The Modulation of Phospho-Extracellular Signal-Regulated Kinase and Phospho-Protein Kinase B Signaling Pathways plus Activity of Macrophage-Stimulating Protein Contribute to the Protective Effect of Stachydrine on Acetaminophen-Induced Liver Injury.

Stachydrine, a prominent bioactive alkaloid derived from Leonurus heterophyllus, is a significant herb in traditional medicine. It has been noted for its anti-inflammatory and antioxidant characteristics. Consequently, we conducted a study of its hepatoprotective effect and the fundamental mechanisms involved in acetaminophen (APAP)-induced liver injury, utilizing a mouse model. Mice were intraperitoneally administered a hepatotoxic dose of APAP (300 mg/kg). Thirty minutes after APAP administration, mice were treated with different concentrations of stachydrine (0, 2.5, 5, and 10 mg/kg). Animals were sacrificed 16 h after APAP injection for serum and liver tissue assays. APAP overdose significantly elevated the serum alanine transferase levels, hepatic pro-inflammatory cytokines, malondialdehyde activity, phospho-extracellular signal-regulated kinase (ERK), phospho-protein kinase B (AKT), and macrophage-stimulating protein expression. Stachydrine treatment significantly decreased these parameters in mice with APAP-induced liver damage. Our results suggest that stachydrine may be a promising beneficial target in the prevention of APAP-induced liver damage through attenuation of the inflammatory response, inhibition of the ERK and AKT pathways, and expression of macrophage-stimulating proteins.

Use of Transcutaneous Electrical Nerve Stimulation to Alleviate Thirst After Surgery: A Randomized Controlled Trial.

PURPOSE: This prospective study investigated the preventive effect of transcutaneous electrical nerve stimulation (TENS) for postoperative thirst. DESIGN: This experimental study was conducted with the CONSORT checklist. METHODS: A total of 105 surgical patients who received general anesthesia were recruited from a medical center. Each patient was randomly assigned to the experimental group (n = 53; 20 min of TENS) or the control group (n = 52; routine care). In each group, oral moisture wetness was measured at 1 min, 20 min, and 50 min post-surgery. Descriptive and inferential statistics (Chi-square test, t test, one-way ANOVA, and generalized estimating equation (GEE) regression analysis) were performed to assess the proposed relationships. FINDINGS: The two groups showed similar characteristics at baseline. The oral moisture wetness was significantly higher in the experimental group than the control group at each post-surgery assessment time (all P < .001). The GEE results showed that patients in the experimental group reported more oral moisture wetness than patients in the control group. CONCLUSIONS: This study demonstrated that TENS can reduce thirst reported by patients after general anesthesia. Thus, this method may have clinical applications for managing postoperative thirst.

Effect of acupuncture on capillary refill time in healthy adults: A clinical study.

BACKGROUND: Pulse examination, which reveals information about bodily qi and blood circulation, is an essential diagnostic tool in traditional Chinese medicine. Capillary refill time (CRT) is a simple test parameter for assessing circulation status. Examining the root of pulse and measuring CRT are extremely similar procedures. The objective of this study was to evaluate the effect of acupuncture on CRT. METHODS: Three acupoints were selected to evaluate the effects of CRT. CRT, quantitative CRT, heart rate, core body temperature, and blood pressure were measured before acupuncture and immediately after removal of needles and 30 min after removal of needles. A total of 15 healthy adults representing both sexes were prospectively included in the study. The acupoints selected were bilateral Taixi (KI3), Hegu (LI4), and Zusanli (ST36). Each participant received acupuncture three times, interventions were separated by at least 2 days, and acupuncture was performed on only one acupoint at each intervention. RESULTS: CRT decreased significantly after acupuncture on only KI3. Quantitative CRT decreased significantly after acupuncture on KI3 and LI4. Heart rate changed significantly after acupuncture on KI3 and ST36. CONCLUSION: Acupuncture on KI3 can reduce CRT in health adults.

Design and synthesis of ß-carboline and combretastatin derivatives as anti-neutrophilic inflammatory agents.

