Ziqi Dihuang decoction ameliorates thrombosis in septic rats by inhitbiting plasminogen activator inhibitor-1.

Introduction: Sepsis is now a global medical burden with high morbility and mortality. The focus of this study was to evaluate the effects of Ziqi Dihuang (ZQDH) decoction on inflammatory and thrombosis-related parameters in septic rats. Mothods: A rat model of sepsis was established by cecal ligation and puncture (CLP). Male Sprague-Dawley rats were randomly divided into Sham group, CLP group, ZQDH-1ow group (0.735 g/kg) and ZQDH-high group (1.47 g/kg). Rats in ZQDH groups were given ZQDH decoction by gavage for 7 days before CLP. White blood cells (WBC), inflammatory cell infiltration of liver, kidney and lung, as well as serum levels of tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and reactive oxygen species (ROS) were used to assess systemic inflammatory response. Coagulation and fibrinolytic indexes included platelet count, coagulation function, fibrin deposition, and levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in serum, liver, kidney and lung. Results: LPS rats showed significant changes in inflammatory and thrombosis-related parameters such as increased WBC and inflammatory factors, decreased platelet counts, and increased tPA and PAI-1 concentrations in serum and organs. ZQDH decoction pretreatment can significantly inhibit the infiltration of inflammatory cells in the lung, and inhibit the production of TNF-α, IL-6 and ROS in a dose-dependent manner. ZQDH decoction also ameliorated thrombocytopenia, renal fibrin deposition, and tPA and PAI-1 levels in serum and organs. Conclusion: These results suggest that ZQDH decoction can dose-dependently relieve systemic inflammatory injury and regulate fibrinolysis system in septic rats, which may be mediated by PAI-1.

Network pharmacology based research into the effect and mechanism of Xijiao Dihuang decoction against sepsis.

Sepsis is a critical illness that contributes a high mortality, while Xijiao Dihuang decoction (XJDHT) has been used in treatment against sepsis for many years by clinical doctors. Clinical studies confirmed a good efficacy of XJDHT against sepsis. The aim of this study is to observe the efficacy of XJDHT in sepsis model rats and macrophages activated by LPS, and to verify the underlying mechanisms. The key components of XJDHT and its targets against sepsis were analyzed and selected by network pharmacology. The potential mechanisms that XJDHT regulates the progress of sepsis were verified in sepsis rats and NR8383 cell lines. XJDHT at a dose of 25 mg/kg was administrated to rats which endured cecal ligation and perforation (CLP). After MTT assay, XJDHT at a dose of 4 mg/mL was selected to treat NR8383 cell lines activated by LPS. In vivo experiment, the survival of the rats was assessed. The content of cytokine in serum were assessed by Enzyme-linked immunosorbent assays (ELISA). Contents of cytokine and key molecules in relative signaling pathway were assessed by immunohistochemical method. The pathway protein expressions were detected by Western blotting. In vitro experiment, immunofluorescence was used to assess the content of cytokine and signaling pathway. A total of 42 targets of XJDHT against sepsis were identified by network pharmacology. After eliminating overlapping compounds and proteins, there were 8 compounds in XJDHT that associating with the 42 sepsis-related targets. NF-κB and HIF-1α signaling pathway were recognized to play important role for XJDHT against sepsis. XJDHT improved survival rate in the XJDHT group compared with the model group. The contents of IL-6 increased in the model group compared with the control group with ELISA and immunohistochemistry, while XJDHT reduced the content of IL-6. The expressions of p65 and HIF-1α reduced significantly in the XJDHT group compared with the model group. In vitro study, the content of IL-6 elevated significantly after LPS stimulation, while XJDHT reduced this increase. Furthermore, expressions of protein of p65 and HIF-1α decreased significantly compared with the LPS group. To conclude, our study demonstrated that XJDHT at a dose of 25 g/kg is capable of improving the survival of sepsis via regulating the NF-κB and HIF-1α signaling pathway.

Sini decoction ameliorates interrelated lung injury in septic mice by modulating the composition of gut microbiota.

Our work used cecal ligation and puncture (CLP) mice model and 16S rDNA sequencing to explore whether the therapeutic mechanism of Sini Decoction (SND) on sepsis was related to the intestinal flora currently of concern. Twenty-four hours after surgery, tissues and serum from three groups (Control, CLP and CLP + SND) were collected for further analysis and colon contents were isolated for 16S rDNA analysis. Mortality, histological examination and inflammatory cytokines levels confirmed that the sepsis model was induced successfully and resulted in serious pathological damage, while all of these could be reversed by SND. In intestinal flora analysis, the microbial richness and abundance were recovered after SND treatment. Furthermore, at the phylum level, the abundance of Proteobacteria showed drastic increase after CLP. Similarly, CLP surgery significantly disrupted the balance of intestinal flora, with a huge increase of Escherichia-Shigella, a Gram-negative genus that might release lipopolysaccharide (LPS) and other genera. And these shifts could be defused by SND, indicating its function of regulating gut microbiota. This study demonstrates that SND could ameliorate the symptoms and pathology associated with sepsis in CLP model via modulating the flora in intestinal tract, which enriches a possible mechanism of SND's therapeutic effect.

