Biomedical subjects
Publications and source records attributed to Jian Sun.
Gene editing of three key genes, G PROTEIN GAMMA SUBUNIT, CYTOKININ OXIDASE, AND IDEAL PLANT ARCHITECTURE 1, improved the salt-tolerant japonica rice variety Lansheng increased yield while maintaining its original salt tolerance and quality.
Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. Although genomics and transcriptomics have delineated parts of the MCL disease spectrum, proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 patients with MCL and 4 healthy donors to investigate the translational and posttranslational dimensions of MCL. Our study identified 1296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed immunoglobulin heavy chain variable mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multiomics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared with single-omics models (concordance index, 0.83 vs 0.74). This study provides, to our knowledge, the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.
In chronic hepatitis B (CHB) patients under antiviral treatment, liver injury, as evidenced by elevated alanine transaminase (ALT), is associated with unfavorable outcomes and needs effective treatment. The interaction between gut microbiota and liver injury in CHB patients remains unclear. Using a case-control design, 28 cases with elevated ALT and 28 matched controls with normal ALT were randomly selected from CHB patients with viral control. Clinical characteristics were comparable between groups. Metagenomic sequencing revealed that Bacteroides fragilis was decreased in cases and exhibited the greatest disparity between cases and controls. Mice colonized by gut microbiota from cases exhibited more severe liver damage in both LPS-induced and MCD diet-induced liver injury models, and had a lower abundance of B. fragilis compared to mice colonized by gut microbiota from controls. Oral gavage of B. fragilis improved both LPS-induced and MCD diet-induced liver injury. Metabolomics analysis revealed that the levels of 7-Ketolithocholic acid (7-Keto-LCA) were positively correlated with B. fragilis and significantly increased in the cultural supernatant of B. fragilis. Consistently, 7-Keto-LCA exerted protective effects against both LPS-induced and MCD diet-induced liver damage. Targeting gut microbiota might be a promising therapeutic treatment for alleviation residual liver inflammation in CHB patients with viral control.
The oxidative deamination of N-methylputrescine is an essential step in both pyridine and tropane alkaloid biosynthesis. Reverse genetic approaches have not resulted in the cloning of a methylputrescine oxidase gene (MPO). However, we have used a homology-based approach to clone a full-length tobacco MPO1 cDNA. The MPO1 gene is part of a small multigene family comprised of approximately six members. MPO1-like transcript levels increased in roots that were either deprived of auxin or treated with methyl jasmonic acid. Similar to other known nicotine biosynthetic genes in domesticated tobacco, MPO1-like mRNA levels were lower in roots with the mutant a and b alleles. The MPO1 protein was expressed in bacteria as a recombinant Thioredoxin-His(6)-MPO1 fusion protein. The recombinant MPO1 protein utilized N-methylputrescine more efficiently than other diamines. Therefore, the kinetic properties of the MPO1 enzyme may play an important role in determining the pyridine alkaloid profiles observed in tobacco roots.
Easily accessible chiral sulfinamide 2 has been developed as the first highly efficient and enantioselective organocatalyst relying solely on a chiral sulfur center for stereochemical induction. In the presence of 20 mol % of 2, a broad range of N-aryl ketimines 1 were reduced by trichlorosilane to produce amines 3 in high yield and enantioselectivity. [reaction: see text]
The performance of a dispersion-compensated acousto-optic deflector (AOD) for steering femtosecond laser pulses was examined with the prism located before or after the AOD, which is regarded as prism-AOD and AOD-prism, respectively. Comparisons are made over parameters including the spot spatial pattern, output pulse width, scanning linearity, the field of view, and the transmission rate. Fluorescence images of 170 nm diameter beads and cells were measured to provide an overall evaluation for these femtosecond laser beam scanning configurations. On the basis of these experiments, the prism-AOD configuration is concluded to be more advantageous for the purpose of simultaneous compensation for the spatial and temporal dispersion.
