Low levels of lead exposure induce oxidative damage and DNA damage in the testes of the frog Rana nigromaculata

We have investigated the chronic effects of low concentrations of lead (Pb) on oxidative damage and DNA damage in testes of the frog Rana nigromaculata. Sixty adult male frogs were randomly divided into six groups of ten. Based on the levels of the Integrated Wastewater Discharge Standard (GB 8978-1996) of China, five groups (II–VI) were treated by epidermal absorption with a PbNO₃ solution at concentrations of 0.1, 0.2, 0.4, 0.8, 1.6 mg/l, respectively. The first group (I), which served as a control, was treated with distilled water only. Thirty days after treatment, all frogs were sacrificed and the testis tissues removed for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels. DNA damage, including indicators of damage rate, DNA tail length (TL), and DNA tail moment (TM), was also analyzed by comet assays. Our data suggest that MDA levels in all treatment groups and GSH levels in the 0.2–1.6 mg/l Pb groups increased significantly relative to the controls (P < 0.01). Treatment with Pb at concentrations >0.4 mg/l also increased DNA damage rate and TM, while TL increased when the Pb level was >0.2 mg/l (P < 0.01 for DNA damage rate and TM, P < 0.05 for TL). Positive correlations were also found between DNA damage levels in the testes and MDA levels (r = 0.796 for DNA damage rate, r = 0.811 for TL, r = 0.796 for TM; P < 0.01 for all) as well between MDA and GSH levels (r = 0.455, P < 0.05) in the testes. Results from MDA measurements indicated that Pb-induced DNA damage in the testes of R. nigromaculata was possibly due to oxidative damage. Taken together, we conclude that Pb can induce male reproductive toxicity in R. nigromaculata.     

Sodium bicarbonate reverts electrophysiologic cardiotoxicity of ropivacaine faster than lipid emulsions in a porcine model

Ropivacaine has been described as a safer local anaesthetic (LA); however, serious cardiotoxic accidents have been reported. Intravenous-lipid-emulsion (ILE) therapy during LA intoxication seems to act as an antidote. Sodium bicarbonate is the standard treatment for sodium channel blocker drug toxicity. We compared both antidotes on the reversion of electrophysiologic toxicity induced by ropivacaine. Ropivacaine 5 mg kg⁻¹ was administered in 24 pigs, and 3 min later, the animals received ILE: 1.5 ml kg⁻¹ + 0.25 ml kg⁻¹ min⁻¹ (ILE group); sodium bicarbonate: 2 mEq kg⁻¹ + 1 mEq kg⁻¹ h⁻¹ (NaHCO₃ group); saline solution (CTL group). Electrophysiological parameters were evaluated for 30 min. The area under the curve (AUC) for the first 5 or 30 min was compared between groups. Ropivacaine induced a lengthening of the PR interval by 17% (P = 0.0001), His-ventricle-interval by 58% (P = 0.001), sinus QRS complex by 56% (P = 0.0001), paced QRS at 150 bpm by 257% (P = 0.0001), and at 120 bpm by 143% (P = 0.0001) in all groups. At 5 min after treatment, sinus QRS in the NaHCO₃ group was shorter than that in the CTL group (AUC_QRS5, P = 0.003) or ILE group (AUC_QRS5, P = 0.045). During the first minute, seven of the animals in the NaHCO₃ group vs. two in the ILE or 0 in the CTL group recovered more than 30% of the sinus QRS previously lengthened by ropivacaine (P = 0.003). Sodium bicarbonate reversed the electrophysiological toxicity of ropivacaine faster than ILE and control groups.     

Tracking anti‐fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: An insight

The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl₄ for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti‐inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α‐smooth muscle actin, transforming growth factor (TGF)‐β1 antibodies and platelet‐derived growth factor receptor β (PDGFRβ) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl₄‐induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF‐β1 levels and tissue expression of its antibody, as well expression of PDGFRβ. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)‐1 and IL‐6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF‐β1 levels and decreasing expression of PDGFRβ.     

Original and generic latanoprost for the treatment of glaucoma and ocular hypertension: Are they really the same?

