RESUMEN
ObjectiveTo explore the therapeutic effect and mechanism of Guipitang on rats with myocardial ischemia. MethodFifty SD rats were divided into five groups： a control group， a model group， low and high-dose Guipitang （7.52， 15.04 g·kg-1） groups， and a trimetazidine group （0.002 g·kg-1）. By intragastric administration of vitamin D3 and feeding rats with high-fat forage and injecting isoproterenol， the rat model of myocardial ischemia was established. After drug treatment of 15 d， an electrocardiogram （ECG） was performed to analyze the degree of myocardial injury. A fully automatic biochemical analyzer was used to detect the changes in the serum levels of total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， triglyceride （TG）， and low-density lipoprotein cholesterol （LDL-C）. Hematoxylin-eosin （HE） staining and Masson staining were used to observe myocardial histopathological changes. TdT-mediated dUTP nick end labeling （TUNEL） staining was used to detect cardiomyocyte apoptosis. Western blot was adopted to detect the protein levels of extracellular signal-regulated kinase 1/2 （ERK1/2）， phospho-ERK1/2 （p-ERK1/2）， p38 mitogen-activated protein kinase （p38 MAPK）， phospho-p38 MAPK （p-p38 MAPK）， B-cell lymphoma-2 （Bcl-2）-associated X （Bax）， Bcl-2， and cleaved cysteine aspartate proteolytic enzyme （cleaved Caspase-3）. ResultCompared with the control group， the ECG S-T segment decreased in the model group. The serum levels of TC， TG， and LDL-C were increased significantly （P<0.05）. The arrangement of myocardial tissue was disordered， and the proportion of cardiomyocyte apoptosis increased. The protein levels of cleaved Caspase-3， Bax， and p-p38 MAPK in the heart were increased， and the Bcl-2 expression was decreased （P<0.05）. Compared with the model group， the S-T segment downward shift was restored in the low and high-dose Guipitang groups and trimetazidine group， and the levels of TC， TG， and LDL-C were decreased. The protein expression of cleaved Caspase-3 and Bax in the heart dropped， and p-p38 MAPK and p-ERK1/2 protein expressions increased significantly （P<0.05）. The degree of myocardial injury was alleviated， and the proportion of cardiomyocyte apoptosis decreased. Bcl-2 protein expression was increased significantly in the low-dose Guipitang group （P<0.05）. ERK1/2 and p38 MAPK proteins had no significant difference among different groups. ConclusionGuipitang could alleviate myocardial injury and inhibit cardiomyocyte apoptosis in rats by activating the expression of ERK1/2 and p38 MAPK.
RESUMEN
Objective:To observe the effects of modified Xuanfuhua Decoction on pain behaviour and spinal cord neuroinflammation mediated by phosphorylated mitogen-activated protein kinase p38 (p38MAPK) signaling pathway in rats with sciatic nerve injury; To analyse the mechanism of its effects.Methods:Totally 108 SD rats were randomly divided into sham-operation group, model group, pregabalin group, decoction low-, medium- and high-dosage groups, with 18 rats in each group. The CCI model was established by ligation of sciatic nerve in other groups except sham-operation group. On the postoperative day, the decoction low-, medium-, high-dosage groups were gavaged with 2.5, 5.0 and 10.0 g/kg of modified Xuanfuhua Decoction concentrate, respectively. The pregabalin group was gavaged with 15 mg/kg of pregabalin. The sham-operation group and the model group were gavaged with equal amounts of saline once/d for 15 days. Pain behavioural assays were performed before, on the 3rd, 7th, 11th and 15th day of administration respectively. The levels of interleukin (IL)-1β, tumour necrosis factor-α (TNF-α), IL-10 were detected by ELISA method. The expressions of Toll-like receptor 4 (TLR4), nuclear factor-κB p65 (NF-κB p65) were detected by immunohistochemistry staining. The phosphorylated p38MAPK (p-p38MAPK) were measured in the spinal cord by Western blot.Results:Compared with the model group, the scores of spontaneous pain in decoction high-dosage group decreased ( P<0.05), the thermal foot shrinkage latency (TWL) was prolonged ( P<0.05), and the mechanical foot shrinkage reflex threshold (MWT) increased ( P<0.05); the levels of IL-1β and TNF-α in spinal cord tissue of decoction low-, medium- and high-dosage groups decreased ( P<0.05), the level of IL-10 increased ( P<0.05), the average gray values of TLR4 and NF-κB p65 in spinal cord decreased ( P<0.05), and the expression of P-P38MAPK protein decreased ( P<0.05). Conclusion:Modified Xuanfuhua Decoction can effectively improve neurogenic pain in CCI rats, and the mechanism may be related to inhibition of p38MAPK-TLR4 signaling pathway activation-mediated spinal cord neuroinflammation.
RESUMEN
Objective:To evaluate the effect of electroacupuncture on P2X4R-p38 mitogen-activated protein kinase (p38 MAPK)-brain-derived neurotrophic factor (BDNF) signaling pathway in trigeminal ganglion of rats with trigeminal neuralgia.Methods:Thirty-six clean-grade healthy adult male Sprague-Dawley rats, weighing 190-230 g, aged 2-3 months, were divided into 3 groups ( n=12 each) using a random number table method: sham operation group (S group), trigeminal neuralgia group (TN group), and electroacupuncture group (E group). The model was developed by chronic constriction of the infraorbital nerve in anesthetized animals. The infraorbital nerve was only exposed without ligation in group S. Rats received electroacupuncture stimulation at the Baihui and Xiaguan acupoints on the affected side for 20 min after developing the model, with a frequency of 80 Hz, twice a day, for 14 consecutive days in E group. Facial mechanical pain threshold (FMT) was measured at 1 day before developing the model and 3, 7, 14, 21 and 28 days after developing the model. The rats were sacrificed after the last behavioral testing, and the trigeminal ganglia were taken for examination of histopathological changes of trigeminal ganglion (by HE staining) and for determination of the expression of P2X4R, p38 MAPK, phosphorylated p38 MAPK (p-p38 MAPK) and BDNF (by Western blot) and contents of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and IL-6 (by enzyme-linked immunosorbent assay). Results:Compared with group S, the FMT was significantly decreased at each time point after developing the model, the expression of P2X4R, p-p38 MAPK and BDNF in trigeminal ganglion was up-regulated, and the contents of TNF-α, IL-1β and IL-6 were increased ( P<0.05), the pathological changes of the trigeminal ganglion were obvious in group TN. Compared with group TN, the FMT was significantly increased at each time point after developing the model, and the expression of P2X4R, p-p38 MAPK and BDNF in trigeminal ganglion was down-regulated, and the contents of TNF-α, IL-1β and IL-6 were decreased ( P<0.05), and the pathological changes of the trigeminal ganglion were significantly attenuated in group E. Conclusions:The mechanism by which electroacupuncture alleviates trigeminal neuralgia may be related to inhibiting the activity of P2X4R-p38MAPK-BDNF signaling pathway and reducing neuroinflammation in rats.
