bub2 pathway prevents premature actin ring assembly, we compared the timing of actin ring formation in wild type, bub2Delta, mad2Delta, and bub2Deltamad2Delta cells both with and without microtubules. There was no difference in the timing of actin ring formation between wild type and mutant cells in a synchronized cell cycle. In the presence of nocodazole, both bub2Delta and mad2Delta cells formed rings after a delay of the same duration. Double mutant bub2Deltamad2Delta and bfa1Deltamad2Delta cells formed rings at the same time with and without nocodazole. To determine if Bub2 has an effect on actomyosin ring contraction through its regulation of Tem1, we used live cell imaging of Myo1-GFP in a bub2Delta strain. We found a significant decrease in the total time of contraction and an increase in rate of contraction compared to wild type cells. We also examined myosin contraction using Myo1-GFP in cells overexpressing an epitope tagged Bub2. Surprisingly, overexpression of Bub2 also led to a significant increase in the rate of contraction, as well as morphological defects. The chained cell phenotype caused by Bub2 overexpression could be rescued by co-overexpression of Tem1, and was not rescued by deletion of BFA1. CONCLUSION: Our data indicate that the Bub2 checkpoint pathway does not have a specific role in delaying actin ring formation. The observed increase in the rate of myosin contraction in the bub2Delta strain provides evidence that the MEN regulates actomyosin ring contraction. Our data suggest that the overexpression of the Bub2 fusion protein acts as a dominant negative, leading to septation defects by a mechanism that is Tem1-dependent.

The anti-angiogenic effects of 1-furan-2-yl-3-pyridin-2-yl-propenone are mediated through the suppression of both VEGF production and VEGF-induced signaling.

Angiogenesis plays a critical role in the pathogenesis of malignant tumor growth and metastases. Since cyclooxygenase (COX)-2 expression is positively correlated with vascular endothelial growth factor (VEGF) expression and enhanced angiogenesis, COX-2 inhibitors have been focused on as angiogenesis-inhibiting drugs that may offer a complementary modality to classical strategies for cancer therapy. In this study, we evaluated the potential antiangiogenic effects of 1-furan-2-yl-3-pyridin-2-yl-propenone (FPP-3), a dual COX/5-LOX inhibitor. In HT1080 cancer cells, FPP-3 significantly suppressed release of VEGF as well as activation of NF-kappaB, a transcriptional factor required for VEGF expression. In a chick chorioallantoic membrane (CAM) assay, FPP-3 dose-dependently suppressed VEGF- and MCF-7 human breast cancer cell-induced angiogenesis. In experiments with human umbilical vein endothelial cells (HUVECs), FPP-3 dose-dependently decreased not only the cell survival and proliferation but also the tube formation and invasion using Matrigel-coated plates. Such antiangiogenic activity correlated with suppression of VEGF-induced matrix metalloproteinase (MMP)-2 expression, reactive oxygen species (ROS) production, and extracellularly regulated kinase (ERK) phosphorylation. Furthermore, in contrast to the case of NS398, a selective COX-2 inhibitor, FPP-3 did not alter the ratio of tissue factor (TF)/tissue factor pathway inhibitor (TFPI) expression, a coagulation index. These results indicate that FPP-3 could be used as an effective antiangiogenic agent without the risk of developing thrombotic complications.

Inhibitory effects of an aqueous extract of Cornus kousa Burg. leaves on TNF-alpha-induced chemokine expression and monocyte adhesion to human colonic epithelial cells.

An aqueous extract of Cornus kousa Burg. leaves (ACK) that contained high amount of polyphenols showed significant antioxidant activity against diphenylpicrylhydrazyl (DPPH) radicals and TNF-alpha-generated reactive oxygen species. ACK at concentrations of 10 and 50 microg/mL significantly inhibited TNF-alpha-induced adhesion of U937 pre-monocytic cells to HT-29 colon epithelial cells in a concentration-dependent manner. The reduced adhesion by ACK correlated with the suppressed expressions of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8, the major inflammatory bowel disease (IBD)-associated chemokines. Moreover, ACK significantly suppressed TNF-alpha-induced translocation of redox-sensitive nuclear factor (NF)-kappaB as well as degradation of cytosolic I-kappaBalpha. The effective concentrations of ACK were much lower than that of 5-aminosalicylic acid (3.06 mg/mL), which is an active metabolite of sulfasalazine, a well-known drug used in the treatment of IBD. The results indicate that ACK may provide a potential benefit for the prevention and treatment of inflammatory diseases such as IBD.

Clotrimazole ameliorates intestinal inflammation and abnormal angiogenesis by inhibiting interleukin-8 expression through a nuclear factor-kappaB-dependent manner.

