The anti-inflammatory activity of flavonoids and alkaloids from Sophora flavescens alleviates psoriasiform lesions: Prenylation and methoxylation beneficially enhance bioactivity and skin targeting.

The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens extracts and compounds can relieve psoriasiform inflammation. The ability of flavonoids (maackiain, sophoraflavanone G, leachianone A) and alkaloids (matrine, oxymatrine) isolated from S. flavescens to inhibit production of cytokine/chemokines was examined in keratinocytes and macrophages. Physicochemical properties and skin absorption were determined by in silico molecular modeling and the in vitro permeation test (IVPT) to establish the structure-permeation relationship (SPR). The ethyl acetate extract exhibited higher inhibition of interleukin (IL)-6, IL-8, and CXCL1 production in tumor necrosis factor-α-stimulated keratinocytes compared to the ethanol and water extracts. The flavonoids demonstrated higher cytokine/chemokine inhibition than alkaloids, with the prenylated flavanones (sophoraflavanone G, leachianone A) led to the highest suppression. Flavonoids exerted anti-inflammatory effects via the extracellular signal-regulated kinase, p38, activator protein-1, and nuclear factor-κB signaling pathways. In the IVPT, prenylation of the flavanone skeleton significantly promoted skin absorption from 0.01 to 0.22 nmol/mg (sophoraflavanone G vs. eriodictyol). Further methoxylation of a prenylated flavanone (leachianone A) elevated skin absorption to 2.65 nmol/mg. Topical leachianone A reduced the epidermal thickness in IMQ-treated mice by 47%, and inhibited cutaneous scaling and cytokine/chemokine overexpression at comparable levels to a commercial betamethasone product. Thus, prenylation and methoxylation of S. flavescens flavanones may enable the design of novel antipsoriatic agents.

A synthesized heterocyclic chalcone inhibits neutrophilic inflammation through K+ -dependent pH regulation.

Human neutrophils have a vital role in host defense and inflammatory responses in innate immune systems. Growing evidence shows that the overproduction of reactive oxygen species and granular proteolytic enzymes from activated neutrophils is linked to the pathogenesis of acute inflammatory diseases. However, adequate therapeutic targets are still lacking to regulate neutrophil functions. Herein, we report that MVBR-28, synthesized from the Mannich bases of heterocyclic chalcone, has anti-neutrophilic inflammatory effects through regulation of intracellular pH. MVBR-28 modulates neutrophil functions by attenuating respiratory burst, degranulation, and migration. Conversely, MVBR-28 has no antioxidant effects and fails to alter elastase activity in cell-free systems. The anti-inflammatory effects of MVBR-28 are not seen through cAMP pathways. Significantly, MVBR-28 potently inhibits extracellular Ca2+ influx in N-formyl-methionyl-leucyl-phenylalanine (fMLF)- and thapsigargin-activated human neutrophils. Notably, MVBR-28 attenuates fMLF-induced intracellular alkalization in a K+ -dependent manner, which is upstream of Ca2+ pathways. Collectively, these findings provide new insight into Mannich bases of heterocyclic chalcone regarding the regulation of neutrophil functions and the potential for the development of MVBR-28 as a lead compound for treating neutrophilic inflammatory diseases.

Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury.