RESUMEN
Objective To explore the effect of oxycodone hydrochloride on inflammation and neuro-nal apoptosis in epileptic rats through c-Jun amino terminal kinase(JNK)/p38 mitogen activated protein kinase(p38 MAPK)signaling pathway.Methods After epileptic rat model was success-fully constructed,72 epileptic rats were randomly divided into model group,low-,medium-and high-dose oxycodone hydrochloride groups(0.125,0.25 and 0.5 mg/kg),anisomycin(JNK activa-tor 5 mg/kg)and combined group(0.5 mg/kg oxycodone hydrochloride+5 mg/kg anisomycin),with 12 rats in each group.Another 12 healthy rats were selected as control group.In 24 h after the end of administration,the frequency and duration of seizures were recorded for all rats.ELISA was used to detect the serum levels of TNF-α and IL-6,HE staining was employed to observe the his-topathological changes in hippocampal CA1 region,and TUNEL staining was applied to detect the apoptosis of CA1 region neurons.The expression of JNK,p-JNK,p38 MAPK,p-p38 MAPK and Caspase-3 in hippocampal CA1 region was detected by Western blotting.Results Compared with the rats from the control group,those of the model group showed higher frequency and longer du-ration of seizures,higher serum TNF-α and IL-6 levels,increased apoptotic rate of hippocampal CA1 neurons,and elevated p-JNK/JNK ratio,p-p38 MAPK/p38 MAPK ratio and Caspase-3 expression(P＜0.05).While low-,medium-and high-dose oxycodone hydrochloride treatment re-versed above changes in frequency and duration of seizures,serum TNF-α and IL-6 levels,neuro-nal apoptosis,p-JNK/JNK ratio,p-p38 MAPK/p38 MAPK ratio and Caspase-3 expression(P＜0.05).In the anisomycin group,higher frequency and longer duration of seizures,elevated serum TNF-α and IL-6 levels,increased neuronal apoptotic rate in hippocampal CA1 region,and en-hanced p-JNK/JNK ratio,p-p38 MAPK/p38 MAPK ratio and Caspase-3 expression(P＜0.05).Lower frequency and shorter duration of seizures,decreased serum TNF-α and IL-6 levels,and re-duced neuronal apoptotic rate in hippocampal CA1 region were observed in the combined group than the anisomycin group(P＜0.05).The combined group obtained statistically lower p-JNK/JNK ratio,p-p38 MAPK/p38 MAPK ratio and Caspase-3 expression in hippocampal CA1 region than the high-dose group,and opposite results than the anisomycin group(0.89±0.12 vs 0.25± 0.05 vs 1.08±0.16,0.81±0.08 vs 0.21±0.04 vs 0.94±0.12,0.79±0.12 vs 0.26±0.04 vs 0.89± 0.14,P＜0.05).Conclusion Oxycodone hydrochloride can reduce inflammatory response,im-prove epileptic symptoms and pathological damages,and protect neurons in epileptic rats,which is related to the inhibition of JNK/p38 MAPK signaling pathway.
RESUMEN
Objective:To evaluate the role of P2X4 receptor (P2X4R) in the maintenance of trigeminal neuralgia and the relationship with p38 mitogen-activated protein kinase (p38 MAPK)/brain-derived neurotrophic factor (BDNF) signaling pathway in rats.Methods:Forty-eight clean-grade healthy adult male Sprague-Dawley rats, weighing 190-230 g, aged 2-3 months, were divided into 4 groups ( n=12 each) using a random number table method: sham operation group (S group), trigeminal neuralgia group (TN group), trigeminal neuralgia+ dimethylsulfoxide (DMSO) group (TN+ DMSO group), and trigeminal neuralgia+ P2X4R specific antagonist 5-BDBD group (TN+ 5-BDBD group). The model was developed by chronic constriction of the infraorbital nerve. The infraorbital nerve was only exposed without ligation in group S. At 3, 7, 10 and 14 days after developing the model, 5 μg/μl 5-BDBD 10 μl was intrathecally injected in TN+ 5-BDBD group, and 2% DMSO 10 μl was intrathecally injected in TN+ DMSO group. The facial mechanical pain withdrawal threshold (MWT) was measured at 1 day before developing the model and 1, 3, 7, 10, 14 and 28 days after developing the model (T 0-6). The rats were sacrificed and the trigeminal ganglia were taken for determination of the expression of P2X4R, p38 MAPK, phosphorylated p38 MAPK (p-p38 MAPK) and BDNF (by Western blot) and contents of tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 (by enzyme-linked immunosorbent assay). Results:Compared with group S, the MWT was significantly decreased at T 1-6, the expression of P2X4R, p-p38 MAPK and BDNF in trigeminal ganglion was up-regulated, and the contents of TNF-α, IL-1β and IL-6 were increased in TN group ( P<0.05). Compared with TN group, the MWT was significantly increased at T 3-6, and the expression of P2X4R, p-p38 MAPK and BDNF in trigeminal ganglion was down-regulated, and the contents of TNF-α, IL-1β and IL-6 were decreased in TN+ 5-BDBD group ( P<0.05), and no significant change was found in the indexes mentioned above in TN+ DMSO group ( P>0.05). Conclusions:P2X4R is involved in the maintenance of trigeminal neuralgia in rats, which may be related to the activation of p38 MAPK/BDNF signaling pathway and the increase in inflammatory mediator release.
