Synthesis,acute toxicity and anti-inflammatory effect of bornyl salicylate,a salicylic acid derivative

Bornyl salicylate (BS) is a salicylic derivative, obtained by sterification of salicylic acid and monoterpene (-)-borneol, and its topical use in inflammatory diseases was described in the early 20th century. It is also known that borneol presents neuroprotective, genoprotective and analgesic properties. The purpose of this study was to evaluate BS in experimental models of acute inflammation. The toxicity of BS was analyzed by measuring water and food intake, weight, mortality and weight of main organs. To assess its anti-inflammatory effect, BS-treated mice were challenged with carrageenan, prostaglandin E2 (PGE2), bradikynin (BK) or histamine (HIS)-induced paw edema, zymosan-induced peritonitis and vascular permeability induced by acetic acid. Nitric oxide (NO) production was analyzed in peritoneal macrophage cultures. There was no sign of acute toxicity of BS in male and female mice. Furthermore, treatment with BS was significantly (p < 0.05) effective in reducing paw edema induced by carrageenan in early and late phases; this effect was related to PGE2 and BK, but HIS independent. Neutrophil migration and cytokine release (TNF-α, IL-1β and IL-6) induced by zymosan and fluid leakage induced by acetic acid were also reduced in BS-treated animals. In vitro, BS (10 µg/mL) reduced NO production in LPS-stimulated macrophages. These data suggest that BS has an anti-inflammatory effect, which is related, at least in part, with decrease of mediators as PGE2, NO and pro-inflammatory cytokines. However, further studies should be done to explore its potential as an anti-inflammatory drug.     

干细胞旁分泌效应在ALI/ARDS治疗中的研究进展

急性肺损伤(acute lung injury,ALI)以及它的严重形式——急性呼吸窘迫综合征(acute respiratorydistress syndrome,ARDS)是危重病人发病和死亡的重要原因之一,最近2个世纪以来,死亡率仍在36%～44%左右。ALI/ARDS的病因众多,发病机制十分复杂,涉及的环节多,受损的靶细胞多,主要涉及的环节有:炎症反应失控、细胞损伤与修复、细胞凋     

Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress

Introduction

Acute lung injury (ALI) is an acute inflammatory disease characterized by excess production of inflammatory factors in lung tissue. Quercetin, a herbal flavonoid, exhibits anti-inflammatory and anti-oxidative properties. This study was performed to assess the effects of quercetin on lipopolysaccharide (LPS)-induced ALI.

Material and methods

Sprague-Dawley rats were randomly divided into 3 groups: the control group (saline alone), the LPS group challenged with LPS (Escherichia coli 026:B6; 100 µg/kg), and the quercetin group pretreated with quercetin (50 mg/kg, by gavage) 1 h before LPS challenge. Bronchoalveolar lavage fluid (BALF) samples and lung tissues were collected 6 h after LPS administration. Histopathological and biochemical parameters were measured.

Results

The LPS treatment led to increased alveolar wall thickening and cellular infiltration in the lung, which was markedly prevented by quercetin pretreatment. Moreover, quercetin significantly (p < 0.05) attenuated the increase in the BALF protein level and neutrophil count and lung wet/dry weight ratio and myeloperoxidase activity in LPS-challenged rats. The LPS exposure evoked a 4- to 5-fold rise in BALF levels of tumor necrosis factor-α and interleukin-6, which was significantly (p < 0.05) counteracted by quercetin pretreatment. Additionally, quercetin significantly (p < 0.05) suppressed the malondialdehyde level and increased the activities of superoxide dismutase, catalase, and glutathione peroxidase in the lung of LPS-treated rats.

Conclusions

Quercetin pretreatment effectively ameliorates LPS-induced ALI, largely through suppression of inflammation and oxidative stress, and may thus have therapeutic potential in the prevention of this disease.     

A study on the role of noninvasive ventilation in mild-to-moderate acute respiratory distress syndrome

Aim:There is sparse data on the role of noninvasive ventilation (NIV) in acute respiratory distress syndrome (ARDS) from India. Herein, we report our experience with the use of NIV in mild to moderate ARDS.Results:A total of 41 subjects (27 women, mean age: 30.9 years) were included in the study. Tropical infections followed by abdominal sepsis were the most common causes of ARDS. The use of NIV was successful in 18 (44%) subjects, while 23 subjects required intubation. The median time to intubation was 3 h. Overall, 19 (46.3%) deaths were encountered, all in those requiring invasive ventilation. The mean duration of ventilation was significantly higher in the intubated patients (7.1 vs. 2.6 days, P = 0.004). Univariate analysis revealed a lack of improvement in PaO₂/FiO₂ at 1 h and high baseline Acute Physiology and Chronic Health Evaluation II (APACHE II) as predictors of NIV failure.Conclusions:Use of NIV in mild to moderate ARDS helped in avoiding intubation in about 44% of the subjects. A baseline APACHE II score of >17 and a PaO₂/FiO₂ ratio <150 at 1 h predicts NIV failure.     

