Objective: Kangxian Pills, containing Angelicae Sinensis, Chuanxiong Rhizoma, radix paeoniae rubra, and 12 other kinds of Chinese materia medica, have the functions of softening and dispersing blood stasis. It has been used for liver injury and liver fibrosis. The current study was designed to evaluate the anti-hepatic injury activity and the mechanism of Kangxian Pills on a CCl4-induced animal model. Methods: To induce chronic liver injury, mice were treated with CCl4 twice a week for four weeks. Kangxian Pills (6 or 12 g/kg) and Compound Biejia Ruangan Tablet (0.901 g/kg) were ig given to mice once daily for four weeks after CCl4 was withdrawal. The anti-hepatic injury activities and mechanisms of Kangxian Pills were assessed by hepatic histology and by measuring the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), and total protein (TP) of serum as well as superoxide dismutase (SOD) and glycogen (Gn) of the liver. Results: Kangxian Pills significantly decreased the levels of liver index, ALT, and AST in mice liver injury models in treatment group. Moreover, Kangxian Pills and Compound Biejia Ruangan Tablet inhibited the CCl4-induced reduction of SOD and Gn levels in the liver. The histological study showed that Kangxian Pills could reduce cellular swelling and infiltration of inflammatory cells in liver injury. Conclusion: Kangxian Pills possess the potent abilities to alleviate chronic liver injury, suggesting that Kangxian Pills exert this effect by enhancing the anti-oxidant ability and metabolism of the liver.

Objective To observe dynamically osteopontin(OPN) expression in the renal tubules of streptozotocin(STZ) induced diabetic rats, and to explore the relationship between OPN and angiotensinⅡ(AngⅡ), nuclear transcription factor-?B(NF-?B), and renal injuries. Methods Male SD rats were injected with STZ to induce diabetes mellitus, which were randomly divided into 5 groups and meanwhile there were other 5 age-matched normal control groups. Immunohistochemistry was employed to observe the expression of OPN, AngⅡ, NF-?B and fibronectin(FN) in renal tubules. The OPN and I-?B protein in renal cortex was detected by Western blot methods. Blood glucose, serum creatinine and 24 h urine protein were examined. The renal morphology was checked through light microscopy.Results The AngⅡand NF-?B expression from DM day 3, OPN expression from day7, FN from week 2 in renal cortex or tubules was increased as compared with control groups, while I-?B protein in renal cortex was gradually decreased since day 3. In DM week 4, there were positive correlations between OPN and AngⅡ, NF-?B, FN and 24 h urine protein. Conclusion An increase of OPN expression in the renal tubules of diabetic rats may be regulated by AngⅡ and NF-?B, and therefore participates the injury mechanisms of renal tubulo-intestitium.

OBJECTIVETo study the effect and potential mechanism of expression of c-jun N-terminal kinase (JNK) signal pathway on neuron autophagy after diffuse brain injury (DBI).

METHODSMale Sprague Dawley rats (n = 216) were randomly divided into four groups: DBI group (n = 54), SP600125 intervene group (n = 54), DMSO group (n = 54) and sham operation group (n = 54). DBI rat model was established according to the description of Marmarou DBI. At different time points (1, 6, 12, 24, 48 and 72 h) after operation, the histopathologic changes of neurons in cortex were observed by HE staining method; The expression of p-JNK, p-P53, DRAM and Beclin-1 were detected by Western blot and immunohistochemistry.

RESULTSThe results showed that under light microscope degenerated and necrotic neurons were observed to be scattered in cortex at 6 h after operation in DBI group, but these changes were low in SP600125 intervene group. Compared with SP600125 intervene group, the expression of p-JNK in DBI group were enhanced obviously at 6, 12 and 24 h (F = 17.902, P < 0.05); the expression of p-P53 in DBI group were enhanced obviously at 12, 24, 48 and 72 h (F = 7.107, P < 0.05); the expression of DRAM in DBI group were enhanced obviously at 6, 12, 24, 48 and 72 h (F = 15.455, P < 0.05); the expression of Beclin-1 in DBI group were enhanced obviously at 6, 12, 24, 48 and 72 h (F = 11.517, P < 0.05). Compared with DBI group, the expression of p-JNK, p-P53, DRAM and Beclin-1 in DMSO group were similar at 1, 6, 12, 24, 48 and 72 h (F = 1.509, P > 0.05).

CONCLUSIONSThe present results indicate that SP600125 can dramatically improve trauma brain injury from autophagy after DBI and the molecular mechanism is related to the modulation of JNK signal pathway following DBI, while it measures the neuron autophagy by means of intervening JNK signal pathway.