BACKGROUND/AIMS: Formyl peptide receptors (FPRs) recognize different endogenous and exogenous molecular stimuli and mediate neutrophil activation. Dysregulation of excessive neutrophil activation and the resulting immune responses can induce acute lung injury (ALI) in the host. Accordingly, one promising approach to the treatment of neutrophil-dominated inflammatory diseases involves therapeutic FPR1 inhibition. METHODS: We extracted a potent FPR1 antagonist from Garcinia multiflora Champ. (GMC). The inhibitory effects of GMC on superoxide anion release and elastase degranulation from activated human neutrophils were determined with spectrophotometric analysis. Reactive oxygen species (ROS) production and the FPR1 binding ability of neutrophils were assayed by flow cytometry. Signaling transduction mediated by GMC in response to chemoattractants was assessed with a calcium influx assay and western blotting. A lipopolysaccharide (LPS)-induced ALI mouse model was used to determine the therapeutic effects of GMC in vivo. RESULTS: GMC significantly reduced superoxide anion release, the reactive oxidants derived therefrom, and elastase degranulation mediated through selective, competitive FPR1 blocking in N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. In cell-free systems, GMC was unable to scavenge superoxide anions or suppress elastase activity. GMC produced a right shift in fMLF-activated concentration-response curves and was confirmed to be a competitive FPR1 antagonist. GMC binds to FPR1 not only in neutrophils, but also FPR1 in neutrophil-like THP-1 and hFPR1-transfected HEK293 cells. Furthermore, the mobilization of calcium and phosphorylation of mitogen-activated protein kinases and Akt, which are involved in FPR1-mediated downstream signaling, was competitively blocked by GMC. In an in vivo study, GMC significantly reduced pulmonary edema, neutrophil infiltration, and alveolar damage in LPS-induced ALI mice. CONCLUSION: Our findings demonstrate that GMC is a natural competitive FPR1 inhibitor, which makes it a possible anti-inflammatory treatment option for patients critically inflicted with FPR1-mediated neutrophilic lung damage.

Bioactive Triterpenoids from the Leaves and Twigs of Lithocarpus litseifolius and L. corneus.

Phytochemical investigation of the leaves and twigs of Lithocarpus litseifolius and Lithocarpus corneus resulted in the isolation of four new triterpenoids (1: -4: ), three triterpenoids (5: -7: ) isolated from a natural source for the first time, and six known compounds (8: -13: ). In addition, four known triterpenoids (14: -17: ) were isolated from L. corneus. Compound 1: is a 3,4-seco-lupane-type triterpenoid, and compounds 2: -4: are lupane-type triterpenoids in different oxidation states. The structures of all isolated compounds were identified by spectroscopic methods, especially NMR and mass spectrometry data. The absolute configuration of 2: and 3: was confirmed by X-ray single crystallographic analysis. The anti-inflammatory activities of 1: -17: and anti-HIV activities of 2: -17: were evaluated. Among them, 3-epi-betulinic acid (8: ) showed a strong anti-HIV activity comparable to abacavir, a drug used for treating HIV/AIDS. 3,4-seco-4(23),20(29)-lupadiene-3,28-dioic acid (5: ) exhibited potent inhibition of superoxide-anion generation with 86.9 ± 2.8% inhibition at 1 µM.

Evaluation of the use of the fourth version FloTrac system in cardiac output measurement before and after cardiopulmonary bypass.

The FloTrac system is a system for cardiac output (CO) measurement that is less invasive than the pulmonary artery catheter (PAC). The purposes of this study were to (1) compare the level of agreement and trending abilities of CO values measured using the fourth version of the FloTrac system (CCO-FloTrac) and PAC-originated continuous thermodilution (CCO-PAC) and (2) analyze the inadequate CO-discriminating ability of the FloTrac system before and after cardiopulmonary bypass (CPB). Fifty patients were included. After exclusion, 32 patients undergoing cardiac surgery with CPB were analyzed. All patients were monitored with a PAC and radial artery catheter connected to the FloTrac system. CO was assessed at 10 timing points during the surgery. In the Bland-Altman analysis, the percentage errors (bias, the limits of agreement) of the CCO-FloTrac were 61.82% (0.16, - 2.15 to 2.47 L min) and 51.80% (0.48, - 1.97 to 2.94 L min) before and after CPB, respectively, compared with CCO-PAC. The concordance rates in the four-quadrant plot were 64.10 and 62.16% and the angular concordance rates (angular mean bias, the radial limits of agreement) in the polar-plot analysis were 30.00% (17.62°, - 70.69° to 105.93°) and 38.63% (- 10.04°, - 96.73° to 76.30°) before and after CPB, respectively. The area under the receiver operating characteristic curve for CCO-FloTrac was 0.56, 0.52, 0.52, and 0.72 for all, ≥ ± 5, ≥ ± 10, and ≥ ± 15% CO changes (ΔCO) of CCO-PAC before CPB, respectively, and 0.59, 0.55, 0.49, and 0.46 for all, ≥ ± 5, ≥ ± 10, and ≥ ± 15% ΔCO of CCO-PAC after CPB, respectively. When CO < 4 L/min was considered inadequate, the Cohen κ coefficient was 0.355 and 0.373 before and after CPB, respectively. The accuracy, trending ability, and inadequate CO-discriminating ability of the fourth version of the FloTrac system in CO monitoring are not statistically acceptable in cardiac surgery.

Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation.

Neutrophils are widely recognized to play an important role in acute inflammatory responses, and recent evidence has expanded their role to modulating chronic inflammatory and autoimmune diseases. Reactive oxygen species (ROS) and microbicidal compounds released from neutrophils that are recruited to the site of inflammation contribute to the pathogenesis of multiple inflammation-associated diseases such as chronic obstructive pulmonary disease, atherosclerosis, and hepatitis. Marine organisms are a valuable source of bioactive compounds with potential for industrial and pharmaceutical application. Marine natural products that inhibit neutrophil activation could be used as drugs for the treatment of inflammatory diseases. Numerous studies investigating marine natural products have reported novel anti-inflammatory agents. Nevertheless, the detailed mechanisms underlying their actions, which could facilitate our understanding of the molecular events occurring in neutrophils, have not been reported in most of the associated research studies. Therefore, in this review, we will present marine products that inhibit neutrophil-associated inflammation. Furthermore, we will be limiting the detailed discussion to agents with well-investigated molecular targets.

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.

Ribociclib leverages phosphodiesterase 4 inhibition in the treatment of neutrophilic inflammation and acute respiratory distress syndrome.

INTRODUCTION: Overwhelming neutrophil activation and oxidative stress significantly contribute to acute respiratory distress syndrome (ARDS) pathogenesis. However, the potential of repurposing ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used clinically in cancer treatment, for treating neutrophilic ARDS remains uncertain. This study illustrated the ability and underlying mechanism of ribociclib for treating ARDS and neutrophilic inflammation. METHODS: Primary human neutrophils were used to determine the therapeutic effects of ribociclib on respiratory bursts, chemotactic responses, and inflammatory signaling. In vitro and silico analyses were performed to determine the underlying molecular mechanisms. The potential of ribociclib repurposing was evaluated using an in vivo ARDS model in lipopolysaccharide (LPS)-primed mice. RESULTS: We found that treatment using ribociclib markedly limited overabundant oxidative stress (reactive oxygen species [ROS]) production and chemotactic responses (integrin levels and adhesion) in activated human neutrophils. Ribociclib was also shown to act as a selective inhibitor of phosphodiesterase 4 (PDE4), thereby promoting the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, leading to the inhibition of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) phosphorylation, and calcium influx. Notably, prophylactic administration and post-treatment with ribociclib ameliorated neutrophil infiltration, lung inflammation, accumulation of oxidative stress, pulmonary destruction, and mortality in mice with LPS-induced ARDS. CONCLUSION: We demonstrated for the first time that ribociclib serves as a novel PDE4 inhibitor for treating neutrophilic inflammation and ARDS. The repurposing ribociclib and targeting neutrophilic PDE4 offer a potential off-label alternative for treating lung lesions and other inflammatory conditions.

Apremilast ameliorates acute respiratory distress syndrome by inhibiting neutrophil-induced oxidative stress.