A series of ß-carboline derivatives was synthesized by the Pictet-Spengler reaction with or without the combretastatin skeleton. The structures of these derivatives were elucidated by spectroscopic techniques. All synthesized compounds were evaluated for their anti-inflammatory activity in human neutrophils. Among them, two compounds, NTU-228 and HK-72, showed significant inhibitory effects on N-formyl-Met-Leu-Phe (fMLF)-induced superoxide anion generation in human neutrophils with IC50 values of 5.58 ± 0.56 and 2.81 ± 0.07 µM, respectively. Neither NTU-228 nor HK-72 caused cytotoxicity in human neutrophils. NTU-228 inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and intracellular Ca2+ levels ([Ca2+]i) in fMLF-activated human neutrophils. Additionally, HK-72 selectively inhibited the fMLF-induced phosphorylation of p38 and [Ca2+]i in human neutrophils. Molecular docking analysis showed a favorable binding affinity of HK-72 toward p38 MAPK. The proposed synthetic strategy opens up new opportunities for the synthesis of novel potential candidates against neutrophilic inflammation.

Multifunctional lipid-based nanocarriers with antibacterial and anti-inflammatory activities for treating MRSA bacteremia in mice.

BACKGROUND: Bacteremia-induced sepsis is a leading cause of mortality in intensive care units. To control a bacterial infection, an immune response is required, but this response might contribute to organ failure. Kidneys are one of the main organs affected by bacteremia. Combination therapies with antibacterial and anti-inflammatory effects may be beneficial in treating bacteremia. This study aimed to develop nanostructured lipid carriers (NLCs) loaded with ciprofloxacin and rolipram that exert a combination of anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-inflammatory effects. Retinol was incorporated into the nanoparticles to transport retinol-binding protein 4 (RBP4) to the kidneys, which abundantly express RBP receptors. The NLCs were fabricated by high-shear homogenization and sonication, and neutrophils were used as a model to assess their anti-inflammatory effects. Mice were injected with MRSA to establish a model of bacteremia with organ injury. RESULTS: The mean nanoparticle size and zeta potential of the NLCs were 171 nm and - 39 mV, respectively. Ciprofloxacin (0.05%, w/v) and rolipram (0.02%) achieved encapsulation percentages of 88% and 96%, respectively, in the nanosystems. The minimum bactericidal concentration of free ciprofloxacin against MRSA increased from 1.95 to 15.63 µg/ml when combined with rolipram, indicating a possible drug-drug interaction that reduced the antibacterial effect. Nanoparticle inclusion promoted the anti-MRSA activity of ciprofloxacin according to time-kill curves. The NLCs were found to be largely internalized into neutrophils and exhibited superior superoxide anion inhibition than free drugs. Retinol incorporation into the nanocarriers facilitated their efficient targeting to the kidneys. The NLCs significantly mitigated MRSA burden and elastase distribution in the organs of MRSA-infected animals, and the greatest inhibition was observed in the kidneys. Bacterial clearance and neutrophil infiltration suppression attenuated the bacteremia-induced cytokine overexpression, leading to an improvement in the survival rate from 22% to 67%. CONCLUSIONS: The dual role of our NLCs endowed them with greater efficacy in treating MRSA bacteremia than that of free drugs.

Oleic acid-based nanosystems for mitigating acute respiratory distress syndrome in mice through neutrophil suppression: how the particulate size affects therapeutic efficiency.