We compared the intraocular pressure (IOP)‐lowering effect and safety profile of latanoprost (Xalatan) with its generic variant, Glautan (Unipharm, Tel Aviv, Israel). After 1 and 4 weeks of treatment, a randomized, prospective, cross‐over comparison was carried out that included patients with open‐angle glaucoma or ocular hypertension, either naïve or treated and well‐controlled, who were attending the Department of Ophthalmology, Tel Aviv Medical Centre, Tel Aviv, Israel, between May 2010 and November 2012. After a 3‐week washout period for the medicated subjects, the participants were randomized to 4 weeks of treatment with either Xalatan or Glautan once every evening and then, after a 3‐week washout period, crossed‐over to the other treatment for an additional 4 weeks. Efficacy was expressed by a change in intraocular pressure at three designated hours of the day after 1 week and 1 month of treatment, and tolerability was determined by ocular side‐effects as reported by the patient in a questionnaire. A total of 19 patients (mean age at initial diagnosis 66 ± 9 years, 14 females) were enrolled, of whom 17 had bilateral open‐angle glaucoma and two had unilateral disease. Both drugs lowered intraocular pressure after 1 week and 1 month (P = 0.06 and P = 0.04, respectively) of treatment. Xalatan had a tendency of greater efficacy than Glautan both after 1 week and 1 month, but the difference was not statistically significant (P =0.69 and P = 0.34, respectively). Drug safety was similar for Xalatan or Glautan, but more ocular side‐effects were reported after treatment with Glautan (21 vs 12 for Xalatan, P = 0.06).     

前列泰胶囊联合左氧氟沙星治疗湿热挟瘀型慢性前列腺炎的临床观察及其对PSA、MIP-2、VCAM-1水平的影响

目的 探讨前列泰胶囊联合左氧氟沙星治疗湿热挟瘀型慢性前列腺炎的临床疗效及其对前列腺特异性抗原（PSA）、巨噬细胞炎性蛋白-2（MIP-2）、血管细胞黏附分子-1（VCAM-1）水平的影响。方法 选取2019年1月—2020年6月于南昌大学第二附属医院就诊的湿热挟瘀型慢性前列腺炎患者84例作为研究对象,根据治疗方法将患者分为对照组（42例）与观察组（42例）。对照组患者口服左氧氟沙星片,0.2 g/次,3次/d。观察组患者在对照组的基础上口服前列泰胶囊,5粒/次,3次/d。两组均持续治疗6周。观察两组患者的临床疗效,比较两组治疗前后的美国国立卫生研究院慢性前列腺炎症状指数（NIH-CPSI）、血清前列腺特异性抗原（PSA）、巨噬细胞炎性蛋白-2（MIP-2）和血管细胞黏附分子-1（VCAM-1）水平与尿动力学指标。结果 治疗后,观察组总有效率为95.24%,显著高于对照组的78.57%（P<0.05）。治疗后,两组疼痛与不适、排尿症状、生活质量评分均低于治疗前（P<0.05）;治疗后,观察组疼痛与不适、排尿症状、生活质量评分均显著低于对照组（P<0.05）。治疗后,两组血清PSA、MIP-2、VCAM-1水平均低于治疗前（P<0.05）;治疗后,观察组血清PSA、MIP-2、VCAM-1水平均显著低于对照组（P<0.05）。治疗后,两组最大尿流率（MFR）、平均尿流率（AFR）和排尿量均大于治疗前（P<0.05）;治疗后,观察组MFR、AFR、排尿量均大于对照组（P<0.05）。结论 前列泰胶囊联合左氧氟沙星治疗湿热挟瘀型慢性前列腺炎疗效肯定,能减轻临床症状,改善尿动力学指标,调节血清PSA、MIP-2、VCAM-1水平,且未增加不良反应发生。     

Effect of glutathione S‐transferase genetic polymorphisms on busulfan pharmacokinetics and veno‐occlusive disease in hematopoietic stem cell transplantation: A meta‐analysis

