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Background: Myocardial infarction (MI) poses a global public health challenge, often associated with elevated mortality rates and a grim prognosis. A crucial aspect of the inflammatory injury and healing process post-MI involves the dynamic differentiation of macrophages. A promising strategy to alleviate myocardial damage after MI is by modulating the inflammatory response and orchestrating the shift from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages, aiming to achieve a reduced M1/M2 ratio. Nuanxinkang (NXK), a simplified herbal decoction, has demonstrated noteworthy cardioprotective, inflammation-regulating, and myocardial energy metabolism-regulating properties. Methods: In this study, we constructed an MI model by ligating coronary arteries to investigate the efficacy of NXK in improving ventricular remodeling and cardiac function. Mice were administered NXK (1.65 g/kg/d) or an equivalent volume of regular saline via gavage for 28 consecutive days, commencing the day after surgery. Then, we conducted echocardiography to assess the cardiac function, Masson staining to illustrate the extent of myocardial fibrosis, TUNEL staining to reveal myocardial apoptosis, and flow cytometry to analyze the polarization of M1 and M2 macrophages in the hearts. Besides, a lipopolysaccharide (LPS)-induced pro-inflammatory macrophage (M1) polarization model was implemented in RAW264.7 cells to elucidate the underlying mechanism of NXK in regulating macrophage polarization. RAW264.7 cells were pre-treated with or without NXK-containing serum. Oxidative stress was detected by MitoSox staining, followed by Seahorse energy metabolism assay to evaluate alterations in mitochondrial metabolic patterns and ATP production. Both In vivo and in vitro, HIF-1α and PDK1 were detected by fluorescent quantitative PCR and Western blotting. Results: In vivo, MI mice exhibited a decline in cardiac function, adverse ventricular remodeling, and an increase in glycolysis, coupled with M1-dominant polarization mediated by the HIF-1α/PDK1 axis. Notably, robust responses were evident with high-dose NXK treatment (1.65 g/kg/day), leading to a significant enhancement in cardiac function, inhibition of cardiac remodeling, and partial suppression of macrophage glycolysis and the inflammatory phenotype in MI mice. This effect was achieved through the modulation of the HIF-1α/PDK1 axis. In vitro, elevated levels of mitochondrial ROS production and glycolysis were observed in LPS-induced macrophages. Conversely, treatment with NXK notably reduced the oxidative stress damage induced by LPS and enhanced oxidative phosphorylation (OXPHOS). Furthermore, NXK demonstrated the ability to modify the energy metabolism and inflammatory characteristics of macrophages by modulating the HIF-1α/PDK1 axis. The influence of NXK on this axis was partially counteracted by the HIF-1α agonist DMOG. And NXK downregulated PDK1 expression, curtailed glycolysis, and reversed LPS-induced M1 polarization in macrophages, similar to the PDK1 inhibitor DCA. Conclusion: In conclusion, NXK protects against MI-induced cardiac remodeling by inducing metabolic reprogramming and phenotypic differentiation of macrophages, achieved through the modulation of the HIF-1α/PDK1 axis. This provides a novel and promising strategy for the treatment of MI. Highlights: Balancing the coordination between M1 and M2 macrophages emerges as a promising therapeutic strategy for addressing myocardial infarction. Metabolic reprogramming plays a crucial role in the activation and differentiation of macrophages. NXK formulation intricately regulates macrophage polarization through the HIF-1α/PDK1 axis within a metabolic-inflammatory network. [ABSTRACT FROM AUTHOR]

