This study investigated the effects and mechanisms of total saponins of Panax japonicus(TSPJ) against liver injury induced by acetaminophen(APAP). Male Kunming mice were randomly divided into a blank control group, TSPJ group(200 mg·kg~(-1), ig), model group, APAP+ TSPJ low-dose group(50 mg·kg~(-1), ig), APAP+ TSPJ medium-dose group(100 mg·kg~(-1), ig), APAP+ TSPJ high-dose group(200 mg·kg~(-1), ig), and APAP+ N-acetyl-L-cysteine group(200 mg·kg~(-1), ip). The administration group received the corresponding medications via ig or ip once a day for 14 consecutive days. After the last administration for one hour, except for the blank control group and TSPJ group, all groups of mice were given 500 mg·kg~(-1) APAP by gavage. After 24 hours, mouse serum and liver tissue were collected for serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), tumor necrosis factor alpha(TNF-α), interleukin-1 beta(IL-1β), cyclooxygenase-2(COX-2), IL-6, IL-4, IL-10, as well as lactate dehydrogenase(LDH), glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and myeloperoxidase(MPO) liver tissue. Hematoxylin-eosin staining was used to observe the morphological changes of liver tissue. The mRNA expression levels of lymphocyte antigen 6G(Ly6G), galectin 3(Mac-2), TNF-α, IL-1β, COX-2, IL-6, IL-4, and IL-10 in liver tissue were determined by quantitative real-time polymerase chain reaction(PCR). Western blot was utilized to detect the protein expression levels of Ly6G, Mac-2, extracellular regulated protein kinases(ERK), phosphorylated extracellular regulated protein kinases(p-ERK), COX-2, inhibitor of nuclear factor κB protein α(IκBα), phosphorylated inhibitor of nuclear factor κB protein α(p-IκBα), and nuclear factor-κB subunit p65(NF-κB p65) in cytosol and nucleus in liver tissue. The results manifested that TSPJ dramatically reduced liver coefficient, serum ALT, AST, ROS, TNF-α, IL-1β, IL-6, and COX-2 levels, LDH, MPO, and MDA contents in liver tissue, and mRNA expressions of TNF-α, IL-1β, and IL-6 in APAP-induced liver injury mice. It prominently elevated serum IL-4 and IL-10 levels, GSH, CAT, SOD, and T-AOC contents, and mRNA expressions of IL-4 and IL-10 in liver tissue, improved the degree of liver pathological damage, and suppressed neutrophil infiltration and macrophage recruitment in liver tissue. In addition, TSPJ lessened the mRNA and protein expressions of neutrophil marker Ly6G, macrophage marker Mac-2, and COX-2 in liver tissue, protein expressions of p-ERK, p-IκBα, and NF-κB p65 in nuclear, and p-ERK/ERK and p-IκBα/p-IκBα ratios and hoisted protein expression of NF-κB p65 in cytosol. These results suggest that TSPJ has a significant protective effect on APAP-induced liver injury in mice, and it can alleviate APAP-induced oxidative damage and inflammatory response. Its mechanism may be related to suppressing ERK/NF-κB/COX-2 signaling pathway activation, thus inhibiting inflammatory cell infiltration, cytokine production, and liver cell damage.
The present study was conducted to investigate whether hydroxysafflor yellow A (HSYA) has a protective effect on acute and chronic heart failure (AHF/CHF) induced by ligation of the left anterior descending coronary artery for 3 h and 8 weeks, respectively. The rats were divided into the following groups: sham operation, coronary artery ligation (CAL), CAL+HSYA (100 mg kg(-1) by gavage) and CAL+diltiazem (20 mg kg(-1) by gavage). In the AHF model, heart function, as determined by haemodynamic studies and echocardiography, was improved significantly by pretreatment with HSYA or diltiazem. Significant reductions in elevated serum creatine phosphokinase, lactate dehydrogenase, malondialdehyde (MDA), glutamic oxalacetic transaminase, glutamic pyruvic transaminase and blood viscosity were observed, and the activity of serum superoxide dismutase (SOD) was enhanced (all P<0.01). In the CHF model, HSYA and diltiazem restored abnormal heart function, and completely suppressed the elevated plasma atrial natriuretic polypeptide (ANP) and endothelin-1 (ET-1), serum and left-ventricular tissue inducible nitric oxide (NO) synthase (iNOS), NO and MDA, and improved the decrease in SOD. HSYA and diltiazem improved cardiac performance in AHF and reduced cardiac remodelling in CHF by reducing tissue weight indices: left ventricular weight/body weight (BW), right ventricular weight/BW, kidney weight/BW and lung weight/BW, and attenuating increases in infarct size, inner diameter of the left ventricle and collagen volume fraction in non-infarcted areas, and the decrease in mean wall thickness of infarcted myocardium. These results suggest that HSYA exerted beneficial actions in cardiac performance in models of both AHF and CHF, mainly by suppressing ET-1, iNOS and oxidative stress in infarcted tissue.