RESUMEN
Objective:To evaluate the role of adenosine monophosphate-dependent protein kinase/p38 mitogen-activated protein kinase/nuclear factor E2-associated factor 2 (AMPK/p38 MAPK/Nrf2) pathway in myocardial ischemia-reperfusion (I/R) injury in diabetic rats.Methods:Clean-grade healthy Sprague-Dawley male rats, aged 2-3 months, weighing 220-280 g, were fed with a high fat diet, and 1% streptozotocin 50 mg/kg was intraperitoneally injected for 4 consecutive days to develop the model of diabetes mellitus.Thirty diabetic rats were divided into 3 groups ( n=10 each) using the random number table method: sham operation group (sham group), myocardial I/R group (I/R group), and AMPK inhibitor compound C+ myocardial I/R group (C+ I/R group). The model of myocardial I/R injury was developed by ligation of the left anterior descending coronary artery for 30 min followed by 120 min reperfusion.Compound C 0.5 mg/kg was injected via the caudal vein at 30 min before ischemia in C+ I/R group, while the equal volume of normal saline was given instead in Sham group and I/R group.At 120 min of reperfusion, the percentage of myocardial infarct size was calculated, the serum concentrations of creatine kinase isoenzymes (CK-MB) and lactic dehydrogenase (LDH) were determined by enzyme-linked immunosorbent assay, the levels of glutathione (GSH), superoxide dismutase (SOD) and reactive oxygen species (ROS) in myocardial tissues were measured by enzyme-linked immunosorbent assay, and the expression of AMPK, phosphorylated AMPK (p-AMPK), phosphorylated p38 MAPK (p-p38 MAPK), Nrf2 and heme oxygenase-1 (HO-1) in myocardium was determined by Western blot. Results:Compared with Sham group, the percentage of myocardial infarct size and serum CK-MB and LDH levels were significantly increased, the levels of GSH and SOD in myocardial tissues were decreased, ROS level was increased, and the expression of AMPK, p-AMPK, p-p38 MAPK, Nrf2 and HO-1 was up-regulated in I/R group ( P<0.05). Compared with I/R group, the percentage of myocardial infarct size and serum CK-MB and LDH levels were significantly increased, the levels of GSH and SOD in myocardial tissues were decreased, ROS level was increased, and the expression of AMPK, Nrf2 and HO-1 was down-regulated in C+ I/R group ( P<0.05). Conclusions:AMPK/p38 MAPK/Nrf2 signaling pathway is involved in the mechanism of endogenous antioxidant stress during myocardial I/R in diabetic rats.
RESUMEN
Objective:To investigate the effects of neutrophil extracellular traps (NETs) on the proliferation and apoptosis of human amniotic epithelial cells.Methods:NETs were induced in vitro from the neutrophil cells obtained from the peripheral blood of normal pregnant women before elective cesarean section at full-term. Human amniotic epithelial cell lines (WISH cells) were cultured in vitro, and were divided into four groups:(1) control group: without any stimulus; (2) NETs group: WISH cells were stimulated with NETs (500 ng/ml); (3) NETs+SB203580 (p38 kinase inhibitor) group: WISH cells were pretreated with SB203580 (5 μmol/L) for 30 min and then NETs (500 ng/ml) was added; (4) SB203580 group: only SB203580 was added. After stimulating for 48 h, cell proliferation assay, lactate dehydrogenase(LDH) assay, and flow cytometry assay were used to detect the cell proliferation rate, LDH level of cell supernatant, and cell apoptosis rate among different groups. The results were analyzed and compared using one-way analysis of variance and LSD- t test. Results:(1) Cell proliferation: The cell proliferation ratio in the NETs group was lower than that in the control group [(9.379±0.775)% vs (36.560±1.208)%, LSD- t=20.78, P<0.001]; and the figure in the NETs+SB203580 group [(27.920±0.926)%] was higher than that in the NETs group (LSD- t=14.18, P<0.001). (2)LDH: There was an increased LDH level in the cell supernatant of the NETs group compared with the control group (1.518±0.038 vs 0.274±0.004, LSD -t=44.25, P<0.05), and the LDH level in the NETs+SB203580 group (0.857±0.009) was decreased than that in the NETs group (LSD -t=23.51, P<0.001). (3) Apoptosis: Compared with the control group, the cell apoptosis level of the NETs group was increased [(14.290±0.141)% vs (10.110±0.044)%, LSD- t=21.76, P<0.001]; but that in the NETs+SB203580 group [(10.500±0.218)%] was lower than in the NETs group (LSD- t=19.70, P<0.001). Conclusion:p38/mitogen-activated protein kinases signaling pathway may be involved in the process of NETs, inhibiting proliferation and promoting apoptosis of human amniotic epithelial cells.
RESUMEN
Objective:To evaluate the role of p38 mitogen-activated protein kinase (MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling pathway in tetramethylpyrazine-induced reduction of hippocampal inflammatory responses in mice with sepsis-associated encephalopathy (SAE).Methods:Sixty healthy male C57BL6 mice, weighing 24-27 g, were divided into 4 groups ( n=15 each) using a random number table method: sham operation group (group Sham), sepsis group (group Sep), tetramethylpyrazine group (group TMP) and p38 MAPK inhibitor SB203580 group (group SB). The model of SAE was established by cecal ligation and puncture in anesthetized mice.Tetramethylpyrazine 10 mg/kg was injected intraperitoneally once a day at 3 days before the establishment of the model in TMP group, and SB203580 2.0 mg/kg was intraperitoneally injected at 30 min after the establishment of the model in SB group.The equal volume of normal saline was given intraperitoneally in Sham and Sep groups.At 1 day after operation, cognitive function was assessed by Morris water maze, and the escape latency and ratio of time spent in the target quadrant were recorded.The animals were sacrificed after the test, and hippocampal tissues were taken for determination of the contents of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and IL-6 (by enzyme-linked immunosorbent assay) and for detection of the expression of phosphorylation of p38 MAPK, GSK3 and CREB and expression of brain-derived neurotrophic factor (BDNF) (by Western blot). Results:Compared with group Sham, the escape latency was significantly prolonged, the ratios of time spent in the target quadrant were decreased, the contents of IL-1β, TNF-α and IL-6 were increased, the phosphorylation of hippocampus p38 MAPK was increased, the phosphorylation of GSK3 and CREB were decreased, and the expression of BDNF was down-regulated in Sep, TMP and SB groups ( P<0.05). Compared with group Sep, the escape latency was significantly shortened, the ratios of time spent in the target quadrant were increased, the contents of IL-1β, TNF-α and IL-6 were decreased, the phosphorylation of hippocampus p38 MAPK was decreased, the phosphorylation of GSK3 and CREB were increased, and the expression of BDNF was up-regulated in TMP and SB groups ( P<0.05). Compared with group TMP, no significant change was found in the parameters mentioned above in group SB ( P>0.05). Conclusion:p38 MAPK/CREB signaling pathway is involved in the process of tetramethylpyrazine-induced reduction of hippocampal inflammatory responses in mice with SAE.