BACKGROUND: The pathogenesis of acute respiratory distress syndrome (ARDS) is attributed to the dysregulation of oxidative stress and neutrophil recruitment. We aimed to investigate the anti-inflammatory effects of apremilast on human neutrophils and assess its efficacy for treating ARDS. METHODS: We analysed superoxide anion generation, integrin expression, and adhesion in activated human neutrophils using spectrophotometry, flow cytometry, and immunofluorescence microscopy. Phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was determined using immunoblotting. A murine lipopolysaccharide (LPS)-induced ARDS model was used to evaluate the therapeutic effects of apremilast. RESULTS: Apremilast significantly decreased superoxide anion production, reactive oxygen species (ROS) generation, cluster of differentiation (CD)11 b expression, and neutrophil adhesion in formyl-l-methionyl-l-leucyl-l-phenylalanine activated human neutrophils. Apremilast elevated cyclic 3',5'-adenosine monophosphate (cAMP) and protein kinase A (PKA) activity in activated neutrophils. It reduced cellular cAMP-specific phosphodiesterase (PDE) activity and selectively inhibited enzymatic PDE4 activity. The activated cAMP/PKA pathway suppressed the phosphorylation of ERK and JNK as well as Ca2+ mobilization in activated neutrophils. All inhibitory effects of apremilast on activated neutrophils were reversed by a PKA inhibitor. In vivo examinations indicated that apremilast alleviated lung neutrophil infiltration, myeloperoxidase (MPO) activity, pulmonary oedema, and alveolar damage in LPS-induced ARDS. CONCLUSION: Apremilast inhibits inflammatory responses after neutrophil activation via cAMP/PKA-dependent inhibition of ERK and JNK activation. Our study revealed apremilast suppresses oxidative stress and chemotaxis by selectively inhibiting PDE4 in neutrophils and thus protects against endotoxin-induced ARDS in mice. Apremilast can be used as an alternative off-label drug in treating acute lung damage.

Carnosic acid inhibits reactive oxygen species-dependent neutrophil extracellular trap formation and ameliorates acute respiratory distress syndrome.

AIMS: Infiltration of activated neutrophils into the lungs is a hallmark of acute respiratory distress syndrome (ARDS). Neutrophilic inflammation, particularly neutrophil extracellular traps (NETs), is proposed as a useful target for treating ARDS. Carnosic acid (CA) is a food additive; however, its anti-neutrophilic activity in the treatment of ARDS has not been well established. The hypothesis of present study is to confirm that CA alleviates ARDS by suppressing neutrophilic inflammation and oxidative damage. MAIN METHODS: Generation of superoxide anions and reactive oxygen species (ROS), induction of elastase degranulation, and formation of NETs by human neutrophils were assayed using spectrophotometry, flow cytometry, and immunofluorescent microscopy. Immunoblotting was performed to determine the cellular mechanisms involved. Cell-free radical systems were used to test antioxidant activities. The therapeutic effect of CA was evaluated in a lipopolysaccharide (LPS)-induced ARDS mouse model. KEY FINDINGS: CA greatly reduced superoxide anion production, ROS production, elastase release, cluster of differentiation 11b expression, and cell adhesion in activated human neutrophils. Mechanistic studies have demonstrated that CA suppresses phosphorylation of extracellular regulated kinase and c-Jun N-terminal kinase in activated neutrophils. CA effectively scavenges reactive oxygen and nitrogen species, but not superoxide anions. This is consistent with the finding that CA is effective against ROS-dependent NET formation. CA treatment significantly improved pulmonary neutrophil infiltration, oxidative damage, NET formation, and alveolar damage in LPS-induced mice. SIGNIFICANCE: Our data suggested the potential application of CA for neutrophil-associated ARDS therapy.

The Impact of Rocuronium and Sugammadex on Length of Stay in Patients Undergoing Open Spine Surgery: A Propensity Score-Matched Analysis.