BACKGROUND: Oleic acid (OA) is reported to show anti-inflammatory activity toward activated neutrophils. It is also an important material in nanoparticles for increased stability and cellular internalization. We aimed to evaluate the anti-inflammatory activity of injectable OA-based nanoparticles for treating lung injury. Different sizes of nanocarriers were prepared to explore the effect of nanoparticulate size on inflammation inhibition. RESULTS: The nanoparticles were fabricated with the mean diameters of 105, 153, and 225 nm. The nanocarriers were ingested by isolated human neutrophils during a 5-min period, with the smaller sizes exhibiting greater uptake. The size reduction led to the decrease of cell viability and the intracellular calcium level. The OA-loaded nanosystems dose-dependently suppressed the superoxide anion and elastase produced by the stimulated neutrophils. The inhibition level was comparable for the nanoparticles of different sizes. In the ex vivo biodistribution study, the pulmonary accumulation of nanoparticles increased following the increase of particle size. The nanocarriers were mainly excreted by the liver and bile clearance. Mice were exposed to intratracheal lipopolysaccharide (LPS) to induce acute respiratory distress syndrome (ARDS), like lung damage. The lipid-based nanocarriers mitigated myeloperoxidase (MPO) and cytokines more effectively as compared to OA solution. The larger nanoparticles displayed greater reduction on MPO, TNF-α, and IL-6 than the smaller ones. The histology confirmed the decreased pulmonary neutrophil recruitment and lung-architecture damage after intravenous administration of larger nanoparticles. CONCLUSIONS: Nanoparticulate size, an essential property governing the anti-inflammatory effect and lung-injury therapy, had different effects on activated neutrophil inhibition and in vivo therapeutic efficacy.

Validity of cancer diagnosis in the National Health Insurance database compared with the linked National Cancer Registry in Taiwan.

PURPOSE: We aimed to evaluate the validity of cancer diagnosis in the National Health Insurance (NHI) database, which has routinely collected the health information of almost the entire Taiwanese population since 1995, compared with the Taiwan National Cancer Registry (NCR). METHODS: There were 26,542,445 active participants registered in the NHI database between 2001 and 2012. National Cancer Registry and NHI database records were compared for cancer diagnosis; date of cancer diagnosis; and 1, 2, and 5 year survival. In addition, the 10 leading causes of cancer deaths in Taiwan were analyzed. RESULTS: There were 908,986 cancer diagnoses in NCR and NHI database and 782,775 (86.1%) in both, with 53,192 (5.9%) in the NHI database only and 73,019 (8.0%) in the NCR only. The positive predictive value of the NHI database cancer diagnoses was 94% for all cancers; the positive predictive value of the 10 specific cancers ranged from 95% (lung cancer) to 82% (cervical cancer). The date of diagnosis in the NHI database was generally delayed by a median of 15 days (interquartile range 8-18) compared with the NCR. The 1, 2, and 5 year survival rates were 71.21%, 60.85%, and 47.44% using the NHI database and were 71.18%, 60.17%, and 46.09% using NCR data. CONCLUSIONS: Recording of cancer diagnoses and survival estimates based on these diagnosis codes in the NHI database are generally consistent with the NCR. Studies using NHI database data must pay careful attention to eligibility and record linkage; use of both sources is recommended.

Use of cilomilast-loaded phosphatiosomes to suppress neutrophilic inflammation for attenuating acute lung injury: the effect of nanovesicular surface charge.

BACKGROUND: Cilomilast is a phosphodiesterase 4 (PDE4) inhibitor for treating inflammatory lung diseases. This agent has a narrow therapeutic index with significant adverse effects on the nervous system. This study was conducted to entrap cilomilast into PEGylated phosphatidylcholine-rich niosomes (phosphatiosomes) to improve pulmonary delivery via the strong affinity to pulmonary surfactant film. Neutrophils were used as a cell model to test the anti-inflammatory activity of phosphatiosomes. In an in vivo approach, mice were given lipopolysaccharide to produce acute lung injury. The surface charge in phosphatiosomes that influenced the anti-inflammatory potency is discussed in this study. RESULTS: The average diameter of the phosphatiosomes was about 100 nm. The zeta potential of anionic and cationic nanovesicles was - 35 and 32 mV, respectively. Cilomilast in both its free and nanocapsulated forms inhibited superoxide anion production but not elastase release in activated neutrophils. Cationic phosphatiosomes mitigated calcium mobilization far more effectively than the free drug. In vivo biodistribution evaluated by organ imaging demonstrated a 2-fold ameliorated lung uptake after dye encapsulation into the phosphatiosomes. The lung/brain distribution ratio increased from 3 to 11 after nanocarrier loading. The intravenous nanocarriers deactivated the neutrophils in ALI, resulting in the elimination of hemorrhage and alveolar wall damage. Only cationic phosphatiosomes could significantly suppress IL-1ß and TNF-α in the inflamed lung tissue. CONCLUSIONS: These results suggest that phosphatiosomes should further be investigated as a potential nanocarrier for the treatment of pulmonary inflammation.

