AIM: To explore the dynamic expression of high mobility group box 1(HMGB1)in scar tissues after glaucoma drainage valve implantation, and to further reveal the role and possible mechanism of HMGB1 in scarring after glaucoma surgery.METHODS: A total of 60 New Zealand white rabbits were randomly divided into control group(n=20), model group(n=20, silicone implantation under conjunctival sac)and model with drug administration group(n=20, silicone implantation under conjunctival sac combined with 5-fluorouracil injection). The conjunctival tissues were collected at 4 and 8 wk after surgery. HE staining and Masson staining were used to detect the proliferation and distribution of fibroblasts and collagen fibers in conjunctival tissues. Immunohistochemistry was utilized to detect the distribution and changes of HMGB1, transforming growth factor(TGF)-β1, Smad3 and α-smooth muscle actin(SMA)in conjunctival tissues. RT-PCR and Western blot were adopted to detect the mRNA and protein expression of HMGB1, TGF-β1, Smad3 and α-SMA in conjunctival tissues.RESULTS: HE staining and Masson staining showed that the proliferation of inflammatory cells, fibroblasts and collagen fibers in the model group was significantly higher than that in the control group at both 4 and 8 wk. Meanwhile, the proliferation of fibroblasts and collagen fibers in the model with drug administration group was significantly lower than that in the model group. Immunohistochemical staining showed that the expression of HMGB1, TGF-β1, Smad3 and α-SMA protein was observed in the conjunctival tissues of the model group both 4 and 8 wk, with brown and significantly deeper staining of the model group at 8 wk. Meanwhile, the positive staining in the model with drug administration group at both 4 and 8 wk was significantly lower than that in the model group. There was positive correlations between the number of fibroblasts stained with HE and the expression of HMGB1 in the conjunctival tissue of the model group at both 4 and 8 wk(r=0.602, 0.703, all P<0.05). RT-PCR and Western blot revealed that the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model group were significantly higher than those in the control group at both 4 and 8 wk(all P<0.05). Meanwhile, the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model with drug administration group were significantly lower than those in the model group(all P<0.05). There was positive correlations between mRNA expressions of HMGB1 and TGF-β1, Smad3 in the model group and the model with drug administration group(all P<0.05).CONCLUSION: The expression of HMGB1 increased at a time-dependent manner after glaucoma valve implantation. HMGB1 acts an indispensable role in the initiation and progression of scar formation after glaucoma surgery, which may be involved in the regulation of TGF-β/Smad signaling pathway.

BACKGROUND:Some patients still have unsatisfactory improvement of operative limb fatigue and pain after total knee arthroplasty.Clinical findings show that Jianpi Yiqi Huoxue Formula can promote recovery after total knee arthroplasty,but the specific efficacy remains to be studied. OBJECTIVE:To observe the effect of Jianpi Yiqi Huoxue Formula on the muscle strength and pain of the operated limb after the primary unilateral total knee arthroplasty. METHODS:A total of 74 patients undergoing primary unilateral total knee arthroplasty were randomly divided into a trial group and a control group with 37 patients in each group.All patients received the same prostheses and surgical methods during the operation.Patients in the control group were treated with routine analgesics,anticoagulant drugs and functional exercise after the operation.The trial group received Jianpi Yiqi Huoxue Formula after the treatment in the control group.Both groups were treated continuously and followed up for 1 month.The changes in isokinetic muscle strength(peak torque and total work amount of extensor and flexor),visual analog scale score and the hospital for special surgery score of the two groups were analyzed. RESULTS AND CONCLUSION:(1)The trial group had better improvement in peak torque and total work amount of extensor and flexor and the hospital for special surgery score than the control group 14 days and 1 month after surgery(P<0.05).(2)In contrast to the control group,the visual analog scale score of the trial group improved better at 7 and 14 days and 1 month after surgery(P<0.05).(3)It is indicated that Jianpi Yiqi Huoxue Formula can effectively improve the muscle strength of the operated limb,enhance the degree of postoperative joint pain,and promote functional rehabilitation after total knee arthroplasty.

Interleukin (IL)-17A, a pro-inflammatory cytokine, is a fundamental function in the onset and advancement of multiple immune diseases. To uncover the primary compounds with IL-17A inhibitory activity, a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions. Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus, Myrothecium gramineum, showed remarkable IL-17A inhibitory activity. Nine new aureane-type sesquiterpene tetraketides, myrogramins A-I ( 1, 4- 11), and two known ones ( 2 and 3) were isolated and identified from the strain. Compounds 1, 3, 4, 10, and 11 exhibited significant IL-17A inhibitory activity. Among them, compound 3, with a high fermentation yield dose-dependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions. Strikingly, compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension. Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity, and hold great promise applications in treating IL-17A-mediated immune diseases.