An increased propensity towards cardiac arrhythmias and aggravated heart function is observed in myocardial infarction (MI), the development of which is associated with the calcium handling system in the myocardium. It was hypothesized that the abnormal changes in the MI model may be a consequence of the abnormal expression and function of the RyR2-FKBP12.6 channel complex and that these abnormalities may be related to an over-activated endothelin (ET) system. Salvianolic acid B is expected to suppress life-threatening arrhythmias and to restore the abnormality of the RyR2-FKBP12.6 complex in rats. MI was produced by ligating the coronary artery for 4 weeks. Salvianolic acid B (100 mg/kg/day, p.o. for 4 weeks) was administered to rats 0.5 h before surgery. Measurements of cardiac arrhythmias, cardiac function, calcium transient, cardiac calcium release channel handling proteins and the endothelin system were conducted. The aggravated arrhythmia and compromised cardiac function in MI rats was accompanied by elevated diastolic Ca(2+) levels in the cytosol and a significant down-regulation of expression of RyR2-FKBP12.6. These were closely linked with an over-activated ET pathway in the myocardium. After a 4-week treatment with salvianolic acid B, all abnormalities were reversed significantly. Salvianolic acid B was capable of normalizing FKBP12.6 expression levels and decreasing the propensity towards arrhythmias by attenuating the up-regulated ET pathway.
We aimed to investigate the effects of Liuwei Dihuang decoction (LW) on the endothelin-1-reactive oxidative species (ET-ROS) system and matrix metalloproteinases (MMPs) in the early diabetic nephropathy induced by streptozotocin (STZ) in rats. Rats were divided into six groups as follows: the control group, the untreated model group, the treated groups with the LW (5, 10 and 15 g kg(-1), p.o.) and the aminoguanidine-treated group (100 mg kg(-1), orally). The treatment was performed for 4 weeks, beginning on the fifth week after one intraperitoneal injection of STZ (65 mg kg(-1)). In the untreated model group, increased blood glucose, decreased plasma insulin level and an impaired renal function were observed. There was an altered redox system shown by an increased malondialdehyde and decreased activity of glutathione peroxidase and superoxide dismutase in the renal cortex. An enhanced inducible nitric oxide synthetase, total nitric oxide synthase and constitutive nitric oxide synthase and a declined nitric oxide were found. An increased extracellular matrix was indicated by an abnormality of MMP-2 and MMP-9 activities and an increase in hydroxyproline. An up-regulated ET-1 level and increased mRNA expression of endothelin-converting enzyme, preproET-1 and ET( A) receptor were presented in the affected renal cortex, but no change in ET(B) receptor mRNA. The LW was most effective in reversing these changes in diabetic rats and was as effective as aminoguanidine. The benefits of the extracts in relieving the abnormalities in early diabetic nephropathy are likely to be mediated by suppression of the renal ET-ROS system and escalating the activity of MMPs.
To explore the cardioprotective effect and its mechanism of total saponins of Panacis Majoris Rhizoma in myocardial infarction (MI) rats.The MI model rats induced by ligating anterior descending branch of coronary artery were randomly divided into four group:model group, total saponins of Panacis Majoris Rhizoma (100 and 200 mg/kg) groups and compound Danshen dripping pills group. The rats were orally administrated with drugs once a day for four weeks. Another rats were selected as sham operation group. After four weeks intervention, cardiac function was examined, the serum levels of TNF-α, IL-1β, IL-6 and IL-8 were measured by using ELISA, respectively. The myocardial hypertrophy index was investigated, the myocardial infarct size, degree of ventricular dilatation, myocardial interstitial collagen volume fraction and tissue morphology were investigated by HE, Masson, picric acid-sirius red staining and observing with alight microscope and electron microscope. Protein expressions of phosphorylation IκB-α( pIκB-α) and NF-κB p65 in heart tissue were detected by Western blotting.Total saponins of Panacis Majoris Rhizoma might significantly decrease the levels of serum TNF-α, IL-1β, IL-6 and IL-8; decrease myocardial hypertrophy indexes, myocardial infarct size, degree of ventricular dilatation and myocardial interstitial collagen volume fraction; improve heart tissue morphology and cardiac function; downregulate protein expression of pIκB-α and NF-κBp65; and upregulate protein expression of SIRT1. The aforementioned action effects of total saponins of Panacis Majoris Rhizoma (200 mg/kg) were similar with compound Danshen dripping pills.Total saponins of Panacis Majoris Rhizoma possesses cardioprotective effect against ligating left anterior descending branch induced MI in rats. The mechanism may be related to strengthening SIRT1 expression, inhibiting the phosphorylation of IκB-α, and finally inhibiting the activation of NF-κB and proinflammatory production.
This study investigated the protective effect of total triterpenoids from Chaenomeles speciosa against Helicobacter pylori(Hp)-induced gastritis in mice and explored its possible mechanism. The chronic atrophic gastritis(CAG) model mice were randomly divided into four groups of model, total triterpenoids from C. speciosa(50 and 100 mg·kg~(-1)) and triple therapy, with C57 BL/6 J mice without Hp infection taken as the normal group. Mice in the treatment groups were given corresponding drugs once a day for 4 weeks. Then the following indexes were detected: the contents of reactive oxygen species(ROS), monocyte chemotactic protein 1(MCP-1), keratinocyte chemokines(KC), TNF-α, IL-1β, IL-6, IL-18, IL-4 and IL-10 in blood and gastric tissue, the activities and contents of LDH, MPO, SOD, GSH-Px, CAT and MDA in gastric tissue and the activities of β-glucuronidase, β-galactosidase, cathepsins B and D in blood, gastric tissue and lysosome. Besides, the mRNA expression levels of Toll-like receptor 4(TLR4), myeloid differentiation factor 88(MyD88), Bcl-2, Bcl-xl, Bax and Bad in gastric tissue were determined by quantitative real-time PCR. Western blot was employed to detect the protein expression levels of TLR4, MyD88, p-IKKβ, p-IκBα, NOD-like receptor 3(NLRP3), apoptosis-associated speck-like protein(ASC), pro-caspase-1, caspase-1, thioredoxin-interacting protein(TXNIP), pro-IL-1β, pro-IL-18, Bcl-2, Bcl-xl, Bax, Bad, cytochrome C, apoptotic protease-activating factor-1(Apaf-1), pro-caspase-9, pro-caspase-3, cleaved-caspase-9, cleaved-caspase-3, poly(ADP-ribose) polymerase 1(PARP-1), cleaved-PARP-1 and cytosol and nucleus NF-κB p65 in gastric tissue. The results indicated that the total triterpenoids from C. speciosa significantly suppressed Hp proliferation, alleviated the damage to gastric mucosa and improved lymphocyte infiltration and gland atrophy. They were also effective in reducing the activities of β-glucuronidase, β-galactosidase, cathepsins B and D in blood and gastric tissue, elevating the activities of β-glucuronidase and cathepsin D in lysosomal organelles, decreasing the contents of ROS, MCP-1, KC, TNF-α, IL-1β, IL-6, IL-18 in blood, MDA content and MPO and LDH activities in gastric tissue and increasing the contents of IL-4 and IL-10 in blood and activities of SOD, CAT and GSH-Px in gastric tissue. Other phenomena were also observed after the treatment with total triterpenoids from C. speciosa, including the down-regulation of the mRNA and protein expression levels of TLR4, MyD88, Bax and Bad, the protein expression levels of p-IKKβ, p-IκBα, NLRP3, ASC, pro-caspase-1, caspase-1, TXNIP, pro-IL-1β, pro-IL-18, cytochrome C, Apaf-1, cleaved-caspase-9, cleaved-caspase-3, cleaved-PARP-1 and nuclear NF-κB p65, reduction of p-IKKβ/IKKβ and p-IκBα/IκBα ratios and up-regulation of the mRNA and protein expression levels of Bcl-2 and Bcl-xl, up-regulation of pro-caspase-9, pro-caspace-3, cytosol NF-κB p65 protein expression levels and Bcl-2/Bax and Bcl-xl/Bad ratios in gastric tissue. These aforementioned results suggest that the total triterpenoids from C. speciosa have significant protective effects against CAG induced by Hp, and its mechanism may be related to enhancing the function of endogenous antioxidant system, suppressing the oxidative stress and inflammatory reaction induced by Hp, correcting lysosomal dysfunction and inflammatory activation of TLR4/NF-κB/NLRP3 inflammasome signaling pathway and thus inhibiting mitochondria-mediated apoptosis.
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