Cardiovascular disease risk in patients receiving organ transplantation: a national cohort study.

Although organ transplantation is the definitive treatment for end-stage organ failure, the post-transplant outcomes can be substantially influenced by cardiovascular complications. A national cohort study was performed to estimate risks of cardiovascular diseases in those with heart, lung, kidney, and liver transplantation. This cohort study consisted of 5978 solid organ transplantations identified using the Taiwan National Health Insurance Database. Cardiovascular and mortality risks in transplant recipients were evaluated using standardized incidence ratios, excess absolute risks, and standardized mortality ratios as compared to those in the general population. In heart, kidney, and liver recipients, the standardized incidence ratios of overall cardiovascular diseases were 9.41 (7.75-11.44), 3.32 (2.29-3.77), and 1.4 (1.15-1.7) and the overall standardized mortality ratios were 5.23 (4.54-6.03), 1.48 (1.34-1.63), and 3.95 (3.64-4.28), respectively. Except for heart organ recipients who were at highest risk for coronary artery disease with a standardized incidence ratio of 13.12 (10.57-16.29), kidney and liver organ recipients had a ninefold increased risk in developing deep vein thrombosis post-transplant. In conclusion, solid organ transplant patients are at risk of cardiovascular disease, in particular, deep vein thrombosis, which may warrant early identification of high-risk patients in addition to prompt and adequate thromboprophylaxis perioperatively.

Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3.

Proteinase 3 (Pr3), and human neutrophil elastase (HNE) are two major neutrophilic serine proteases (NsPs) expressed in neutrophil azurophil granules. Emerging data suggest that excessive release of proteases mediates tissue damage, and therefore prolonged neutrophil accumulation has an important role in the pathogenesis of many diseases. Thus, HNE and Pr3 inhibitors may prove to be targets for the generation of agents in the treatment of neutrophilic inflammatory disease. Sivelestat is the only commercially available selective HNE inhibitor. Therefore, sivelestat was chosen as the model structure in an attempt to obtain more potent anti-NsPs agents. In the present study, a series 2-aminobenzaldehyde oxime and 2-aminobenzoate analogs were synthesized and their inhibitory effects on NsPs (CatG, Pr3, and HNE) were determined, respectively. The results of structure-activity relationships studies concluded that a hydroxyl oxime moiety plays an important role in ligand-enzyme affinity through hydrogen bonding. As compound 6 had more potency and showed dual inhibitory effects on NE and Pr3, both in vitro and in vivo experiments were carried out to evaluate its selectivity, effects in cell-based assays, and efficacy in models of inflammation and damage. Compound 6 had the potential to reduce paw edema induced by LPS and HNE, as well as acute lung injury, and may be approved as a candidate for the development of new agents in the treatment of neutrophilic inflammatory diseases.

Anti-Inflammatory and Organ-Protective Effects of Resveratrol in Trauma-Hemorrhagic Injury.

Resveratrol, a natural polyphenolic compound of grape and red wine, owns potential anti-inflammatory effects, which results in the reduction of cytokines overproduction, the inhibition of neutrophil activity, and the alteration of adhesion molecules expression. Resveratrol also possesses antioxidant, anti-coagulation and anti-aging properties, and it may control of cell cycle and apoptosis. Resveratrol has been shown to reduce organ damage following traumatic and shock-like states. Such protective phenomenon is reported to be implicated in a variety of intracellular signaling pathways including the activation of estrogen receptor, the regulation of the sirtuin 1/nuclear factor-kappa B and mitogen-activated protein kinases/hemeoxygenase-1 pathway, and the mediation of proinflammatory cytokines and reactive oxygen species formation and reaction. In the recent studies, resveratrol attenuates hepatocyte injury and improves cardiac contractility due to reduction of proinflammatory mediator expression and ameliorates hypoxia-induced liver and kidney mitochondrial dysfunction following trauma and hemorrhagic injuries. Moreover, through anti-inflammatory effects and antioxidant properties, the resveratrol is believed to protect organ function in trauma-hemorrhagic injury. In this review, the organ-protective and anti-inflammatory effects of resveratrol in trauma-hemorrhagic injury will be discussed.