This meta‐analysis was conducted to derive an integrated conclusion about the influence of glutathione S‐transferase (GST) genetic polymorphisms on busulfan pharmacokinetic (PK) parameters and veno‐occlusive disease (VOD). Studies which analysed the effect of GST genetic polymorphisms on area under the curve (AUC), clearance (CL) or VOD were searched for and selected. A pooled analysis was conducted using Comprehensive Meta‐Analysis programme. Nineteen studies were included in this meta‐analysis. GSTA1*B and GSTM1 null genotypes significantly decreased CL_IV of busulfan (standardized difference in means (SDM) = ?1.103; P = 0.019 and SDM = ?0.418; P = 0.002, respectively). GSTA1*B significantly increased AUC_IV of busulfan (SDM = 0.832; P = 0.046), whereas GSTM1 did not (SDM = 0.155; P = 0.478). The PK parameters of oral busulfan did not differ according to GST genotype. GSTA1, GSTM1 and GSTP1 were not significantly associated with VOD occurrence. GSTA1 and GSTM1 genotypes affected CL_IV of busulfan, but only GSTA1 affected AUC_IV. There was no significant difference in the PK parameters of oral busulfan (CL_PO and AUC_PO) and VOD when only GST genotypes were considered.     

Impact of Custodiol-N cardioplegia on acute kidney injury after cardiopulmonary bypass

Myocardial protection during cardiopulmonary bypass (CPB) can be achieved using cardioplegic solutions. Although, acute kidney injury (AKI) is a common complication following CPB, the effects of cardioplegic solutions on AKI have rarely been investigated. Within this study, the effects of the cardioplegic solutions histidine-tryptophan-ketoglutarate (HTK; Custodiol) and HTK-N (Custodiol-N) on AKI in a large animal model were compared. Therefore, Landrace pigs underwent median sternotomy, CPB at 34°C, 90 minutes of cardiac arrest and 120 minutes of reperfusion. Animals were randomized for single-shot cardioplegia with either HTK (n = 10) or HTK-N (n = 10). Renal biopsies and sera were analyzed to determine AKI biomarkers and apoptosis. Compared to HTK, HTK-N induced a decreased extent of proximal tubule swelling (48.3 ± 1.6 µm vs 52.3 ± 1.1 µm, P = .05) and decreased cytochrome c release (0.26 ± 0.04 vs 0.46 ± 0.08, P = .04) without reaching statistical significance due to Bonferroni correction. Comparing baseline and postreperfusion levels, the hemoglobin (Hb) and blood calcium levels were lower in HTK-N (Hb_baseline: 6.0 ± 0.6 mmol/L, Hb_reperfusion: 6.2 ± 0.7 mmol/L, P = .12; Ca²⁺_baseline: 1.36 ± 0.05 mmol/L, Ca²⁺_reperfusion: 1.28 ± 0.05 mmol/L, P = .16) compared to the HTK group (Hb_baseline: 5.9 ± 0.4 mmol/L, Hb_reperfusion: 4.7 ± 0.8 mmol/L, P < .01; Ca²⁺_baseline: 1.34 ± 0.07 mmol/L, Ca²⁺_reperfusion: 1.24 ± 0.06 mmol/L, P < .01). The present study showed that HTK-N could positively affect the kidney during CPB. Hb and calcium levels were stabilized. A statistical trend was found showing that AKI-related proximal tubule swelling and cytochrome c release were diminished.     

LUNG INJURY,INFLAMMATION, AND INFLAMMATORY STIMULI IN RATS EXPOSED TO OZONE

The effects of ozone (O₃) on airway epithelia, inflammation, and expression of inflammatory stimuli were investigated to delineate the mechanisms of inflam matory reactions relevant to lung injury. Because the airway responses to O₃ develop gradually, this investigation included a time-sequence analysis. Rats exposed for 3 h to 1 ppm O₃ were studied at 4-h intervals up to 20 h postexposure. Bronchoalveolar lavage fluid (BAL) was analyzed for albumin as an indicator of increased permeability, polymorphonuclear leukocytes (PMNs) to assess the inflammatory status, macrophage inflammatory protein-2 (MIP-2, an inflammatory chemokine), and cell adhesion molecules for their role in inflammation and PMN functions. The time-related increase in album in was matched by a similar significant increase for PMNs, MIP-2, and intercellular adhesion molecule-1 (ICAM-1). However, no marked change occurred for b-2 integrin (CD-18) and leukotriene B₄ (LTB₄). The results establish a temporal correlation of epithelial permeability with changes in inflammatory activity and stimuli responsible for PMN recruitment in the lung. The observations of elevated MIP-2 and ICAM-1 levels are consistent with their role in injury and inflammation. An early expression of MIP-2 mRNA in BAL cells, that is, immediately post O₃ exposure, and the peak increase in BAL MIP-2 levels 4 h later support the chem otactic role of MIP-2 in PMN recruitm ent at 4- and 12-h time points. The rapid drop in MIP-2 and ICAM-1 levels appears to signal the termination of inflammatory cell recruitment, which is accompanied by an onset of recovery.     

Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients

Objective  The objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation. Methods  A total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C₀ and C₂, respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated. Results  Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C₂, 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16–30, and for C₀, 39.7% (P = 0.012) during days 16–30. The dose-adjusted C₀ was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C₀ in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8–15 (P = 0.011) and days 16–30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C₀ was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C_2. Conclusion  The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.     

Additional role of serum 25‐hydroxyvitamin D3 levels in atherosclerosis in Chinese middle‐aged and elderly men

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Pulse pressure variation does not reflect stroke volume variation in mechanically ventilated rats with lipopolysaccharide‐induced pneumonia

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The cardioprotective and inotropic components of the postconditioning effects of GLP-1 and GLP-1(9–36)a in an isolated rat heart

GLP-1 and its metabolite GLP-1(9–36)a have been shown to exert cardiotropic effects, and were demonstrated to be cardioprotective agents in isolated, postischemic rat or mouse hearts. An agent's total effect on myocardial performance in a postconditioning paradigm is a sum of its myocyte-preserving (cardioprotective) and contractility-affecting (negative or positive inotropic) action components. These components may not always be explicitly separated by the experimental protocol. We propose an analytical approach to identify and quantify the cardioprotective and inotropic components in a postconditioning protocol, as exemplified by use of GLP-1 and GLP-1(9–36)a following a global ischemia in isolated rat hearts. Peptides were administered during the first 15 min of 120 min reperfusion. GLP-1 0.3 nM reduced infarct size from 23.2 ± 2.4% to 14.1 ± 2.3% of area-at-risk (n = 15, P = 0.0223), an effect abolished by the GLP-1 receptor antagonist, exendin(9–39) 5 nM. GLP-1 showed only a small, non-significant tendency to increase mechanical performance (increase of LVDP by 26.7%, P = 0.1621; RPP 33.5%, P = 0.0858; dP/dt_max 28.5%, P = 0.1609). This could be accounted for by the cardioprotective component of GLP-1 action, rather than any true inotropic effect. In contrast, GLP-1(9–36)a did not reduce infarct size significantly, but acted as a strong negative inotrope in postischemic hearts, causing a contractility deficit (LVDP 58.8%, P = 0.0004; RPP 58.2%, P = 0.0007; dP/dt_max = 58.2%, P = 0.0012), quantifiable by an analysis of infarct size-mechanical performance plots. These results help resolve certain apparent discrepancies between some of the published effects of GLP-1 and GLP-1(9–36)a.     

Inflammatory Response and Barrier Properties of a New Alveolar Type 1-Like Cell Line (TT1)

Purpose  To evaluate the inflammatory response and barrier formation of a new alveolar type 1-like (transformed type I; TT1) cell line to establish its suitability for toxicity and drug transport studies. Methods  TT1 and A549 cells were challenged with lipopolysaccharide (LPS). Secretion of inflammatory mediators was quantified by ELISA. The barrier properties of TT1 cells were evaluated by transepithelial electrical resistance (TEER), fluorescein sodium (flu-Na) apparent permeability (P _app) and staining of zona occludens-1 (ZO-1). Results  LPS stimulated similar levels of secretion of IL-6 and IL-8 in TT1 and A549 cells. TNF-α was not produced by either cell line. In contrast to A549 cells, TT1 cells did not secrete SLPI or elafin. TT1 cells produced maximal TEER of ~55 Ω cm² and flu-Na P _app of ~6.0 × 10⁻⁶ cm/s. ZO-1 staining was weak and discontinuous. Attempts to optimise culture conditions did not increase the barrier properties of the TT1 cell layers. Conclusions  The TT1 cell line models the alveolar inflammatory response to LPS challenge and provides a valuable complement to cell lines currently used in toxicity assays. However, under the experimental conditions used the TT1 cell line did not form the highly restrictive tight junctions which exist in vivo.     

