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SUMOylation is an important post-translational modification of proteins. Similar to ubiquitylation, SUMOylation is the process that the small ubiquitin-like modifier (SUMO) proteins are specifically and covalently binding to lysine residues of substrate proteins. Through SUMOylation, the physiological functions and pathological processes of cells are well controlled and balanced, and its abnormal activation has been reported in various tumors. Therefore, SUMOylation has been a potential target for anti-tumor drug development. In this review, we summarize recent advances on development of inhibitors targeting SUMOylation pathway and their antitumor properties.
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ObjectiveTo investigate the therapeutic effect and the possible mechanism of Mankuining decoction on dextran sulfate sodium （DSS）-induced ulcerative colitis （UC） in mice. MethodA total of 90 male SPF C57BL/6 mice were randomly classified into normal group， model group， mesalazine group （0.266 g·kg-1）， and high-， and medium-， low-dose （20， 10， 5 g·kg-1） Mankuining decoction groups， with 15 rats in each group. Mice， except the normal group， drank 3% DSS solution for 7 days to induce UC， and administration （ig） started on the day of modeling. The model group and the normal group were given equivalent amount of 0.9% normal saline once a day for 7 days. The general conditions of mice were recorded every day and the disease activity index （DAI） was calculated. On the 8th day， mice were killed by cervical dislocation. All the colons and feces were collected. The length of colon was recorded， and the histopathological changes of colon were observed based on hematoxylin-eosin （HE） staining. The content of inflammatory factors in colon was detected by enzyme-linked immunosorbent assay （ELISA）， and the changes of intestinal flora in mouse feces were determined based on 16SrRNA sequencing. ResultCompared with the normal group， the model group had severe colon damage， reduction in colon length （P<0.01）， increase in DAI （P<0.01）， decrease in interleukin-10 （IL-10） and transforming growth factor-β1 （TGF-β1） in colon（P<0.01）， rise of interleukin-1β （IL-1β）， interleukin-6 （IL-6）， interleukin-17α （IL-17α）， and tumor necrosis factor-α （TNF-α） in colon （P<0.05， P<0.01）， and decrease in abundance and diversity of intestinal flora. Compared with the model group， mesalazine and high-， medium-， low-dose Mankuining decoction alleviated the colon injury， recovered the length of colon （P<0.01）， decreased DAI （P<0.01）， increased IL-10 and TGF-β1 in colon （P<0.01）， and decreased IL-1β， IL-6， IL-17α， and TNF-α in colon （P<0.01）. Moreover， they raised the abundance and diversity of intestinal flora compared with the model group， as manifested by the increase in the abundance of Firmicutes， Akkermansia， Dubosiella， and Blautia and the decrease in the abundance of Bacteroidetes， Muribaculaceae， Clostridia_UCG-014， and Alistipes. ConclusionMankuining decoction has definite effect in treating UC mice， and the effect is positively correlated with the concentration. In addition， different concentration has different influence on the structure of flora. The mechanism is the likelihood that it alleviates the disorder of intestinal flora to restore intestinal immune balance and further promote the recovery of colonic mucosa.
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Background@#The high sensitivity of individuals toward safety information in production activities, that is, attentional bias toward safety (ABS), can positively predict safe behaviors. It has become a hot topic in current organizational safety behavior research. However, there is no literature on its modification method. @*Methods@#Based on the modified dot-probe task, we designed a modification training method of ABS. The training method required subjects to respond to the location of detection points that presented after safety stimulus and neutral stimulus pictures. Subjects' attentional bias values of safety and neutral pictures were measured during the experiment. Twenty-one students were selected and divided into a control group and training group to gain comparable results. @*Results@#A novel training method was developed in this study to promote the efficacy of safety stimulus by activating ABS of the subjects. Moreover, repeated trainings and preacquired relative knowledge can enhance this effect. @*Conclusion@#This study develops an experimental approach to evaluate the effectiveness of safety education and safety training, and also provides a new research idea for accident prevention.
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Background@#The high sensitivity of individuals toward safety information in production activities, that is, attentional bias toward safety (ABS), can positively predict safe behaviors. It has become a hot topic in current organizational safety behavior research. However, there is no literature on its modification method. @*Methods@#Based on the modified dot-probe task, we designed a modification training method of ABS. The training method required subjects to respond to the location of detection points that presented after safety stimulus and neutral stimulus pictures. Subjects' attentional bias values of safety and neutral pictures were measured during the experiment. Twenty-one students were selected and divided into a control group and training group to gain comparable results. @*Results@#A novel training method was developed in this study to promote the efficacy of safety stimulus by activating ABS of the subjects. Moreover, repeated trainings and preacquired relative knowledge can enhance this effect. @*Conclusion@#This study develops an experimental approach to evaluate the effectiveness of safety education and safety training, and also provides a new research idea for accident prevention.