Background: At the therapeutic doses, diclofenac sodium (DFS) has few toxic side effects on mammals. On the other hand, DFS exhibits potent toxicity against birds and the mechanisms remain ambiguous. Objectives: This paper was designed to probe the toxicity of DFS exposure on the hepatic proteome of broiler chickens. Methods: Twenty 30-day-old broiler chickens were randomized evenly into two groups (n = 10).DFS was administered orally at 10 mg/kg body weight in group A, while the chickens in group B were perfused with saline as a control. Histopathological observations, serum biochemical examinations, and quantitative real-time polymerase chain reaction were performed to assess the liver injury induced by DFS. Proteomics analysis of the liver samples was conducted using isobaric tags for relative and absolute quantification (iTRAQ) technology. Results: Ultimately, 201 differentially expressed proteins (DEPs) were obtained, of which 47 were up regulated, and 154 were down regulated. The Gene Ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to screen target DEPs associated with DFS hepatotoxicity. The regulatory relationships between DEPs and signaling pathways were embodied via a protein-protein interaction network. The results showed that the DEPs enriched in multiple pathways, which might be related to the hepatotoxicity of DFS, were “protein processing in endoplasmic reticulum,” “retinol metabolism,” and “glycine, serine, and threonine metabolism.” Conclusions The hepatotoxicity of DFS on broiler chickens might be achieved by inducing the apoptosis of hepatocytes and affecting the metabolism of retinol and purine. The present study could provide molecular insights into the hepatotoxicity of DFS on broiler chickens.

Background::Ciprofol (HSK3486; Haisco Pharmaceutical Group Co., Ltd., Chengdu, China), developed as a novel 2,6-disubstituted phenol derivative showed similar tolerability and efficacy characteristics as propofol when applicated as continuous intravenous infusion for 12 h maintenance sedation in a previous phase 1 trial. The phase 2 trial was designed to investigate the safety, efficacy, and pharmacokinetic characteristics of ciprofol for sedation of patients undergoing mechanical ventilation.Methods::In this multicenter, open label, randomized, propofol positive-controlled, phase 2 trial, 39 Chinese intensive care unit patients receiving mechanical ventilation were enrolled and randomly assigned to a ciprofol or propofol group in a 2:1 ratio. The ciprofol infusion was started with a loading infusion of 0.1-0.2 mg/kg for 0.5-5.0 min, followed by an initial maintenance infusion rate of 0.30 mg·kg -1·h -1, which could be adjusted to an infusion rate of 0.06 to 0.80 mg·kg -1·h -1, whereas for propofol the loading infusion dose was 0.5-1.0 mg/kg for 0.5-5.0 min, followed by an initial maintenance infusion rate of 1.50 mg·kg -1·h -1, which could be adjusted to 0.30-4.00 mg·kg -1·h -1 to achieve -2 to +1 Richmond Agitation-Sedation Scale sedation within 6-24 h of drug administration. Results::Of the 39 enrolled patients, 36 completed the trial. The median (min, max) of the average time to sedation compliance values for ciprofol and propofol were 60.0 (52.6, 60.0) min and 60.0 (55.2, 60.0) min, with median difference of 0.00 (95% confidence interval: 0.00, 0.00). In total, 29 (74.4%) patients comprising 18 (69.2%) in the ciprofol and 11 (84.6%) in the propofol group experienced 86 treatment emergent adverse events (TEAEs), the majority being of severity grade 1 or 2. Drug- and sedation-related TEAEs were hypotension (7.7% vs. 23.1%, P = 0.310) and sinus bradycardia (3.8% vs. 7.7%, P = 1.000) in the ciprofol and propofol groups, respectively. The plasma concentration-time curves for ciprofol and propofol were similar. Conclusions::ciprofol is comparable to propofol with good tolerance and efficacy for sedation of Chinese intensive care unit patients undergoing mechanical ventilation in the present study setting.Trial registration::ClinicalTrials.gov, NCT04147416.