RESUMEN
Objective:To investigate the effect of resveratrol on the expression of inflammatory cytokines and related genes in human SZ95 sebocytes induced by benzo (a) pyrene.Methods:Human SZ95 sebocytes were cultured in vitro, and divided into 4 groups: control group treated with 1‰ dimethyl sulfoxide for 27 hours, resveratrol group treated with 1 × 10 -5 mol/L resveratrol for 24 hours, benzo (a) pyrene group treated with 1 × 10 -5 mol/L benzo (a) pyrene for 3 hours, resveratrol+benzo (a) pyrene group treated with 1 × 10 -5 mol/L resveratrol for 24 hours followed by 1 × 10 -5 mol/L benzo (a) pyrene for 3 hours. Real-time fluorescence-based quantitative PCR was performed to determine the mRNA expression of interleukin (IL) -1α, IL-6, aryl hydrocarbon receptor (AhR) , cytochrome P4501A1 (CYP1A1) and cytochrome P4501B1 (CYP1B1) in SZ95 sebocytes in the above groups; Western blot analysis was conducted to determine the phosphorylation level of p38 mitogen-activated protein kinase (p38 MAPK, expressed as the ratio of phosphorylated to total p38 MAPK) and AhR protein expression; enzyme-linked immunosorbent assay (ELISA) was conducted to detect levels of IL-1α and IL-6 in the cell culture supernatant in each group. One-way analysis of variance was used for comparison of means among multiple groups, and least significant difference- t test was used for multiple comparisons. Results:The mRNA and protein expression of IL-1α in SZ95 sebocytes significantly differed among the control group, resveratrol group, benzo (a) pyrene group and resveratrol+benzo (a) pyrene group (mRNA: 2.045 ± 0.272, 2.058 ± 0.154, 3.124 ± 0.094, 2.185 ± 0.337, protein: 9.132 ± 1.181, 9.429 ± 0.771, 20.361 ± 0.907, 9.917 ± 0.897, F=14.662, 101.705, P < 0.01, < 0.001, respectively) , and were significantly lower in the resveratrol+benzo (a) pyrene group than in the benzo (a) pyrene group (both P < 0.01) . In addition, the phosphorylation level of p38 was significantly higher in the benzo (a) pyrene group than in the control group, resveratrol group and resveratrol+benzo (a) pyrene group ( F=303.129, P < 0.000 1) . The mRNA expression of AhR, CYP1A1 and CYP1B1 was significantly lower in the resveratrol+benzo (a) pyrene group than in the benzo (a) pyrene group ( t=10.64, 33.599, 18.327, respectively, all P < 0.001) . The benzo (a) pyrene group showed significantly decreased protein expression of AhR compared with the resveratrol+benzo (a) pyrene group ( P < 0.001) . Conclusion:Resveratrol can inhibit the environmental pollutant benzo (a) pyrene-induced expression of inflammatory factor IL-1α in SZ95 sebocytes, which is likely mediated by the AhR and p38MAPK pathways.
RESUMEN
Objective:To investigate the effect of erigeron breviscapus (EBHM) on ocular hypertension and the protective effect of retinal ganglion cells (RGCs) in rats by regulating mitogen activated protein kinase (MAPK) signaling pathway.Methods:Sixty male Sprague-Dawley rats were divided into control group, model group, low-dose EBHM group (group A), medium-dose EBHM group (group B), and high-dose EBHM group (group C) by random number table method. There were 12 rats in the group, the left eye was used as the experimental eye. The rats of model group, group A, group B, and group C were infused with normal saline through the anterior chamber to construct an acute ocular hypertension model; the control group was given general anesthesia only. Then, 2-30 days after modeling, rats in the control group and model group were given 3 ml of normal saline once a day; rats in group A, group B, and group C were given 0.30, 0.45, and 0.60 g/100 g EBHM by intragastric administration, respectively, 1 time/d. The rat intraocular pressure was measured before modeling and 1, 14, and 30 days after modeling, and the proportion of high intraocular pressure model was measured. Thirty days after modeling, hematoxylin-eosin (HE) staining was used to observe the pathological changes of retinal tissue; immunofluorescence staining was used to detect the changes in the number of RGCs; real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was used to detect p38 in the retinas of rats in each group. The relative expression of MAPK and Caspase-3 mRNA; western blot was used to detect p38MAPK and phosphorylation in the retina of rats in each group relative expression of phosphorylate-p38MAPK (p-p38MAPK) and Caspase-3 protein. One-way analysis of variance was used for multi-sample comparison, and SNK-q test was used for comparison between two samples. Results:One day after modeling, none of the rats in the control group developed acute ocular hypertension, and the other groups were successfully modeled. Compared with the model group, the rates of acute ocular hypertension at 14 days after modeling in groups B and C were lower ( χ2=98.701, P<0.05), and the rates of acute ocular hypertension at 30 days after modeling in groups A, B, and C were 0. There was no statistically significant difference in the rates of acute ocular hypertension between 14 and 30 days after modeling in the A, B, and C groups ( P>0.05). The results of HE staining showed that the structure of the retina in the control group was complete, and the layers were clearly visible; the RGCs count was not abnormal, and the morphology was plump and round. The retina of rats in the model group became thinner; the number of RGCs was greatly reduced, the morphology was vacuolated, and the arrangement was sparse. The retina of rats in groups A, B, and C became thicker, and the number of RGCs increased, and the retina structure in group C was better restored. The results of immunofluorescence staining showed that the RGCs counts of rats in groups A, B, and C were higher than those in the model group, and the difference was statistically significant ( F=297.514, P<0.05); pairwise comparison between groups, group A was lower than that of group B and C Group ( q=2.842, 5.263), group B was lower than group C ( q=2.457), the difference was statistically significant ( P<0.05). The results of RT-qPCR and Western blot showed that compared with the model group, the relative expression of Caspase-3 mRNA ( F=267.912) and protein ( F=692.279) and the relative expression of p-p38MAPK protein in the retina of rats in groups A, B and C. The expression level ( F=150.061) all decreased, and the difference was statistically significant ( P<0.05); pairwise comparisons between groups showed that Caspase-3 mRNA ( q=6.977, 15.642) and protein ( q=6.997, 15.642) relative expression levels and p-p38MAPK protein ( q=12.443, 24.358) relative expression levels are lower than groups A and B, group B was lower than group A ( q=11.678, 12.471, 10.204), the difference was statistical academic significance ( P<0.05). Conclusions:EBHM can significantly reduce intraocular pressure in rats with acute ocular hypertension, increase RGCs counts, and reduce retinal damage. Its regulatory mechanism may be related to the MAPK pathway.
