Malignant transformation rate of oral leukoplakia in the past 20 years: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis aimed to assess the rate of malignant transformation (MT) of oral leukoplakia (OL) and to study potential risk factors for the MT of OL into oral squamous cell carcinoma (OSCC). METHOD: We performed a bibliographic search on nine electronic databases, including PubMed, MEDLINE, and Wanfang Data, for data on the MT rate of OL. Possible risk factors were calculated using Comprehensive Meta-Analysis and Open Meta [Analyst] software. RESULTS: The pooled proportion of OL MT for the total population described in the 26 selected studies was 7.20% (95% confidence interval: 5.40-9.10%). Nonhomogeneous type lesions, higher grades of dysplasia, the location of the lesion (tongue and multifocal), and female sex had significant effects on the MT of OL. CONCLUSION: OL tended to develop into OSCC (7.2%), and those with significant MT risk factors should be subjected to regular follow-up and observation. However, we require large-scale prospective studies to validate these results, together with unified clinicopathological diagnostic criteria, standardized risk factor recording/assessment methods, and long-term follow-up guidelines.

The protective effects and mechanism of Ruyi Zhenbao Pill, a Tibetan medicinal compound, in a rat model of osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ruyi Zhenbao Pill (RZP) is a prescribed Tibetan formulation for the treatment of white-pulse-disease, yellow-water-disease as well as pain-related disease. RZP is composed of 30 medicinal materials including herbal medicine, animal medicine and mineral medicine. They are widely used in the Tibetan area to treat cerebrovascular disease, hemiplegia, rheumatism, and pain diseases for centuries. AIM OF THE STUDY: The aim of the present study was to evaluate the anti-osteoarthritis function of RZP and to clarify the underlying mechanisms. MATERIALS AND METHODS: The active components in RZP were identified using HPLC methods. Osteoarthritis (OA) animal model was established via intra-articular injection of papain in rat knees. After the administration of RZP (0.45, 0.9 g/kg) for 28 days, the clinical observation was conducted, and pathological changes as well as serum biochemical indexes were detected. Moreover, therapeutic targets and pathways of RZP were discussed. RESULTS: The results showed that RZP could suppress knee joint swelling and arthralgia, thus relieving joint pain and inflammation in OA rats. Microcomputed tomography (µCT)-based physiological imaging and staining pictures confirmed the therapeutic effects of RZP on OA symptoms including knee joint swelling and structural changes with progressive inflammation in OA rats. RZP could promote the synthesis or inhibit the degradation of COLⅡ, attenuate OA-induced OPN up-regulation and thus relieve the OA symptom. Furthermore, RZP (0.45-0.9 g/kg) could all ameliorate the imbalance of biomarkers related to OA such as MMP1, TNF-α, COX2, IL-1ß and iNOS in knee joints or serum. CONCLUSION: In conclusion, RZP could effectively relieve inflammatory reaction induced by OA injury and the formulation could be applied to the treatment of OA therapy.

Targeted Antagonism of Vascular Endothelial Growth Factor Reduces Mortality of Mice with Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is associated with a mortality of 45%. Our previous research indicated that anti-vascular endothelial growth factor (VEGF) could maintain the normal structure and function of the respiratory barrier. However, systemic application of VEGF antagonists would lead to animal death. This study attempts to study the targeted drug delivery for ARDS. In this study, we used soluble fms-like tyrosine kinase-1 (sFlt)-targeted ultrasound microbubbles to antagonize the effect of VEGF on lung tissue. Ninety male BALB/c mice were randomly assigned to 6 groups: phosphate buffer saline (PBS) group (PBS+PBS); blank group (PBS+empty microbubbles); lipopolysaccharide (LPS) group (LPS+PBS); ARDS group (LPS+empty microbubbles); control group (PBS+sFlt microbubbles); and treatment group (LPS+sFlt microbubbles). After administration of LPS or PBS in the corresponding groups, the sFlt-targeted microbubbles or empty microbubbles were injected into the blood circulation. Then the lungs were irradiated with ultrasound, which ruptured the drug-loaded microbubbles and helped release drugs to the lung tissues targeted. The lung injury score, lung wet/dry ratio (W/D), liver and kidney functions, and the mortality of the mice in all groups were investigated at the predetermined time point. The difference in mortality between groups was examined by Fisher test. Other data were analyzed by one-way analysis of variance (ANOVA). A value of P<0.05 indicates that the difference was significant. The results showed that the PaO2 levels were normal in the PBS group, the blank group, and the control group. The LPS group and ARDS group showed significant hypoxia. PaO2 was improved significantly in the treatment group. The lung injury score and W/D were normal in the PBS group, the blank group, and the control group. The lung injury score and W/D increased significantly in the LPS group and ARDS group and decreased in the treatment group (P<0.05). The mortality rate of the ARDS model was 60% (95% confidence interval 47.5%-72.5%), and that with sFlt-targeted microbubbles was significantly lower at only 40% (95% confidence interval 27.5%-52.5%, P<0.05). It was concluded that anti-VEGF with sFlt targeted ultrasound microbubbles attenuated the lung injury and ultimately reduced the 7-day mortality effectively. It might be a suitable therapeutic tool for the treatment of ARDS.

