OBJECTIVE To investigate the role and mechanisms of the soluble guanylate cyclase(sGC)stimulator sGC003 in improving high altitude pulmonary edema(HAPE)in mice.METHODS Mice were randomly assigned to a normal control group,model group,model+dexamethasone 4 mg·kg-1 group(before modeling,intragastric administration of saline was performed once daily for 6 d,followed by intragastric administration of dexamethasone 4 mg·kg-1 on days 7 and 8),model+riociguat 10 mg·kg-1 group(before modeling,intragastric administration once a day for 7 d),and model+sGC003 5 and 10 mg·kg-1 groups(before modeling,intragastric administration once a day for 7 d).All groups except the normal control group received intratracheal instillation of lipopolysaccharide at a dose of 4 mg·kg-11 h after drug administration on day 7,followed by placement in a hypoxic environment to establish the HAPE model.After 24 h of modeling,the expiratory time,end-inspiratory pause,enhanced pause,and breathing frequency were measured,Lung tissue morphology was examined using HE staining,and lung tissue edema was assessed by determining the wet to dry weight ratio(W/D).The level of interleukin-1β(IL-1β)was determined using immunofluorescence staining.The phosphorylation level of vasodilator-stimulated phosphoprotein(VASP)in lung tissue was analyzed by Western blotting.Additionally,levels of sGC,hypoxia inducible factor-1α(HIF-1α),cyclic guanosine monophosphate(cGMP),IL-6,and IL-1βin serum were quantified using ELISA.RESULTS Compared with the normal control group,the model group had obvious pulmonary edema,and the lung W/D,IL-1β levels,expiratory time,end-inspiratory pause,enhanced pause,as well as serum levels of IL-1β,HIF-1α and IL-6 were significantly increased.Concurrently,the frequency of breathing and serum levels of sGC and cGMP were significantly decreased.Compared with model group,the expiratory time,end-inspiratory pause,enhanced pause,lung W/D and IL-1β levels,and serum levels of IL-1β,HIF-1α and IL-6 were significantly decreased in the model+sGC003 10 mg·kg-1 group;while the frequency of breathing,serum sGC and cGMP levels,phosphorylation level of VASP in lung tissues were significantly increased.CONCLUSION sGC003 can improve lung function,suppress pulmonary inflammation,and mitigate pulmonary edema in HAPE mice by activating the sGC/cGMP pathway.

OBJECTIVE To investigate the effect and mechanism of soluble guanylate cyclase stimulator sGC003F on cardiac function in mice with chronic heart failure(CHF).METHODS C57BL/6J male mice were randomly divided into the sham operation(sham)group,transverse aortic constriction induced CHF mouse model group,model+veliciguat(Ver,3 mg·kg-1)group(positive control)and model+sGC003F(3 and 10 mg·kg-1)group.Four weeks after modeling,drugs were ig given,once a day,for 28 d.Echocardiography was used to measure the changes in cardiac function,and the myocardial hypertrophy related indexes were calculated.The levels of serum N-terminal pro-brain natriuretic peptide(NT-pro-BNP),N-terminal pro-atrial natriuretic peptide(NT-pro-ANP),soluble guanylate cyclase(sGC),cyclic guanosine monophosphate(cGMP)and inflammatory factors interleukin-6(IL-6),tumor necrosis factor-α(TNF-α)and IL-1β were detected by ELISA.The pathological changes of left heart tissue were observed with HE and Masson staining.Image was used to analyze the percentage of fibrosis in cardiac tissus stained with Masson.The activity of superoxide dismutase(SOD),content of malondialdehyde(MDA)in myocardial tissue,and level of nitric oxide(NO)in serum were detected by biochemical detection kits.The protein expression levels of p-mammalian target of rapamycin(p-mTOR),p-protein kinase B(p-Akt),TNF-α and IL-6 in cardiac tissue were detected by Western blotting.RESULTS Com-pared with the sham group,the left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFs)in the model group decreased significantly(P<0.01),the cardiac structure changed significantly,the percentage of myocardial fibrosis increased significantly(P<0.05),so were serum NT-pro-BNP and NT-pro-ANP levels(P<0.01).Compared with the model group,the above indexes of the model+Ver group and the model+sGC003F 3 mg·kg-1 group were significantly improved(P<0.05,P<0.01).The sGC003F 10 mg·kg-1 group had a significant improvement in LVEF,LVFs,and NT-pro-BNP(P<0.01).Compared with the sham group,the serum levels of NO,sGC and cGMP in the model group decreased significantly(P<0.05,P<0.01).Compared with the model group,the serum levels of NO,sGC and cGMP were significantly increased in the model+sGC003F 3 mg·kg-1 group(P<0.01),but only serum cGMP levels were significantly increased in model+Ver and model+sGC003F 10 mg·kg-1 groups(P<0.01).Compared with the sham group,the serum levels of TNF-α,IL-1β and IL-6 in the model group were significantly increased(P<0.05,P<0.01).Compared with the model group,the serum levels of TNF-α,IL-1β and IL-6 were significantly decreased in the model+sGC003F 3 mg·kg-1 group(P<0.05,P<0.01),and only the TNF-α level was significantly decreased in the model+sGC003F 10 mg·kg-1 group(P<0.01).Compared with the sham group,the SOD activity of the model group was significantly decreased(P<0.01),but the MDA content significantly increased(P<0.01).Compared with the model group,SOD and MDA were significantly improved in the model+sGC003F 3 mg·kg-1 group(P<0.05,P<0.01),but in the model+Ver group only the SOD activity significantly increased(P<0.05).Western blotting showed that the expressions of p-mTOR,p-Akt,TNF-α and IL-6 protein in myocardial tissue of the model group were significantly higher than in the sham group(P<0.05).Compared with the model group,the expressions of the above proteins in the model+sGC003F 3 mg·kg-1 group were significantly decreased(P<0.05,P<0.01),so were the expressions of TNF-α protein in the model+sGC003F 10 mg·kg-1 group and model+Ver group(P<0.01).CONCLUSION sGC003F can improve cardiac function,and reduce myocardial fibrosis in CHF model mice,which may be related to the inhibition of myocardial oxidative stress and inflammation,and the regulation of NO/sGC/cGMP and AKT/mTOR signaling pathways.