OBJECTIVE: This study was designed to investigate the effects of Astragalus membranaceus (AM) and its main components, astragalus saponin (ASP), astragalus polysaccharide (APS) and aminobutyric acid (GABA), on homocysteine (Hcy) induced acute impairment of vascular tone and to explore whether the antioxidant mechanism was involved in AM protective effect. METHODS: Inhibitory effects of Hcy and protective effects of AM and its main components on endothelium-dependent relaxation of aortic rings were determined by isometric tension recordings and nitric oxide signaling was assayed with 125I-cGMP RIA Kit. Furthermore, generation of reactive oxygen species (ROS) in endothelial cells was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCF-DA). RESULTS: Hcy significantly inhibited endothelium-dependent relaxation to acetylcholine (ACh) in a dose-dependent manner, and decreased cGMP levels increased by ACh in aorta. Furthermore, superoxide dismutase (SOD), AM, and ASP markedly attenuated inhibition of vasorelaxation and downregulation of cGMP level by Hcy, and APS exerted a tendency to reverse both of the depressive responses, while GABA had no similar effects. Additionally, partially impaired relaxation by Hcy was completely blocked due to the presence of N(omega)-nitro-L-arginine-methyl ester (L-NAME), which could not be further altered by treatment with AM, ASP, APS or GABA. Finally, Hcy significantly increased intracellular ROS levels in endothelial cells as measured by CM-H2DCF-DA fluorescence. SOD, AM, ASP, and APS, but not GABA, inhibited Hcy-stimulated ROS generation. CONCLUSION: This study demonstrated that AM and ASP, potently protected endothelium-dependent relaxation against the acute injury from Hcy through nitric oxide regulatory pathways, in which antioxidation played a key role.
BAFF-R is the predominant receptor that mediates B-cell activating factor (BAFF)-dependent B-cell signalling and plays a critical role in late-stage B-cell maturation and survival. BAFF has been implicated in the development of autoimmunity and systemic lupus erythematosus (SLE). To define the role of BAFF-R in autoimmunity and SLE, we crossed A/WySnJ mice with MRL-lpr mice and generated BAFF-R-mutant MRL-lpr mice. The BAFF-R mutation markedly impaired the development of immature, mature and marginal zone B cells in the spleens of MRL-lpr mice. Unexpectedly, the BAFF-R mutation in MRL-lpr mice did not result in decreased autoantibody production, hypergammaglobulinaemia or immune complex-mediated glomerulonephritis. Rather, the ability of BAFF-R-mutant lpr splenic B cells to produce immunoglobulins in vitro was not decreased, although germinal centre formation, antibody response and B-cell proliferation were impaired. Further studies found increased numbers of B cells in the bone marrow of BAFF-R-mutant MRL-lpr mice compared to the BAFF-R-intact lupus mice. ELISPOT analysis revealed that BAFF-R-mutant MRL-lpr mice had more antibody-secreting cells in their bone marrow than the control mice. Thus, these findings could explain the development of autoimmunity and hypergammaglobulinaemia observed in BAFF-R-mutant MRL-lpr mice.
PURPOSE: The aim of the study is to develop a method to estimate osteoarthritis (OA) incidence by using administrative health care databases. METHODS: Using actual counts of OA diagnoses in different periods, we generated an equation that estimated the number of new OA diagnoses based on the length of time used for excluding prevalent OA cases. Physicians billing files from 1983 to 2002 maintained at Alberta Health and Wellness were used to verify the proposed method. Age- and sex-specific and crude OA incidences in 2002 were calculated by using this method. RESULTS: Women aged 50 to 59 years had the greatest incidence. For men, the greatest incidence was in the 60- to 69-year age category. Crude incidences for women and men were 1103 and 934 per 100,000 person-years, respectively. The overall crude rate was 1040 per 100,000 person-years. CONCLUSIONS: Modified power function accurately summarizes the relationship between number of first OA diagnoses and length of the clearance period and thus provides an effective model to estimate OA incidence. Not restricted to OA, this model also can be implemented to estimate incidences of other chronic conditions.