Characterization of thrombogenic,endothelial and inflammatory markers in supraventricular tachycardia: a study in patients with structurally normal hearts

Patients with atrial fibrillation (AF) are at an increased risk of thromboembolism and stroke primarily from the development of thrombi within the left atrium. Pathological changes in blood constituents and atrial endothelial damage promote left atrial thrombus formation. It is not known whether factors predisposing to left atrial thrombus formation in AF are disease specific or also evident within the normal heart. The present study examined whether there are differences in platelet reactivity, endothelial function and inflammation in blood samples obtained from intracardiac and peripheral sites in subjects within structurally normal hearts. Sixteen patients with diagnosed left‐sided supraventricular tachycardia (SVT) undergoing a routine elective electrophysiological study and ablation were investigated. Blood samples were taken simultaneously from the femoral vein, right atrium and left atrium, immediately following trans‐septal puncture and prior to heparin bolus administration. Between peripheral and atrial sample sites, patients with SVT showed no change in platelet reactivity or aggregation (P‐selectin (CD62P) P = 0.91; platelet‐derived soluble CD40 ligand P = 0.9), thrombus formation (thrombin–antithrombin complex; P = 0.55), endothelial function (von Willebrand factor P = 0.75; asymmetric dimethylarginine (ADMA) P = 0.97; nitric oxide P = 0.61), or inflammation (vascular cell adhesion molecule‐1 P = 0.59; intercellular adhesion molecule‐1 (ICAM‐1) P = 0.69). However, SVT patients had lower ADMA and ICAM‐1 levels than AF patients. The present study demonstrates, for the first time, that SVT subjects with structurally normal hearts have consistent haemostatic function between atrial and peripheral sites. These results suggest that the atria of SVT patients do not contain predisposing thrombogenic, endothelial or inflammatory factors that promote and/or initiate thrombus formation.     

Optimal teicoplanin loading regimen to rapidly achieve target trough plasma concentration in critically ill patients

Teicoplanin is used for the treatment of Methicillin‐resistant Staphylococcus aureus infection. It has been demonstrated that conventional loading regimen was insufficient for teicoplanin to achieve target trough plasma concentration (C_min > 10 mg/L). Therefore, a Chinese expert group recommended an optimal loading dose regimen of teicoplanin to treat severe Gram‐positive infection. However, there was no report about the teicoplanin concentration, and the safety and efficacy of teicoplanin therapy in Chinese patients since the consensus was published. The objective of this study was to compare the teicoplanin C_min and clinical response in critically ill Chinese patients after the administration of conventional or optimal loading regimen, and to reveal the potential factors that may affect teicoplanin C_min in addition to loading regimen. Fifty‐five patients were retrospectively divided into two groups based on teicoplanin loading regimen: (a) CD group (conventional loading dose group, n = 18, loading dose was 400 mg); (b) OD group (optimal loading dose group, n = 37, loading dose was 800 mg). Initially, three loading doses were administered every 12 hours, while the fourth loading dose was injected 24 hours after the third dose. The maintenance dose was 400 mg (CD group) or 800 mg (OD group), respectively. The mean teicoplanin C_min on day 2 and day 4 in the OD group was significantly higher than those in the CD group, which were 14.75 ± 5.93 mg/L vs 8.26 ± 4.87 mg/L (P < .001) and 14.90 ± 5.20 mg/L vs 9.13 ± 4.75 mg/L (P = .019), respectively. The percentages of patients in the OD group achieving the target teicoplanin C_min on day 2 and day 4 were also significantly higher than those in the CD group, which were 83.7% vs 33.3% (P < .001) and 82.4% vs 28.6% (P = .0013), respectively. Furthermore, multivariate linear regression analysis showed that body‐weight exerted significant effect on teicoplanin C_min in the OD group. The percentage of favourable clinical response in the OD group was significantly higher than that in the CD group (83.8% vs 55.6%, P = .025). There was no difference between teicoplanin adverse effects in the two groups. The study demonstrated that the optimal loading dose regimen of teicoplanin can rapidly reach target C_min, and result in a good clinical efficacy and low adverse effect in critically ill Chinese patients.     