OBJECTIVE To investigate the role and mechanisms of the soluble guanylate cyclase(sGC)stimulator sGC003 in improving high altitude pulmonary edema(HAPE)in mice.METHODS Mice were randomly assigned to a normal control group,model group,model+dexamethasone 4 mg·kg-1 group(before modeling,intragastric administration of saline was performed once daily for 6 d,followed by intragastric administration of dexamethasone 4 mg·kg-1 on days 7 and 8),model+riociguat 10 mg·kg-1 group(before modeling,intragastric administration once a day for 7 d),and model+sGC003 5 and 10 mg·kg-1 groups(before modeling,intragastric administration once a day for 7 d).All groups except the normal control group received intratracheal instillation of lipopolysaccharide at a dose of 4 mg·kg-11 h after drug administration on day 7,followed by placement in a hypoxic environment to establish the HAPE model.After 24 h of modeling,the expiratory time,end-inspiratory pause,enhanced pause,and breathing frequency were measured,Lung tissue morphology was examined using HE staining,and lung tissue edema was assessed by determining the wet to dry weight ratio(W/D).The level of interleukin-1β(IL-1β)was determined using immunofluorescence staining.The phosphorylation level of vasodilator-stimulated phosphoprotein(VASP)in lung tissue was analyzed by Western blotting.Additionally,levels of sGC,hypoxia inducible factor-1α(HIF-1α),cyclic guanosine monophosphate(cGMP),IL-6,and IL-1βin serum were quantified using ELISA.RESULTS Compared with the normal control group,the model group had obvious pulmonary edema,and the lung W/D,IL-1β levels,expiratory time,end-inspiratory pause,enhanced pause,as well as serum levels of IL-1β,HIF-1α and IL-6 were significantly increased.Concurrently,the frequency of breathing and serum levels of sGC and cGMP were significantly decreased.Compared with model group,the expiratory time,end-inspiratory pause,enhanced pause,lung W/D and IL-1β levels,and serum levels of IL-1β,HIF-1α and IL-6 were significantly decreased in the model+sGC003 10 mg·kg-1 group;while the frequency of breathing,serum sGC and cGMP levels,phosphorylation level of VASP in lung tissues were significantly increased.CONCLUSION sGC003 can improve lung function,suppress pulmonary inflammation,and mitigate pulmonary edema in HAPE mice by activating the sGC/cGMP pathway.