Enhanced Recovery After Surgery (ERAS), an all-encompassing perioperative care approach, has been demonstrated to enhance surgical results, mitigate postoperative issues, and decrease the length of hospital stay (LOS) in diverse surgical specialties. In this retrospective study, our objective was to examine the influence of muscle relaxant selection on LOS and perioperative results in adult patients undergoing open spine surgery. Specifically, we compared 201 patients who received cisatracurium and neostigmine with 201 patients who received rocuronium and sugammadex, after 1:1 propensity score matching. The utilization of the rocuronium and sugammadex combination in anesthesia for open spinal surgery did not lead to a reduction in the LOS but was associated with a decreased incidence of postoperative chest radiographic abnormalities, including infiltration, consolidation, atelectasis, or pneumonia (p = 0.027). In our secondary analysis, multivariate analysis revealed multiple determinants influencing the prolonged LOS (>7 days) during open spine surgery. Bispectral index-guided anesthesia emerged as a protective factor, while variables such as excessive intraoperative blood loss and fluid administration as well as postoperative chest radiographic abnormalities independently contributed to prolonged LOS.

Association of regional anesthesia with oncological outcomes in patients receiving surgery for bladder cancer: A meta-analysis of observational studies.

Background: This meta-analysis was conducted to compare cancer recurrence and survival rates in patients with bladder cancer receiving surgery under general anesthesia alone (i.e., GA group) or regional anesthesia (RA) with or without GA (i.e., RA ± GA group). Methods: Literature search on Cochrane library, EMBASE, Google scholar, and Medline databases was performed to identify all relevant studies from inception to April 30, 2022. The primary outcome was cancer recurrence rate, while the secondary outcomes included overall survival rate and cancer-specific survival rate. Subgroup analyses were performed based on study design [(Propensity-score matching (PSM) vs. no-PSM)] and type of surgery [transurethral resection of bladder tumor (TURBT) vs. radical cystectomy]. Results: Ten retrospective studies with a total of 13,218 patients (RA ± GA group n=4,884, GA group n=8,334) were included. There was no difference between RA ± GA group and GA group in age, the proportion of males, severe comorbidities, the proportion of patients receiving chemotherapy, and the pathological findings (all p >0.05). Patients in the RA ± GA group had significantly lower rate of bladder cancer recurrence [odds ratio (OR): 0.74, 95%CI: 0.61 to 0.9, p=0.003, I2 = 24%, six studies] compared to those in the GA group. Subgroup analyses based on study design revealed a consistent finding, while the beneficial effect of RA ± GA on reducing cancer recurrence was only significant in patients receiving TURBT (p=0.02), but not in those undergoing radical cystectomy (p=0.16). There were no significant differences in overall survival rate and cancer-specific survival rate between RA ± GA and GA groups. Conclusions: For patients receiving surgery for bladder cancer, the application of regional anesthesia with or without general anesthesia is associated with significant decrease in cancer recurrence, especially in patients undergoing TURBT for non-muscle invasive bladder cancer. Because of the limited number of studies included and potential confounding factors, our results should be interpreted carefully. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022328134.

Combined Programmed Intermittent Bolus and Patient-Controlled Bolus Is a More Favorable Setting for Epidural Pain Relief Than Continuous Infusion.

Epidural analgesia is a suitable and effective treatment for labor pain. However, the preferable modality setting for delivery remains debatable. This study adopted a programmed intermittent epidural bolus (PIEB) setting in conjunction with a patient-controlled epidural analgesia (PCEA) setting to improve the quality of labor analgesia and reduce the number of medical staff. We conducted a prospective observational analysis of primigravida parturients scheduled for spontaneous labor, which required epidural analgesia for painless labor. A total of 483 healthy primigravida parturients with singleton pregnancies were included in this cohort; 135 nulliparous patients were assigned to the continuous infusion setting (CEI) group and 348 to the PIEB + PCEA group. Compared to the CEI setting, the PIEB + PCEA setting significantly reduced the manual rescue by the clinician, extended the time required for the first manual rescue dose, and acclaimed good maternal satisfaction. The use of the CEI mode increased for poor performance requiring more than two rescues with an odds ratio of 2.635 by a binary logistic regression analysis. Using the PIEB + PCEA setting as the maintenance infusion had a longer duration for the first requested manual rescue, fewer manual rescue boluses, excellent satisfaction, and no significant increase in adverse events compared to the CEI setting.