Background: Chelidonium majus is a well-known traditional Chinese medicine, and has been reported of the effect in relieving cough and asthma. However, the mechanism of action is still unknown. Methods: Asthmatic SD rats were first sensitized and established through ovalbumin (OVA) motivation. Subsequently, Hematoxylin and eosin (H&E) staining, Masson's trichrome (Masson) staining, Periodic acid-Schiff (PAS) staining and inflammatory cytokines assay of interleukin (IL)-4, IL-6, IL-17 were implemented to evaluate the protective effects of Chelidonium majus on asthma. Then, the effects of Chelidonium majus and their molecular mechanisms of action on asthma were detected based on the integration of transcriptomics and metabolomics analyses. Results: After administration with Chelidonium majus, the histological injuries of inflammation, collagen deposition and mucus secretion in lungs were attenuated and the serum inflammatory cytokines perturbations were also converted. Furthermore, integrated analysis revealed that after Chelidonium majus treatment, 7 different expression genes (DEGs) (Alox15, P4ha1, Pla2g16, Pde3a, Nme1, Entpd8 and Adcy9) and 9 metabolic biomarkers (ADP, Xanthosine, Hypoxanthine, Inosine, prostaglandin E2 (PGE2), prostaglandin F2a (PGF2a), phosphatidylserine, Creatine and LysoPC (10:0)) were discovered to be connected with the enrichment metabolic pathways, including Purine metabolism, Arachidonic acid metabolism, Arginine and proline metabolism and Glycerophospholipid metabolism. The obtained metabolic biomarkers and DEGs were mainly related to energy metabolism and inflammation, and may be potential therapeutic targets. Conclusion: Chelidonium majus relieved OVA-induced asthma in rats by regulating the Alox15, P4ha1, Pla2g16, Pde3a, Nme1, Entpd8 and Adcy9 genes expression to restore the disorders in energy metabolism and inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: In the genus Curculigo, Curculigo orchioides Gaertn, Curculigo capitulata (Lour) O. Ktze and Curculigo pilosa (Schumach. & Thonn.) Engl are often used in traditional medicine. Curculigo orchioides is used for the treatment of impotence, limb limpness, arthritis of the lumbar and knee joints, and watery diarrhea in traditional Chinese medicine, and also used as a potent immunomodulator and aphrodisiac in the Ayurvedic medical system. Curculigo capitulata is used for the treatment of consumptive cough, kidney asthenia, impotence and spermatorrhea, hemorrhoids, asthma, jaundice, diarrhea, colic and gonorrhea in traditional Chinese and India medicine, and to treat urinary tract infection, acute renal pelvis and nephritis, nephritis-edema, cystitis, nephrolithiasis, hypertension and rheumatic arthritis in traditional Dai medicine. Curculigo pilosa are applied to treat gastrointestinal and heart diseases in Africa. Aim of the review: This review aims to exhibit up-to-date and comprehensive information about traditional uses, phytochemistry, pharmacology and toxicology of medicinal plants in the genus Curculigo, and has an insight into the opportunities for the future research and development of Curculigo plant. Methods: A bibliographic investigation was performed by analyzing the information available on Curculigo plant from worldwide accepted scientific databases (Pubmed, Scopus and Web of Science, SciFinder, Google Scholar, Yahoo). Furthermore, information also was obtained from some local and foreign books on ethnobotany and ethnomedicines. Results: Curculigo orchioides, Curculigo capitulata and Curculigo pilosa have been used as traditional medicine to treat kinds of diseases such as impotence, limb limpness, gastrointestinal and heart diseases, etc. Phytochemical investigation of eight species of the genus Curculigo has resulted in identification of more than 110 compounds. The content of curculigoside is used as an indicator to evaluate the quality of rhizome of Curculigo orchioides. The medicinal plants have showed a wide spectrum pharmacological activities, including adaptive, immunostimulatory, taste-modifying and sweet-tasting, antioxidant, mast cell stabilization, antihistaminic and antiasthmatic, hepatoprotective and neuroprotective activity. Toxicological test indicated that Curculigo orchioides at the dose of 120g/kg after administrating rats for 180 days may cause injury of liver and kidney. Conclusion: The medicinal plants of genus Curculigo have emerged as a good source of the traditional medicines. Some uses of these plants in the traditional medicines have been validated by pharmacological investigation. However, the mechanism of their actions should be further elucidated; the particular constituent responsible for toxicity should be isolated and identified, and the target tissue and mechanism of toxic ingredients also deserve to be further investigated; more reference substances should be prepared, and sophisticated analytical technologies should be developed to comprehensively assess the quality of Curculigo herbs. These investigations will be helpful for further utilization of the plants of genus Curculigo. [Copyright &y& Elsevier]