RESUMEN
Objective:To evaluate the relationship between the mechanism underlying methylprednisolone-induced alleviation of ventilator-induced lung injury (VILI) and p38 mitogen-activated protein kinase (p38 MAPK)/nucleotide binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) pathway in lung tissues of rats.Methods:Sixty clean-grade male Sprague-Dawley rats, weighing 270-320 g, aged 4-5 months, were divided into 3 groups ( n=20 each) using a random number table method: control group (group C), mechanical ventilation group (group V), and methylprednisolone group (group M). Group C breathed air spontaneously for 4 h without mechanical ventilation.Group V was mechanically ventilated (RR 40 times/min, V T 40 ml/kg, I∶E 1∶1, PEEP 0, FiO 2 21%) for 4 h. Group M received intravenous methylprednisolone 10 mg/kg at 20 min before mechanical ventilation.At 4 h of mechanical ventilation, broncho-alveolar lavage fluid (BALF) was collected to measure the concentrations of interleukin-1beta (IL-1β), IL-18, and tumor necrosis factor-alpha (TNF-α) and wet/dry lung weight ratio (W/D ratio), and lung tissues were obtained for microscopic examination of the histopathological changes and for detection of the expression of p38MAPK, phosphorylated p38MAPK (p-p38MAPK), NLRP3, apoptosis-related speck-like protein containing a CARD (ASC), and cysteinyl aspartate-specific protease-1 (caspase-1) (using Western blot). Results:Compared with group C, the W/D ratio of lung tissues and concentrations IL-1β, IL-18 and TNF-α in BALF were significantly increased, and the expression of p-p38MAPK, NLRP3, ASC and caspase-1 was up-regulated in group V ( P<0.05), and no significant change was found in group M ( P>0.05). Compared with group V, the W/D ratio of lung tissues and concentrations of IL-1β, IL-18 and TNF-α in BALF were significantly decreased, and the expression of p-p38MAPK, NLRP3, ASC and caspase-1 was down-regulated in group M ( P<0.05). Conclusion:The mechanism by which methylprednisolone alleviates VILI may be related to inhibition of p38MAPK/NLRP3 pathway activity and reduction of inflammatory responses in lung tissues of rats.
RESUMEN
ABSTRACT Purpose To demonstrate the effect of IL-33 on the macrophage pyroptosis in mice with sepsis through the NF-kB/p38 MAPK signal pathway. Methods In total, 24 C57BL/6 mice were divided into the sham operation group (sham) and the cecal ligation and puncture group (CLP). After CLP, 24 IL-33-/- mice were divided into the IL-33-/- group and the IL-33-/- intervention group. The latter group was intraperitoneally injected with IL-33. Mouse mortality was observed after CLP. Macrophage apoptosis in peritoneal lavage fluid was detected by flow cytometry. Serum inflammatory factor level was detected by ELISA. Apoptotic protein expression and NF-κB/p38 MAKP signaling pathway protein expression were detected by qRT-PCR and Western blot. Results Knocking out IL-33 significantly reduced the mortality of CLP mice, as well as the mRNA expression of IL-33 and the levels of serum inflammatory factors, including IL-33, IL-1β, and IL-18. It also reduced the rate of macrophage apoptosis and the expression of the apoptotic protein caspase-1 p10; increased the expression of IκBα; and reduced the protein expression of NF-κB and p38 MAPK. These effects were reversed after exogenous injection of IL-33. Conclusions IL-33 can increase the level of macrophage pyroptosis in mice with sepsis (by activating the NF-kB/p38MAPK signal pathway) and the mortality of these mice.
Asunto(s)
Animales , Ratones , FN-kappa B/metabolismo , Sepsis , Transducción de Señal , Factor de Necrosis Tumoral alfa , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Interleucina-33 , Piroptosis , Macrófagos/metabolismo , Ratones Endogámicos C57BLRESUMEN
Objective@#To investigate the effects of curcumin on pneumococcal pneumonia-induced pneumonia, apoptosis and p38 MAPK expression in infant mice.@*Methods@#A total of 60 male infant C57BL/6 mice at three weeks of age were randomly divided into 6 groups: control group, model group, high-dose curcumin treatment group, middle-dose curcumin treatment group, low-dose curcumin treatment group and SB203580 treatment group. The Curcumin and SB203580 were intraperitoneally applied at doses of 200, 60, and 20 mg/kg (for curcumin) and 100 mg/kg (for SB203580) from two days before bacterial infection to three days post-infection. The control group and model group were intraperitoneally injected with an equal volume of saline. The model group, curcumin treatment groups and SB203580 treatment group were transnasally inoculated with approximately 106 CFU/ml of pneumococcal pneumonia in 50 μl of PBS applied to the tip of the nose to establish the experimental pneumococcal pneumonia. Subsequently, all the mice were killed and lung tissues were harvested for hematoxylin-eosin staining, calculation of lung score indexes, measurement of IL-1β and TNF-α contents by ELISA, and measurement of Bax, Bcl-2and p38 MAPK expression by Western blot.@*Results@#Compared to the model group, the edema score (0.50 ± 0.10, 1.51 ± 0.16, 1.38±0.11, vs. 2.50 ± 0.20), hemorrhage score (0.32 ± 0.09, 1.01 ± 0.11, 0.85±0.09 vs. 1.80 ± 0.20), inflammatory cell infiltrate score (0.35 ± 0.09, 1.61 ± 0.16, 1.52±0.10 vs. 3.21 ± 0.22), small airway damage score (0.12 ± 0.03, 0.53 ± 0.14, 0.50±0.04 vs. 1.12 ± 0.19) in the medium-, high-dose group and SB203580 treatment group significantly decreased (P<0.01). Compared to the model group, the contents of IL-1β (20.38 ± 1.69 pg/ml, 25.73 ± 2.08 pg/ml vs. 40.22 ± 5.70 pg/ml) and TNF-α (160.39 ± 15.81 pg/ml, 198.67 ± 18.97 pg/ml vs. 282.22 ± 25.30 pg/ml), Bax/Bcl-2 (0.31 ± 0.05, 0.53 ± 0.06 vs. 1.79 ± 0.17) and expression of phosphorylated p38 MAPK (0.69 ± 0.05, 0.81 ± 0.07 vs. 1.71 ± 0.14) in the high-dose group and SB203580 treeatment group significantly decreased (P<0.01).@*Conclusions@#Curcumin can inhibit the inflammatory response and cellular apoptosis in the lungs of mice with pneumococcal pneumonia, and the mechanisms maybe related to its inhibition of p38 MAPK expression.