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Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor
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Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors (ICIs) have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity. Particularly, the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S. Food and Drug Administration (FDA)-approved anti-programmed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies. However, the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity. Indeed, the cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS‒STING‒TBK1) axis is now appreciated as the major signaling pathway in innate immune response across different species. Aberrant signaling of this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection and cancers. In this perspective, we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy. Meanwhile, highlights on the clinical candidates, limitations and challenges, as well as future directions in this field are also discussed. Further, small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.
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Objective To obtain a mouse CD40-specific single-chain antibody (scFv) with high purity and to investigate its in vivo and in vitro agonistic activity on natural killer(NK) cells against tumor. Methods Agonistic anti-mouse CD40 scFv with high purity was obtained by genetic engineering. Mouse dendritic cells (DCs) were treated with different strategies including anti-CD40 monoclonal antibody (McAb),anti-CD40 scFv and negative control. Expression of IL-12 in the supernatants of DC cultures was measured by ELISA. Then DCs and NK cells were co-cultured to obtain activated NK cells,which were co-cultured with T6-17 cells. WST-8 was used to test the cytotoxic effects of NK cells on T6-17 cells. A mouse tumor model was established by injecting BALB/c nude mice with T6-17 cells. Anti-CD40 scFv was injected into tumor to evaluate its inhibitory effect on tumor growth. Levels of IL-12 and IFN-γ in the tumor microen-vironment were detected by ELISA. Changes in the percentages of tumor-infiltrating NK cells and the expres-sion of NKG2D protein(natural-killer group 2,member D) were detected by flow cytometry and immunohis-tochemistry,respectively. Results The recombinant plasmid CD40 scFv-pET28a was confirmed to be con-structed correctly. Results of SDS-page and His-tag Western blot revealed that anti-CD40 scFv could be ex-pressed successfully with a relative molecular mass of 27×103. The level of IL-12 in the supernatant of DC culture of anti-CD40 scFv group was (555.86 ±40.48) pg/ml, which was significantly higher than that of negative control group (P<0.05). The killing ability of NK cells in anti-CD40 scFv group was (72.23 ± 3.99)%,which was significantly higher than that in negative control group (P<0.05). Anti-CD40 scFv significantly inhibited the tumor growth in BALB/c nude mice as compared with negative control group(P<0.05). The levels of IL-12 and IFN-γ in tumor microenvironment of anti-CD40 scFv group were(188.801± 32.718) pg/ml and(121.428±30.994) pg/ml,respectively,which were significantly higher than those in normal saline(NS) group(P<0.05). The positive rate of NKG2D protein and the percentage of CD3-DX5+cells in anti-CD40 scFv group were respectively(8.18±2.01)% and(19.15±2.24)%,which were signifi-cantly higher than those in NS group (P<0.05). Conclusion Agonistic anti-mouse CD40 scFv could en-hance the anti-tumor ability of NK cells by activating DCs.