MARESIN 1 PREVENTS LIPOPOLYSACCHARIDE-INDUCED NEUTROPHIL SURVIVAL AND ACCELERATES RESOLUTION OF ACUTE LUNG INJURY.

Acute lung injury (ALI) is characterized by lung inflammation and diffuse infiltration of neutrophils. Neutrophil apoptosis is recognized as an important control point in the resolution of inflammation. Maresin 1 (MaR1) is a new docosahexaenoic acid-derived proresolving agent that promotes the resolution of inflammation. However, its function in neutrophil apoptosis is unknown. In this study, isolated human neutrophils were incubated with MaR1, the pan-caspase inhibitor z-VAD-fmk, and lipopolysaccharide (LPS) to determine the mechanism of neutrophil apoptosis. Acute lung injury was induced by intratracheal instillation of LPS. In addition, mice were treated with MaR1 intravenously at the peak of inflammation and administered z-VAD-fmk intraperitoneally. We found that culture of isolated human neutrophils with LPS dramatically delayed neutrophil apoptosis through the phosphorylation of AKT, ERK, and p38 to upregulate the expression of the antiapoptotic proteins Mcl-1 and Bcl-2, which was blocked by pretreatment with MaR1 in vitro. In mice, MaR1 accelerated the resolution of inflammation in LPS-induced ALI through attenuation of neutrophil accumulation, pathohistological changes, and pulmonary edema. Maresin 1 promoted resolution of inflammation by accelerating caspase-dependent neutrophil apoptosis. Moreover, MaR1 also reduced the LPS-induced production of proinflammatory cytokines and upregulated the production of the anti-inflammatory cytokine interleukin-10. In contrast, treatment with z-VAD-fmk inhibited the proapoptotic action of MaR1 and attenuated the protective effects of MaR1 in LPS-induced ALI. Taken together, MaR1 promotes the resolution of LPS-induced ALI by overcoming LPS-mediated suppression of neutrophil apoptosis.

Comparison of cardiac output and hemodynamic responses of intubation among different videolaryngoscopies in normotensive and hypertensive patients.

Tracheal intubation with Macintosh laryngoscope (MAC) might result in severe cardiovascular complications. The results of conducted studies investigating the effects of videolaryngoscopies on hemodynamic response of tracheal intubation are conflicting. We know little about the effects of videolaryngoscopies on cardiac output changes during tracheal intubation. We compared cardiac output (COP) and hemodynamic responses in normal blood pressure (n=60) and hypertensive patients (n=60) among 3 intubation devices: the MAC, the UE videolaryngoscopy ® (UE), and the UE video intubation stylet ® (VS). Cardiac index (CI), stroke volume index (SVI), heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded using LidcoRapid (V2)® preinduction, preintubation, and every minute for the first 5 min after intubation. We assessed oropharyngeal and laryngeal structures injury as well. Intubation time was significantly shorter than MAC groups (P<0.001) only in UE group of normotensive and hypertensive patients. In normotensive patients, there were no significant differences in any of COP variables or hemodynamic variables among the three devices. In hypertensive patients, SBP and DBP in the MAC group were significantly higher (P<0.05 or <0.01) than the UE and VS groups at 1, 2 and 3 min after intubation, but there were no significant differences in CI, SVI and HR among the three devices. There was no significant difference in oropharyngeal and laryngeal structures injury among all groups. It was concluded that both the UE and VS attenuate only the hemodynamic response to intubation as compared with the MAC in hypertensive patients, but not in normotensive patients.

Maresin 1 mitigates LPS-induced acute lung injury in mice.