RESUMEN
Objective@#To investigate the effect of p38 mitogen-activated protein kinase (p38 MAPK) inhibitor on liver function and tissue in rats with hepatic hydatidosis.@*Methods@#A model of liver echinococcosis was established in 100 female Wistar rats, 60 of 100 were, randomly divided into three groups, Control group (0.3 ml normal saline), Low dose group (50 μmol/L p38MAPK inhibitor SB-202190), High dose group (100 μmol/L SB-202190B). The reagents were given via the hepatic artery 1, 3, 7, 14 and 42 days after the rat model was generated. Rats were sacrificed 42 days after the intervention, liver tissue and blood samples were collected for liver function study.@*Results@#Alanine aminotransferase levels were (49.58±2.38) U/L, (38.35±1.34) U/L and (30.93±1.51) U/L and aspartic aminotransferase levels were (67.45±5.14) U/L, (54.86±1.09) U/L and (45.76±1.04) U/L in the Control group, the Low-dose group and High-dose group, showing a decreasing trend, with statistically significant differences (all P<0.05). Triglycerides in the Low-dose group were higher than those in Control group and the High-dose group, with statistically significant differences (all P<0.05). In the Control group, the hepatocytes were severely injured, with almost no normal hepatocytes left, and the normal hepatocyte boundaries were also disrupted, he normal hepatic lobule was replaced by the pseudolobules. In the Low-dose group, there were more inflammatory cells, and less replacement of normal liver cells by pseudolobules. High dose group of a small amount of inflammatory cells infiltration, roughly normal liver cells, normal liver cell line is clear, visible central vein of liver cells.@*Conclusion@#p38MAPK inhibitor SB-202190 improved liver function and reduced liver tissue damage in rats with hepatic hydatidosis.
RESUMEN
Objective To investigate the effect of p38 mitogen-activated protein kinase(p38 MAPK)inhibitor on liver function and tissue in rats with hepatic hydatidosis.Methods A model of liver echinococcosis was established in 100 female Wistar rats,60 of 100 were,randomly divided into three groups,Control group(0.3 ml normal saline),Low dose group(50 p,mol/L p38MAPK inhibitor SB-202190),High dose group(100 μmol/L SB-202190B).The reagents were given via the hepatic artery 1,3,7,14 and 42 days after the rat model was generated.Rats were sacrificed 42 days after the interven-tion,liver tissue and blood samples were collected for liver function study.Results Alanine aminotrans-ferase levels were(49.58±2.38)U/L,(38.35±1.34)U/L and(30.93±1.51)U/L and aspartic ami-notransferase levels were(67.45±5.14)U/L,(54.86±1.09)U/L and(45.76±1.04)U/L in the Control group,the Low-dose group and High-dose group,showing a decreasing trend,with statistically sig-nificant differences(all P＜0.05).Triglycerides in the Low-dose group were higher than those in Control group and the High-dose group,with statistically significant differences(all P＜0.05).In the Control group,the hepatocytes were severely injured,with almost no normal hepatocytes left,and the normal hepato-cyte boundaries were also disrupted,he normal hepatic lobule was replaced by the pseudolobules.In the Low-dose group,there were more inflammatory cells,and less replacement of normal liver cells by pseud-olobules.High dose group of a small amount of inflammatory cells infiltration,roughly normal liver cells,normal liver cell line is clear,visible central vein of liver cells.Conclusionp38MAPK inhibitor SB-202 190 improved liver function and reduced liver tissue damage in rats with hepatic hydatidosis.
RESUMEN
Objective To explore the mechanism of transforming growth factor-beta/p38 mitogen-activated protein kinases (TGF-β/P38MAPK) signaling pathway that transformed corallin into a transforming growth factor-beta/p38 mitogen activated protein kinases (TGF-β/P38MAPK).Methods The hair follicle stem cells (HFSCs) were divided into blank group,positive group and 10-10,10-9,10-8,10-7,10-6,10-5,10-4,10-3 mol/L mycoralin solution groups according to the random number table method.After 24 h,the cell proliferation rate was determined by MTT assay.The HFSCs were divided into blank group,positive group and low,medium and high dose groups according to the random number table method.The positive group was added with 5 mol/L of alkaline fibroblast growth factor solution,while the low,medium and high dose groups were added with 10-7,10-6 and 10-5 mol/L of mycoralin solution for intervention.The cell proliferation rate was determined by MTT assay.The protein expressions ofTGF-β,phosphorylated P38(p-p38),P38,Bax and bcl-2 in cells were detected by Western blot,and mRNA expressions of Bax and bcl-2 in cells of each group were detected by real-time quantitative PCR.Results Compared with the blank group,the productivity of the cells (0.418 ± 0.031,0.412 ± 0.014,0.468 ± 0.024 vs.0.353 ± 0.006) in the 10-7,10-6 and 10-5 mol/L aucubin groups significantly increased (P＜0.01).Compared with the blank group,the protein expression of TGF-β (0.377 ± 0.027,0.338 ± 0.021,0.322 ± 0.017 vs.0.557 ± 0.017),p-p38 (0.270 ± 0.020,0.228 ± 0.013,0.216 ± 0.012 vs.0.461 ± 0.012),Bax (0.450 ± 0.017,0.365 ± 0.011,0.279 ± 0.006 vs.0.551 ± 0.015) in the low,medium and high dose groups significantly down-regulated,while the Bcl-2 (0.450 ± 0.017,0.365 ± 0.011,0.279 ± 0.006 vs.0.358 ± 0.011) protein expression significantly increased.Compared with the blank group,the expression of Bcl-2 (1.714 ± 0.028,2.514 ± 0.054,3.382 ± 0.084 vs.1.000 ± 0) mRNA increased,Bax (0.415 ± 0.020,0.353 ± 0.090,0.235 ± 0.114 vs.1.000 ± 0) mRNA in the low,medium and high dose groups significantly down-regulated (P＜0.01).Conclusions By regulating the TGF-β/p38MAPK signaling pathway,mycoralin can reduce the expression of downstream apoptotic factors,and promote the repair of damaged skin.