In vitro studies have demonstrated that bovine angiogenin (ANG) significantly stimulates both the migration of endothelial cells and the formation of tubelike structures. The aim of this study was to explore whether ANG gene transfer could enhance vascularization, modify left ventricular remodeling, and attenuate cardiac dysfunction in rats with myocardial infarction (MI). We constructed a recombinant adeno-associated virus vector encoding the ANG gene (rAAV-ANG) and evaluated its angiogenic potential after regional transfection by intramyocardial injection immediately after left anterior descending artery ligation in rats. Four weeks after coronary artery ligation, rAAV-ANG transfection upregulated the myocardium ANG protein expression level in both normal and MI rats, and immunohistochemistry showed that the overexpressed ANG was distributed in the cytoplasm of cardiomyocytes. In rats with MI, rAAV-ANG treatment altered left ventricular remodeling, as indicated by a decrease in left ventricular end diastolic diameter, left ventricular end systolic diameter, cardiomyocyte diameter, ventricular weight to body weight ratio and interstitial fibrosis infiltration. We also found an increase in capillary density and partly restored cardiac function in the group receiving rAAV-ANG treatment. These results confirmed that in rats with MI, ANG gene transfer could induce angiogenesis, alter left ventricular remodeling, and attenuate cardiac dysfunction. This study provides a new choice of treatment for ischemic heart disease.
OBJECTIVE: To observe the effects of HBV genotypes on the level of HBsAg in serum and hepatocytes in chronic hepatitis B patients without antiviral therapy. METHODS: Seventy-six chronic hepatitis B inpatients were enrolled into this study, and liver biopsies and histologic diagnosis were performed, and serum samples were collected at the time point of liver biopsy. PCR-RFLP method was adopted to determine the genotype of hepatitis B virus and Abbott Architect HBsAg assay was used to quantify the serum HBsAg. Immunostaining for antigens in liver tissues with monoclonal antibody (for HBsAg) or polyclonal antibodies (for HBcAg) was carried out in consecutive slides. The percentages of hepatocytes for HBsAg stain, hepatocytes for HBcAg nuclear stain and hepatocytes for HBcAg cytoplasm stain were estimated in the ranges of 0 (negative), < or = 1%, 1+; 2% - 5%, 2+; 6% - 25%, 3+; 26% - 50%, 4+; and > 50%, 5+. The distributions of positive cells in slides are described as single or isolated, cluster or widespread. Surface gene was directly sequenced with the serum HBV DNA from 6 patients with genotype B and 8 with genotype C HBV infection, respectively. RESULTS: Four HBV genotypes were detected in 76 patients: 47 patients with B, 21 with C, 3 with D and 5 were infected by genotype B mixed with C HBV infection. Age, gender, serum HBV DNA level, ALT, AST or histological evaluation (grades and stages scores) were not different between the patients infected with genotype B or C HBV. The level of serum HBsAg was not significantly different between the patients infected with genotype B or C HBV, but the proportions of hepatocytes stained with HBsAg was greater in patients with C type HBV infection than B (P < 0.01). In the liver slides from the patients infected HBV genotype B, HBsAg was stained frequently in single or isolated hepatocytes (22/47), and widespread HBsAg-positive hepatocytes were often seen in the patients with C type HBV (8/21), P < 0.01. In the patients with B type HBV, serum HBsAg was positively correlated with serum HBV DNA (r = 0.674, P = 0.000), proportion of hepatocytes with HBcAg in nucleus (r = 0.534, P = 0.000) and in cytoplasm (r = 0.405, P = 0.004). In the patients with C type HBV infection, serum HBsAg had positive correlation only with serum HBV DNA (r = 0.503, P = 0.017). Proportion of HBsAg positive hepatocytes was positively correlated only with the proportion of HBcAg cytoplasm positive hepatocytes in the patients with B type HBV (r = 0.318, P = 0.029) and no correlation with serum HBsAg, HBV DNA, or proportions of hepatocytes with HBcAg in nucleus. Analysis of the first 40 amino acid sequences of surface antigen showed that variations most existed at amino acid 3, 4, 5 and 8. CONCLUSION: Proportion of HBsAg in hepatocytes is significantly greater in the patients with C type HBV than those with B type HBV. Positive correlation between serum HBsAg and viral replication was seems to be more significant in the patients with HBV genotype B infection.
[reaction: see text] l-Piperazine-2-carboxylic acid derived N-formamides have been developed as highly enantioselective Lewis basic catalysts for the hydrosilylation of N-aryl imines with trichlorosilane. The arene sulfonyl group on N4 was found to be critical for the high enantioselectivity of the catalyst. High isolated yields (up to 99%) and enantioselectivities (up to 97%) were obtained for a broad range of substrates, including aromatic and aliphatic ketimines, particularly those with R(2) as relatively bulky alkyl groups.