Corilagin Inhibits Neutrophil Extracellular Trap Formation and Protects against Hydrochloric Acid/Lipopolysaccharide-Induced Acute Lung Injury in Mice by Suppressing the STAT3 and NOX2 Signaling Pathways.

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are characterized by uncontrolled inflammatory responses, neutrophil activation and infiltration, damage to the alveolar capillary membrane, and diffuse alveolar injury. Neutrophil extracellular traps (NETs), formed by activated neutrophils, contribute significantly to various inflammatory disorders and can lead to tissue damage and organ dysfunction. Corilagin, a compound found in Phyllanthus urinaria, possesses antioxidative and anti-inflammatory properties. In this study, we investigated the protective effects and underlying mechanisms of corilagin in hydrochloric acid (HCl)/lipopolysaccharide (LPS)-induced lung injury. Mice received intraperitoneal administration of corilagin (2.5, 5, or 10 mg/kg) or an equal volume of saline 30 min after intratracheal HCl/LPS administration. After 20 h, lung tissues were collected for analysis. Corilagin treatment significantly mitigated lung injury, as evidenced by reduced inflammatory cell infiltration, decreased production of proinflammatory cytokines, and alleviated oxidative stress. Furthermore, corilagin treatment suppressed neutrophil elastase expression, reduced NET formation, and inhibited the expression of ERK, p38, AKT, STAT3, and NOX2. Our findings suggest that corilagin inhibits NET formation and protects against HCl/LPS-induced ALI in mice by modulating the STAT3 and NOX2 signaling pathways.

Neutrophil-targeted combinatorial nanosystems for suppressing bacteremia-associated hyperinflammation and MRSA infection to improve survival rates.

There is currently no specific and effective treatment for bacteremia-mediated sepsis. Hence, this study engineered a combinatorial nanosystem containing neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles to enable the dual mitigation of bacteremia-associated inflammation and methicillin-resistant Staphylococcus aureus (MRSA) infection. The targeted nanoparticles were developed by conjugating anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibody fragment on the nanoparticulate surface. The particle size and zeta potential of the as-prepared nanosystem were about 200 nm and -25 mV, respectively. The antibody-conjugated nanoparticles showed a three-fold increase in neutrophil internalization compared to the unfunctionalized nanoparticles. As a selective phosphodiesterase (PDE) 4 inhibitor, the roflumilast in the nanocarriers largely inhibited cytokine/chemokine release from the activated neutrophils. The fusidic acid-loaded nanocarriers were vital to eliminate biofilm MRSA colony by 3 log units. The nanoparticles drastically decreased the intracellular bacterial count compared to the free antibiotic. The in vivo mouse bioimaging demonstrated prolonged retention of the nanosystem in the circulation with limited organ distribution and liver metabolism. In the mouse bacteremia model, the multifunctional nanosystem produced a 1‒2 log reduction of MRSA burden in peripheral organs and blood. The functionalized nanosystem arrested the cytokine/chemokine overexpression greater than the unfunctionalized nanocarriers and free drugs. The combinatory nanosystem also extended the median survival time from 50 to 103 h. No toxicity from the nanoformulation was found based on histology and serum biochemistry. Furthermore, our data proved that the active neutrophil targeting by the versatile nanosystem efficiently alleviated MRSA infection and organ dysfunction caused by bacteremia. STATEMENT OF SIGNIFICANCE: Bacteremia-mediated sepsis poses a significant challenge in clinical practice, as there is currently no specific and effective treatment available. In our study, we have developed a novel combinatorial nanosystem to address this issue. Our nanosystem consists of neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles, enabling the simultaneous mitigation of bacteremia-associated inflammation and MRSA infection. Our nanosystem demonstrated the decreased neutrophil activation, effective inhibition of cytokine release, elimination of MRSA biofilm colonies, and reduced intracellular bacterial counts. In vivo experiments showed prolonged circulation, limited organ distribution, and increased survival rates in a mouse bacteremia model. Importantly, our nanosystem exhibited no toxicity based on comprehensive assessments.