QiShen'YiQi Pills (QSYQ) is a compound Chinese medicine used for treatment of cardiovascular diseases. The present study investigated the effects of QSYQ on the Doxorubicin- (DOX-) induced disorders in rat cardiac structure and function and the possible mechanism underlying. A total of 24 male Sprague-Dawley rats were administrated by intraperitoneal injections with DOX at a dose of 2.5 mg/kg, once every day for a total of 6 times. After the 6th injection, the rats were evaluated by echocardiographic analysis, and the animals with injured heart (n = 14) were divided into 2 groups and further treated with (n = 7) or without (n = 7) QSYQ by gavage at a dose of 0.2 g/day, once a day, over the next 2 weeks. Two weeks after QSYQ treatment, the following variables were assessed: myocardial blood flow (MBF) by Laser-Doppler Perfusion Imager, the ratio of heart weight to body weight (HW/BW), myocardial histology, myocardial content of ATP, AMP, free fatty acids (FFAs) and AMP/ATP by ELISA, and expression of PPARa, PGC- la, and ATP 5D by Western blot. Statistical analysis was performed using one-way ANOVA followed by Turkey test for multiple comparisons. DOX challenge significantly increased left ventricular internal diameter and HW/BW and decreased the thickness of the left ventricular posterior wall, the left ventricle ejection fraction, and the left ventricle fractional shortening. DOX also increased AMP, FFA, and AMP/ATP, decreased ATP, and downregulated the protein content of ATP 5D, PPAR α, and PGC-1 α. All these DOX-induced cardiac insults were attenuated significantly by QSYQ treatment. These results show the potential of QSYQ to ameliorate DOX-induced disorders in cardiac structure and function; this effect may be related to the increase in myocardial ATP content via the upregulation of ATP 5D, PPAR α, and PGC-1 α and the oxidation of FFA. [ABSTRACT FROM AUTHOR]

Abstract: Pseudodactylogyrus is a significant monogenean parasite of the gills of aquacultured European eels, and can cause severe gill pathology. In this study, effects of the crude extracts, fractions and compounds of exopleura of Ginkgo biloba against Pseudodactylogyrus were investigated under in vivo conditions by bio-assay guided isolation method. Four solvents (petroleum ether, ethyl acetate, n-butanol and water) were applied for the extraction of exopleura of G. biloba. Among them, only the petroleum ether extract showed strong activity and therefore, subjected to further separation and purification using various chromatographic techniques. Two compounds showing potent activity were identified by comparing spectral data (IR, NMR, and EI-MS) with literature values to be ginkgolic acid C13:0 and C15:1. They were found to be 100% effective at the concentration of 2.5mg l-1 and 6.0mg l-1, with ED50 values of 0.72mg l-1 and 2.88mg l-1, respectively. In the 5-days safety test, ginkgolic acid C13:0 and C15:1 were shown to be safe for healthy juvenile eels when the concentration were up to 10.0 and 18.0mg l-1, respectively. The two compounds exhibited potential results and can be explored as plant-derived antiparasitic for the control of Pseudodactylogyrus. [Copyright &y& Elsevier]

Abstract: Airway inflammation plays important roles in the pathogenesis of acute respiratory distress syndrome (ARDS), asthma and chronic obstructive pulmonary disease (COPD), and anti-inflammatory treatment effectively improves the symptoms of these diseases. To develop the potentially therapeutic compounds for the treatment of pulmonary inflammation, we investigated the effects of licorice flavonoids (LF) extracted from the roots of Glycyrrhiza uralensis (licorice) on lipopolysaccharide (LPS)-induced acute pulmonary inflammation in mice. Acute pulmonary inflammation was induced by intracheal instillation with LPS, treatment with LF at dosages of 3, 10 and 30 mg/kg significantly reduced the LPS-induced inflammatory cells, including neutrophils, macrophages and lymphocytes accumulation in bronchoalveolar lavage fluids (BALF), among these inflammatory cells, LF predominately inhibited neutrophil infiltration, and the maximal effect (30 mg/kg) was as comparable as dexamethasone treatment at 1 mg/kg. Consistent with its effects on neutrophil infiltration, LF treatment significantly increased LPS-induced BALF superoxide dismutase activity, and significantly decreased lung myeloperoxidase activity as well. Furthermore, treatment with LF at 30 mg/kg significantly reduced LPS-induced lung TNFα and IL-1β mRNA expression at 6 h and 24 h after LPS instillation, respectively. Finally, LF at different dosages not only significantly decreased the elevation of lung water content, but also markedly attenuated LPS-induced histological alteration. Therefore, we suggest that LF effectively attenuates LPS-induced pulmonary inflammation through inhibition of inflammatory cells infiltration and inflammatory mediator release which subsequently reduces neutrophil recruitment into lung and neutrophil-mediated oxidative injury, and this study provides with the potential rationale for development of anti-inflammatory compounds from flavonoid extracts of licorice. [Copyright &y& Elsevier]