Targeting formyl peptide receptor 1 with anteiso-C13-surfactin for neutrophil-dominant acute respiratory distress syndrome.

BACKGROUND AND PURPOSE: Acute respiratory distress syndrome (ARDS) is a catastrophic pulmonary inflammatory dysfunction with a high mortality rate. An overwhelming immune response by neutrophils is a key feature in infective or sterile ARDS. The formyl peptide receptor 1 (FPR1) is a crucial damage-sensing receptor for inflammatory reactions in the initiation and progression of neutrophil-mediated ARDS. However, effective targets for controlling dysregulated neutrophilic inflammatory injuries in ARDS are limited. EXPERIMENTAL APPROACH: Human neutrophils were used to explore the anti-inflammatory effects of cyclic lipopeptide anteiso-C13-surfactin (IA-1) from marine Bacillus amyloliquefaciens. The lipopolysaccharide-induced model of ARDS in mice was used to determine the therapeutic potential of IA-1 in ARDS. Lung tissues were harvested for histology analyses. KEY RESULTS: The lipopeptide IA-1 inhibited immune responses of neutrophils, including respiratory burst, degranulation, and expression of adhesion molecules. IA-1 inhibited the binding of N-formyl peptides to FPR1 in human neutrophils and in hFPR1-transfected HEK293 cells. We identified IA-1 as a competitive FPR1 antagonist, thus diminishing the downstream signalling pathways involving calcium, mitogen-activated protein kinases and Akt. Furthermore, IA-1 ameliorated the inflammatory damage to lung tissue, by decreasing neutrophil infiltration, reducing elastase release and oxidative stress in endotoxemic mice. CONCLUSION AND IMPLICATIONS: The lipopeptide IA-1 could serve as a therapeutic option for ARDS by inhibiting FPR1-mediated neutrophilic injury.

Application of Bispectral Index System (BIS) Monitor to Ambulatory Pediatric Dental Patients under Intravenous Deep Sedation.

Purpose Intravenous sedation has been well accepted to allow dental restoration in uncooperative children while avoiding aspiration and laryngospasm; however, intravenous anesthetics such as propofol may lead to undesired effects such as respiratory depression and delayed recovery. The use of the bispectral index system (BIS), a monitoring system reflective of the hypnotic state, is con-troversial in the reduction in the risk of respiratory adverse events (RAEs), recovery time, the in-travenous drug dosage, and post-procedural events. The aim of the study is to evaluate whether BIS is advantageous in pediatric dental procedures. Methods A total of 206 cases, aged 2-8 years, receiving dental procedures under deep sedation with propofol using target-controlled infusion (TCI) technique were enrolled in the study. BIS level was not monitored in 93 children whereas it was for 113 children, among which BIS values were maintained between 50-65. Physiological variables and adverse events were recorded. Statistical analysis was conducted using Chi-square, Mann Whitney U, Independent Samples t and Wilcoxon signed tests, with a p value of <0.05 considered to be statistically significant. Results Although no statistical significance in the post-discharge events and total amount of propofol used was observed, a clear significance was identified in periprocedural adverse events (hypoxia, apnea, and recurrent cough, all p value < 0.05) and discharge time (63.4 ± 23.2 vs. 74.5 ± 24.0 min, p value < 0.001) between these two groups. Conclusions The application of BIS in combination with TCI may be beneficial for young children undergoing deep sedation for dental procedures.

Palbociclib blocks neutrophilic phosphatidylinositol 3-kinase activity to alleviate psoriasiform dermatitis.

BACKGROUND AND PURPOSE: Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil-associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil-associated psoriasiform dermatitis. EXPERIMENTAL APPROACH: The anti-inflammatory effects of palbociclib were determined in activated human neutrophils. The therapeutic feasibility of palbociclib in psoriasis was demonstrated in a mouse model of imiquimod-induced psoriasiform dermatitis. The in vitro enzymatic assays and in silico analyses were used to identify the underlying pharmacological mechanisms. KEY RESULTS: This study found that palbociclib inhibited neutrophilic inflammation, including superoxide anion generation, reactive oxygen species (ROS) formation, elastase degranulation and chemotactic responses. The mechanistic studies identified that the anti-inflammatory effects of palbociclib involved the targeting of phosphatidylinositol 3-kinase (PI3K) but not CDK4/6 in human neutrophils. Palbociclib preferentially targeted the p110δ catalytic subunit of PI3K and thereby blocked signalling via the PI3K/protein kinase B (Akt) pathway. Furthermore, topical application of palbociclib significantly ameliorated imiquimod-induced psoriasiform dermatitis in mice, including psoriatic symptoms, neutrophil infiltration, Akt activation and cytokine up-regulation. CONCLUSIONS AND IMPLICATIONS: This is the first study to demonstrate that palbociclib can potentially be used to treat neutrophil-associated psoriasiform dermatitis through the targeting of neutrophilic PI3K activity. Our findings prompt further research to explore the potential of palbociclib and PI3K in psoriasis and other inflammatory diseases.

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).

Effect of electroacupuncture in postanesthetic shivering during regional anesthesia: a randomized controlled trial.

BACKGROUND: Shivering during regional anesthesia is a common complication and is related to a decrease in the patient's core body temperature. Previous studies have shown that acupuncture on specific acupoints can preserve core body temperature. The present study evaluated the effect of electroacupuncture in preventing the shivering caused by regional anesthesia. METHODS: This prospective and randomized controlled study analyzed the data from 80 patients undergoing urological surgery, who were classified as ASA I or II. Spinal anesthesia was performed in all patients using 15 mg of bupivacaine. The patients were randomly allocated to receive either placebo acupuncture (Group P, n=40) or electroacupuncture (Group A, n=40) for 30 min before administration of spinal anesthesia. Shivering score was recorded at 5 min intervals, with 0 representing no shivering and 4 representing the most severe shivering possible. Heart rate, blood pressure, and tympanic temperature were recorded before the intrathecal injection, and again every 5 min thereafter until 30 min. RESULTS: After spinal anesthesia, the decrease in tympanic temperature was less for Group A patients than Group P, with the difference being statistically significant. After 15 min, 13 patients in Group P attained a shivering score of 3 or more, compared with 3 patients in Group A. Significantly more patients in Group P attained a shivering score of at least 1. CONCLUSIONS: The prophylactic use of electroacupuncture might maintain core body temperature, and may effectively prevent the shivering that commonly develops during regional anesthesia. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000096853.

Effect of Mycophenolate Mofetil Therapy on Recurrence of Hepatocellular Carcinoma after Liver Transplantation: A Population-Based Cohort Study.

Hepatocellular carcinoma (HCC) recurrence after liver transplantation is associated with immunosuppressants. However, the appropriate immunosuppressant for HCC recipients is still debated. Data for this nationwide population-based cohort study were extracted from the National Health Insurance Research Database of Taiwan. A total of 1250 liver transplant recipients (LTRs) with HCC were included. We analyzed the risk factors for post-transplant HCC recurrences. Cumulative defined daily dose (cDDD) represented the exposure duration and was calculated as the amount of dispensed defined daily dose (DDD) of mycophenolate mofetil (MMF). The dosage effects of MMF on HCC recurrence and liver graft complication rates were investigated. A total of 155 LTRs, having experienced post-transplant HCC recurrence, exhibited low survival probability at 1-, 3-, 5-, and 10-year observations. Our results demonstrated increased HCC recurrence rate after liver transplantation (p = 0.0316) following MMF administration; however, no significant increase was demonstrated following cyclosporine, tacrolimus, or sirolimus administration. Notably, our data demonstrated significantly increased HCC recurrence rate following MMF administration with cDDD > 0.4893 compared with cDDD ≤ 0.4893 or no administration of MMF (p < 0.0001). MMF administration significantly increases the risk of HCC recurrence. Moreover, a MMF-minimizing strategy (cDDD ≤ 0.4893) is recommended for recurrence-free survival.