BACKGROUND AND PURPOSE: Acute lung injury (ALI) is a severe illness with a high rate of mortality. Maresin 1 (MaR1) was recently reported to regulate inflammatory responses. We used a LPS-induced ALI model to determine whether MaR1 can mitigate lung injury. EXPERIMENTAL APPROACH: Male BALB/c mice were injected, intratracheally, with either LPS (3 mg·kg(-1) ) or normal saline (1.5 mL·kg(-1) ). After this, normal saline, a low dose of MaR1 (0.1 ng per mouse) or a high dose of MaR1 (1 ng per mouse) was given i.v. Lung injury was evaluated by detecting arterial blood gas, pathohistological examination, pulmonary oedema, inflammatory cell infiltration, inflammatory cytokines in the bronchoalveolar lavage fluid and neutrophil-platelet interactions. KEY RESULTS: The high dose of MaR1 significantly inhibited LPS-induced ALI by restoring oxygenation, attenuating pulmonary oedema and mitigating pathohistological changes. A combination of elisa and immunohistochemistry showed that high-dose MaR1 attenuated LPS-induced increases in pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), chemokines [keratinocyte chemokine, monocyte chemoattractant protein-5, macrophage inflammatory protein (MIP)-1α and MIP-1γ], pulmonary myeloperoxidase activity and neutrophil infiltration in the lung tissues. Consistent with these observations, flow cytometry and Western blotting indicated that MaR1 down-regulated LPS-induced neutrophil adhesions and suppressed the expression of intercellular adhesion molecule (ICAM)-1, P-selection and CD24. CONCLUSIONS AND IMPLICATIONS: High-dose MaR1 mitigated LPS-induced lung injury in mice by inhibiting neutrophil adhesions and decreasing the levels of pro-inflammatory cytokines.

BML-111 attenuates hemorrhagic shock-induced acute lung injury through inhibiting activation of mitogen-activated protein kinase pathway in rats.

BACKGROUND: Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. Mitogen-activated protein kinase (MAPK) acts as a sensor of tissue injury in models of ischemia-reperfusion injury. Lipoxins are endogenous lipid mediators with potent anti-inflammatory and pro-resolving actions. We hypothesized that BML-111 (a lipoxin A4-receptor agonist) attenuates hemorrhagic shock-induced acute lung injury (ALI) through inhibiting activation of the MAPK pathway. METHODS: We randomized Sprague-Dawley rats into four groups: sham, hemorrhagic shock-resuscitation (HS), HS plus BML-111 (BML-111), and HS plus BML-111 and BOC-2 (BOC-2). Two hours after resuscitation, we collected samples of lung. We obtained bronchoalveolar lavage fluid for neutrophil count. We performed optical microscopy to examine pathologic changes in lungs. Wet/dry ratios, myeloperoxidase expression, interleukin (IL)-1ß and IL-6 levels in lung were measured. We evaluated MAPK activation and the DNA binding activity of activator protein-1 in lung. RESULTS: Treatment with BML-111 reduced the lung damage and wet/dry ratio, neutrophil count in bronchoalveolar lavage fluid, expression of myeloperoxidase, and production of IL-1ß and IL-6 in lung. Phosphorylation of MAPK was also decreased by BML-111 in lung. Furthermore, the DNA binding activity of activator protein-1 was blocked by BML-111. An antagonist of the lipoxin A4-receptor, BOC-2, reversed the protective effect of BML-111 on ALI induced by hemorrhagic shock. CONCLUSIONS: This study indicates that BML-111 attenuated hemorrhagic shock-induced ALI via the MAPK/activator protein-1 signaling pathway. Therefore, BML-111 may have therapeutic potential for hemorrhagic shock-induced ALI.

Melatonin reduces acute lung injury in endotoxemic rats.