Animals ; Anthracenes ; pharmacology ; Autophagy ; Brain Injuries ; metabolism ; pathology ; Disease Models, Animal ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Male ; Neurons ; pathology ; Rats ; Rats, Sprague-Dawley

BACKGROUNDOnabotulinumtoxinA is widely used in treating neurogenic detrusor overactivity (NDO). We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug for treating NDO.

METHODSWe searched the following databases: Medline, EMBASE, and the Cochrane Controlled Trials Register. All published randomized double-blind, placebo-controlled trials of onabotulinumtoxinA for the treatment of NDO were identified in the analysis. The reference lists of the retrieved studies were also investigated.

RESULTSFour publications involving a total of 807 patients were identified in the analysis, which compared onabotulinumtoxinA with placebo. The changes of the mean number of urinary incontinence per week (the standardized mean difference [SMD] = -10.91, 95% confidence intervals [CIs] = -14.18--7.63, P < 0.0001); maximum cystometric capacity (SMD = 146.09, 95% CI = 126.19-165.99, P < 0.0001) and maximum detrusor pressure (SMD = -32.65, 95% CI = -37.83--27.48, P < 0.0001) indicated that onabotulinumtoxinA was more effective than the placebo, despite the doses of onabotulinumtoxinA. Safety assessments primarily localized to the urinary tract indicated onabotulinumtoxinA were often associated with more complications. Urinary tract infections (relative risk [RR] =1.48, 95% CI = 1.20-1.81, P = 0.0002); hematuria (RR = 1.81, 95% CI = 1.00-3.24, P = 0.05) and urinary retention (RR = 5.87, 95% CI = 3.61-9.56, P < 0.0001).

CONCLUSIONSThis meta-analysis indicates that onabotulinumtoxinA to be an effective treatment for NDO with side effects primarily localized to urinary tract.

Botulinum Toxins, Type A ; adverse effects ; therapeutic use ; Humans ; Urinary Bladder, Overactive ; drug therapy

BACKGROUNDActivation of c-Jun NH(2)-terminal kinase (JNK) has been implicated in neuron apoptosis as well as autophagy in response to various stressors after traumatic brain injury (TBI). However, the underlying molecular pathway remains unclear. Our study assessed whether JNK-mediated p53 phosphorylation might be an important mechanism for enhancing neuron autophagy in response to TBI.

METHODSA total of 186 male Sprague-Dawley (SD) rats (300 - 350 g) were used in this study. By randomized block method rats were randomly divided into four groups: sham-operated (n = 46), TBI (n = 60), TBI + dimethyl sulfoxide (DMSO) (n = 40), and TBI + SP600125 (n = 40). JNK was treated with SP600125, a specific JNK inhibitor. JNK, p-P53, Beclin-1, damage-regulated autophagy modulator (DRAM) and p-bcl-2 were evaluated by Western blotting analysis. The cellular localization and expression of Beclin-1 and DRAM was observed by immunofluorescence and immunohistochemistry, and the expression of Beclin-1-Bcl-2/Bcl-xL complexes was evaluated by immunoprecipitation. Multiple-group comparisons were conducted using analysis of variance (ANOVA). P values of less than 0.05 were considered statistically significant.

RESULTSIt was observed that the expression of JNK, p-P53, Beclin-1, DRAM and p-bcl-2 was increasing after TBI, and the expression of Beclin-1 and DRAM was mainly located in the cytoplasm of neurons. But these were significantly inhibited in SP600125 group compared with sham group and TBI + SP600125 group (P < 0.05). The expression of Beclin-1-Bcl-2/Bcl-xL complexes was reduced after TBI.

CONCLUSIONJNK-mediated p53 phosphorylation might be an important mechanism for enhancing neuron autophagy in response to TBI.

Animals ; Apoptosis Regulatory Proteins ; metabolism ; Autophagy ; Beclin-1 ; Blotting, Western ; Brain Injuries ; metabolism ; Fluorescent Antibody Technique ; Hippocampus ; cytology ; metabolism ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Male ; Microscopy, Fluorescence ; Neurons ; cytology ; metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; Tumor Suppressor Protein p53 ; metabolism ; bcl-X Protein ; metabolism

OBJECTIVETo investigate the influence of ambroxol on paraquat poisoning induced acute lung tissue injury and the change of pulmonary surfactant associated protein A in the experimental rats.