Inherited retinal degeneration (RD) comprises a heterogeneous group of retinopathies that rank among the main causes of blindness. Tauroursodeoxycholic acid (TUDCA) is taurine conjugate hydrophilic bile acid that demonstrates profound protective effects against a series of neurodegenerative diseases related to oxidative stress. This study sought to evaluate the TUDCA induced effects of on a pharmacologically induced RD animal model by electroretinogram (ERG) examination, behavior tests, morphological analysis and immunochemistry assay. Massive photoreceptor degeneration in mice retina was induced by an intraperitoneal administration of N -methyl -N- nitrosourea(MNU). Subcutaneous delivery of TUDCA inhibits effectively the photoreceptor loss and visual impairments in the MNU administered mice. In the retinal flat-mounts of TUDCA treated mice, the cone photoreceptors were efficiently preserved. Furthermore, the multi-electrodes array (MEA) was used to detect the firing activities of retinal ganglion cells within the inner retinal circuits. TUDCA therapy could restrain the spontaneous firing response, enhance the light induced firing response, and preserve the basic configurations of ON-OFF signal pathway in degenerative retinas. Our MEA assay provided an example to evaluate the potency of pharmacological compounds on retinal plasticity. TUDCA affords these protective effects by modulating apoptosis and alleviating oxidative stress in the degenerative retina. In conclusion, TUDCA therapy can ameliorate the photoreceptor degeneration and rectify the abnormities in visual signal transmission. These findings suggest that TUDCA might act as a potential medication for these retinopathies with progressive photoreceptor degeneration. [ABSTRACT FROM AUTHOR]

Background: Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery.Methods: We did this randomised, double-blind, placebo-controlled trial in two tertiary-care hospitals in Beijing, China. We enrolled patients aged 65 years or older, who were admitted to intensive care units after non-cardiac surgery, with informed consent. We used a computer-generated randomisation sequence (in a 1:1 ratio) to randomly assign patients to receive either intravenous dexmedetomidine (0·1 μg/kg per h, from intensive care unit admission on the day of surgery until 0800 h on postoperative day 1), or placebo (intravenous normal saline). Participants, care providers, and investigators were all masked to group assignment. The primary endpoint was the incidence of delirium, assessed twice daily with the Confusion Assessment Method for intensive care units during the first 7 postoperative days. Analyses were done by intention-to-treat and safety populations. This study is registered with Chinese Clinical Trial Registry, www.chictr.org.cn, number ChiCTR-TRC-10000802.Findings: Between Aug 17, 2011, and Nov 20, 2013, of 2016 patients assessed, 700 were randomly assigned to receive either placebo (n=350) or dexmedetomidine (n=350). The incidence of postoperative delirium was significantly lower in the dexmedetomidine group (32 [9%] of 350 patients) than in the placebo group (79 [23%] of 350 patients; odds ratio [OR] 0·35, 95% CI 0·22-0·54; p<0·0001). Regarding safety, the incidence of hypertension was higher with placebo (62 [18%] of 350 patients) than with dexmedetomidine (34 [10%] of 350 patients; 0·50, 0·32-0·78; p=0·002). Tachycardia was also higher in patients given placebo (48 [14%] of 350 patients) than in patients given dexmedetomidine (23 [7%] of 350 patients; 0·44, 0·26-0·75; p=0·002). Occurrence of hypotension and bradycardia did not differ between groups.Interpretation: For patients aged over 65 years who are admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first 7 days after surgery. The therapy is safe.Funding: Braun Anaesthesia Scientific Research Fund and Wu Jieping Medical Foundation, Beijing, China. Study drugs were manufactured and supplied by Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China. [ABSTRACT FROM AUTHOR]