Sini decoction ameliorates sepsis-induced acute lung injury via regulating ACE2-Ang (1-7)-Mas axis and inhibiting the MAPK signaling pathway.

Sepsis, as life-threatening organ dysfunction caused by a dysregulated host response to infection, is characterized by the extensive release of cytokines and other mediators. Sini decoction (SND), a traditional Chinese prescription medicine, has been used clinically for the treatment of sepsis. But its explicit mechanism of action is still unclear. The present study aims to evaluate the potential protective effects of SND on sepsis-induced acute lung injury (ALI). After SND intervention, the lung tissues of each experimental group were collected. H&E sections were used to observe the pathological changes of lung tissue, and alveolar lavage fluid was collected to detect the infiltration of inflammatory cells. Level of inflammatory factors in lung tissue were analyzed by qRT-PCR. The change of Renin angiotensin system (RAS), as well as downstream MAPK/NF-κB signaling pathways were measured by Western blot. For in vitro experiments, human umbilical vein endothelial cells (HUVECs) were pretreated with lipopolysaccharide (LPS) and treated with SND. Subsequently, the expression levels of RAS and MAPK/NF-κB signaling pathways were measured by Western blot. In vivo, we found that SND significantly attenuated sepsis-induced pathological injury in the lung. SND also inhibited LPS-mediated inflammatory cell infiltration, the expression of pro-apoptotic proteins and the production of IL-6, IL-1ß, TNF-α and MCP-1. In vitro, experiments using a co-culture of HUVECs with SND showed that there was a decrease in pro-apoptotic protein and pro-inflammatory mediator. In this research, we also found that SND protective action could be attributed to the regulation of renin-angiotensin system (RAS). MAPKs and NF-κB pathways. To conclude, our study demonstrated that SND ameliorates sepsis-induced-ALI via regulating ACE2-Ang (1-7)-Mas axis and inhibiting the MAPK signaling pathway.

[A Meta-analysis of Qingre Jiedu and Liangxue Sanyu method in the treatment of sepsis].

OBJECTIVE: To systematically review the effect of Qingre Jiedu and Liangxue Sanyu method in patients with sepsis, and to discuss its effect in the treatment of sepsis. METHODS: The randomized controlled trials (RCTs) on the treatment of Qingre Jiedu and Liangxue Sanyu method for sepsis published on PubMed, Embase, Web of Science, CNKI and Wanfang database from the construction to December 31st, 2017 were searched by electronical way. Conventional treatment measures for sepsis, such as fluid resuscitation, maintenance of hemodynamic stability, anti-infection, improvement of tissue perfusion, maintenance of organ function and nutritional support were used in the control group. While traditional Chinese medicine treatment based on Qingre Jiedu and Liangxue Sanyu method were applied in the experimental group besides the conventional treatment, including Chinese patent medicine or Chinese herbal medicine. The main outcome was 28-day mortality, and the second outcome was acute physiology and chronic health evaluation II (APACHE II), coagulation function, inflammatory mediators, procalcitonin (PCT), lactic acid (Lac), and the length of intensive care unit (ICU) stay. Two researchers independently searched literatures, collected data and evaluated risk bias. The statistical analysis was completed by RevMan 5.3 and STATA 13.0 software. The funnel plot and Egger test were used to evaluate the potential publication bias of the main outcomes. RESULTS: A total of 20 RCTs were enrolled in this Meta-analysis, including 1 347 patients, with 667 patients in the control group and 680 patients in the experimental group. Comprehensive risk bias assessment showed that the risk bias of 11 RCT items was unknown, and the risk bias of 9 RCT items was high. Meta-analysis results showed that compared with the control group, the 28-day mortality of the experimental group was significantly lowered [relative risk (RR) = 0.54, 95% confidence interval (95%CI) = 0.45-0.65, P < 0.000 01], the 7-day APACHE II score was significantly lowered [mean difference (MD) = -3.86, 95%CI = -4.82 to -2.90, P < 0.000 01], the 7-day prothrombin time (PT) and activated partial thromboplastin time (APTT) were significantly shortened (PT: MD = -1.72, 95%CI = -2.29 to -1.14, P < 0.000 01; APTT: MD = -4.36, 95%CI = -5.81 to -2.91, P < 0.000 01), the 7-day D-dimer was slightly improved (MD = -0.13, 95%CI = -0.37-0.11, P = 0.29), the 10-day interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were significantly decreased (IL-6: MD = -40.33, 95%CI = -59.55 to -21.11, P < 0.000 1; TNF-α: MD = -7.26, 95%CI = -11.31 to -3.21, P = 0.000 4), the 7-day Lac was significantly declined (MD = -1.30, 95%CI = -1.91 to -0.68, P < 0.000 1), but no significance in PCT (MD = -1.57, 95%CI = -3.25-0.11, P = 0.07) or the length of ICU stay (MD = -4.02, 95%CI = -8.60-0.56, P = 0.09) was found. The results of publication bias assessment showed that 19 studies reported 28-day mortality were basically "funnel-shaped" distribution without potential publication bias (P = 0.336). CONCLUSIONS: The Meta-analysis showed that Qingre Jiedu and Liangxue Sanyu method may reduce the release of inflammatory mediators, improve the coagulation function, and reduce the 28-day mortality in patients with sepsis.