Low preoperative serum uric acid is associated with early acute kidney injury after living donor liver transplantation.

BACKGROUND: Liver transplantation is treatment option for patients with end-stage liver disease and hepatocellular carcinoma. Renal function deterioration significantly impacts the survival rates of liver recipients, and serum uric acid (SUA) is associated with both acute and chronic renal function disorders. Thus, our study aimed to assess the relationship and predictive value of preoperative SUA level and postoperative acute kidney injury (AKI) in living donor liver transplantation (LDLT). METHODS: We conducted a prospective observational study on 87 patients undergoing LDLT. Blood samples were collected immediately before LDLT, and renal function status was followed up for 3 consecutive days postoperatively. RESULTS: Low SUA levels (cutoff value 4.15 mg/dL) were associated with a high risk of early posttransplantation AKI. The area under the curve was 0.73 (sensitivity, 79.2%; specificity, 59.4%). Although not statistically significant, there were no deaths in the non-AKI group but two in the early AKI group secondary to liver graft dysfunction in addition to early AKI within the first month after LDLT. CONCLUSION: AKI after liver transplantation may lead to a deterioration of patient status and increased mortality rates. We determined low preoperative SUA levels as a possible risk factor for early postoperative AKI.

Role of NADPH Oxidase-Derived ROS-Mediated IL-6/STAT3 and MAPK/NF-κB Signaling Pathways in Protective Effect of Corilagin against Acetaminophen-Induced Liver Injury in Mice.

Acetaminophen (APAP) overdose causes acute liver injury via oxidative stress, uncontrolled inflammatory response, and subsequent hepatocyte death. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a potent source of cellular reactive oxygen species (ROS) and may contribute to oxidative stress in many inflammatory processes. Corilagin, a component of Phyllanthus urinaria, possesses antioxidant, anti-inflammatory, and hepatoprotective effects. We evaluated the mechanisms underlying the protective effect of corilagin against acetaminophen-induced liver injury. Mice were intraperitoneally administrated 300 mg/kg APAP or equal volume of saline (control), with or without various concentrations of corilagin (0, 1, 5, or 10 mg/kg) administered after 30 min. All animals were sacrificed 16 h after APAP administration, and serum and liver tissue assays including histology, immunohistochemistry, and Western blot assay were performed. Corilagin post-treatment significantly attenuated APAP-induced liver injury (p < 0.005), inflammatory cell infiltration, hepatic proinflammatory cytokine levels, and hepatic oxidative stress. Furthermore, corilagin attenuated the protein levels of NOX1, NOX2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) in APAP-induced liver injury. These results indicated that the antioxidant, anti-inflammatory, and protective effects of corilagin in APAP-induced liver injury might involve the regulation of interleukin (IL)-6/STAT3 and mitogen-activated protein kinase (MAPK)/NF-κB signaling pathways through NOX-derived ROS.

ERK/NF-kB/COX-2 Signaling Pathway Plays a Key Role in Curcumin Protection against Acetaminophen-Induced Liver Injury.

Recent experimental studies have highlighted the beneficial effects of curcumin on liver injury induced by acetaminophen (APAP). However, the specific molecular mechanisms underlying curcumin's hepatoprotective effects against APAP-induced liver injury remain to be fully elucidated. This study aimed to investigate the therapeutic effect of curcumin on APAP-induced liver injury using a mouse model. In the experiment, mice were subjected to an intraperitoneal hepatotoxic dose of APAP (300 mg/kg) to induce hepatotoxicity. After 30 min of APAP administration, the mice were treated with different concentrations of curcumin (0, 10, 25, or 50 mg/kg). After 16 h, mice with hepatotoxicity showed elevated levels of serum alanine transaminase (ALT), aspartate transaminase (AST), hepatic myeloperoxidase (MPO), TNF-α, and IL-6, and decreased levels of glutathione (GSH). Moreover, there was an increased infiltration of neutrophils and macrophages following intraperitoneal injection of APAP. However, curcumin-treated mice displayed a pronounced reduction in serum ALT, AST, hepatic MPO, TNF-α, and IL-6 levels, coupled with a notable elevation in GSH levels compared to the APAP-treated hepatotoxic mice. Moreover, curcumin treatment led to reduced infiltration of neutrophils and macrophages. Additionally, curcumin inhibited the phosphorylation of ERK and NF-kB proteins while reducing the expression of cyclooxygenase-2 (COX-2). These findings highlight the hepatoprotective potential of curcumin against APAP-induced liver injury through the suppression of the ERK, NF-kB, and COX-2 signaling pathways.