Objective:To determine the expression of matrix metalloproteinase 13 (MMP13) in patients with psoriasis, and to evaluate the effect of tazarotene and narrow-band ultraviolet B (NB-UVB) on the expression of MMP13 in mice with psoriasis-like dermatitis.Methods:Lesional skin tissues and normal skin tissues were collected from 18 patients with psoriasis vulgaris and 10 healthy controls respectively, who were enrolled from General Hospital of Tianjin Medical University between May 2019 and August 2019, and serum samples were collected from all the subjects. A total of 25 specific pathogen-free (SPF) male BALB/c mice were randomly divided into control group, imiquimod group, imiquimod+NB-UVB group, imiquimod+tazarotene group and imiquimod+tazarotene+NB-UVB group. The control group received topical vaseline cream on the back once every morning; imiquimod group and imiquimod+NB-UVB group received imiquimod cream on the back once every morning; imiquimod+tazarotene group and imiquimod+tazarotene+NB-UVB group received imiquimod cream on the back once every morning, and tazarotene cream on the back once at night; imiquimod+NB-UVB group and imiquimod+tazarotene+NB-UVB group received NB-UVB irradiation on the back every other day at noon, with the dose being 300 mJ/cm 2 in the first session and increasing by 50 mJ/cm 2 in every session. The modeling lasted 7 days. After successful modeling, blood samples were obtained from the eyeballs of the mice, and skin tissues were resected from the back of the mice after being sacrificed by cervical dislocation on day 8. Changes in the epidermal thickness and pathological manifestations were observed by hematoxylin and eosin (HE) staining, protein expression of MMP13 in skin tissues was determined by immunohistochemical study, and the serum level of MMP13 was detected by enzyme-linked immunosorbent assay. Comparisons between 2 groups were performed by using two-independent-sample t test, comparisons among several groups by using one-way analysis of variance, multiple comparisons by using least significant difference- t test, and comparisons of enumeration data by using chi-square test. Results:The skin lesions of the patients with psoriasis were strongly positive for MMP13, and the MMP13 expression levels in the epidermis and serum (84.11±17.16, 13.29±3.95 μg/L, respectively) were significantly higher in the patients with psoriasis than in the healthy controls (11.98±4.08, 7.46±1.58 μg/L, respectively, both P< 0.01) . Compared with the control group (1.26±0.04 μm, 25.40±2.34, 185.76±7.22 μg/L, respectively) , a significant increase was observed in the epidermis thickness (7.93±0.59 μm, P< 0.01) , as well as MMP13 levels in the epidermis and serum in the imiquimod group (147.14±5.53, 215.98±15.17 μg/L, respectively, both P< 0.01) . Compared with the imiquimod group, the imiquimod+tazarotene group, imiquimod+NB-UVB group, and imiquimod+tazarotene+NB-UVB group all showed significantly decreased epidermal thickness (3.56±0.37 μm, 3.83±0.39 μm, 2.14±0.34 μm, respectively, all P< 0.05) , MMP13 levels in the epidermis (120.42±3.23, 91.08±0.46, 71.12±7.11, respectively, all P< 0.05) and serum (197.39±3.92 μg/L, 196.13±11.76 μg/L, 183.21±14.99 μg/L, respectively, all P< 0.05) . Conclusions:MMP13 protein expression markedly increased in the skin lesions and sera of patients with psoriasis, and decreased in skin lesions and sera of mice with psoriasis-like dermatitis after the treatment with tazarotene and NB-UVB. MMP13 may be involved in the development of psoriasis, and tazarotene and NB-UVB may inhibit the development of psoriasis by reducing the expression of MMP13.

Krüppel-like factors (KLFs) play extremely important roles in genesis and development of tumors. Simultaneously, KLFs have been proven to affect the proliferation, differentiation and migration of hepatocellular carcinoma cells. Nine members in the KLFs family (KLF2, KLF4, KLF5, KLF6, KLF8, KLF9, KLF10, KLF14 and KLF17) are involved in the occurrence and development of hepatocellular carcinoma in various ways as an oncogene and tumor suppressor gene. Therefore, the KLFs family will hopefully become biological therapeutic targets for hepatocellular carcinoma.