RESUMEN
Objective To investigate the effects of curcumin on pneumococcal pneumonia-induced pneumonia, apoptosis and p38 MAPK expression in infant mice. Methods A total of 60 male infant C57BL/6 mice at three weeks of age were randomly divided into 6 groups: control group, model group, high-dose curcumin treatment group, middle-dose curcumin treatment group, low-dose curcumin treatment group and SB203580 treatment group. The Curcumin and SB203580 were intraperitoneally applied at doses of 200, 60, and 20 mg/kg (for curcumin) and 100 mg/kg (for SB203580) from two days before bacterial infection to three days post-infection. The control group and model group were intraperitoneally injected with an equal volume of saline. The model group, curcumin treatment groups and SB203580 treatment group were transnasally inoculated with approximately 106 CFU/ml of pneumococcal pneumonia in 50 μl of PBS applied to the tip of the nose to establish the experimental pneumococcal pneumonia. Subsequently, all the mice were killed and lung tissues were harvested for hematoxylin-eosin staining, calculation of lung score indexes, measurement of IL-1β and TNF-α contents by ELISA, and measurement of Bax, Bcl-2and p38 MAPK expression by Western blot. Results Compared to the model group, the edema score (0.50 ± 0.10, 1.51 ± 0.16, 1.38±0.11, vs. 2.50 ± 0.20), hemorrhage score (0.32 ± 0.09, 1.01 ± 0.11, 0.85±0.09 vs. 1.80 ± 0.20), inflammatory cell infiltrate score (0.35 ± 0.09, 1.61 ± 0.16, 1.52±0.10 vs. 3.21 ± 0.22), small airway damage score (0.12 ± 0.03, 0.53 ± 0.14, 0.50±0.04 vs. 1.12 ± 0.19) in the medium-, high-dose group and SB203580 treatment group significantly decreased (P<0.01). Compared to the model group, the contents of IL-1β (20.38 ± 1.69 pg/ml, 25.73 ± 2.08 pg/ml vs. 40.22 ± 5.70 pg/ml) and TNF-α (160.39 ± 15.81 pg/ml, 198.67 ± 18.97 pg/ml vs. 282.22 ± 25.30 pg/ml), Bax/Bcl-2 (0.31 ± 0.05, 0.53 ± 0.06 vs. 1.79 ± 0.17) and expression of phosphorylated p38 MAPK (0.69 ± 0.05, 0.81 ± 0.07 vs. 1.71 ± 0.14) in the high-dose group and SB203580 treeatment group significantly decreased (P<0.01). Conclusions Curcumin can inhibit the inflammatory response and cellular apoptosis in the lungs of mice with pneumococcal pneumonia, and the mechanisms maybe related to its inhibition of p38 MAPK expression.
RESUMEN
Objective@#To investigate the role and mechanism of nonreceptor tyrosine kinase Tec in the production of pro-inflammatory cytokine interleukin-8 (IL-8) induced by endotoxin/lipopolysaccharide (LPS) in human alveolar epithelial cells A549.@*Methods@#Human alveolar epithelial cells A549 were routinely cultured and passaged in Roswell Park Memorial Institute-1640 medium containing 10% fetal bovine serum. The second or third passage of cells were collected for subsequent experiments. (1) Cells were collected and divided into 6 groups with 4 wells in each group according to the random number table. Cells in blank control group were routinely cultured for 2 h. Cells in simple LPS group were routinely cultured for 1 h and then stimulated by 1 μg/mL LPS for 1 h. Cells in simple LFM-A13 group were cultured with conventional culture medium adding 75 μmol/L LFM-A13 for 1 h and then cultured with replaced conventional culture medium for 1 h. Cells in 25 μmol/L LFM-A13+ LPS group, 75 μmol/L LFM-A13+ LPS group, and 100 μmol/L LFM-A13+ LPS group were cultured with conventional culture medium adding 25, 75, and 100 μmol/L LFM-A13 respectively for 1 h and then all stimulated by 1 μg/mL LPS added into the replaced conventional culture medium for 1 h. The protein expression of Tec in cells of each group was detected by Western blotting, and the content of IL-8 in cell culture supernatant of each group was determined by enzyme-linked immunosorbent assay. (2) Cells were collected and divided into 5 groups with 4 wells in each group according to the random number table. Cells in blank control group were routinely cultured for 2 h. Cells in small interfering RNA (siRNA) control+ LPS group were transfected with empty lentivirus for 10 h and then stimulated by 1 μg/mL LPS added into the conventional culture medium for 2 h. Cells in Tec mus-298 RNA interference (RNAi)+ LPS group, Tec mus-299 RNAi+ LPS group, and Tec mus-300 RNAi+ LPS group were transfected with lentivirus loaded with Tec mus-298 RNAi, Tec mus-299 RNAi, and Tec mus-300 RNAi respectively for 10 h and then stimulated by 1 μg/mL LPS added into the conventional culture medium for 2 h. The protein expression of Tec in cells of each group was detected by Western blotting to screen Tec-siRNA with the best silencing effect on Tec gene. (3) Cells were collected and divided into 4 groups with 4 wells in each group according to the random number table. Cells in blank control group were routinely cultured for 2 h. Cells in virus control group were transfected with empty lentivirus for 10 h and then routinely cultured for 2 h. Cells in simple LPS group were stimulated by 1 μg/mL LPS added into the conventional culture medium for 2 h. Cells in Tec-siRNA+ LPS group were transfected with lentivirus loaded with Tec-siRNA with the best silencing effect on Tec gene for 10 h and then stimulated by 1 μg/mL LPS added into the conventional culture medium for 2 h. The protein expressions of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) MAPK of cells in each group were detected by Western blotting. Data were processed with one-way analysis of variance and the least significant difference-t test.@*Results@#(1) Compared with that of blank control group, the protein expression of Tec of cells in simple LPS group was obviously increased (t=9.72, P<0.05), but the protein expression of Tec of cells in simple LFM-A13 group was not obviously changed (t=4.31, P=0.05). Compared with that of simple LPS group, the protein expression of Tec of cells in 25 μmol/L LFM-A13+ LPS group, 75 μmol/L LFM-A13+ LPS group, or 100 μmol/L LFM-A13+ LPS group was obviously decreased (t=9.72, 9.07, 16.33, P<0.05 or P<0.01). Compared with (189±22) pg/mL of blank control group, the content of IL-8 in culture supernatant of cells in simple LPS group was obviously increased [(214±10) pg/mL, t=2.18, P<0.05], but the content of IL-8 in culture supernatant of cells in simple LFM-A13 group was not obviously changed [(173±43) pg/mL, t=0.64, P>0.05]. Compared with that of simple LPS group, the content of IL-8 in culture supernatant of cells in 25 μmol/L LFM-A13+ LPS group was not obviously changed [(204±38) pg/mL, t=0.54, P>0.05], but the content of IL-8 in culture supernatant of cells in 75 μmol/L LFM-A13+ LPS group and 100 μmol/L LFM-A13+ LPS group was obviously decreased [(144±44), (137±51) pg/mL, t=3.63, 2.55, P<0.05 or P<0.01]. (2) Compared with that of blank control group, the protein expression of Tec of cells in siRNA control+ LPS group was obviously increased (t=14.24, P<0.01). Compared with that of siRNA control+ LPS group, the protein expression of Tec of cells in Tec mus-298 RNAi+ LPS group or Tec mus-299 RNAi+ LPS group was obviously decreased (t=36.03, 18.23, P<0.01), but the protein expression of Tec of cells in Tec mus-300 RNAi+ LPS group was not obviously changed (t=4.08, P>0.05). The protein expression of Tec was the lowest in cells of Tec mus-298 RNAi+ LPS group, so Tec mus-298 RNAi was used in subsequent experiment. (3) Compared with 1.16±0.16 and 0.78±0.11 of blank control group, the protein expressions of p38 MAPK and ERK MAPK of cells in virus control group were not obviously changed (1.66±0.13, 0.89±0.11, t=11.09, 3.60, P>0.05), but the protein expressions of p38 MAPK and ERK MAPK of cells in simple LPS group were obviously increased (2.83±0.29, 1.86±0.37, t=9.70, 7.23, P<0.05). Compared with those of simple LPS group, the protein expression of p38 MAPK and protein expression of ERK MAPK of cells in Tec-siRNA+ LPS group were obviously decreased (0.69±0.16, 1.03±0.24, t=13.78, 4.12, P<0.05 or P<0.01).@*Conclusions@#Tec may mediate the production and release of pro-inflammatory cytokine IL-8 from human alveolar epithelial cells A549 induced by LPS via the p38 MAPK and ERK MAPK signal pathways.