In vitro the differences of inflammatory and oxidative reactions due to sulfur mustard induced acute pulmonary injury underlying intraperitoneal injection and intratracheal instillation in rats

This study was to investigate the differences of inflammatory reaction and oxidative stress due to sulfur mustard (SM)-induced acute pulmonary injury via two ways in rats. In intraperitoneal and tracheal SM groups, injected intraperitoneally and instilled intratracheally with 0.1 mL diluted SM (0.96 LD₅₀ = 8 mg/kg) and SM (0.98 LD₅₀ = 2 mg/kg) were administered in rats. In bronchoalveolar lavage fluid, serum, and alveolar septum, lactate dehydrogenase, glutathione peroxidase, tumor necrosis factor-α, interleukin-1β, interleukin-6, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, l-selectin, r-glutamyl transpeptidase, thiobarbituric acid reactive substances levels as well as the expression of CD4, CD20, CD68, 8-hydroxy deoxyguanosine, nuclear factor-E2-related factor 2, and heme oxygenase-1 measured by ELISA, immune scatter turbidimetry and immunohistochemical method in the intraperitoneal SM group were increased at each time-point compared with the tracheal SM groups, respectively. These data demonstrated an increased inflammatory reaction and oxidative stress indices in rat via intraperitoneal injection under similar SM LD₅₀ doses.     

Aflatoxins B1, B2 and G1 modulate cytokine secretion and cell surface marker expression in J774A.1 murine macrophages

Aflatoxins are fungal products which occur in food and feed. They are potent hepatocarcinogens, and are known to cause immunosuppression. We investigated the effect of aflatoxin B₁ (AFB₁), aflatoxin B₂ (AFB₂) and aflatoxin G₁ (AFG₁) exposure, alone and in combination, on the secretion of key pro- and anti-inflammatory cytokines from the murine macrophage cell line, J774A.1. Exposure of macrophages to low doses of aflatoxin (0.01 or 0.1 ng/mL) resulted in a statistically significant change in the secretion of a number of cytokines following stimulation with lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls. Specifically, treatment with AFB₁ or AFB₂ alone significantly decreased (P < 0.01) the secretion of the anti-inflammatory cytokine interleukin (IL) 10 (IL-10), while the secretion of the pro-inflammatory cytokine IL-6 was significantly increased (P < 0.01). In addition, aflatoxin exposure affected expression levels of key cell surface markers involved in the inflammatory response. Toll-like receptor 2 (TLR2) and Cluster of Differentiation 14 (CD14) expression levels decreased significantly (P < 0.01), but Toll-like receptor 4 (TLR4) expression was unaffected. This data provides further insight into the mechanisms by which aflatoxins modulate the host immune response to exert their immunosuppressive activity.     

Telomere attrition and inflammatory load in severe psychiatric disorders and in response to psychotropic medications