Incidence and outcome of acute lung injury and acute respiratory distress syndrome in the surgical intensive care unit

Introduction:

To determine the incidence and mortality of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in a cohort of patients with risk factors admitted to the Surgical Intensive Care Unit (SICU).

Materials and Methods:

A prospective observational inception cohort study with no intervention was conducted over 12 months. All patients with at least one known risk factor for ALI/ARDS admitted to the SICU were included in the study. The APACHE II severity of disease classification system scoring was performed within 1 h of admission. The ventilatory parameters and chest radiographs were recorded every 24 h. The P/F ratio, PEEP and Lung Injury Score were calculated each day until the day of discharge from the Intensive Care Unit or for the first 7 days of admission, whichever was shorter.

Results:

The incidence of ARDS among those who were mechanically ventilated was 11.4%. Sepsis was the most common (34.6%) etiology. Among those with risk factors, the incidence of ARDS was 30% and that of ALI was 32.7%. The mortality in those with ARDS was 41.8%. Those who develop ARDS had higher APACHE II scores, lower pH and higher PaCO₂ at admission compared with those who developed ALI or no lung injury.

Conclusion:

The incidence and mortality of ARDS was similar to other studies. Identifying those with risk factors for ARDS or mortality will enable appropriate interventional measures.     

Protective effect of sesamin in lipopolysaccharide-induced mouse model of acute kidney injury via attenuation of oxidative stress,inflammation, and apoptosis

Abstract

Context: Acute kidney injury (AKI) is considered a major public health concern in today’s world. Sepsis‐induced AKI is large as a result of exposure to lipopolysaccharide (LPS) that is the major outer membrane component of Gram‐negative bacteria. Sesamin is the main lignan of sesame seeds with multiple protective effects.

Objective: In this research, we tried to demonstrate the protective effect of sesamin pretreatment in LPS-induced mouse model of AKI.

Methods: LPS was injected at a single dose of 10?mg/kg (i.p.) and sesamin was given p.o. at doses of 25, 50, or 100?mg/kg, one hour prior to LPS.

Results: Treatment of LPS-challenged mice with sesamin reduced serum level of creatinine and blood urea nitrogen (BUN) and returned back renal oxidative stress-related parameters including glutathione (GSH), malondialdehyde (MDA), and activity of catalase and superoxide dismutase (SOD). Moreover, sesamin alleviated inappropriate changes of renal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-6, DNA fragmentation (an apoptotic index), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, sesamin diminished magnitude of kidney tissue damage due to LPS.

Conclusion: In summary, sesamin could dose-dependently abrogate LPS-induced AKI via attenuation of renal oxidative stress, inflammation, and apoptosis.     

前列腺素E1对脂多糖诱导的大鼠急性肺损伤的拮抗作用

目的: 建立急性肺损伤（ALI）大鼠模型，初步探讨lipo-PGE1对ALI的拮抗作用机制。方法: 将雄性SD健康大鼠45只随机分成3组，A：对照组；B：LPS模型组；C：lipo-PGE1＋LPS治疗组，各组分1、2和4 h 3个时点各5只观察肺组织变化，计数肺泡灌洗液（BALF）细胞数和分类，ELISA法测血清细胞因子IL-1β、TNF-α、IL-12、IL-10的浓度。结果: 模型组肺组织肉眼观体积增大，肺表面色泽暗红，可见包膜下点状、片状出血,充血、水肿明显，BALF中白细胞总数及中性粒细胞百分比及血清中IL-1β、TNF-α和IL-10浓度明显高于正常对照组；治疗组临床表现及肉眼观肺组织充血出血情况明显轻于模型组，BALF白细胞总数及中性粒细胞百分比和血清IL-1β、TNF-α浓度显著低于模型组，IL-10浓度明显高于模型组。结论: 前列腺素E1可以通过降低肺血管的通透性，减少中性粒细胞渗出，同时下调炎症因子的表达来拮抗LPS诱导的急性肺损伤。     