RESUMEN
Objective To evaluate the endotoxin-induced endogenous protective mechanism of alveolar type Ⅱ epithelial cells of rats and the relationship with p38 mitogen-activated protein kinase (p38MAPK)-HO-1-mitochondrial fusion signaling pathway.Methods Rat alveolar type Ⅱ epithelial cells were seeded in 6-well plates at a density of 2× 105 cells/ml and divided into 5 groups (n =15 each) using a random number table method:control group (group C),lipopolysaccharide (LPS) group (group L),LPS plus p38MAPK inhibitor SB203580 group (group LS),LPS plus dimethyl sulfoxide group (group LD),and SB203580 group (group S).Cells were conventionally cultured in group C.The model of endotoxin-challenged alveolar type Ⅱ epithelial cells was established by giving LPS 10 μg/ml in L,LS and LD groups.SB203580 10 μmol and 0.1％ dimethyl sulfoxide 100 μμmol were added at 1 h before giving LPS in group LS and group LD,respectively.SB203580 10 μ mol was added to the culture medium in group S.All the cells were incubated for 24 h.The malonaldehyde (MDA) content and superoxide dismutase (SOD) activity in the culture medium were determined by thiobarbituric acid assay and xanthine oxidase method,respectively.The expression of p38MAPK,phosphorylated p38MAPK (p-p38MAPK),hemeoxygenase-1 (HO-1),mitofusin 1 (Mfn1),Mfn2,and optical atrophy-1 (OPA1) was measured by Western blot.Results Compared with group C,the MDA content was significantly increased,the SOD activity was decreased,and the expression of p-p38MAPK and HO-1 was up-regulated,and the expression of Mfn1,Mfn2 and OPA1 was down-regulated in L,LS and LD groups (P＜0.05).Compared with group L,the MDA content was significantly increased,the SOD activity was decreased,and the expression of pp38MAPK,HO-1,Mfn1,Mfn2 and OPA1 was down-regulated in group LS (P＜0.05),and no significant change was found in the indices mentioned above in group LD (P＞0.05).Conclusion The endotoxin-induced endogenous protective mechanism of alveolar type Ⅱ epithelial cells is related to p38MAPK-HO-1-mitochondrial fusion signaling pathway in rats.
RESUMEN
Objective To evaluate the role of Toll-like receptor 4 (TLR4)-p38 mitogen-assoliated protein kinase (p38MAPK)-nuclear factor kappa B (NF-κB) signaling pathway in sevoflurane-induced decrease in cognitive function of aged rats.Methods Sixty SPF healthy male Sprague-Dawley rats,aged 20 months,weighing 550-750 g,were divided into 5 groups (n =12 each) using a random number table method:control group (C group),sevoflurane group (S group),TAK242 plus sevoflurane group (TS group),SB202190 plus sevoflurane group (SS group),and PDTC plus sevoflurane group (PS group).All the rats were intubated after anesthesia and connected to an animal ventilator.TAK242,SB202190 and PDTC 10 μl were injected into the lateral cerebral ventricle in TS,SS and PS groups,respectively,and normal saline containing the equal volume of DMSO was given in C and S groups.Starting from 10 min after lateral cerebral ventricle injection,4％ sevoflurane was inhaled for 6 h via the tracheal tube,with the inhaled oxygen concentration 30％ and oxygen flow rate 2 L/min.The mixture of air and oxygen was inhaled in C group.The learning and memory ability was assessed by Morris water maze test at 7 days after the end of sevoflurane anesthesia,and the escape latency and swimming distance were recorded.Animals were sacrificed after the end of Morris water maze test,and brains were removed and hippocampi were isolated for determination of neural apoptosis (by TUNEL),contents of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) in hippocampal tissues (by enzyme-linked immunosorbent assay),and expression of caspase-3,phosphorylated p38MAPK (p-p38MAPK),total p38MAPK (t-p38MAPK) and NF-κB in nucleus (by Western blot).The apoptosis rate and p-p38MAPK/t-p38MAPK ratio were calculated.Results Compared with C group,the escape latency and swimming distance were significantly prolonged at each time point,the apoptosis rate and contents of TNF-oα and IL-1β were increased,the expression of caspase-3,p-p38MAPK and NF-κB was up-regulated,and p-p38MAPK/t-p38MAPK ratio was increased in the other four groups (P＜0.05).Compared with S group,the escape latency and swimming distance were significantly shortened at each time point,the apoptosis rate and contents of TNF-α and IL-1β were decreased,and the expression of caspase-3 was down-regulated in TS,SS and PS groups,the expression of NF-κB was significantly down-regulated in TS and SS groups,and the expression of p-p38MAPK was significantly down-regulated,and p-p38MAPK/t-p38MAPK ratio was decreased in TS group (P＜0.05).Compared with TS group,the escape latency and swimming distance were significantly prolonged at each time point,the apoptosis rate and contents of TNF-α and IL-1β were increased,the expression of caspase-3 and p-p38MAPK was up-regulated,and p-p38MAPK/t-p38MAPK ratio was increased in SS and PS groups,and the expression of NF-κB was significantly up-regulated in PS group (P＜0.05).The expression of NF-κB was significantly up-regulated in PS group when compared with SS group (P＜0.05).Conclusion TLR4-p38MAPKNF-κB signaling pathway is involved in sevoflurane-induced decrease in cognitive function of aged rats.