Targeting anti-inflammatory immunonanocarriers to human and murine neutrophils via the Ly6 antigen for psoriasiform dermatitis alleviation.

Psoriasis is a refractory and difficult-to-treat skin disorder. The neutrophil-targeting approach represents a promising option for psoriasis therapy. This study developed and examined NIMP-R14-conjugated immunonanoparticles for specific targeting to neutrophils associated with psoriasiform dermatitis. In the process, roflumilast (RFL), as a phosphodiesterase (PDE) 4 inhibitor, was encapsulated in the nanocarriers to assess the anti-inflammatory capability against primary neutrophil activation and murine psoriasiform lesion. The average size and surface charge of the immunonanocarriers were 305 ± 36 nm and -18 ± 6 mV, respectively. The monovalent antibody-conjugated nanoparticles offered precise uptake by both human and mouse neutrophils but failed to exhibit this effect in monocytes and lymphocytes. The intracellular RFL concentration of the immunonanocarriers was five-fold superior to that of the passive counterparts. The immunonanocarriers specifically recognized the neutrophils through the Ly6 antigen with no apparent cytotoxicity. The antibody-conjugated nanoparticles mitigated superoxide anion production and migration of the activated human neutrophils. The in vivo biodistribution in the psoriasiform mice, found using an in vivo imaging system (IVIS) and liquid chromatography (LC)-mass-mass analysis, showed that the antibody conjugation increased the nanoparticle residence in systemic circulation after intravenous administration. On the other hand, most of the nanoparticles were accumulated in the lesional skin after subcutaneous injection. The actively-targeted nanocarriers were better than the free RFL and unfunctionalized nanoparticles in suppressing psoriasiform inflammation. The immunonanocarriers reduced neutrophil recruitment and epidermal hyperplasia in the plaque. Intravenous and subcutaneous treatments with the immunonanocarriers significantly reduced the overexpressed cytokines and chemokines in the inflamed skin, demonstrating that the nanosystems could both systematically and locally alleviate inflammation. The results indicated that the NIMP-R14-conjugated RFL-loaded nanoparticles have potential as an anti-autoimmune disease delivery system for neutrophil targeting.

Role of Akt-dependent pathway in resveratrol-mediated cardioprotection after trauma-hemorrhage.

BACKGROUND: Resveratrol has been shown to have protective effects for patients in shock-like states, and Akt (protein kinase B) is known to play a role in pro-inflammatory events in response to injury. The aim of this study is to determine whether resveratrol provides cardioprotection mediated via an Akt-dependent pathway in trauma-hemorrhaged animals. METHODS: Male Sprague-Dawley rats underwent trauma-hemorrhage and resuscitation. A single dose of resveratrol (30 mg/kg body weight) with or without a PI3K inhibitor (wortmannin) or vehicle was administered intravenously during the resuscitation. Two hours after either the trauma-hemorrhage or sham operation, the cardiac output, the positive maximal pressure increase of the left ventricle (+dP/dt(max)), and the negative maximal pressure decrease of the left ventricle (-dP/dt(max)) were measured. Cardiac myeloperoxidase (MPO) activity, interleukin (IL)-6, and intercellular adhesion molecule (ICAM)-1 levels, Akt activity, and apoptosis were measured. One-way ANOVA and Tukey's test were used for statistical analysis. RESULTS: Cardiac output and ± dP/dt(max) decreased significantly after trauma-hemorrhage. Administration of resveratrol significantly improved these cardiac function parameters. Trauma-hemorrhage increased cardiac MPO activity, IL-6 levels, and ICAM-1 levels, and these parameters were significantly improved in the resveratrol-treated rats subjected to trauma-hemorrhage. Although trauma-hemorrhage decreased cardiac Akt phosphorylation (p-Akt), resveratrol treatment following trauma-hemorrhage prevented the same decrease in cardiac p-Akt. The increase in cardiac apoptosis was attenuated in rats that received resveratrol. Co-administration of wortmannin prevented the beneficial effects of resveratrol on the attenuation of pro-inflammatory responses and cardiac injury after trauma-hemorrhage. CONCLUSION: Resveratrol attenuates cardiac injury following trauma-hemorrhage, which is, at least in part, due to its anti-inflammatory effects via Akt-dependent pathways.

