Diabetic vascular smooth muscle cells (VSMCs) exhibit significantly increased rates of proliferation and migration, which was the most common pathological change in atherosclerosis. In addition, the ...study about the role for miRNAs in the regulation of VSMC proliferation is just beginning to emerge and additional miRNAs involved in VSMC proliferation modulation should be identified.
The expression of miR-138 and SIRT1 were examined in SMCs separated from db/db mice and in SMC lines C-12511 exposed to high glucose with qRT-PCR and western blot. The regulation of miR-138 on the expression of SMCs was detected with luciferase report assay. VSMCs proliferation and migration assays were performed to examine the effect of miR-138 inhibitor on VSMCs proliferation and migration.
We discovered that higher mRNA level of miR-138 and reduced expression of SIRT1 were observed in SMCs separated from db/db mice and in SMC lines C-12511. Moreover, luciferase report assay showed that the activity of SIRT1 3′-UTR was highly increased by miR-138 inhibitor and reduced by miR-138 mimic. In addition, we examined that the up-regulation of NF-κB induced by high glucose in SMCs was reversed by resveratrol and miR-138 inhibitor. MTT and migration assays showed that miR-138 inhibitor attenuated the proliferation and migration of smooth muscle cells.
In this study, we revealed that miR-138 might promote proliferation and migration of SMC in db/db mice through suppressing the expression of SIRT1.
•Higher mRNA level of miR-138 was observed in SMCs from db/db mice.•The mRNA and protein level of SIRT1 in SMCs from db/db mice were greatly reduced.•miR-138 could regulate the expression of SIRT1 in SMCs.•SIRT1 overexpression reversed the up-regulation of acetylized p65 and NF-κB induced by high glucose.•MiR-138 inhibitor reversed VSMCs proliferation and migration induced by high glucose.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The C-glycosylation of C-nucleophiles including allyltrimethylsilane, silyl enol ethers and phenols with N-(glycosyloxy)acetamides as glycosyl donors has been realized. This protocol provides a ...convenient and practical route for the synthesis of alkyl C-glycosides and aryl 2-deoxy-β-C-glycosides under mild reaction conditions.
Abstract Background The inappropriate proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in the atherosclerotic process. SENCR was reported to be associated with cell ...migration in human smooth muscle cells. However, the regulation role of SENCR in SMCs is still not fully understood. Methods qRT-PCR and Western blotting were performed to detect the mRNA and protein levels of SENCR, FOXO1 and TRPC6 in SMCs of db/db mice and SMCs exposed to high glucose. The regulation of SENCR on the expression of FoxO1 and TRPC6 were examined with luciferase report assays. Furthermore, we investigated the effect of SENCR on VSMCs proliferation and migration using MTT assay and cell migration assay, respectively. Results Here, we found that SENCR was down-regulated in db/db mice and in SMCs exposed to high glucose. According to the result of luciferase assays, it was shown that SMCs knockdown enhanced the expression of FoxO1 and FoxO1 overexpression increased the expression of TRPC6. In addition, qRT-PCR revealed that SENCR overexpression reversed the effect of high glucose on mouse VSMCs proliferation and migration. Conclusion In this study, our data indicated that down-regulation of SENCR promoted smooth muscle cells proliferation and migration in db/db mice through up-regulation of FoxO1 and TRPC6.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The synthesis of tumor-associated KH-1 antigen core nonasaccharide was achieved. All key glycosidic linkages were efficiently constructed by photo-induced glycosylation. The success of this total ...synthesis provides an example for the preparation of complex oligosaccharides using light-driven glycosylation reactions.
An efficient aqueous Wittig reaction was enabled on protein bioconjugation for the first time. By investigating the reaction on small molecules, peptides, and proteins, a site-specific reaction ...targeting "aldehyde tag" was presented. A variety of functional groups could be introduced into the protein of interest.
Recent advances in glycan synthesis Li, Bo-Han; Ye, Xin-Shan
Current opinion in chemical biology,
October 2020, 2020-10-00, 20201001, Volume:
58
Journal Article
Peer reviewed
Carbohydrates play important roles in life science, but their synthesis is always hampered by their complicated chemical structures. Scientists have never stopped trying to solve the problem of ...glycan synthesis from various aspects. Here a brief overview of recent progress in glycan synthesis, including chemical approaches, chemoenzymatic approaches, and automated synthesis, will be discussed, focusing on the efficiency of new glycosylation methods, the stereoselectivity of coupled products, and their applications in the assembly of complex glycan chains.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•GPC3 mutation in primary osteosarcoma becomes abundant in its metastasis.•Mutant GPC3 is over-produced in metastatic spheroids with multidrug resistance.•Anti-GPC3 antibody effectively commits ...metastatic spheroids to apoptosis.•GPC3 would be a promising therapeutic target of osteosarcomas.
Drug resistance and the lack of molecular therapeutic target are the main challenges in the management of osteosarcomas (OSs). Identification of novel genetic alteration(s) related with OS recurrence and chemotherapeutic resistance would be of scientific and clinical significance.
To identify potential genetic alterations related with OS recurrence and chemotherapeutic resistance, the biopsies of a 20-year-old male osteosarcoma patient were collected at primary site (p-OS) and from its metastatic tumor (m-OS) formed after 5 months of adjuvant chemotherapy. Both OS specimens were subjected to cancer-targeted next generation sequencing (NGS) and their cell suspensions were cultured under three-dimensional condition to establish spheroid therapeutic model. Transcript-oriented Sanger sequencing for GPC3, the detected mutated gene, was performed on RNA samples of p-OS and m-OS tissues and spheroids. The effects of anti-GPC3 antibody and its combination with cisplatin on m-OS spheroids were elucidated.
