Intervention effect and mechanism of breviscapine on hepatic fibrosis in rats / 中国药房

OBJECTIVE To investigate the intervention effect and potential mechanism of breviscapine on hepatic fibrosis （HF） in rats based on the transforming growth factor-β（1 TGF-β1）/Smad2/extracellular signal-regulated protein kinase 1（ERK1） and Kelch-like epichlorohydrin-associated protein 1（Keap1）/nuclear factor-erythroid 2-related factor 2（Nrf2）/heme oxygenase-1（HO-1） pathways. METHODS Totally 60 rats were randomly divided into normal control group， model group， breviscapine low-dose， medium-dose and high-dose groups （5.4， 10.8， 21.6 mg/kg）， and colchicine group （positive control， 0.45 mg/kg）， with 10 rats in each group， half male and half female. Except for the normal control group， HF model of the other groups was induced by carbon tetrachloride. Subsequently， each drug group was given corresponding medicine by gavage once a day for 28 days. The liver appearance of rats in each group was observed and their liver coefficients were calculated. The levels of alanineaminotransferase （ALT） and aspartate aminotransferase （AST）in serum， those of ALT， AST， superoxide dismutase （SOD），malondialdehyde （MDA） and glutathione peroxidase （GSH- Px） in liver tissue were detected. The liver tissue inflammatory and fibrotic changes were observed. The protein and mRNA expressions of TGF-β1， Smad2， ERK1， Nrf2， Keap1 and HO-in liver tissue were detected. RESULTS Compared with the normal control group， the model group showed large areas of white nodular lesions in the liver， obvious inflammatory cell infiltration and collagen fiber deposition. The body weight， the levels of SOD and GSH-Px in liver tissue， the protein and mRNA expressions of Nrf2 and HO-1 were significantly lowered in the model group （P＜0.05）； the liver coefficient， the percentage of Masson staining positive area， ALT and AST levels of serum and liver tissue， MDA level of liver tissue， the protein and mRNA expressions of TGF-β1， Smad2， ERK1 and Keap1 were significantly increased （P＜0.05）. Compared with the model group， the liver lesions of rats in each drug group were improved， and the above quantitative indexes were generally reversed （P＜0.05）. CONCLUSIONS Breviscapine has a good intervention effect on HF rats， which may be related to inhibiting TGF-β1/Smad2/ERK1 pathway for anti-fibrosis and regulating Keap1/Nrf2/HO-1 pathway to inhibit oxidative stress.

Network analysis and experimental verification of Schisandrin B reduces intestinal ischemia reperfusion injury / 中国临床药理学与治疗学

AIM: To explore schisandrin B (Sch B) pretreatment reduces intestinal ischemia reperfusion injury (IIRI) through inhibiting apoptosis by activation of Nrf2/HO-1 signing pathway in mice by network pharmacology and in vivo experiment. METHODS: (1) The targets of Sch B and IIRI were searched from online databases, Drawing Venn diagram to obtain the common target of them. Cytoscape software was imported to construct the protein-protein interaction (PPI) network to establish the "Drugs-Disease-core target gene" network. The mechanism of Sch B against IIRI was predicted through GO and KEGG enrichment analysis. (2) Thirty-six C57BL/6J mice were randomly divided into six groups (n = 6). The model of IIRI was established in four groups except the sham operation group. Three of the groups were pretreated with Sch B, Nrf2 inhibitor ML385, and Sch B + ML385, respectively. After the experiment, intestinal tissue samples were taken for HE staining, Chiu ' s score, apoptosis staining, immunohistochemistry (IHC), and immunoblotting (Western blot). RESULTS: A total of 412 Sch B related tar- gets, 2 166 IIRI related targets and 153 common targets were screened out through network pharmacology. There were 88 "Sch B-IIRI-core target gene" included NFE2L2 (Nrf2), HMOX1 (HO-1), BCL2, CASP3 (caspase 3), and so on. KEGG enrichment analysis screened 163 related pathways, apoptosis pathway ranked high showing that the pathway may play a key role in the treatment of IIRI by Sch B. The animal experiment had shown that Sch B reduced the Chiu's score and apoptotic while upregulating Nrf2, HO-1, Bcl-2 protein expression levels and Bcl-2/Bax, downregulating Bax, and cleaved caspase-3 expression levels, thereby reducing IIRI in mice, and that Nrf2 inhibitor ML385 reversed this process (P < 0.05). CONCLUSION: This study reveals that Sch B has the characteristics of multi-target and multi-pathway in the reduction of IIRI, and Sch B can reduce IIRI through inhibiting apoptosis by activation of Nrf2/ HO-1 pathway.

Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway / 中国中药杂志

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1β), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1β and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1β and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

Protective effects of polysaccharides from Platycarya strobilacea Sieb.et Zucc on cerebral ischemia-reperfusion injury in rat / 中国生化药物杂志

Objective To investigate protective effects of polysaccharides from Platycarya strobilacea Sieb.et Zucc on cerebral ischemia-reperfusion injury in rats.MethodsForty Wistar rats were randomly divided into four groups:sham group,model group,Rehmannia glutinosa polysaecharide low,and high dose groups.Each group was given oral administration for 7 days.After 1 h of last administration, the CIRI (cerebral ischemia-reperfusion injury) group was produced inserting 5-0 line into the internal carotid artery.Neurological functional score was evaluated according to the method of Zea longa's score, meanwhile,infarct size was detected by TTC staining.Levels of superoxide dismutase (SOD) activity,malondialdehyde (MDA), IL-10, IL-1β and TNF-α contents in cerebral tissues were measured.TUNEL staining was used to assess the number of TUNEL-positive cells of the ischemic cortex.Western blot was used to analyze the expressions of Nrf2 and HO-1 in cerebral tissues.ResultsCompared to model group, Platycarya strobilacea a polysaccharides could significantly improve neurogical functions,greatly decrease the contents of MDA, IL-10 and IL-1β in cerebral tissues,improve SOD activity and IL-10 content in cerebral tissues,and effectively reduce cerebral infarct range.Meanwhile Platycarya strobilacea polysaccharides could enhance the expressions of Nrf2 and HO-1 in cerebral tissues.ConclusionPlatycarya strobilacea polysaccharides have beneficial effects on rats with cerebral ischemia-reperfusion injury, which may be mediated at least in part by the Nrf2/HO-1 pathway.

Protective Mechanism of Tempol on Hypobaric Hypoxia-Induced Heart Damage in Mice / 中国药学杂志

OBJECTIVE: To study the effect mechanism of tempol against hypobaric hypoxia-induced heart damage in mice. METHODS: One hundred and ten BALB/c mice were randomly divided into normal control group, hypoxia model group, acetazolamide group and tempol group. After single intraperitoneal injection for 30 min, the mice were exposed to a simulated high altitude of 8 000 m for 12 h. After hypoxic exposure, blood was collected from the eye sockets and separated into serum to measure the activities of lactic dehydrogenase (LDH)and creatine kinase (CK). Then the mice were sacrificed and the content of H2O2 and malondialdehyde (MDA) as well as ATPase and antioxidant enzyme activity in heart were determined. HIF-1, VEGF, Nrf2, and HO-1 were detected by immunohistochemistry. RESULTS: Compared with normal control group, the activities of plasma CK and LDH in hypoxia model group significantly increased. In addition, the content of H2O2 and MDA in hypoxia model group significantly increased while ATPase and antioxidant enzymes activity markedly decreased compared with the normal control group. Moreover, the expression of HIF-1α, VEGF, Nrf2 and HO-1 increased. Prior administration of tempol effectively decreased the activities of plasma CK and LDH as well as the content of H2O2 and MDA in heart tissue. Tempol could increase ATPase and antioxidant enzyme activities and decreased the expression of HIF-1α and VEGF compared with hypoxia model, while it could further increase the expression of Nrf2 and HO-1. CONCLUSION: Tempol has protective effect on heart injury induced by hypobaric hypoxia in mice. Its mechanism may be attributed to the amelioration of energy metabolism, scavenging free radical, improvement of antioxidant enzyme activity the activation of the Nrf2/HO-1 pathway as well as alleviation of oxidative stress.