METHODSOne hundred and twenty healthy adult male Sprague-Dawley rats were randomizedly assigned into normal saline (NS) group (n = 24), paraquat poisoning induced lung tissue injury model (PQ) group (n = 48) and ambroxol treatment (AT) group (n = 48). The indexes were observed among the three groups comprising the mortality rate, the change of arterial blood PaCO(2) and PaO(2), the ratio of wet to dry lung tissue (W/D), the change of the lung tissue under light and electric microscope respectively, and the expression of pulmonary surfactant associated protein A.

RESULTSThe mortality rate of rats in the PQ group was 50.0% on the seventh day while the mortality rate in the AT group was 25.0%. The level of arterial blood PaCO(2) in the PQ group (6.94 +/- 0.8) kPa was significantly higher than that in the AT group (6.12 +/- 0.5) kPa and the NS group (4.6 +/- 0.4) kPa. The level of arterial blood PaO(2) in the PQ group (6.98 +/- 1.1) kPa was significantly lower than that in the AT group (8.25 +/- 0.7) kPa and the NS group (12.7 +/- 0.8) kPa. There were significant differences among the groups (P < 0.05). The degree of lung tissue injury was severe in PQ group and relieved in AT group. The expression of pulmonary surfactant associated protein A was significantly decreased in PQ group 13.22% +/- 2.21% on the seventh day, compared with that in the AT group (21.82% +/- 3.67%) (P < 0.05). The expression of pulmonary surfactant associated protein A in AT group was significantly higher in the AT group (18.97% +/- 0.91%) than that in the PQ group on the seventh day (P < 0.05).

CONCLUSIONAmbroxol plays a role in facilitating synthesis and secretion of pulmonary surfactant protein A and relieves the lung tissue injury induced by paraquat poisoning.

Ambroxol ; pharmacology ; Animals ; Immunohistochemistry ; Lung ; metabolism ; pathology ; Male ; Paraquat ; poisoning ; Pulmonary Surfactant-Associated Protein A ; biosynthesis ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome, Adult ; chemically induced ; metabolism ; pathology

OBJECTIVETo evaluate the protective effect of high dose ambroxol, a mucoactive drug, on acute lung injury caused by paraquat in rats.

METHODSOne hundred and thirty-six healthy male Sprague-Dawley rats were randomly divided into three groups: control group (n = 24) injected with normal saline intraperitoneally, PQ group (n = 56) [(2% paraquat (25 mg/kg) injected into peritoneal cavity on the first day)] and AT group (n = 56) ambroxol 35 mg/kg was injected into peritoneum daily after paraquat intoxication once daily for 7 consecutive days. The arterial gas was determined and the extent of lung injury was assessed by measuring the ratio of wet to dry weight (W/D) and protein content in BALF, the WBC count, the percentage of PMN, the content of malondialdehyde (MDA) and the levels of superoxide dismutase (SOD) in the blood and BALF respectively. Left lung tissue was observed through both light microscope and electron microscope (TEM).

RESULTSThe white cell count and the content of protein in the blood and the BALF of PQ group were significantly higher than those of the control group (P < 0.05 or P < 0.01). On the 7th day, the content of MDA 9 [(8.12 +/- 1.12) nmol/ml] in the serum of PQ group was significantly higher than the control group and the GSH-Px activity [(1256.8 +/- 133.2) U/ml] was significantly lower than the control group (P < 0.01). The white cell count and the content of protein in the blood and the BALF of AT group were significantly lower than the PQ group (P < 0.05 or P < 0.01). On the 7th day, the content of MDA in the serum of the AT group [(4.86 +/- 0.75) nmol/ml] was significantly lower than the PQ group and the GSH-Px activity [(1509.5 +/- 183.0) U/ml] and the SOD activity [(3903.2 +/- 374.7) U/ml] were significantly higher than the PQ group (P < 0.01). Under optical and electronic microscopes, the injury of lung tissue was reduced after large dose of ambroxol was administered.

CONCLUSIONTreatment with ambroxol (35 mg/kg) could influence the status of oxidative stress in lung and alleviate lung injury induced by paraquat. Ambroxol has obviously therapeutic effect on paraquat poisoning.