Lin X-Y, Fan C-F, Dong X-J, Yu J-H, Dai S-D & Wang E-H (2012) Histopathology 61, 178-185 Expression and significance of stem cell markers in pulmonary sclerosing haemangioma Aims: The two major types of cells of pulmonary sclerosing haemangioma (PSH) with the same origin show significant differences in morphological phenotype. Whether these differences are caused by their different differentiation status is still uncertain. The aim of this study was to analyse their differentiation status by detecting the expression of several stem cell markers in PSH. Methods and results: The expression of stem cell markers was examined by using streptavidin peroxidase (SP) immunohistochemisty in 45 PSH specimens. Also, the two types of cells were, respectively, captured by laser capture microdissection (LCM) from 28 PSH specimens, and total RNA was then extracted followed by reverse transcription-polymerase chain reaction (RT-PCR). The results demonstrated that the expression rates of ABCG2, Notch1 and Notch3 in polygonal cells were significantly higher than those in cuboidal cells ( P < 0.05), and the expression levels of ABCG2, Notch3 and Jagged1 in polygonal cells were clearly higher than those in cuboidal cells ( P < 0.05). Conclusion: The data obtained provided evidence that the two types of cells in PSH may be different in differentiation status. The differentiation difference between the two types of cells might lead to variation in their morphological phenotype. [ABSTRACT FROM AUTHOR]

Background: Information on the prevalence and resistance spectrum of nontuberculous mycobacteria (NTM) in China is mainly based on regional or local data. To estimate the proportion of NTM cases in China, a national survey of NTM pulmonary disease was carried out based on acid-fast positive sputum samples collected in 2013. Methods: Sputum samples collected from enrolled presumptive cases in 72 nationwide tuberculosis surveillance sites from the 31 provinces in the mainland of China were cultured using L-J medium at the National tuberculosis reference laboratory (NTRL). MALDI-TOF MS identified the species of re-cultured strains, and minimal inhibitory concentrations (MICs) were determined to evaluate the drug susceptibility of NTM isolates. Data analysis used statistical software SPSS version 22.0 for Windows statistical package. Results: Of 4917 mycobacterial isolates cultured, 6.4% [317/4917, 95% confidence interval (CI) 5.8%–7.2%] were confirmed as NTM, among which 7.7% (287/3709, 95% CI 6.9%–8.6%) were from the southern region. In inland and coastal China, 87.7% (95% CI 78.7%–93.2%) and 50.0% (95% CI 43.7%–56.3%) of isolates, respectively, were slow-growing mycobacteria (SGM), with the remaining rapid growing mycobacteria (RGM). A total of 29 species were detected, Mycobacterium abscessus had higher clarithromycin-inducible resistance rates than M. massiliense (65.67% vs 2.22%). M. kansasii presented lower resistance rates in linezolid and moxifloxacin than M. avium-intracellulare complex (3.23% vs 66.67%, 0 vs 47.22%) and other SGM (3.23% vs 38%, 0 vs 26%). Conclusions: More NTM pulmonary disease was observed in the south and coastal China (P < 0.01). SGM was widely distributed, and more RGM are present in southern and coastal China (P < 0.01). The antimicrobial resistance spectrum of different NTM species was significantly different and accurate species identification would be facilitated to NTM pulmonary disease treatment. [ABSTRACT FROM AUTHOR]

Background: Current evidences show that regional anesthesia is associated with decreased risk of complications after major surgery. However, the effects of combined regional-general anesthesia remain controversial. The purpose of our study was to analyze the impact of anesthesia (combined epidural-general anesthesia vs. general anesthesia) on the risk of postoperative complications in patients undergoing open surgery for pheochromocytoma. Methods: This was a retrospective cohort study. 146 patients who underwent open surgery for pheochromocytoma (100 received combined epidural-general anesthesia and 46 received general anesthesia) in Peking University First Hospital from January 1, 2002 to December 31, 2015 were enrolled. The primary outcome was the occurrence of postoperative complications during hospital stay after surgery. Multivariate Logistic regression models were used to analyze the association between the choice of anesthetic method and the risk of postoperative complications. Results: 17 (11.6%) patients developed complications during postoperative hospital stay. The incidence of postoperative complications was lower in patients with combined epidural-general anesthesia than in those with general anesthesia (6% [6/100] vs. 23.9% [11/46], P = 0.006). Multivariate Logistic regression analysis showed that use of combined epidural-general anesthesia (OR 0.219, 95% CI 0.065–0.741; P = 0.015) was associated with lower risk, whereas male gender (OR 5.213, 95% CI 1.283–21.177; P = 0.021) and perioperative blood transfusion (OR 25.879; 95% CI 3.130–213.961; P = 0.003) were associated with higher risk of postoperative complications. Conclusions: For patients undergoing open surgery for pheochromocytoma, use of combined epidural-general anesthesia may decrease the occurrence of postoperative complications. [ABSTRACT FROM AUTHOR]