Nasogastric tube insertion in anesthetized and intubated patients: a new and reliable method.

BACKGROUND: The "Rusch" intubation stylet is used to make endotracheal tube intubation easy. We designed this study to evaluate the usage of this equipment in the guidance of nasogastric tube (NGT) insertion. METHODS: A total of 103 patients, aged 23 to 70 years, undergoing gastrointestinal or hepatic surgeries that required intraoperative NGT insertions were enrolled into our study. The patients were randomly allocated to the control group (Group C) or the stylet group (Group S) according to a computerized, random allocation software program. In the control group, the NGT was inserted with the patient's head in an intubating position. In the stylet group, the NGT was inserted with the assistance of a "Rusch" intubation stylet tied together at the tips by a slipknot. The success rates of the two methods, the durations of the insertions, and the occurrences of complications were recorded. All of the failed cases in the control group were subjected to the new technique used in the stylet group, and the successful rescue rate was also evaluated. RESULTS: Successful insertions were recorded for 52/53 patients (98.1%) in Group S and for 32/50 patients (64%) in Group C. The mean insertion times were 39.5 ± 19.5 seconds in Group C and 40.3 ± 23.2 seconds in Group S. Successful rescues of failure cases in Group C were achieved in 17/18 patients (94.4%) with the assistance of a "Rusch" intubation stylet. CONCLUSIONS: The "Rusch" intubation stylet-guided method is reliable with a high success rate of NGT insertion in anesthetized and intubated patients. TRIAL REGISTRATION: Institutional Review Board of Chang Gung Memorial Hospital (IRB: 98-2669B) and Australian New Zealand Clinical Trials Registry (ACTRN12611000423910).

The questionable efficacy of topical pharyngeal anesthesia in combination with propofol sedation in gastroscopy.

BACKGROUND: Topical pharyngeal anesthesia as an adjunct to intravenous sedation to facilitate gastroscopy has been widely acknowledged; however, its efficacy has not been established when it is used in patients under deep sedation with propofol. AIMS: To demonstrate the limited value of topical pharyngeal anesthesia in patients under moderate to deep sedation with propofol. METHODS: One hundred and twenty-nine patients undergoing gastroscopy were prospectively randomized to receive 10 % lidocaine or distilled water topical spray as an adjunct to intravenous propofol via target-controlled infusion. Verbal and somatic responsiveness, presence of gag reflex and hiccup to esophageal intubation, and the overall ease of the procedure were evaluated by the anaesthetists and gastroenterologists. Hemodynamic parameters including peripheral oxygen saturation, systolic/diastolic blood pressure (SBP/DBP), heart rate (HR), bispectral index, and SBP × HR were compared at 5 time points: on arrival, after 5 spontaneous breaths, when estimated brain concentration of propofol, Ce, reached 3.5 µg/ml, on esophageal intubation, and on awakening. RESULTS: No statistical difference was observed between the lidocaine and distilled water group in verbal or somatic responses, gag reflex or hiccups on esophageal intubation. Similarly, BIS, SBP, DBP, and HR showed no significant difference between the groups. CONCLUSIONS: The use of topical pharyngeal anesthesia in combination with target-controlled infusion with propofol in the performance of diagnostic gastroscopy might be eliminated without adversely affecting patient care or outcomes.