Increased interleukin (IL)-8 plays an important role not only in activation and recruitment of neutrophils but also in inducing exaggerated angiogenesis at the inflamed site. In the present study, we investigated the fact that clotrimazole (CLT) inhibits intestinal inflammation, and the inhibitory action is mediated through suppression of IL-8 expression. In the trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model, CLT dose-dependently protected from the TNBS-induced weight loss, colon ulceration, and myeloperoxidase activity increase. In the lesion site, CLT also suppressed the TNBS-induced angiogenesis, IL-8 expression, and nuclear factor (NF)-kappaB activation. In a cellular model of colitis using tumor necrosis factor (TNF)-alpha-stimulated HT29 colon epithelial cells, treatment with CLT significantly suppressed TNF-alpha-mediated IL-8 induction and NF-kappaB transcriptional activity revealed by a luciferase reporter gene assay. Furthermore, cotreatment with CLT and pyrrolidine dithiocarbamate, a NF-kappaB inhibitor, synergistically reduced the NF-kappaB transcriptional activity as well as IL-8 expression. In an in vitro angiogenesis assay, CLT suppressed IL-8-induced proliferation, tube formation, and invasion of human umbilical vein endothelial cells. The in vivo angiogenesis assay using chick chorioallantoic membrane also showed that CLT significantly inhibited the IL-8-induced formation of new blood vessels. Taken together, these results suggest that CLT may prevent the progression of intestinal inflammation by not only down-regulating IL-8 expression but also inhibiting the action of IL-8 in both colon epithelial and vascular endothelial cells during pathogenesis of intestinal inflammation.

Chloroquine-induced nitric oxide increase and cell death is dependent on cellular GSH depletion in A172 human glioblastoma cells.

Chloroquine (CQ) is used to treat malaria and a variety of inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis. However, CQ is known to cause cytotoxicity of which mechanism is still uncertain. This study investigated the molecular mechanism responsible for the cell death in CQ-treated A172 human glioblastoma cells. CQ-induced apoptotic cell death of the cells in a time- and concentration-dependent manner. CQ also increased the production of nitric oxide in the cells. However, the pretreatment with aminoguanidine (AG) and N-Omega-nitro-l-arginine methyl ester (NAME), nitric oxide synthase inhibitors, did not block the CQ-induced cell death. In contrast to NO level increase, the level of intracellular reactive oxygen species (ROS) and their extracellular release were transiently and mildly increased by CQ. In addition, CQ depleted cellular GSH content, which was accompanied with time-dependent increase in GSH peroxidase without any significant change in GSH reductase activity. Glutathione (GSH) S-transferase activity was only transiently increased at 15 min treatment with CQ. Furthermore, the CQ-induced cell death was significantly suppressed when intracellular GSH decrease was prevented by the pretreatment with N-acetylcysteine (NAC) or glutathione ethylester (GSH-EE). At the same time, the pretreatment of the cells with NAC and GSH-EE significantly blocked the CQ-induced NO increase, representing that CQ-induced NO increase was resulted from the depletion of GSH. CQ also induced time-dependent increase in Bax level and caspase-3 activity with no change in Bcl-2 level. Overall, these results suggest that CQ-induced NO increase and cell death are dependent on GSH depletion, the cellular redox changes.

Inhibitory effect of simvastatin on the TNF-alpha- and angiotensin II-induced monocyte adhesion to endothelial cells is mediated through the suppression of geranylgeranyl isoprenoid-dependent ROS generation.

Vascular endothelial cell activation by cytokines and other pro-inflammatory mediators is an initial event in atherosclerosis and in other vascular diseases. Simvastatin, a HMG-CoA reductase inhibitor, suppressed both tumor necrosis factor (TNF)-alpha- and angiotensin (Ang) II-induced monocyte adhesion to endothelial cells (an initial step in vascular inflammation) and reactive oxygen species (ROS) production. Diphenyleneiodonium and apocynin, both NADPH oxidase inhibitors, also suppressed TNF-alpha-induced ROS and monocyte-endothelial cell adhesion, demonstrating that TNF-alpha-induced monocyte adhesion is mediated through ROS produced by NADPH oxidase activation. Furthermore, exogenously applied mevalonate or geranylgeranylpyrophosphate in combination with simvastatin completely prevented the inhibitory effects of simvastatin on ROS generation and monocyte-endothelial cell adhesion by TNFalpha and Ang II. These results suggest that monocyte adhesion to endothelial cells induced by TNF-alpha or Ang II is mediated via the geranylgeranyl isoprenoid-dependent generation of ROS, and that this is inhibited by simvastatin.

Involvement of NF-kappaB in the inhibitory actions of Platycarya strobilacea on the TNF-alpha-induced monocyte adhesion to colon epithelial cells and chemokine expression.

Oxidative stress and the activation of nuclear factor (NF)-kappaB play crucial roles in the pathogenesis of inflammatory bowel disease (IBD). In the present study, we examined the effects of the ethanol extract of Platycarya strobilacea Sieb. stem (EPS) on TNF-alpha-induced monocyte adhesion to HT29 human colon epithelial cells, an initial step of colon inflammation. EPS contained high amount of polyphenols (0.241+/-0.017 mg of catechin equivalent/g of extract) and showed substantial DPPH radical scavenging activity. In addition, EPS significantly suppressed TNF-alpha-induced reactive oxygen species (ROS) increase. Moreover, TNF-alpha-induced monocyte adhesion to HT29 colon epithelial cells was significantly suppressed by EPS in a concentration-dependent manner. The reduced adhesion by EPS was correlated with suppressed expression of MCP-1 and IL-8, the major chemokines in IBD. EPS also prevented the TNF-alpha-induced nuclear translocation of NF-kappaB, one of the redox-sensitive transcription factors, in a concentration-dependent manner. Taken together, our results suggest that the anti-oxidant components of EPS prevent TNF-alpha-induced NF-kappaB activation, chemokine induction, and monocyte adhesion at the site of intestinal inflammation.