[Clinical Trial of Electroacupuncture Treatment for Relieving Stress Responses in Patients Undergoing Gastrointestinal Surgery].

OBJECTIVE: To observe the therapeutic effect of electroacupuncture (EA) at Zusanli (ST 36) and Neiguan (PC 6) on stress responses of patients undergoing gastrointestinal surgery. METHODS: A total of 40 patients undergoing gastrointestinal surgery were randomized into conventional treatment group (control) and EA group (n＝20 in each group). Patients of the EA group received conventional treatment (pre- and post-surgical fasting, measures for gastrointestinal decompression, parenteral nutrition support, and patient controlled analgesia pump, etc.) and EA stimulation (2 Hz, 30 min) of bilateral ST 36 and PC 6 (twice after surgery, at an interval of 6 h), and patients of the control group received conventional treatment only. The visual analogue scale (VAS) score was used to assess the patients' pain severity and the blood glucose levels were detected once every 4－6 h within 24 h after operation. Serum cortisol (Cort) and adrenocorticotropic hormone (ACTH) levels were detected by chemiluminescence method, and serum D-lactic acid level (for assessing gastrointestinal mucosal injury) was assayed by ELISA. RESULTS: After the treatment, the levels of serum Cort, ACTH, D-lactate acid and the highest blood glucose were significantly lower in the EA group than those in the control group (P<0.05, P<0.01), suggesting a reduction of stress reactions after EA. But no significant difference was found between the control and EA groups in the VAS score (P>0.05). CONCLUSION: EA at ST 36 and PC 6 can alleviate stress responses and reduce intestinal mucosal damage in patients undergoing gastrointestinal surgery.

Sinomenine protects against E.coli-induced acute lung injury in mice through Nrf2-NF-κB pathway.

Acute lung injury (ALI) is a common disease characterized by pulmonary inflammation and oxidative stress. Sinomenine (SIN) is an alkaloid originally extracted from the Chinese medicinal plant Sinomenium acutum. It has been shown to have anti-inflammatory and anti-oxidative effect. However, it's unclear whether SIN can alleviate ALI. In this study, we assessed the effect of SIN on Escherichia coli (E.coli)-induced ALI mouse model. Mice were conditioned with SIN or placebo 1 h before intratracheally instilled with E.coli. Lung water content, malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, Myeloperoxidase (MPO) levels and inflammatory cytokines production were measured. Immunohistochemistry and western blot were performed to measure target protein expression. E.coli induced histological changes indicating tissues damage and increased W/D ratio, MPO activity, MDA content, and inflammatory cytokines production in the Lung. Whereas in mice pretreated with SIN, these changes were absent. E.coli-induced NF-κB activation was also inhibited by SIN. In addition, SIN increased the expression of HO-1, NQO1 and Nrf2 in lung tissues. Our results suggest that SIN attenuates ALI through the inhibition of inflammation and oxidative stress.

Sini decoction alleviates E. coli induced acute lung injury in mice via equilibrating ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis.

AIMS: Acute respiratory distress syndrome (ARDS), one of the serious form of acute lung injury (ALI), is the primary cause of death in patients with ALI. Sini decoction (SND) is a widely used Traditional Chinese Medicine (TCM). However, the application of SND in ALI is rarely reported. Previous studies have found that renin-angiotensin-aldosterone system (RAAS) played vital and bidirectional roles in ALI. Therefore, the aim of the present study was to investigate protective effect of SND on ALI model induced by E. coli, as well as to further explore relations between RAAS and SND. MATERIALS AND METHODS: The ALI model was evaluated by morphological observations and biochemical assays. The expression levels of angiotensin converting enzyme (ACE), Angiotensin II type 1 receptor (AT1R) and angiotensin converting enzyme 2 (ACE2) were examined by Western blotting. The expression levels of angiotensinII (AngII) and angiotensin-(1-7) (Ang-(1-7)) were measured through ELISA. MasR, IL-6, IL-1ß and TNFα were all measured using qRT-PCR. KEY FINDINGS: SND significantly ameliorated E. coli-induced ALI, including reducing inflammatory factors in lung tissue and the activity of MPO in serum. Furthermore, SND could obviously decrease the expression of ACE, AngII and AT1R, which were induced by E. coli. On the other hand, SND could markedly activate ACE2-Ang-(1-7)-Mas pathway. SIGNIFICANCE: In this paper, we demonstrated that SND alleviates E. coli induced acute lung injury in mice via equilibrating ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis.