Objective:To explore the protective effect of sesquiterpene lactones of Eupatorium lindleyanum DC.(SLEL)on lipopolysac-charide(LPS)-induced acute lung injury(ALI)in rats using metabolomics.Methods:Forty-eight male SD rats were randomly divided into a blank control group(CG),a model control group(MG),low-,medium-,and high-dose SLEL groups(50,100,and 200 mg/kg),and a positive control group(dexamethasone acetate tablets,5 mg/kg).CG and MG groups were given phosphate-buffered saline.All groups received intragastric administration at a dose volume of 10 mL/kg once a day for 7 consecutive days.One hour after the last ad-ministration,LPS(5 mg/kg)was instilled into the trachea of all groups except the CG group to establish the ALI rat model.Twenty-four hours after model establishment,blood was collected from the abdominal aorta and bronchoalveolar lavage fluid(BALF)was col-lected from the left lung.The total number of inflammatory cells,neutrophils,lymphocytes,and eosinophils in BALF was counted by Wright-Giemsa staining.The levels of interleukin-18(IL-18)and interferon-γ(IFN-γ)in serum and BALF were measured by enzyme-linked immunosorbent assay.The pathological changes of lung tissue were observed using hematoxylin-eosin staining.The ex-pression levels of tight junction protein-1(ZO-1)and occludin in lung tissue were determined by Western blot.The mRNA expression levels of IL-18,IFN-γ,ZO-1,and occludin in the lung were measured by real-time fluorescence quantitative PCR.Non-targeted me-tabolomics analysis of serum and lung tissue was performed using ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry.Results:Compared with the MG group,all SLEL groups had significantly reduced wet/dry weight ratio of lung tissue,lung coefficient,and total number of inflammatory cells,neutrophils,lymphocytes,and eosinophils in BALF.SLEL signifi-cantly decreased the levels of IL-18 and IFN-γ in serum and BALF and the mRNA expression of IL-18 and IFN-γ in lung tissue,and significantly promoted the protein and mRNA expression of ZO-1 and occludin.Under light microscopy,the degree of lung tissue edema,alveolar hemorrhage,and inflammatory cell infiltration were significantly reduced,indicating a certain protective effect on ALI rats.The results of non-targeted metabolomics studies showed that there were 91 and 33 significantly different metabolites in the serum and lung tissue of rats treated with SLEL,respectively.Among them,the main differential metabolites in the serum were sphingosine,L-lactic acid,nicotinic acid,D-nucleotide,and mevalonate-5P,while the main differential metabolites in the lung tissue were tauro-cholic acid.This suggests that SLEL may mainly affect the metabolic pathways of sphingolipids,pyruvate,nicotinic acid,nicotinamide,and tryptophan in the serum and the metabolic pathways of taurine and hypotaurine in the lung tissue to improve ALI.Conclusion:SLEL has a significant protective effect on rats against LPS-induced ALI,and its mechanism of action may be related to the inhibition of inflammatory factors,improvement of lung barrier function,and regulation of related metabolic pathways.