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Objective:To explore the agonistic CD40 antibody(CD40ScFv and CD40mAb)-mediated suppression of mouse breast cancer cell growth and change in tumor tissue Th1/Th2 balance,as well as the mechanism underlying its antitumor effect.Methods:The re-combinant plasmid containing the CD40ScFv gene fragment was transformed into the Rosetta strain of Escherichia coli to express and purify the recombinant functional CD40ScFv protein.The 4T1 mouse breast cancer cells were cultured in vitro.Balb/C tumor model mice were divided into CD40ScFv,CD40mAb agonist,and saline(NS group)groups,which were administered CD40ScFv,CD40mAb ago-nist,and saline,respectively,to observe the change in tumor volume.The tumor tissues were removed and enzyme-linked immunosor-bent assay(ELISA)was used to determine IL-12 concentration in the tumor tissue supernatants.The tumor infiltrating lymphocytes (TILs)were extracted by enzymatic digestion.The proportion of Th1 and Th2 cells in TILs was determined by flow cytometry.Results:The CD40ScFv protein was successfully identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot.The molecular size and concentration of the purified protein were 27kDa and 1.12 mg/mL,respectively.The tumor sizes of the CD40ScFv and CD40mAb groups were(3.044±0.239)cm3and(2.749±0.261)cm3,respectively,which were significantly smaller(P<0.05)than that of the NS group(3.933±0.326)cm3.The tumor IL-12 concentration(determined by ELISA)in the CD40ScFv group(396.27±48.13)pg/mL and the CD40mAb agonist group(457.63±58.37)pg/mL were significantly higher(P<0.05)than that of the NS group(79.51±14.97) pg/mL.The results of flow cytometry showed that the excited Th1/Th2 cell ratios were 6.32±0.87 and 5.54±0.71 for the CD40ScFv and CD40mAb groups,respectively,which were significantly higher(P<0.05)than that of the NS group(1.79±0.38).Conclusions:The agonis-tic CD40 antibody inhibited tumor growth by regulating the Th1/Th2 ratio and IL-12 secretion via promotion of DC activation,which is one of the important mechanisms affecting Th1/Th2 balance in the tumor microenvironment
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The three-points five-needles acupuncture method developed by professor SHAO Jing-ming had achieved a significant efficacy in the treatment of asthma, and had been widely accepted by patients. After decades of development, SHAO's three-points five-needles acupuncture method had developed into a treatment with a complete theoretical system and numerous clinical study results. This article was to review the current clinical study progress of SHAO's three-points five-needles acupuncture method in treating asthma.
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The three-points five-needles acupuncture method developed by professor SHAO Jing-ming had achieved a significant efficacy in the treatment of asthma, and had been widely accepted by patients. After decades of development, SHAO's three-points five-needles acupuncture method had developed into a treatment with a complete theoretical system and numerous clinical study results. This article was to review the current clinical study progress of SHAO's three-points five-needles acupuncture method in treating asthma.
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Objective To investigate the inhibitory effect of agonistic CD40 monoclonal antibody on the colon cancer cells (HCT116) proliferation in vitro.Methods The DCs (dendritic cells) loaded with tumor cells (HCT116) antigens were activated by different methods.According to the activation method,the cells were divided into three groups:agonistic CD40 monoclonal antibody group,blank control group and TNF-α positive control group.The cells were cultured for 7 days,and the expression rates of CD80,CD83,CD86 and HLA-DR on DC surface in each group were detected by flow cytometry.The concentration of cytokine IL-12(p70) in DCs culture supernatant was determined by ELISA kit.The proliferation activity of the T lymphocytes was evaluated by MTT (methyl thiazolyl tetrazolium).Then the inhibition rate of colon cancer HCT116 cells proliferation,which induced by the tumor-specific effector T lymphocytes,was assayed.Results Compared with the blank control group,the agonistic CD40 monoclonal antibody group had a significantly higher expression rates of CD80,CD83,CD86 and HLA-DR on DC surface (P＜0.05).The concentration of IL-12 in the supernatant of DC was also much higher in the agonistic CD40 monoclonal antibody group (P＜0.05,(716.80±53.43) pg/ml vs.(405.51 ±12.17) pg/ml).The DCs activated by CD40 monoclonal antibody had stronger ability to stimulate proliferation of T lymphocytes (P＜0.05,the stimulation index was (2.006 2±0.438 3) to (1.365 0±0.209 8)).The tumor-specific CTLs induced by DCs in the agonistic CD40 monoclonal antibody group had stronger ability to inhibit colon cancer HCT116 cells (P＜0.05,the inhibition rate was (66.08±0.41)％ vs.(46.60± 1.10)％).However,there was no statistical significance between the agonistic CD40 monoclonal antibody group and the TNF-α positive control group (P＞0.05).Conclusion Agonistic CD40 monoclonal antibody in vitro can promote activation and mature of DCs,then the activated DCs can induce the production of tumor-specific CTL,which can significantly inhibit the proliferation of colon cancer HCT116 cells.