Anti-inflammatory,analgesic, antipyretic and related properties of meloxicam,a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance

The anti-inflammatory, analgesic and antipyretic properties of the new non-steroidal anti-inflammatory agent, meloxicam, were investigated in a variety of animal models and compared with the properties of piroxicam, diclofenac, indomethacin and several other NSAIDs.With respect to the total effect of a single oral dose, the anti-exudative effect of meloxicam on carrageenaninduced oedema in the rat exceeded that of all the NSAIDs included in the comparison. Additionally, meloxicam showed the greatest potency of all the compounds examined with respect to adjuvant-induced arthritis in the rat, the granuloma pouch model and the cotton pellet test in the rat. Unlike indomethacin, in the carrageenan pleurisy model in the rat, meloxicam caused both a dose-dependent reduction in exudate volume and also inhibition of leucocyte migration.Meloxicam showed a strong and lasting effect on inflammatory pain in the rat. Like other NSAIDs, but unlike dipyrone, meloxicam had no effect in the hot plate and tail clamp tests, which are used to identify weak central analgesic effects. Unlike dipyrone and like indomethacin, meloxicam had no effect in a model of visceral distention pain.In common with other NSAIDs, meloxicam had no influence on the body temperature of normothermic rats in the anti-inflammatory dose range, but did reduce yeastinduced fever in the rat in a dose-dependent manner. Like piroxicam, meloxicam had a uricosuric effect on rats treated with oxonic acid.Low-dose meloxicam inhibited both bradykinin-induced and PAF-induced bronchospasm in the guinea-pig, but had no effect on acetylcholine-induced bronchospasm.Piroxicam had greater ulcerogenic effects in the rat stomach than meloxicam.The therapeutic range of meloxicam in the rat, with regard to inhibition of adjuvant arthritis, was several times greater than that of piroxicam, indomethacin, diclofenac and naproxen.     

部分液体通气治疗家猪急性肺损伤的抗炎效应

目的：探讨部分液体通气治疗肺灌洗诱导的 急性肺损伤家猪模型时，是否具有抗炎作用。方法：16只健康家猪，采 用生理盐水肺内灌洗复制急性肺损伤模型，随机分为部分液体通气组及机械通气组给予不同 治疗，观察其肺脏湿/干比值及肺通透指数，观察其血浆、支气管肺泡灌洗液及肺组织匀浆 中TNF-α、MDA含量及SOD、MPO活性。结果：（1）部分液体通气组家猪 肺脏湿/干比值、肺通透指数及支气管肺泡灌洗液中白细胞计数明显低于机械通气组。（2） 肺组织MDA、MPO含量部分液体通气组明显低于机械通气组，但两组间SOD活性无明显差别。 （3）部分液体通气组支气管肺泡灌洗液及肺组织匀浆中TNF-α含量明显低于机械通气组。 结论：部分液体通气改善动物肺损伤指标，提示以氟碳化合物为呼吸媒 介的部分液体通气对肺灌洗诱导的急性肺损伤家猪具有抗炎效应。     

Protective effect of xanthohumol on toxin-induced liver inflammation and fibrosis

Xanthohumol, the major prenylated chalcone found in hops, is known for its anti-inflammatory properties. We have recently shown that xanthohumol inhibits hepatic inflammation and fibrosis in a murine model of nonalcoholic steatohepatitis. The aim of this study was to investigate the effect of xanthohumol in an acute model of liver injury. Carbon tetrachloride (CCl(4)), an industrial solvent, is a hepatotoxic agent and its administration is widely used as an animal model of toxin-induced liver injury. Xanthohumol was applied orally at a dose of 1 mg/g body weight 2 days prior as well as during and after exposure to CCl(4). 72 h after a single CCl(4) application histomorphology and serum levels of transaminases revealed considerable hepatocellular necrosis, which was accompanied by significantly enhanced hepatic expression of pro-inflammatory cytokines. Furthermore, elevated hepatic alpha-smooth muscle actin expression indicated activation of hepatic stellate cells, and in accordance, we detected enhanced hepatic expression levels of TGF-β and collagen type I reflecting a marked fibrogenic response to CCl(4) exposure. While the degree of hepatocellular damage in response to CCl(4) was similar in mice which received xanthohumol and the control group, pro-inflammatory and profibrogenic hepatic gene expression were almost completely blunted in xanthohumol fed mice. Furthermore, xanthohumol fed mice revealed decreased hepatic NFκB activity. These results suggest that the protective effects of xanthohumol in this toxic liver injury model involves direct mechanisms related to its ability to block both hepatic inflammation and the activation of hepatic stellate cells, presumable at least in part via decreasing NFκB activity. Thus, this study further indicates the potential of xanthohumol application to prevent or ameliorate the development and progression of liver fibrosis in response to hepatic injury.     