NGS revealed 4 mutations (GPC3, SOX10, MDM4 and MAPK8) and 6 amplifications (MDM2, CDK4, CCND3, RUNX2, GLI1 and FRS2) in p-OS, and 3 mutations (GPC3, SOX10 and EGF) and 10 amplifications (CDK4, CCND3, MDM2, RUNX2, GLI1, FRS2, CARD11, RAC1, SLC16A7 and PMS2) in m-OS. Among those alterations, the mutation abundance of GPC3 was the highest (56.49%) in p-OS and showed 1.54 times increase in m-OS. GPC3 transcript-oriented Sanger sequencing confirmed the mutation at 1046 in Exon 4, and immunohistochemical staining showed increased GPC3 production in m-OS tissues and its spheroids. EdU cell proliferation and Calcein/PI cell viability assays revealed that of the anti-OS first line drugs (doxorubicin, cisplatin, methotrexate, ifosfamide and carboplatin), 10 μM carboplatin exerted the best inhibitory effects on the p-OS but not the m-OS spheroids. 2 μg/mL anti-GPC3 antibody effectively committed m-OS spheroids to death by itself (76.43%) or in combination with cisplatin (92.93%).
This study demonstrates increased abundance and up-regulated expression of mutant GPC3 in metastatic osteosarcoma and its spheroids with multidrug resistance. As GPC3-targeting therapy has been used to treat hepatocellular carcinomas and it is also effective to OS PDSs, GPC3 would be a novel prognostic parameter and therapeutic target of osteosarcomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
A wealth of preclinical information, as well as a modest amount of clinical information, indicates that dendritic cell vaccines have therapeutic potential. The aim of this work was to assess ...the immune response, disease progression, and post-treatment survival of ER/PR double-negative stage II/IIIA breast cancer patients vaccinated with autologous dendritic cells pulsed with autologous tumor lysates.
Methods
Dendritic cell (DC) vaccines were generated from CD14+ precursors pulsed with autologous tumor lysates. DCs were matured with defined factors that induced surface marker and cytokine production. Individuals were immunized intradermally four times. Specific delayed type IV hypersensitivity (DTH) reaction, ex vivo cytokine production, and lymphocyte subsets were determined for the evaluation of the therapeutic efficiency. Overall survival and disease progression rates were analyzed using Kaplan–Meier curves and compared with those of contemporaneous patients who were not administered DC vaccines.
Results
There were no unanticipated or serious adverse effects. DC vaccines elicited Th1 cytokine secretion and increased NK cells, CD8+ IFN-γ+ cells but decreased the percentage of CD3+ T cells and CD3+ HLA-DR+ T cells in the peripheral blood. Approximately 58% (18/31) of patients had a DTH-positive reaction. There was no difference in overall survival between the patients with and without DC vaccine. The 3-year progression-free survival was significantly prolonged: 76.9% versus 31.0% (with vs. without DC vaccine,
p
< 0.05).
Conclusion
Our findings strongly suggest that tumor lysate-pulsed DCs provide a standardized and widely applicable source of breast cancer antigens that are very effective in evoking anti-breast cancer immune responses.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abnormal glycosylation is a hallmark of tumor development, and tumor-associated carbohydrate antigens are potential immune targets for tumor therapy. Tumor-associated extracellular microvesicles are ...subcellular vesicles released from cell membranes that have immunogenicity similar to that of precursor cells. However, unmodified tumor-derived microvesicles have weaknesses, such as low immunogenicity, poor biostability, and short half-life in vivo. For the first time, we herein generated extracellular microvesicles containing modified tumor-associated carbohydrate antigens by constructing a cell line with highly expressed antigen-processing enzymes utilizing fluorine-modified monosaccharide substrates via a metabolic oligosaccharide engineering strategy. The microvesicles were applied to tumor immunity, achieving enhanced immunoprophylaxis and immunotherapy effects. Furthermore, the mechanisms of antitumor immunity were explored. Our findings may provide new insights into the adhibition of suitably modified extracellular microvesicles and the development of more effective carbohydrate-based anticancer vaccines.
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IJS, KILJ, NUK, PNG, UL, UM
Heme oxygenase-1 (HO-1) plays a key role in anti-oxidation, anti-apoptosis, and anti-proliferation in various types of cancers. However, the relationship between HO-1 expression and gastric cancer ...development remains largely unknown. In this study, the protein expression of HO-1 in human gastric cancer was measured by immunohistochemistry on paraffin sections of 89 paired gastric carcinoma tissues and adjacent non-cancer tissues. The correlation of HO-1 expression with 5-year overall survival rate was estimated. The effects of decreased HO-1 expression by two strands of small interfered RNAs (siRNAs) on cell apoptosis, proliferation, and invasion of gastric cancer cell lines were examined by flow cytometry, the MTT assay, and the cell migration assay, respectively. High expression of HO-1 was detected in 11.2% (10/89) of gastric carcinoma tissues, compared with 1.1% (1/89) in matched adjacent normal tissues, and correlated with a decreased survival rate in gastric cancer patients. There were no significant correlations between HO-1 expression and clinical characteristics. Downregulation of HO-1 expression using two strands of siRNAs promoted apoptosis and inhibited the proliferation and invasion of two gastric cancer cell lines, SGC7901 and MKN-28 cells. This study demonstrated that HO-1 plays a vital role in the development of gastric cancer and may serve as a therapeutic target of this type of cancer.
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