Objective:To explore the effect of Annexin A1(ANXA1)peptidomimetic Ac2-26 on acute kidney injury(AKI)and neutrophil apoptosis in septic rats.Methods:Experimental groups included control group,Ac2-26 group,AKI group,AKI+Ac2-26 group,with 15 rats in each group.After cecal ligation and perforation were used to establish a sepsis-induced AKI model,Ac2-26 was intravenously infused for treatment,once a day for 14 days;after the end,ELISA was used to detect levels of serum creatinine(Scr),urea nitrogen(BUN),IL-1β,IL-6 and TNF-α;HE staining and periodic acid Schiff(PAS)staining were used to observe the pathological changes of rat kidney tissues in each group;immunohistochemical staining was used to detect expression of ANXA1 in kidney tissue of each group of rats;neutrophils were isolated from rat peripheral blood,Giemsa staining and trypan blue staining were used to detect cell purity and viability;Annexin V-FITC/PI double staining method and TUNEL staining were used to determine apop-tosis level of neutrophils in each group.Results:Compared with control group,levels of Scr and BUN in serum of rats in AKI group were increased(P<0.05),levels of IL-1β,IL-6 and TNF-α also increased(P<0.05),renal tubules and glomeruli in kidney tissue were both significantly damaged,accompanied by a large number of inflammatory cell infiltration,and pathological score increased(P<0.05),while proportion of ANXA1 positive staining area was decreased(P<0.05);neutrophils identified by Giemsa staining and trypan blue staining had complete morphology and high activity;compared with control group,apoptosis rate of neutrophils in AKI group was decreased(P<0.05),and the positive rate of TUNEL was decreased(P<0.05).Compared with AKI group,levels of Scr and BUN in serum of rats in AKI+Ac2-26 group were decreased(P<0.05),levels of IL-1β,IL-6 and TNF-α also decreased(P<0.05),pathological manifestations of renal tubules and glomeruli in renal tissue were significantly reduced,and pathological score was reduced(P<0.05),while the proportion of ANXA1 positive staining area was increased(P<0.05),at the same time,apoptosis rate of rat neu-trophils was increased(P<0.05),positive rate of TUNEL was also increased(P<0.05).Conclusion:ANXA1 peptidomimetic Ac2-26 can increase expression of ANXA1 in kidney tissue of AKI in septic rats,promote neutrophil apoptosis,and have a protective effect on kidney tissue damage in rats caused by sepsis.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious global health threat.This raises an urgent need for the devel-opment of effective drugs against the deadly disease.SARS-CoV-2 non-structural protein 14 (NSP14)carrying RNA cap guanine N7-methyltransferase and 3'-5'exoribonuclease activities could be a potential drug target for intervention.NSP14 of SARS-CoV-2 shares 98.7％ of similarity with the one (PDB 5NFY) of acute respiratory syndrome (SARS) by ClustalW.Then,the SARS-CoV-2 NSP14 structures were modelled by Modeller 9.18 using SARS NSP14 (PDB 5NFY) as template for virtual screening.Based on the docking score from AutoDock Vina1.1.2,18 small molecule drugs were selected for further evaluation.Based on the 5 ns MD simulation trajectory,binding free energy (AG) was calculated by MM/GBSA method.The calculated binding free energies of Saquinavir,Hypericin,Baicalein and Bromocriptine for the N-terminus of the homology model were-37.2711 ± 3.2160,-30.1746 ± 3.1914,-23.8953 ± 4.4800,and-34.1350 ± 4.3683 kcal/mol,respectively,while the calculated binding free energies were-60.2757 ± 4.7708,-30.9955 ± 2.9975,-46.3099 ± 3.5689,and-59.8104 ± 3.5389 kcal/mol,respectively,when binding to the C-terminus.Thus,the compounds including Saquinavir,Hypericin,Baicalein and Bromocriptine could bind to the N-terminus and C-terminus of the homology model of the SARS-CoV-2 NSP14,providing a candidate drug against SARS-CoV-2 for further study.

Objective To observe the myocardial protective effect of dexmedetomidine in patients undergoing open-heart surgery under cardiopulmonary bypass (CPB).Methods 50 patients of open-heart surgery under CPB were randomly divided into two groups equally, namely observation group and control group.Observation group was treated with injection of dexmedetomidine at 0.5 μg/kg for 15 min, and then maintained at 0.4 μg/kgoh.The control group was given equal volume of normal saline.Concentrations of IMA and cTnI were determined before anaesthesia (t0), after 30 minutes of CPB (t1) and after surgery (t2).Results IMA and cTnI concentrations of t1 and t2 in the observation group were significantly lower than those in the control group (P<0.05).Conclusion Dexmedetomidine has obvious protective effect on myocardium, which can reduce open-heart surgery of patients with myocardial ischemia reperfusion injury (MIRI).