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Background The conventional therapies for childhood amblyopia mainly include optometry,occluding therapy,atropine application,fine eyesight training,instrument or regular comprehensive therapy,but the clinical effectiveness of each method had its limitation.Chinese herbs have been used to the treatment of childhood amblyopia,however,their effects are still in controversy.Objective This study was to assess the evidence of efficacy of Chinese herbs combined with moderate methods for childhood amblyopia.Methods The published papers of randomized controlled trials (RCT) and controlled clinical trials (CCT) of Chinese herbs combined with moderate comprehensive therapy for childhood amblyopia from 2000 to 2015 were searched in China National Knowledge Infrastructure (CNKI),Wanfang database and PubMed database with computer.The methodology quality of included papers was evaluated according to the criteria of Cochrane and advanced Jadad scale.Data synthesis was facilitated using Reviewer Manager 5.1 software.The overall effect,or odds ratio (OR) of the treatment was analyzed by fixed effective model.Results Thirty-three RCT or CCT papers meeting inclusion criteria were included with the total sample size 6 666,and matched demography was showed in 25 papers;referential diagnosis criteria and effective criteria were described in 29 papers and 30 papers,respectively.Advanced Jadad scale showed 6,3 and 1-2 scores in 1,2 and 30 papers,respectively.The evidence showed that the total effectiveness of treatment within the group receiving Chinese herbs combined with conventional methods was higher than that in conventional group,with a statistically significant difference between groups (polled fixed effects model [OR] =3.92,95％ confidence interval [CI]:3.30-4.64,Z=15.74,P＜0.01).Conclusions The total effectiveness rate of Chinese herbs combined with conventional methods for childhood amblyopia is superior to only conventional treatment,indicating that Chinese herbs is effective for childhood amblyopia.More well-designed RCTs are needed to confirm the effect.
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Objective To assess the capability of serum and urine neutrophil gelatinase-associated lipocalin (NGAL) in predicting acute kidney injury (AKI) in septic patients.Methods From July 1, 2014 through December 31, 2014, a prospective observational study of septic patients without AKI was carried out in Renmin Hospital, Tianjin Hospital, and Nankai Hospital, Tianjin.The patients with AKI which was developed after admission to intensive care unit (ICU) were assigned to AKI group and the patients without AKI were assigned to non-AKI group.Clinical data and serum and urine sample were collected at the admission, and at 12, 24, 36, 48, 60, 72 ,84 and 96 hours after admission for detecting creatinine and NGAL.The measurement data accorded with normal distribution were used for t test or variance analysis of repeated measures;comparison of measurement data in non-normal distribution was carried out using the Mann-Whitney U test or Fridman test;comparison of count data was performed using Fisher exact probability method.ROC curve of serum or urine NGAL was plotted and the diagnostic values of serum or urine NGAL in predicting AKI were assessed by calculation of the area under the receiver operating characteristic curve (AuROC).Results Fifty septic patients were included.Thirty-five patients were in AKI group and fifteen in non-AKI group.The median age of AKI group was 73 and the median age of non-AKI group was 60 (IQR, 47-82).The urine NGAL (uNGAL) concentration in AKI group was higher than that in non-AKI group at the every interval and serum NGAL (sNGAL) was higher in AKI group than that in non-AKI group at only first twointervals.The uNGAL showed the capability of prediction for AKI progression at the 48 hour (AuROC=0.83,95% CI:0.70-0.97), 36 hours (AuROC=0.75,95%CI:0.59-0.91), 24 hours (AuROC=0.83,95%CI:0.70-0.95), 12 hours (AuROC=0.73,95%CI:0.60-0.88) prior to AKI occurred.The sNGAL showed capability of prediction at the 48 hours (AuROC=0.69,95%CI:0.51-0.88), 36 hours (AuROC=0.69,95%CI:0.52-0.87) prior to AKI occurred.Conclusions The sNGAL and uNGAL both were useful biomarker that predicted development of AKI in early stage.But the performance of sNGAL was slightly inferior to that of uNGAL for predicting development of AKI.
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Through analyzing the research literature about the mechanism of acupuncture intervention on vision in recent years, this article reviewed the mechanism of acupuncture intervention on vision from the aspects of central processing of visual information, the influnce of information transmission in the retina, the changes in visual microcirculation, optic nerve and neurotransmitter transmission, visual electrophysiology, visual plasticity. This article also proposed the future research idea for this field.
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Electrophysiology examination is an important technique in studying amblyopia, which mainly includes electrooculography( EOG), electroretinography ( ERG), visual evoked potential( VEP). This study does not only summarizes the definition, the mechanisms and the meaning of these indexes in the relevant research progress in recent years, but also makes a comment on the controversies among the relevant research conclusions.