Acute Lung Injury ; chemically induced ; drug therapy ; metabolism ; pathology ; Ambroxol ; pharmacology ; therapeutic use ; Animals ; Disease Models, Animal ; Lung ; drug effects ; metabolism ; pathology ; Male ; Oxidative Stress ; Paraquat ; poisoning ; Rats ; Rats, Sprague-Dawley

Background Activation of c-Jun NH2-terminal kinase (JNK) has been implicated in neuron apoptosis as well as autophagy in response to various stressors after traumatic brain injury (TBI).However,the underlying molecular pathway remains unclear.Our study assessed whether JNK-mediated p53 phosphorylation might be an important mechanism for enhancing neuron autophagy in response to TBI.Methods A total of 186 male Sprague-Dawley (SD) rats (300-350 g) were used in this study.By randomized block method rats were randomly divided into four groups:sham-operated (n=46),TBI (n=60),TBI + dimethyl sulfoxide (DMSO) (n=40),and TBI + SP600125 (n=40).JNK was treated with SP600125,a specific JNK inhibitor.JNK,p-P53,Beclin-1,damage-regulated autophagy modulator (DRAM) and p-bcl-2 were evaluated by Western blotting analysis.The cellular localization and expression of Beclin-1 and DRAM was observed by immunofluorescence and immunohistochemistry,and the expression of Beclin-1-Bcl-2/Bcl-xL complexes was evaluated by immunoprecipitation.Multiple-group comparisons were conducted using analysis of variance (ANOVA).P values of less than 0.05 were considered statistically significant.Results It was observed that the expression of JNK,p-P53,Beclin-1,DRAM and p-bcl-2 was increasing after TBI,and the expression of Beclin-1 and DRAM was mainly located in the cytoplasm of neurons.But these were significantly inhibited in SP600125 group compared with sham group and TBI+SP600125 group (P ＜0.05).The expression of Beclin-1-Bcl-2/Bcl-xL complexes was reduced after TBI.Conclusion JNK-mediated p53 phosphorylation might be an important mechanism for enhancing neuron autophagy in response to TBI.

Objective:To investigate the effect of hourly ambient temperature exposure on emergency calls in Xuchang city and Zhengzhou city.Methods:The hourly meteorological data, air pollution data and emergency calls of Xuchang city and Zhengzhou city were collected from January 1, 2017 to October 31, 2019. A distributed lag non-linear model was used to calculate the excess relative risk ( ERR). The lag effect and cumulative effect of extreme temperature exposure on emergency calls were evaluated. Results:The relationship between hourly temperature exposure and emergency calls was a U-shaped curve. In Xuchang city and Zhengzhou city, both low and high temperatures would increase the number of hourly emergency calls. The earliest effect of low temperature occurred at a lag of 22 h and 52 h, with ERR values (95% CI) about 0.20% (0.00%, 0.39%) and 0.11% (0.00%, 0.22%), respectively. The earliest effect of high temperature occurred at a lag of 0 h with ERR values about 1.59% (1.09%, 2.09%) and 1.45% (1.22%, 1.69%), respectively. High temperature had the greatest impact on the number of emergency calls of cardiovascular disease at a lag of 4-8 h. The cumulative ERR values (95% CI) of the two cities were 8.70% (4.98%, 12.75%) and 3.89% (2.61%, 5.22%), respectively. Conclusion:High temperature exposure could increase the number of emergency calls within a few hours, while the effect of low temperature would not occur until 22 hours later.

Objective:To investigate the effect of hourly ambient temperature exposure on emergency calls in Xuchang city and Zhengzhou city.Methods:The hourly meteorological data, air pollution data and emergency calls of Xuchang city and Zhengzhou city were collected from January 1, 2017 to October 31, 2019. A distributed lag non-linear model was used to calculate the excess relative risk ( ERR). The lag effect and cumulative effect of extreme temperature exposure on emergency calls were evaluated. Results:The relationship between hourly temperature exposure and emergency calls was a U-shaped curve. In Xuchang city and Zhengzhou city, both low and high temperatures would increase the number of hourly emergency calls. The earliest effect of low temperature occurred at a lag of 22 h and 52 h, with ERR values (95% CI) about 0.20% (0.00%, 0.39%) and 0.11% (0.00%, 0.22%), respectively. The earliest effect of high temperature occurred at a lag of 0 h with ERR values about 1.59% (1.09%, 2.09%) and 1.45% (1.22%, 1.69%), respectively. High temperature had the greatest impact on the number of emergency calls of cardiovascular disease at a lag of 4-8 h. The cumulative ERR values (95% CI) of the two cities were 8.70% (4.98%, 12.75%) and 3.89% (2.61%, 5.22%), respectively. Conclusion:High temperature exposure could increase the number of emergency calls within a few hours, while the effect of low temperature would not occur until 22 hours later.