Individuals with severe psychiatric disorders have a reduced life expectancy compared to the general population. At the biological level, patients with these disorders present features that suggest the involvement of accelerated aging, such as increased circulating inflammatory markers and shorter telomere length (TL). To date, the role of the interplay between inflammation and telomere dynamics in the pathophysiology of severe psychiatric disorders has been scarcely investigated. In this study we measured T-lymphocytes TL with quantitative fluorescent in situ hybridization (Q-FISH) and plasma levels of inflammatory markers in a cohort comprised of 40 patients with bipolar disorder (BD), 41 with schizophrenia (SZ), 37 with major depressive disorder (MDD), and 36 non-psychiatric controls (NPC). TL was shorter in SZ and in MDD compared to NPC, while it was longer in BD (model F_{6, 137} = 20.128, p = 8.73 × 10⁻¹⁷, effect of diagnosis, F₃ = 31.870; p = 1.08 × 10⁻¹⁵). There was no effect of the different classes of psychotropic medications, while duration of treatment with mood stabilizers was associated with longer TL (Partial correlation controlled for age and BMI: correlation coefficient = 0.451; p = 0.001). Levels of high-sensitivity C-Reactive Protein (hsCRP) were higher in SZ compared to NPC (adjusted p = 0.027), and inversely correlated with TL in the whole sample (r = −0.180; p = 0.042). Compared to NPC, patients with treatment resistant (TR) SZ had shorter TL (p = 0.001), while patients with TR MDD had higher levels of tumor necrosis factor-α (TNFα) compared to NPC (p = 0.028) and to non-TR (p = 0.039). Comorbidity with cardio-metabolic disorders did not influence the observed differences in TL, hsCRP, and TNFα among the diagnostic groups. Our study suggests that patients with severe psychiatric disorders present reduced TL and increased inflammation.Subject terms: Schizophrenia, Diagnostic markers, Bipolar disorder, Depression     

康柏西普眼内注射对糖尿病性视网膜病变行玻璃体切割手术的影响分析

目的 探讨康柏西普眼内注射对糖尿病性视网膜病变行玻璃体切割手术的影响。方法 选取100例糖尿病视网膜病变患者,按术前眼内是否注射药物分为两组,注射组（49例）玻璃体切割术前7 d眼内注射康柏西普,对照组（51例）单纯行玻璃体切割术。通过观察并记录患者手术情况、预后情况、术前术后视力情况,评价康柏西普眼内注射对糖尿病性视网膜病变行玻璃体切割手术的影响。结果 与对照组相比,注射组所需手术时间更短（P<0.05）,注射组出血眼数6例,对照组出血眼数20例,注射组出血眼数明显少于对照组（P<0.05）。此外,注射组术中电凝眼数、硅油使用眼数、医源性裂孔眼数均明显少于对照组（P<0.05）;术后随访1个月,注射组少量出血例数和大量活动性出血例数均明显少于对照组（P<0.05）;术前两组视力相比,差异没有统计学意义（P<0.05）。术后1个月,两组视力均明显提高且注射组视力明显高于对照组（P<0.05）。结论 康柏西普眼内注射有利于玻璃体切割手术的进行,可降低手术难度,缩短手术时间,减少术中、术后出血症状,提高患者矫正视力。     

Anti-inflammatory effect and selectivity profile of AS1940477, a novel and potent p38 mitogen-activated protein kinase inhibitor

Given the key role p38 mitogen-activated protein kinase (MAPK) plays in inflammatory responses through the production of cytokines and inflammatory mediators, its inhibition is considered a promising therapeutic strategy for chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. Here, we evaluated the anti-inflammatory effect and selectivity profile of the novel p38 MAPK inhibitor AS1940477. AS1940477 inhibited the enzymatic activity of recombinant p38α and β isoforms but showed no effect against other 100 protein kinases including p38γ and δ isoforms. We also confirmed the selectivity of AS1940477 in the intracellular signaling pathway. In human peripheral blood mononuclear cells, AS1940477 inhibited lipopolysaccharide (LPS)- or phytohemagglutinin A (PHA)-induced production of proinflammatory cytokines, including TNFα, IL-1β, and IL-6 at low concentrations (LPS/TNFα, IC₅₀=0.45 nM; PHA/TNFα, IC₅₀=0.40 nM). In addition, equivalent concentrations of AS1940477 that inhibited cytokine production also inhibited TNFα- and IL-1β-induced production of IL-6, PGE₂, and MMP-3 in human synovial stromal cells. AS1940477 was also found to potently inhibit TNF production in whole blood (IC₅₀=12 nM) and effectively inhibited TNFα production induced by systemically administered LPS in rats at less than 0.1 mg/kg (ED₅₀=0.053 mg/kg) with an anti-inflammatory effect lasting for 20 h after oral administration. Overall, this study demonstrated that AS1940477 is a novel and potent p38 MAPK inhibitor and may be useful as a promising anti-inflammatory agent for treating inflammatory disorders.