Objective To investigate the outcome of fetus with abnormal increase of pulmonary artery systolic pressure at second and third trimester by color Doppler ultrasound . Methods Ninety-five fetuses with a little or mild tricuspid regurgitation ( control group) and 60 fetuses with moderate and severe tricuspid regurgitation (observation group) were included . The degree ,velocity ,and differential pressure of tricuspid regurgitation were measured and the variations of baseline information and the measured value of pulmonary systolic pressure between the two groups were compared . As for the follow -up on observation group ,the pressure of fetus with high pulmonary systolic pressure ( > 20 mmHg) was repeatedly measured every 4 weeks until it return to normal . Results There were significant differences in terms of gestational weeks ,velocity and pressure of tricuspid regurgitation ,as well as pulmonary systolic pressure between the two groups ( P < 0 .001) . Pulmonary systolic pressure was positively correlated with gestational weeks , velocity and pressure of tricuspid regurgitation ( r = 0 .442 ,0 .998 ,0 .999 ;all P < 0 .001 ) ,but had no correlations with the age of pregnant women ( r = - 0 .001 , P = 0 .674) . The follow-up revealed that ,in observation group , 47 cases ( 78 .3％ , systolic pressure < 50 mmHg ) presented with the decreased pulmonary systolic pressure ,the disappeared or the slight appeared regurgitation before birth ,meanwhile , 13 ( 21 .7％ ,systolic pressure ≥ 50 mmHg) exhibited severe tricuspid regurgitation and persistent pulmonary elevation ,with the highest of more than 70 mmHg accompanying the varying degrees of right heart failure . Only one of 13 fetuses died due to persistent pulmonary hypertension and hypoxia ( oxygen saturation <45％ ) . The fetal pulmonary artery systolic pressure of the remaining 12 cases recovered from 5 to 105 days after birth ,with normal heart function . Conclusions The majority of fetal pulmonary arterial hypertension complicated with obvious tricuspid regurgitation is reversible functional alteration , which can restore normality in most cases before or after birth .

Objective To explore the follow‐up value of ultrasound in fetal tricuspid regurgitation . Methods 44 fetuses who presented with moderate tricuspid regurgitation with differential pressure over 20 mmHg ,dilation of right atria and ventricles were chosen as the observation group .Examinations ,in terms of the degree ,velocity and differential pressure of reflux ,size of heart chamber and the presence pericardial or pleural effusion were carried out once every four weeks from 24 weeks of pregnancy to 9 weeks after birth . Results 40 9.% (18/44) of cases had been getting better before birth .The degree of regurgitation of 56 8.%(25/44) cases significantly decreased or even disappeared from 1 to 62 days after birth .Especially ,3 cases whose regurgitation velocity reached to 4 2. m/s with the differential pressure over 70 mmHg as well as onset of heart failure symptoms had been recovered gradually after born in advance 1. case (2 3.% ) with the persistence of both tricuspid regurgitation and heart failure symptoms after birth died in right heart failure , even though using different active treatments ,such as oxygen ,strong heart and diuresis .Conclusions High‐speed tricuspid regurgitation in fetuses without pathological changes can be almost reversed ,and the prognosis is good .Once the fetal tricuspid regurgitation pressure is over 70 mmHg or a fetus appears the onset of heart failure symptoms ,pre‐term delivery should be advised in a bid to prevent accidents in uterine cavity .

Objective To investigate the value of MR imaging methods for the quantification of fat content in a customized lipid phantom at 3.0 T.Methods Eleven homogeneous fat-water phantoms (50 ml)with fat volume percentages from 0 to 100％ were constructed with reference to Bernard's methods.Fat tractions of the lipid phantom were acquired using water selective saturation (WS),fat selective saturation (FS),in-and out-of-phase imaging (IOP),iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) gradient echo imaging and IDEAL Quant imaging methods on a 3.0 T MRI system.For statistical comparisons,paired-sample t test,Pearson correlation test,and Bland-Ahman maps were applied.Results Evaluated fat fractions acquired by WS,IDEAL Gradient echo imaging and IDEAL Quant were (49.6±28.8)％,(46.0±28.4)％,(51.0±32.0)％,the result has no significant difference with the true fat contents(t values were-0.186,-2.218,2.713;P values were 0.856,0.051,0.055).Evaluated fat fractions acquired by FS,corrected algorithm and IOP were (64.2±26.7)％,(58.9±31.9)％ and (45.3±32.3)％,these three kinds of methods have significant difference with the true fat contents (t values were 5.168,4.273,-6.441;P＜0.01).All the chemical shift imaging methods correlated with the true phantom model fat fractions,r values were 0.977(FS),0.978 (corrected algorithm),0.982 (WS),0.99 8(IOP),0.993 (IDEAL Gradient echo imaging),0.999 (IDEAL Quant) (all P＜0.01).Each method's 95％ confidence interval of the mean difference acquired by Bland-Altman map was WS (-14.7％ to 13.8％),FS (-3.6％ to 32.0％),corrected algorithm (-4.6％ to 22.5％),IOP(-9.4％ to 0.0％),IDEAL gradient echo imaging (-15.9％ to 7.8％),IDEAL Quant(-2.0％ to 4.0％).IDEAL Quant had the best correlation and confidence with the true fat fraction.Conclusions Chemical shift imaging methods (IOP,IDEAL Gradient echo imaging,IDEAL Quant) can acquire more accurate fat quantification results than chemical saturation imaging methods (FS,Corrected algorithm,WS) in a customized lipid phantom at 3.0 T.IDEAL Quant can acquire the best fat quantification result compared with the other imaging methods.