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Objective:To observe the clinical efficacy of buccal acupuncture plus exercise therapy in treating scapulohumeral periarthritis (SP). Methods:Sixty-three SP patients were intervened by buccal acupuncture plus exercise therapy. The treatment was given once every day, 5 sessions as a course, with a 2-3 d interval between two courses. The therapeutic efficacy was observed after 3 courses of treatment. Results:Thirty-five patients were recovered, 23 cases were improved, while 5 cases showed ineffective, and the total effective rate was 92.1%. Conclusion:Buccal acupuncture plus exercise therapy can produce a significant efficacy in treating SP, and thus is worth promotion in clinic.
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Objective:This study aims to compare the difference in the expression levels of prostaglandin E2 (PGE2), vascular endotheli-al growth factor (VEGF), and the clinicopathological features among gastric carcinoma patients with and without hyperlipidemia and to assess whether hyperlipidemia promotes gastric carcinoma progression. Methods:We analyzed the PGE2 and VEGF serum levels and the VEGF expression in gastric carcinoma tissues in 102 gastric carcinoma patients. The PGE2 and VEGF serum levels were detected by enzyme-linked immunosorbent assay, and the VEGF expression in gastric carcinoma tissues was detected by SABC immunohistochemi-cal staining. Results:Among the 102 gastric carcinoma patients, 49 patients had hyperlipidemia, and 53 did not have the condition. The PGE2 and VEGF expressions in the serum and the VEGF expression in gastric carcinoma tissues were higher in hyperlipidemic pa-tients than in those without hyperlipidemia (P<0.05). The degrees of differentiation, depths of invasion, lymph node metastasis, and TNM staging in the two groups also showed statistical differences (P<0.05). Conclusion:Hyperlipidemia possibly contributes to the pro-gression of gastric carcinoma by upregulating the PGE2 and VEGF expressions.
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The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y.
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Objective To explore the efficacy of multiple target therapy in treatment of patients with chronic moderate and severe IgA nephropathy with hyperuricemia.Methods Seventy-six patients with chronic progressive moderate and severe IgA nephropathy with hyperuricemia were enrolled the current study and randomly divided into observation group and control group.Patients in control group were treated with allopurinol,prednisone,benner pury and valsartan,while those in observation group were treated with urokinase,mycophenolate mofetil besides the basis of control group for 6 months.The blood uric acid (UA),24 h urine protein,mean arterial pressure (MAP) and creatinine clearance rate (Ccr) were determined and analyzed.Results The levels of UA,24 h urinary protein,MAP and Ccr in observation group and control group were same before treatment (P ＞ 0.05).After 6 months treatment,the levels of UA,24 h urine protein,MAP and Ccr in observation group were (413.7 ± 90.7) μmol/L,(1.15 ± 0.57) g/L,(87.7 ± 10.6) mmHg and (81.9 ± 3.7) ml/min respectively,significantly different from those of the control group ((369.6 ± 67.2) μ mol/L,(0.77 ±0.51) g/L,(81.6 ±12.3) mmHg and (86.4 ±6.8) ml/min;t =2.219,2.802,2.132,3.230;P ＜0.05).The rate of adverse reactions in two groups was not significantly differnent(9.7％ (3/31) vs 9.1％ (3/33) ; x2 =0.006,P =0.936).Conclusion Multiply target therapy is effective and safe in terms of treating chronic progressive moderate and severe IgA nephropathy with hyperuricemia.
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Objective To analyze the correlation between kidney deficiency and fear stress by investigating the difference in behavior between groups of model rats.Methods The rats were divided randomly into 3 groups.To create kidney deficiency models as the experimental group by intramuscular injection of hydrocortisone; giving high-fat and high-salt diet by gastric perfusion to create spleen deficiency models as the control group; normal rats were used as the blank control group.Using light stimulation,thermo stimulation and food stimulation as the factors,to observe and analyze the difference of behavior among groups under each type of environmental stimulus.Results The behavior experiment showed the difference among groups,both kidney deficiency group and spleen deficiency group acted out more apparent fear stress than normal group (without food stimulation P=0.039,with food stimulation P=0.037).For example,under the environmental stimulus of light and no food,3 groups leaned out for different frequency in 15 min:normal group showed(5.70± 1.636)times,spleen deficiency group showed(2.30±0.949)times and kidney deficiency group showed (0.05±0.224)times,which demonstrated fear stress and physical constitution are relevant; kidney deficiency group showed the most obvious fear stress among 3 groups,which proved the correlation between kidney deficiency and fear stress was more significant.Conclusion Kidney deficiency was a significant factor of fear stress,the correlation between them could be direct.