Background: Migraine is now ranked as the second most disabling disorder worldwide reported by the Global Burden of Disease Study 2016. As a noninvasive neurostimulation technique, transcutaneous electrical nerve stimulation(TENS) has been applied as an abortive and prophylactic treatment for migraine recently. We conduct this meta-analysis to analyze the effectiveness and safety of TENS on migraineurs.Methods: We searched Medline (via PubMed), Embase, the Cochrane Library and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials, which compared the effect of TENS with sham TENS on migraineurs. Data were extracted and methodological quality assessed independently by two reviewers. Change in the number of monthly headache days, responder rate, painkiller intake, adverse events and satisfaction were extracted as outcome.Results: Four studies were included in the quantitative analysis with 161 migraine patients in real TENS group and 115 in sham TENS group. We found significant reduction of monthly headache days (SMD: -0.48; 95% CI: -0.73 to − 0.23; P < 0.001) and painkiller intake (SMD: -0.78; 95% CI: -1.14 to − 0.42; P < 0.001). Responder rate (RR: 4.05; 95% CI: 2.06 to 7.97; P < 0.001) and satisfaction (RR: 1.85; 95% CI: 1.31 to 2,61; P < 0.001) were significantly increased compared with sham TENS.Conclusion: This meta-analysis suggests that TENS may serve as an effective and well-tolerated alternative for migraineurs. However, low quality of evidence prevents us from reaching definitive conclusions. Future well-designed RCTs are necessary to confirm and update the findings of this analysis.Systematic review registration: Our PROSPERO protocol registration number: CRD42018085984. Registered 30 January 2018. [ABSTRACT FROM AUTHOR]

The herbal pair Zhimu-Baihe (Zhimu: Anemarrhena asphodeloides ; Baihe: Lilium brownii var. viridulum ) is a traditional Chinese medicament used for the treatment of depression. However, the relevant mechanisms of action has not been clarified. This study investigated the anti-depressant activity of the total saponins from Zhimu and Baihe and the mechanisms underlying using a chronic unpredictable mild stress (CUMS)-induced rat model of depression. High performance liquid chromatography with electrochemical detection (HPLC-ECD) was applied to determine the levels of three monoamine neurotransmitters, 5-hydroxytryptamine (5-HT), noradrenaline (NE) and dopamine (DA), in the rat hippocampus. Optimized pretreatment of samples and mass spectrometry conditions were used to analyse the metabonomic profile of the hippocampus. The 5-HT and NE levels in the CUMS group were reduced compared with the control group, whereas all groups had similar DA levels. The metabonomic profile of the hippocampus revealed 32 differential metabolites between the CUMS and control group, among which 18 metabolites were significantly recovered in the Anemarrhena saponins and Lilium saponins (AL) combination intervention group. These results suggested an anti-depressant effect of AL. Moreover, 24 metabolites in AL group were better recovered compared with the Anemarrhena saponins (AS) or Lilium saponins (LS) intervention groups, suggesting a synergetic effect of AS and LS in the treatment of depression. The anti-depressant effect might be related to the regulation of several metabolic pathways, including monoamine neurotransmitter synthesis (especially 5-HT and NE), and amino acid, fatty acid, and phospholipid metabolism in rats. [ABSTRACT FROM AUTHOR]

Inhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists (LABA) is the most important treatment for allergic asthma, although the mechanism still remains unclear. However, mast cells play a central role in the pathogenesis of asthma. In this study, we explored the sole or synergetic effects of des-ciclesonide (ICS) and formoterol (LABA) on the cytokines IL-4 and IL-13 and on histamine release from mast cells (RBL-2H3 cells). We found that des-ciclesonide (0.1, 1 and 10 nM) and formoterol (0.1, 1 and 10 μM) alone attenuated DNP–BSA-induced IL-4 and IL-13 production, respectively, in a concentration-dependent manner in DNP-IgE-sensitized mast cells. Des-ciclesonide (0.2 nM) and formoterol (1 μM) alone also reduced histamine production. However, the combination of des-ciclesonide (0.2 nM) and formoterol (1 μM) had a synergistic inhibition effect on IL-4 mRNA expression and protein production but not IL-13 and histamine release. The JNK inhibitor SP600125 (10 μM) inhibited antigen-induced mRNA expression and protein production of IL-4. Des-ciclesonide and formoterol alone inhibited the activation of JNK in a concentration-dependent manner, and the combination of des-ciclesonide (0.2 nM) and formoterol (1 μM) exhibited greater inhibition effect compared with des-ciclesonide (0.2 nM) or formoterol (1 μM) alone. Taken together, these synergistic effects on mast cells might provide the rationale for the development of the most recent ICS/LABA combination approved for asthma therapy. [ABSTRACT FROM AUTHOR]

Abstract: Glycopyrronium bromide (GB) is a muscarinic receptor antagonist that has been used as a long-acting bronchodilator in chronic obstructive pulmonary disease (COPD) patients. The aim of this study was to investigate the anti-inflammatory activity of inhaled GB in a cigarette smoke-induced acute lung inflammation mouse model. We found that aerosol pre-treatment with GB suppresses the accumulation of neutrophils and macrophages in the bronchoalveolar lavage fluid (BALF) in cigarette smoke (CS)-exposed mice. GB at doses of 300 and 600μg/ml significantly inhibited the CS-induced increases in the mRNA and protein expression levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1 and transforming growth factor (TGF)-β1 in lung tissues and the BALF. Moreover, GB at a dose of 600μg/ml significantly inhibited the CS-induced changes in glutathione (GSH) and myeloperoxidase (MPO) activities in the BALF, decreased the CS-induced expression of matrix metalloproteinases (MMP)-9, and increased the CS-induced expression of tissue inhibitor of metalloproteinases (TIMP)-1, as determined through the immunohistochemical staining of lung tissue. Our results demonstrate the beneficial effects of inhaled GB on the inflammatory reaction in COPD. [Copyright &y& Elsevier]

Cigarette smoking is associated with an increased incidence of chronic obstructive pulmonary disease (COPD). In this study, we hypothesized that liquiritin apioside (LA), a main flavonoid component from Glycyrrhiza uralensis, had antioxidant properties by inducing glutathione (GSH) biosynthesis via the inhibition of cytokines and protected lung epithelial cells against cigarette smoke-mediated oxidative stress. A549 cells were treated with cigarette smoke extract (CSE) and/or LA. ICR mice were exposed to cigarette smoke (CS) for four days with increasing exposure time for up to 6 h per day to elicit epithelial cells injury. One hour before smoke exposure, mice were treated with LA by gavage; 18 h after the last CS exposure all examinations were performed. Treatment with LA concentration-dependently prevented CSE-induced cytotoxicity, increase of TGF-β and TNF-α mRNA expression, depletion of GSH and apoptosis in A549 cells. LA at doses 3, 10 and 30 mg/kg dose-dependently inhibited pulmonary neutrophil and macrophage inflammation. Lung sections of the CS-exposed LA treated mice showed an apparently reduced pulmonary inflammation and a significant inhibitory effect on mucus containing goblet cells in the large airways. Furthermore, the CS-induced pulmonary release of TGF-β, TNF-α and myeloperoxidase activity was reduced, and superoxide dismutase activity was enhanced.These results indicate that protective roles of LA on CS-induced the lung epithelial cell injury are mediated by inhibiting TGF-β and TNF-α expression and increasing anti-oxidative levels of GSH, suggesting that LA might be effective as protective agent against epithelial injury in COPD. [ABSTRACT FROM AUTHOR]