OBJECTIVE To investigate the effect and mechanism of soluble guanylate cyclase stimulator sGC003F on cardiac function in mice with chronic heart failure(CHF).METHODS C57BL/6J male mice were randomly divided into the sham operation(sham)group,transverse aortic constriction induced CHF mouse model group,model+veliciguat(Ver,3 mg·kg-1)group(positive control)and model+sGC003F(3 and 10 mg·kg-1)group.Four weeks after modeling,drugs were ig given,once a day,for 28 d.Echocardiography was used to measure the changes in cardiac function,and the myocardial hypertrophy related indexes were calculated.The levels of serum N-terminal pro-brain natriuretic peptide(NT-pro-BNP),N-terminal pro-atrial natriuretic peptide(NT-pro-ANP),soluble guanylate cyclase(sGC),cyclic guanosine monophosphate(cGMP)and inflammatory factors interleukin-6(IL-6),tumor necrosis factor-α(TNF-α)and IL-1β were detected by ELISA.The pathological changes of left heart tissue were observed with HE and Masson staining.Image was used to analyze the percentage of fibrosis in cardiac tissus stained with Masson.The activity of superoxide dismutase(SOD),content of malondialdehyde(MDA)in myocardial tissue,and level of nitric oxide(NO)in serum were detected by biochemical detection kits.The protein expression levels of p-mammalian target of rapamycin(p-mTOR),p-protein kinase B(p-Akt),TNF-α and IL-6 in cardiac tissue were detected by Western blotting.RESULTS Com-pared with the sham group,the left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFs)in the model group decreased significantly(P<0.01),the cardiac structure changed significantly,the percentage of myocardial fibrosis increased significantly(P<0.05),so were serum NT-pro-BNP and NT-pro-ANP levels(P<0.01).Compared with the model group,the above indexes of the model+Ver group and the model+sGC003F 3 mg·kg-1 group were significantly improved(P<0.05,P<0.01).The sGC003F 10 mg·kg-1 group had a significant improvement in LVEF,LVFs,and NT-pro-BNP(P<0.01).Compared with the sham group,the serum levels of NO,sGC and cGMP in the model group decreased significantly(P<0.05,P<0.01).Compared with the model group,the serum levels of NO,sGC and cGMP were significantly increased in the model+sGC003F 3 mg·kg-1 group(P<0.01),but only serum cGMP levels were significantly increased in model+Ver and model+sGC003F 10 mg·kg-1 groups(P<0.01).Compared with the sham group,the serum levels of TNF-α,IL-1β and IL-6 in the model group were significantly increased(P<0.05,P<0.01).Compared with the model group,the serum levels of TNF-α,IL-1β and IL-6 were significantly decreased in the model+sGC003F 3 mg·kg-1 group(P<0.05,P<0.01),and only the TNF-α level was significantly decreased in the model+sGC003F 10 mg·kg-1 group(P<0.01).Compared with the sham group,the SOD activity of the model group was significantly decreased(P<0.01),but the MDA content significantly increased(P<0.01).Compared with the model group,SOD and MDA were significantly improved in the model+sGC003F 3 mg·kg-1 group(P<0.05,P<0.01),but in the model+Ver group only the SOD activity significantly increased(P<0.05).Western blotting showed that the expressions of p-mTOR,p-Akt,TNF-α and IL-6 protein in myocardial tissue of the model group were significantly higher than in the sham group(P<0.05).Compared with the model group,the expressions of the above proteins in the model+sGC003F 3 mg·kg-1 group were significantly decreased(P<0.05,P<0.01),so were the expressions of TNF-α protein in the model+sGC003F 10 mg·kg-1 group and model+Ver group(P<0.01).CONCLUSION sGC003F can improve cardiac function,and reduce myocardial fibrosis in CHF model mice,which may be related to the inhibition of myocardial oxidative stress and inflammation,and the regulation of NO/sGC/cGMP and AKT/mTOR signaling pathways.

Objective:To investigate the effects of surgery with the Yeung endoscopic spine system (YESS) technique on lumbar range of motion and limb function in patients with lumbar disc herniation.Methods:A total of 148 patients with lumbar intervertebral disc herniation admitted to Liaocheng Second Hospital Affiliated to Shandong First Medical University from April 2018 to April 2021 were included in this study. They were randomly divided into control and observation groups ( n = 74/group). The control group was treated with laminectomy, and the observation group was treated with an intervertebral foramen mirror YESS. The lumbar range of motion, Oswestry disability index score, and incidence of surgical complications were compared between the two groups. Results:At postoperative 7 days, ranges of motion in lumbar flexion, lumbar extension, left lumbar lateral flexion, and right lumbar lateral flexion in the observation group were (87.45 ± 7.38)°, (26.87 ± 3.41)°, (28.58 ± 3.41)°, (28.39 ± 3.41)°, which were significantly higher than (68.98 ± 6.51)°, (15.69 ± 3.23)°, (18.69 ± 2.32)°, (14.56 ± 2.96)° in the control group ( t = 16.15, 20.48, 20.63, 26.35, all P < 0.001). At postoperative 7 days, the Oswestry Disability Index in each group was significantly decreased compared with before treatment (both P < 0.05). At postoperative 7 days, the score of each dimension of the Oswestry Disability Index in the observation group was significantly lower compared with the control group ( t = 49.13, 50.20, 54.78, 37.79, 32.04, 36.68, 43.69, 28.92, 39.31, 64.12, all P < 0.001). There were no significant differences in the incidences of perioperative incision infection, nerve injury, cerebrospinal fluid leaks, lumbar spondylolisthesis, and foot drop between the two groups (all P > 0.05). Conclusion:Treatment of lumbar intervertebral disc herniation with the YESS technique is helpful to improve lumbar mobility and reduce lumbar dysfunction and is highly safe.