慢性酗酒与急性肺损伤/急性呼吸窘迫综合征

急性肺损伤/急性呼吸窘迫综合征(acute lung injury/accute respiratory distress syndrome,ALI/ARDS)是在非心源性疾病过程中.     

Antiinflammatory effects of adalimumab,tocilizumab, and steroid on lipopolysaccharide-induced lung injury

Background/aimAcute lung injury (ALI) is a major cause of death in the intensive care unit. Lipopolysaccharide (LPS) induced lung injury is the most widely used experimental ALI model and provides opportunities for new targeting therapy. In this study, we investigated the effects of tocilizumab, adalimumab, and methylprednisolone in LPS-induced acute lung injury.Materials and methodsLung injury was established by intratracheal instillation of LPS. The rats were randomly divided into six groups: LPS, control, and treatment groups (adalimumab, tocilizumab, methylprednisolone, adalimumab + tocilizumab). Bronchoalveolar lavage (BAL) and lung tissues were collected at 48 h and 96 h following LPS administration from each group. For histological analysis, hematoxylin–eosin (H&E) staining was performed. The sections were obtained for immunohistochemical analysis. IL-6 and TNF-alpha immunoreactivity were measured. ResultsIntratracheal LPS application resulted in inflammatory cell infiltration of interstitial and alveolar spaces and thickening of the alveolar wall. All treatment groups showed significantly amelioration compared to LPS at 48 h. Interestingly, adalimumab and adalimumab + tocilizumab groups showed a significant amelioration of the lung histoarchitecture, compared to the prednisolone group at 96 h (p = 0.028, p = 0.025, respectively). Compared to the control group, LPS stimulation resulted in a significant increase in IL-6 and TNF-alpha immunoreactivity (p < 0.001). IL-6 and TNF-alpha expression were markedly reduced in all treatment groups at 48 h but the reduction was greater in the adalimumab and tocilizumab group than in the steroid. Administration with adalimumab and/or tocilizumab effectively decreased expression of TNF-alpha (p = 0.001) and IL-6 (p < 0.001) at 96 h, but prednisolone did not exert an effective decrease (p > 0.05). ConclusionAdalimumab and/or tocilizumab significantly reduce the release of proinflammatory cytokines and improve the tissue inflammation in the experimental model of ALI. Our results suggest that adalimumab and/or tocilizumab have a more potent antiinflammatory effect on lung injury than the steroid.     

Preparation,characterization, and anti-inflammatory effect of the chelate of Flammulina velutipes polysaccharide with Zn

The optimal conditions for preparing Zn-Flammulina velutipes polysaccharide (Zn-FVP) chelate were studied by using L₉ (3⁴) orthogonal test. The results showed that the optimized conditions for the chelating reaction were as follows: initial concentration of Zn (II), 6?mg/mL; ratio of purified polysaccharide (FVPp) to Zn (II), 1:2; chelating time, 8?h; and pH, 5. Chelating rate achieved 98.11% under the optimal conditions. Characteristic bands for OH stretching at 3000–3500?cm^?1 and bands corresponding to C-H variable angle vibration between 1000–1100?cm^?1 showed some obvious differences for chelation of polysaccharides and zinc. The qualitative spectrum of Zn-FVP indicated the presence of ZnSO₄ and the abundant Zn (II) groups were widely present in the chelated samples. The anti-inflammatory effect of FVPp and Zn-FVP on Lipopolysaccharide-stimulated RAW 264.7 cells was evaluated. In the range of 5–50?μg/mL, Zn-FVP did not exhibit obvious inhibition of the survival rate of cells. Zn-FVP in noncytotoxic levels showed strong suppressive effect on the inflammatory cytokines (IL-6, TNF-α, INF-γ and NO) and these provided a theoretical base for the anti-inflammatory mechanism of Zn-FVP.     

