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.

Gastrodin Alleviates Acetaminophen-Induced Liver Injury in a Mouse Model Through Inhibiting MAPK and Enhancing Nrf2 Pathways.

Gastrodin is a major active phenolic glycoside extract from Gastrodia elata, an important herb used in traditional medicine. Previous research has reported that gastrodin possesses anti-inflammatory and anti-oxidant properties. Therefore, we aimed to investigate its hepatoprotective effects and mechanisms on acetaminophen (APAP)-induced liver injury in a mouse model. Mice included in this study were intraperitoneally administered with a hepatotoxic APAP dose (300 mg/kg). At 30 min after APAP administration, gastrodin was intraperitoneally injected at concentrations of 0, 15, 30, and 45 mg/kg. Then, all mice were sacrificed at 16 h after APAP injection for further analysis. The results showed that gastrodin treatment ameliorated acute liver injury caused by APAP, as indicated by serum alanine aminotransferase level, hepatic myeloperoxidase activity, and cytokine (TNF-α, IL-1ß, and IL-6) production. It also significantly decreased hepatic malondialdehyde activity but increased superoxide dismutase activity. In addition, gastrodin decreased ERK/JNK MAPK expression but promoted Nrf2 expression. These results demonstrated that gastrodin may be a potential therapeutic target for the prevention of APAP-induced hepatotoxicity via amelioration of the inflammatory response and oxidative stress, inhibition of ERK/JNK MAPK signaling pathways, and activation of Nrf2 expression levels.

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.

Corilagin reduces acetaminophen-induced hepatotoxicity through MAPK and NF-κB signaling pathway in a mouse model.

Corilagin is a major active polyphenolic tannins extracted from Phyllanthus urinaria, an important herb used in traditional medicine. Previous reports demonstrated that corilagin possesses antioxidant and anti-inflammatory properties. Therefore, this study aimed to evaluate its hepatoprotective effects and mechanisms on acetaminophen (APAP)-induced liver injury in mice. Mice included in this study were intraperitoneally injected with a hepatotoxic APAP dose (300 mg/kg). After a 30 min of APAP administration, corilagin was injected intraperitoneally at concentrations of 0, 1, 5, 10, and 20 mg/kg. Then, after 16 h of corilagin treatment, mice were sacrificed for further analysis. APAP overdose significantly elevated the serum ALT level, hepatic myeloperoxidase (MPO) activity, cytokines (TNF-α, IL-1ß, and IL-6) production, malondialdehyde (MDA) activity, and ERK/JNK MAPK and NF-κB protein expressions. Corilagin treatment significantly decreased these parameters in a dose-dependent manner (1-20 mg/kg). This study demonstrated that corilagin may be a potential therapeutic target for the prevention of APAP-induced hepatotoxicity by down-regulating the inflammatory response and by inhibiting ERK/JNK MAPK and NF-κB signaling pathways.

A novel NOX2 inhibitor attenuates human neutrophil oxidative stress and ameliorates inflammatory arthritis in mice.

Neutrophil infiltration plays a significant pathological role in inflammatory diseases. NADPH oxidase type 2 (NOX2) is a respiratory burst oxidase that generates large amounts of superoxide anion (O2•-) and subsequent other reactive oxygen species (ROS). NOX2 is an emerging therapeutic target for treating neutrophilic inflammatory diseases. Herein, we show that 4-[(4-(dimethylamino)butoxy)imino]-1-methyl-1H-benzo[f]indol-9(4H)-one (CYR5099) acts as a NOX2 inhibitor and exerts a protective effect against complete Freund's adjuvant (CFA)-induced inflammatory arthritis in mice. CYR5099 restricted the production of O2•- and ROS, but not the elastase release, in human neutrophils activated with various stimulators. The upstream signaling pathways of NOX2 were not inhibited by CYR5099. Significantly, CYR5099 inhibited NOX2 activity in activated human neutrophils and in reconstituted subcellular assays. In addition, CYR5099 reduced ROS production, neutrophil infiltration, and edema in CFA-induced arthritis in mice. Our findings suggest that CYR5099 is a NOX2 inhibitor and has therapeutic potential for treating neutrophil-dominant oxidative inflammatory disorders.