Abstract: The HIV-1 Tat protein is released by infected cells and has numerous biological activities which might contribute either to the impairment of the immune response or to viral dissemination and pathogenesis. To date, the effects of Tat protein on metabolites remain unclear. In this study, a metabolomic study on serum of HIV-1 Tat-induced ICR mice was performed to research the pathologic mechanism of Tat protein by using gas chromatography coupled to mass spectrometry (GC/MS). Clear separations among the HIV-1 Tat-induced mice and the inaTat-induced or control mice were observed by principal component analysis and partial least-squares discriminant analysis based on the GC/MS spectral data. Additionally, 16 significantly changed metabolites in HIV-1 Tat-induced mice were identified that are involved in multiple perturbed metabolic pathways, which contributed to the elucidation of the complex pathogenic mechanism of Tat protein and may shed new lights on future improvement of HIV-1 therapy. [Copyright &y& Elsevier]

Abstract: Aims: Cinnarizine, a piperazine derivative, is currently used for the treatment of cerebral thrombosis, cerebral arteriosclerosis, subarachnoid hemorrhage and some other diseases. However, it exhibits variable dissolution and low bioavailability after oral administration. Cinnarizine for injection was developed in order to enhance its bioavailability and make the practice more convenient for patients suffering from dysphagia. The aim of the present study was to compare the pharmacokinetics and toxicokinetics of cinnarizine following intravenous and oral administration in dogs and provide scientific basis for the development of cinnarizine for injection. Methods: Beagle dogs were given single- or multiple-dose of cinnarizine by oral (single-dose: 10mg/kg; multiple-dose: 21.5, 12.9, 4.3mg/kg) and intravenous (single-dose: 10mg/kg; multiple-dose: 10, 6, 2mg/kg) routes. HPLC was applied to detect the plasma concentration of cinnarizine. The pharmacokinetics and toxicokinetics parameters were calculated and compared. Results: The pharmacokinetics of cinnarizine following oral administration in dogs was found to fit the one-compartment mode. That of cinnarizine following intravenous injection in dogs was found to fit the two-compartment model. The relative bioavailability of oral administration was 46.4%. Cinnarizine cumulated significantly in dogs when 10mg/kg cinnarizine was injected repeatedly. Multiple-dose of cinnarizine over 6mg/kg induced reversible kidney injury in dogs. Conclusion: The present study indicates that pharmacokinetics and toxicokinetics properties of cinnarizine for injection show advantages over the oral preparation. But caution should be taken with the cumulative action when cinnarizine is injected and the dose of cinnarizine should be lower than 6mg/kg. [Copyright &y& Elsevier]

Abstract: Clinically sublingual immunotherapy (SLIT) by using allergen extracts effectively alleviates the symptoms of allergic rhinitis and asthma. Supposed that oral administration of high-dose of allergen extracts imitates SLIT and may prevent IgE-related responses in allergic diseases, we investigated the effects of oral administration of allergen extracts from Dermatophagoides farinae (Derf) on allergen-induced inflammation and airway hyperresponsiveness (AHR) in a model of asthmatic rat. After administration to the specific Derf-sensitized rats with Derfdrop solution containing Derf1 and Derf2 extracts derived from Derf, the effects of Derfdrop on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, as well as serum IgE and IgG levels were investigated. Results indicated that Derfdrop not only dose-dependently prevented the AHR in response to methacholine, but also significantly reduced the serum total and allergen-specific IgE levels, all the maximal effects were achieved at dose of 5 mg/kg/d, and were as comparable as those of dexamethasone at dose of 1.0 mg/kg/d. Furthermore, oral administration of Derfdrop not only dose-dependently elevated allergen-specific serum IgG levels and reduced total and allergen-specific IgE levels, but also normalized the imbalance between the Th1 cytokine, IFN-γ and Th2 cytokine, IL-4. Finally, oral administration of Derfdrop significantly reduced Goblet cell hyperplasia and eosinophilia in the Derf-sensitized allergic rat model. These data suggest that Derfdrop effectively improves specific allergen-induced inflammation and AHR in Derf-sensitized and -challenged rats and provide with the rationale for clinical SLIT by using Derfdrop in a specific allergen-induced asthma. [Copyright &y& Elsevier]