大黄对内毒素诱导急性肺损伤大鼠的保护作用

探讨脂多糖（LPS）致急性肺损伤（ALI）的作用机制及大黄的保护作用。用Wistar大鼠复制LL的的动物模型,观察组织病理学变化,测定ALI生物学指标及NO和iNOs。结果显示：LPS组肺间质水肿,肺泡腔内可见大量细胞润滑和血浆蛋白渗出;肺管内皮细胞损伤。肺湿干重比,肺泡灌洗液中中性粒细胞比例,蛋白含量及肺泡通透指数,肺毛细管通透性均显著升高,NO和iNOs也显著升高。地塞米松和大黄组,上述指标均较LPS组显著。LPS致LI的机制主要是直接损伤肺泡上和血管内皮细胞,大黄及地塞米松对血管内皮和肺泡上皮具有保护作用,其机制可能是通过抑制NO和iNOs活性实现。     

Ultrastructural changes in the pulmonary mechanical barriers in a rat model of severe acute pancreatitis-associated acute lung injury

This study examined the ultrastructural changes in the pulmonary mechanical barriers in a rat model of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). Animals were randomized into the SAP group (n = 60) and the control group (n = 60). SAP was induced by retrograde injection of 5% taurocholic acid into the biliopancreatic duct. The morphological abnormalities assessed by histology and the lung wet/dry weight ratio and the ultrastructural abnormalities assessed by transmission electron microscope and scanning electron microscope examinations plus lanthanum nitrate tracing were compared between the two groups at 6, 12, and 24 h post-SAP induction (n = 10/group/time point). The SAP group had significantly greater extravascular effusion than the control group at each time point as assessed by the lung wet/dry weight ratio (p < .001). The severity of the tissue damage increased in the lung and pancreas over time in the SAP group (all p < .001). In the SAP group, ultrastructural damages to the endothelial, epithelial, and pleural barriers were apparent and the damages to the endothelial barrier were detected earlier than the other two barriers, suggesting its fundamental role in preventing the further development of SAP-associated ALI. Moreover, the ultrastructural abnormalities were detected earlier than symptoms and morphological changes. The ultrastructural damages in the endothelial, epithelial, and pleural barriers occurred in the early stage of SAP. The endothelial barrier is likely to be the first line to prevent the further development in this rat model of SAP-associated ALI.     

Modified Xiaoqinglong decoction alleviates lipopolysaccharide-induced acute lung injury in mice by regulating arachidonic acid metabolism and exerting anti-apoptotic and anti-inflammatory effects

Effective therapeutics are not available for acute lung injury (ALI) and acute respiratory distress syndrome. Modified Xiaoqinglong decoction (M-XQL) is reported to effectively treat pneumonia, but the underlying mechanisms are unclear. In this study, the therapeutic effect and mechanism of M-XQL were examined using a lipopolysaccharide (LPS)-induced ALI mouse model. The effects of M-XQL on lung injury, inflammatory responses, and cell apoptosis were analyzed. Additionally, high-throughput sequencing was performed to evaluate the therapeutic mechanism of M-XQL. Pretreatment with M-XQL significantly and dose-dependently mitigated the pathological changes and upregulation of pulmonary, nitric oxide content and cell apoptosis and serum tumor necrosis factor-alpha contents in the LPS-induced ALI mouse model. RNA sequencing analysis revealed that the expression of several arachidonic acid metabolism-associated genes in the LPS + high-dose M-XQL group differed from that in the LPS group. In particular, the Cbr2, Cyp4f18, and Cyp2e1 levels were upregulated, whereas the Alox12, Ptges, and Ptges2 levels were downregulated in the LPS + high-dose M-XQL group. These results suggest that M-XQL exerts therapeutic effects in ALI mice by regulating arachidonic acid metabolism and exerting anti-apoptotic and anti-inflammatory effects. Thus, M-XQL is a potential agent for the clinical treatment of ALI.     

Acute respiratory distress syndrome: Pulmonary and extrapulmonary not so similar

Acute respiratory distress syndrome (ARDS) is characterized by acute onset respiratory failure with bilateral pulmonary infiltrates and hypoxemia. Current evidence suggests different respiratory mechanics in pulmonary ARDS (ARDSp) and extrapulmonary ARDS (ARDSexp) with disproportionate decrease in lung compliance in the former and chest wall compliance in the latter. Herein, we report two patients of ARDS, one each with ARDSp and ARDSexp that were managed using real-time esophageal pressure monitoring using the AVEA ventilator to tailor the ventilatory strategy.