Even though mutations in LMNA have been reported in patients with typical dilated cardiomyopathy (DCM) and atrioventricular block (AVB) previously, the purpose of this study was to disclose this novel genetic abnormality in one Chinese family with the atypical phenotype of progressive AVB followed by DCM with normal QRS interval. Genome-wide linkage analysis mapped the AVB gene in this family to a marker at chromosome 1q21.2, where the LMNA gene was located. Direct DNA sequence analysis revealed a heterozygous G to A transition at nucleotide 244 in exon 1 of LMNA, which resulted in an E82K mutation. The E82K mutation co-segregated with all affected individuals in the family, and was not present in 200 normal controls. Further clinical evaluation of mutation carriers showed that 5 of 6 AVB patients exhibited mild DCM with a late onset of age in the fourth and fifth decades. Ejection fractions were documented in 5 patients with DCM, but 4 showed a normal value of [Symbol: see text]50%. Echocardiography showed that atrial dilatation occurred earlier than ventricular dilatation in the patients. This study suggests that progressive AVB with normal QRS interval and accompanying DCM at later stages may represent a distinct type of DCM. The molecular mechanism by which the E82K mutation causes AVB as the prominent phenotype in DCM may be a focus of future studies.

Even though mutations in LMNA have been reported in patients with typical dilated cardio-myopathy(DCM)and atrioventricular block(AVB)previously,the purpose of this study was to disclose this novel genetic abnormality in one Chinese family with the atypical phenotype of progressive AVB followed by DCM with normal QRS interval.Genome-wide linkage analysis mapped the AVB gene in this family to a marker at chromosome 1q21.2,where the LMNA gene was located.Direct DNA sequence analysis revealed a heterozygous G to A transition at nucleotide 244 in exon 1 of LMNA,which resulted in an E82K mutation.The E82K mutation co-segregated with all affected individuals in the family,and was not present in 200 normal controls.Further clinical evaluation of mutation carriers showed that 5 of 6 AVB patients exhibited mild DCM with a late onset of age in the fourth and fifth decades.Ejection fractions were documented in 5 patients with DCM,but 4 showed a normal value of ≥50%.Echocardiography showed that atrial dilatation occurred earlier than ventricular dilatation in the patients.This study suggests that progressive AVB with normal QRS interval and accompanying DCM at later stages may represent a distinct type of DCM.The molecular mechanism by which the E82K mutation causes AVB as the prominent phenotype in DCM may be a focus of future studies.

Objective To investigate the effects of multiple doses of propofol or/and monosialotetrahexosyl ganglioside (GM1) on cognitive function and caspase-3 expression in immature rats.Methods Seventy-seven immature SD rats,17-18-day old and weighted 33-40g,were randomly divided into 7 groups (11 each):control group (NS),propofol 50mg/kg group (P50),propofol 100mg/kg group (P_ 100 ),propofol 200mg/kg group (P_ 200 ),GM1 10mg/kg group (G),propofol 100mg/kg and GM1 10mg/kg group (P_ 100 G),and propofol 200mg/kg and GM1 10mg/kg group (P_ 200 G).Each group received normal saline,propofol 50mg/(kg?d),100 mg/(kg?d),200mg/(kg?d),GM1 10mg/(kg?d),propofol 100mg/(kg?d) and GM1 10mg/(kg?d),or propofol 200 mg/(kg?d) and GM1 10mg/(kg?d) intraperitoneally in a bolus or divided doses,respectively,for 6 consecutive days.The tests of learning and memory were performed in Morris water maze everyday at the 3rd hour after the rats waked up from anesthesia.The animals were sacrificed on the 6th day after the Morris water maze test to obtain the brain specimen,and the expression of caspase-3 was detected by immunohistochemistry and Western blotting.Results Latency period of water maze test was significantly longer in groups P_ 100,P_ 200 and P_ 200 G than in group NS,and the frequency of crossing platform were fewer in P_ 100,P_ 200 and P_ 200 G groups (P