Objective To discuss the clinical efficacy of improved TIPS of percutaneous portal vein puncture in treatment of acute upper gastrointestinal bleeding induced by portal hypertension.Methods 28 patients with acute upper gastrointestinal bleeding underwent improved TIPS therapy in our hospital were enrolled.The clinical data,laboratory parameters and hemodynamic changes were collected and analyzed before and after operation.Results The success rate for the first time and hemostatic rate of postoperative 24 hours in all patients was 100%.2(7.14%)patients underwent mild hepatic encephalopathy.After TIPS operation,the concentration of serum albumin increased,whereas,concentration of total bilirubin and alanine aminotransferase decreased(P<0.01).Portal vein pressure (PVP)of pre-and post-operation was(41.48 ± 3.72)mmHg and(28.91 ± 2.59)mmHg,and the hepatic venous pressure gradient (HVPG)was(20.30 ± 2.76)mmHg and(8.81 ± 2.04)mmHg.PVP and HVPG were both decreased significantly after operation(P<0.01).Conclusion Improved TIPS therapy can obtain good clinical efficacy and safety for esophageal and gastric varicose bleeding in acute cirrhosis.

Objective To compare the rates of successful intubation between light-stylet and adjustable McCoy laryngoscope for the management of difficult airway with active oral bleeding. Method Thirty casualties traumatized with active oral bleeding were enrolled after failure of endotracheal intubation tried twice by an attending doctor with Macintosh laryngoscope. The patients were randomly( random number) divided into light-stylet (LS)group and McCoy laryngoscope(MC) group ( n = 15 in each group). The rate of successful intubation and the time consumed for intubation were recorded. Results The rate of successful intubation at the first attempt and the total rate of successful intubation in LS group were higher than those in MC group (14/15 vs. 6/15, P =0.005, 15/15 vs. 9/15, P =0.017, respectively). The time consumed for intubation was less in LS group than that in MC group (24 seconds in average,ranged from 23 ～ 34 seconds vs 48 seconds in average, ranged from 31 ～ 119 seconds, P =0.011). Conclusions The light-stylet is a novel tool for intubation in casualties with difficult airway and active oral bleeding with high success rate.

Objective To investigate The effect of Heat shock protein 70(HSP70) antisense oligonucleotides (ASO)to bladder carcinoma in mouse loaded with tumor.Methods The 40 mice loaded with tumor subcutaneously were established by cultured BIU-87 cells,and divided into 4 groups randomly when the subcutaneous neoplasms grew to about 100 mm3,namely,HSP70 mRNA ASO plus mitomycin C(MMC)group;HSP70 mRNA ASO group;MMC and blank control.HSP70 mRNA ASO were injected into neoplasms,10mmg/kg weight,twice every week,and MMC 0.1mg/kg weight,twice every week,and the above schemes were replaced with normal saline to blank.The neoplasms were peeled off,photograghed and weighed in 30 days.HSP70 expressions were examined with reverse transcription polymerase chain reaction (RT-PCR),mierovaseular density(MVD)was evaluated by immunohis to chemical staining and the tumor cells apoptosis was detected by terrainal deoxynucleotidyl transferase(TdT)-mediated dUTP-biotin nick end labeling technique (TUNEL).Results The tumor inhibition rate in ASO+MMC surpassed 50%.more than ASO or MMC respectively,and the differences were significantly(P＜0.05).The ASO and MMC exceeded blank group respectively(P＜0.05).The ASO was the same as the MMC(P＞0.05).The apoptotic index(AI)in ASO+MMC surpassed the other three groups (P＜0.05).The difference between ASO and MMC was not significant (P＞0.05),while the A1 of ASO or MMC was more than blank respectively(P＜0.05).The results of MVD were in accordance with the above results.Conclusion The injection of HSP70 mRNA ASO in tumor locally can inhibit neoplasm growth,and this effect might correlate with the inhibition of apoptosis and microvascular forming resulting from the ASO.