Prostate resected weight and postoperative prostate cancer incidence after transurethral resection of the prostate: A population-based study.

To analyze whether different volumes of tissue resected during transurethral resection of the prostate (TURP) would associate with the subsequent development of prostate cancer.This population-based retrospective cohort study recruited 49,206 patients with benign prostate hyperplasia (BPH) undergoing TURP between 2005 and 2012. Patients were recruited from the Taiwan National Health Insurance Research Database. Patients were separated into three groups, based on different volumes of tissue resected during TURP (5-15 g, 15-50 g, >50 g).Of the 49,206 patients, 633 patients were diagnosed with new onset of prostate cancer following TURP. Older age was a risk factor contributing to the onset of prostate cancer (P = .0196) and different volumes of tissue resected were significantly related to the incidence of postoperative prostate cancer (P = .0399). The group of patients with a smaller volume of prostate resected had a higher risk of prostate cancer with a hazard ratio (HR) of 1.221 (95% confidence interval [CI]: 1.035, 1.440; P = .0179). However, the risk in the group of patients with a larger volume of prostrate resected was not significantly different, with an HR of 1.277 (95% CI: 0.981, 1662; P = .0690). The incidence of prostate cancer in Taiwanese males over 30 years of age has previously been reported to be 0.0560%; the mean incidence was 0.2282% in our present study.This study shows that BPH patients who had a smaller volume of tissue resected during TURP show a higher incidence of prostate cancer postoperatively. Currently, no clear mechanism is shown to demonstrate the relationship between resected prostate weight and the incidence of tumors. Patients with a larger prostate volume might have lower urinary tract symptoms earlier and then seek professional help. It is possible that surgical procedures might remove the potentially carcinogenic prostate tissue and thus reduce the risk of an aggressive tumor developing in the future.

Honokiol suppresses formyl peptide-induced human neutrophil activation by blocking formyl peptide receptor 1.

Formyl peptide receptor 1 (FPR1) mediates bacterial and mitochondrial N-formyl peptides-induced neutrophil activation. Therefore, FPR1 is an important therapeutic target for drugs to treat septic or sterile inflammatory diseases. Honokiol, a major bioactive compound of Magnoliaceae plants, possesses several anti-inflammatory activities. Here, we show that honokiol exhibits an inhibitory effect on FPR1 binding in human neutrophils. Honokiol inhibited superoxide anion generation, reactive oxygen species formation, and elastase release in bacterial or mitochondrial N-formyl peptides (FPR1 agonists)-activated human neutrophils. Adhesion of FPR1-induced human neutrophils to cerebral endothelial cells was also reduced by honokiol. The receptor-binding results revealed that honokiol repressed FPR1-specific ligand N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein binding to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells. However, honokiol did not inhibit FPR2-specific ligand binding to FPR2 in human neutrophils. Furthermore, honokiol inhibited FPR1 agonist-induced calcium mobilization as well as phosphorylation of p38 MAPK, ERK, and JNK in human neutrophils. In conclusion, our data demonstrate that honokiol may have therapeutic potential for treating FPR1-mediated inflammatory diseases.

ERK Signaling Pathway Plays a Key Role in Baicalin Protection Against Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15-60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent.

Hepatoprotective Effects of Corilagin Following Hemorrhagic Shock are Through Akt-Dependent Pathway.