B lymphocyte stimulator (BLyS) is a member of tumor necrosis factor (TNF) family. Because of its roles in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren syndrome (SS), BLyS antagonists have been tested to treat SLE- and RA-like symptoms in mice and obtained optimistic results. So far, reported BLyS antagonists were mostly decoyed BLyS receptors or anti-BLyS antibodies. In this study, a novel BLyS antagonist peptide, PT, was designed based on the modeling 3-D complex structure of BCMA and BLyS. The interaction mode of PT with BLyS was analyzed theoretically. The results of competitive ELISA demonstrated that PT could inhibit the binding of BCMA-Fc and anti-BLyS antibody to BLyS in vitro. In addition, PT could partly block the proliferating activity of BLyS on mice splenocytes. The BLyS antagonizing activity of PT was significant (p<0.05). This study highlights the possibility of using BLyS antagonist peptide to neutralize BLyS activity. Further optimization of PT with computer-guided molecular design method to enhance its biopotency may be useful in developing new BLyS antagonists to treat BLyS-related autoimmune diseases.
AIM: To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapamune, rapamycin) in a consecutive cohort of 248 liver allograft recipients. METHODS: Thirty-six liver transplant patients with hepatocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n = 18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT. RESULTS: The patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT. Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo posttransplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable. CONCLUSION: The conversion to SRL-based immunosuppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.
OBJECTIVE: To analyze the risk factors influencing the prognosis of orthotopic liver transplantation for hepatocellular carcinoma (HCC) and sum up the relevant clinical experience in diagnosis and treatment of HCC. METHODS: The clinical data of 198 HCC patients, 177 males and 21 females, aged 49 (24-83), were analyzed. RESULTS: The 0.5-, 1-, and 2-year survival rates were 89%, 78%, and 65 respectively. The rates of disease-free survival (DFS) were 85%, 73, and 67% respectively. Univariate analysis revealed that tumor size, presence of vascular invasion, Edmondson grade, TNM classification, and preoperative alpha-fetoprotein (AFP) were significantly related to DFS, and the 4 foregoing factors were also related to the survival rate. Cox regression analysis suggested that presence of vascular invasion was an independent prognostic factor of survival rate and DFS. CONCLUSION: Vascular invasion plays a leading role in evaluating the prognosis of orthotopic liver transplantation for HCC. It is important to discover the micro-metastasis and explore more effective approaches to prevent recurrence after transplantation.
Human interleukin-6 is involved in the maintenance and progression of several diseases such as multiple myeloma (MM), rheumatoid arthritis, or osteoporosis. Our previous work demonstrated that an interleukin-6 antagonist peptide (named PT) possessed potential bioactivity to antagonize the function of hIL-6 and could efficiently induce the growth arrest and apoptosis of XG-7 and M1 cells in a dose-dependent manner. In this study, the theoretical interaction of the peptide PT with its receptor was analyzed further more with molecular docking and molecular dynamics methods. The theoretical studies showed that PT possessed very high affinity to interleukin-6R and offered a practical means of imposing long-term blockade of interleukin-6 activity in vivo. According to the theoretical results, the biological evaluation of PT was researched on two different cells models with more sensitive approaches: (1) The antagonist activity of PT was studied on the interleukin-6 dependent MM cells (XG-7) cultured with interleukin-6. In the other interleukin-6 dependent MM cells (SKO-007), they survived themselves by auto/paracrine without the exogenous interleukin-6, and also could be antagonized by PT. The therapeutic value of PT only limited on the interleukin-6 dependent category in MM. (2) Myeloid leukemia M1 cells were induced for growth arrest and apoptosis in response to interleukin-6. The results supported our previous findings and showed that PT could be evaluated by protecting the cells from interleukin-6 induced apoptosis. In conclusion, PT could induce interleukin-6-dependent XG-7 and SKO-007 cells to apoptosis while inhibit interleukin-6-stimulated apoptosis in M1 cells.
L-Pipecolinic acid derived formamides have been developed as highly efficient and enantioselective Lewis basic organocatalysts for the reduction of N-aryl imines with trichlorosilane. Catalyst 4b afforded high isolated yields (up to 98%) and enantioselectivities (up to 96%) under mild conditions with an unprecedented substrate spectrum.
A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.