BACKGROUND: Treatment with melatonin significantly reduces lung injury induced by bleomycin, paraquat and ischemia reperfusion. In the present study, we investigated the possible protective roles of melatonin in pulmonary inflammation and lung injury during acute endotoxemia. METHODS: Thirty-two male Sprague-Dawley rats were randomly assigned to four groups: vehicle + saline group, melatonin + saline group, vehicle + lipopolysaccharide group, melatonin + lipopolysaccharide group. The rats were treated with melatonin (10 mg/kg, intraperitoneal injection (i.p.)) or vehicle (1% ethanol saline), 30 minutes prior to lipopolysaccharide administration (6 mg/kg, intravenous injection). Four hours after lipopolysaccharide injection, samples of pulmonary tissue were collected. Blood gas analysis was carried out. Optical microscopy was performed to examine pathological changes in lungs and lung injury score was assessed. Wet/dry ratios (W/D), myeloperoxidase activity, malondialdehyde concentrations and tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels in lungs were measured. The pulmonary expression of nuclear factor-kappa B (NF-kappaB) p65 was evaluated by Western blotting. RESULTS: PaO(2) in the vehicle + lipopolysaccharide group decreased compared with that in the vehicle + saline group. This decrease was significantly reduced in the melatonin + lipopolysaccharide group. The lung tissues from the saline + lipopolysaccharide group were significantly damaged, which were less pronounced in the melatonin + lipopolysaccharide group. The W/D ratio increased significantly in the vehicle + lipopolysaccharide group (6.1 +/- 0.18) as compared with that in the vehicle + saline group (3.61 +/- 0.3) (P < 0.01), which was significantly reduced in the melatonin + lipopolysaccharide group (4.8 +/- 0.25) (P < 0.01). Myeloperoxidase activity and malondialdehyde levels increased significantly in the vehicle + lipopolysaccharide group compared with that in the vehicle + saline group, which was reduced in the melatonin + lipopolysaccharide group. The TNF-alpha level of pulmonary tissue increased significantly in the vehicle + lipopolysaccharide group ((8.7 +/- 0.91) pg/mg protein) compared with that in the vehicle + saline group ((4.3 +/- 0.62) pg/mg protein, P < 0.01). However, the increase of TNF-alpha level of pulmonary tissue was significantly reduced in the melatonin + lipopolysaccharide group ((5.9 +/- 0.56) pg/mg protein, P < 0.01). Pulmonary IL-10 levels were elevated markedly in the vehicle + lipopolysaccharide group in contrast to that in the vehicle + saline group, whereas the elevation was augmented in the melatonin + lipopolysaccharide group. The nuclear localization of p65 increased markedly in the vehicle + lipopolysaccharide group and this enhancement of nuclear p65 expression was much less in the melatonin + lipopolysaccharide group. CONCLUSION: Melatonin reduces acute lung injury in endotoxemic rats by attenuating pulmonary inflammation and inhibiting NF-kappaB activation.

Reduction of pulmonary inflammatory response by erythropoietin in a rat model of endotoxaemia.

BACKGROUND: Erythropoietin elicits protective effects in lung tissue injury induced by ischaemic reperfusion and hyperoxia. We investigated the protective roles of erythropoietin in pulmonary inflammation and lung injury during acute endotoxaemia. METHODS: A total of 32 male Sprague-Dawley rats were randomly assigned to four groups: saline group, erythropoietin + saline group, saline + lipopolysaccharide group and erythropoietin + lipopolysaccharide group. Rats were treated with erythropoietin (3000 U/kg, i.p.) or saline, 30 minutes prior to lipopolysaccharide administration (6 mg/kg, i.v.). Four hours after lipopolysaccharide injection, samples of pulmonary tissue were collected. Optical microscopy was performed to examine pathological changes in lungs. Wet/dry (W/D) ratios, myeloperoxidase activity, malondialdehyde concentrations and tumour necrosis factor-alpha (TNF-alpha) as well as interleukin 1 beta (IL-1beta) levels in lungs were measured. The pulmonary expression of nuclear factor kappaB (NF-kappaB) p65 was evaluated by Western blotting. Differences between the different groups were analysed by one-way analysis of variance (ANOVA). RESULTS: The lung tissues from the saline + lipopolysaccharide group were significantly damaged, which were less pronounced in the erythropoietin + lipopolysaccharide group. The W/D ratio increased significantly in the saline + lipopolysaccharide group (5.75 +/- 0.22) as compared with the saline group (3.85 +/- 0.20) (P < 0.01), which was significantly reduced in the erythropoietin + lipopolysaccharide group (4.50 +/- 0.35) (P < 0.01). Myeloperoxidase activity and malondialdehyde levels increased significantly in the saline + lipopolysaccharide group compared with the saline group, which was reduced in the erythropoietin + lipopolysaccharide group. The TNF-alpha level of pulmonary tissue increased significantly in the saline + lipopolysaccharide group ((9.80 +/- 0.82) pg/mg protein) compared with the saline group ((4.20 +/- 0.42) pg/mg protein, P < 0.01). However, the increase of TNF-alpha level of pulmonary tissue was significantly reduced in the erythropoietin + lipopolysaccharide group ((6.50 +/- 0.66) pg/mg protein, P < 0.01). Similarly, pulmonary IL-1beta levels were elevated markedly in the saline + lipopolysaccharide group in contrast to the saline group, whereas the elevation was much less in the erythropoietin + lipopolysaccharide group. The nuclear localization of p65 increased markedly in the saline + lipopolysaccharide group and this enhancement of nuclear p65 expression was much less in the erythropoietin + lipopolysaccharide group. CONCLUSION: Erythropoietin attenuates pulmonary inflammation and suppresses TNF-alpha and IL-1beta overproduction during acute endotoxaemia, which is partially mediated by inhibition of NF-kappaB.