Corilagin, a component of Phyllanthus urinaria extract, possesses antioxidant, thrombolytic, antiatherogenic, and hepatoprotective properties, but the mechanism underlying these effects remains unclear. Previous studies showed that the Akt (protein kinase B) signaling pathway exerts anti-inflammatory and organ protective effects. The aim of this study was to investigate the mechanism of action of corilagin and determine whether these effects are mediated through the Akt-dependent pathway in a trauma-hemorrhagic shock-induced liver injury rodent model. Hemorrhagic shock was induced in male Sprague-Dawley rats; mean blood pressure was maintained at 35 mm Hg to 40 mm Hg for 90 min, followed by fluid resuscitation. During resuscitation, three doses of corilagin alone (1 mg/kg, 5 mg/kg, or 10 mg/kg, intravenously) were administered. Furthermore, a single dose of corilagin (5 mg/kg) with and without Wortmannin (1 mg/kg, PI3K inhibitor), Wortmannin alone, or vehicle was administered. Twenty-four hours after resuscitation, plasma alanine aminotransferase and aspartate aminotransferase concentration and hepatic parameters were measured. One-way ANOVA was used for statistical analysis. Hepatic myeloperoxidase activity and the concentrations of plasma alanine aminotransferase and aspartate aminotransferase, interleukin-6, tumor necrosis factor-α, intercellular adhesion molecule-1, and cytokine-induced neutrophil chemoattractant-1 (CINC-1) and CINC-3 increased following hemorrhagic shock. These parameters were significantly attenuated in corilagin-treated rats following hemorrhagic shock. Hepatic phospho-Akt expression was also higher in corilagin-treated rats than in vehicle-treated rats. The elevation of phospho-Akt was abolished by combined treatment with Wortmannin and corilagin. Our results suggest that corilagin exerts its protective effects on hemorrhagic shock-induced liver injury, at least, via the Akt-dependent pathway.

Tropisetron attenuates cardiac injury in a rat trauma-hemorrhage model.

Tropisetron is widely used for antiemesis. Recent evidence shows that tropisetron possesses anti-inflammatory properties. Protein kinase B (Akt) is known to play an important role in negating proinflammatory response in injury. The aim of this study was to determine whether tropisetron provides cardioprotection mediated via an Akt-dependent pathway in trauma-hemorrhaged animals. Male Sprague-Dawley rats underwent trauma-hemorrhage and resuscitation. Tropisetron (1 mg/kg) with or without a PI3K inhibitor (wortmannin, 1 mg/kg) or vehicle was administered intravenously during the resuscitation. At 24 h after either the trauma-hemorrhage or sham operation, the cardiac function parameters (cardiac output, left ventricle pressure variability) were measured. Cardiac myeloperoxidase activity, interleukin 6 and intercellular adhesion molecule 1 levels, Akt activity, and apoptosis were measured. One-way analysis of variance and Tukey test were used for statistical analysis. Cardiac function was depressed and cardiac myeloperoxidase activity, interleukin 6 and intercellular adhesion molecule 1 levels, and cardiac apoptosis were markedly increased after trauma-hemorrhage. Administration of tropisetron significantly improved cardiac function and proinflammatory parameters in the tropisetron-treated rats subjected to trauma-hemorrhage. The increase in cardiac apoptosis was attenuated in rats that received tropisetron. Although trauma-hemorrhage decreased cardiac Akt phosphorylation (p-Akt), tropisetron treatment prevented the same decrease in cardiac p-Akt following trauma-hemorrhage. Coadministration of wortmannin prevented the beneficial effects of tropisetron on the attenuation of proinflammatory responses and cardiac injury after trauma-hemorrhage. Tropisetron attenuates cardiac injury following trauma-hemorrhage, which is, at least in part, through Akt-dependent anti-inflammatory pathway.

Broken needle in the cervical spine: a previously unreported complication of Xiaozendao acupuncture therapy.

Xiaozendao (meaning "small-needle-knife," in Chinese) is a form of alternative medical instrument shaped like an acupuncture needle with a flat edge on the needle tip. It is widely used for the treatment of many different disorders in Asian countries, especially in the People's Republic of China. Its use has gained increasing popularity. To our knowledge, there are no reports of practitioners' experiences or adverse events related to "small-needle-knifed" therapy until now. We reported the first case of spinal-cord injury with delayed onset of neurologic symptoms from a broken small-needle-knife insertion into the spinal cord.