Weiping Min - Academia.edu (original) (raw)

Papers by Weiping Min

Journal of translational medicine, Jan 15, 2010

Apoptosis is an early event involved in cardiomyopathy associated with diabetes mellitus. Toll-li... more Apoptosis is an early event involved in cardiomyopathy associated with diabetes mellitus. Toll-like receptor (TLR) signaling triggers cell apoptosis through multiple mechanisms. Up-regulation of TLR4 expression has been shown in diabetic mice. This study aimed to delineate the role of TLR4 in myocardial apoptosis, and to block this process through gene silencing of TLR4 in the myocardia of diabetic mice. Diabetes was induced in C57/BL6 mice by the injection of streptozotocin. Diabetic mice were treated with 50 μg of TLR4 siRNA or scrambled siRNA as control. Myocardial apoptosis was determined by TUNEL assay. After 7 days of hyperglycemia, the level of TLR4 mRNA in myocardial tissue was significantly elevated. Treatment of TLR4 siRNA knocked down gene expression as well as diminished its elevation in diabetic mice. Apoptosis was evident in cardiac tissues of diabetic mice as detected by a TUNEL assay. In contrast, treatment with TLR4 siRNA minimized apoptosis in myocardial tissues. M...

Transplantation Journal, 2004

Aims: To determine the effect of Campath 1-H induction therapy compared to basiliximab on outcome... more Aims: To determine the effect of Campath 1-H induction therapy compared to basiliximab on outcomes of kidney transplant recipients followed for 2 years. Methods: This is a single-center, retrospective study. The Campath 1-H [nϭ123 (cads 31, LD 92)] and basiliximab [nϭ155 (cads 58, LD 97)] cohorts were sequentially treated groups. The demographics of the groups were similar. The meanϮSD follow-up time for the Campath group was 21.8Ϯ4.7 mo. (tx dates: 10/01-9/02) and the basiliximab group was 45.8Ϯ10.0 mo. (tx dates: 9/98-9/01). The induction dose of Campath was 30 mg as a single dose intra-operatively, and Basiliximab 20 mg days 0 and 2. All kidney transplant recipients received a prednisone-free maintenance immunosuppression protocol of tacrolimus and MMF. Patient and graft survival and rejection rates were determined by Kaplan-Meier life table analysis. Rejections were biopsy-proven. Results: The table below shows the pertinent results. There were no statistically significant differences between groups in 2-year patient and graft survival rates. The 1-year rejection rates were similar, however, the mean time to rejection in the first year was significantly earlier in the basiliximab group (33.4 d.) vs Campath (116 d). Throughout the 2-year follow-up interval the Campath recipients consistently required less MMF immunosuppression. Important viral and fungal infectious disease occurred in 10% of Campath recipients and 15% of basiliximab recipients. One PTLD occurred in each group. Statistical analysis: a pϭ0.10; b pϭ0.15; c pϭ0.52; d pϽ0.001. Conclusions: This series is the largest long-term experience with Campath in kidney transplantation. The 2-year patient and graft survival results using Campath in a prednisone-free maintenance protocol compared favourably with basiliximab. The advantages of Campath were: it prevented very early rejection, a lower dose of maintenance MMF was required, a slight decrease in important infectious complications was observed, and it was less costly than basiliximab. Campath is a safe and effective induction agent for kidney transplant recipients.

Journal of Translational Medicine, 2009

Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like stem cells having pluri... more Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like stem cells having pluripotent differentiation activity and ability to induce neoangiogenesis. In vitro and animal studies suggest ERC are immune privileged and in certain situations actively suppress ongoing immune responses. In this paper we describe the production of clinical grade ERC and initial safety experiences in 4 patients with multiple sclerosis treated intravenously and intrathecally. The case with the longest follow up, of more than one year, revealed no immunological reactions or treatment associated adverse effects. These preliminary data suggest feasibility of clinical ERC administration and support further studies with this novel stem cell type.

The Journal of Immunology, 2008

Small interfering RNA (siRNA) is a potent means of inducing gene-specific silencing. Gene silenci... more Small interfering RNA (siRNA) is a potent means of inducing gene-specific silencing. Gene silencing strategies using siRNA have demonstrated therapeutic benefits in animal models of various diseases, and are currently in clinical trials. However, the utility of gene silencing as a treatment for allergic diseases has not yet been reported. In this study, we report a novel therapy for allergy through gene silencing of CD40, a critical costimulatory molecule and a key factor in allergic immune responses. Silencing CD40 resulted in generation of immunoregulatory dendritic cells (DCs). Administration of CD40 siRNA remarkably reduced nasal allergic symptoms and local eosinophil accumulation in the OVA-induced allergic mice. The OVA-specific T cell response was inhibited after the CD40 siRNA treatment. Additionally, anti-OVA specific IgE and production of IL-4 and IL-5 of T cells stimulated by OVA were significantly decreased in CD40 siRNA-treated mice. Furthermore, we demonstrated that th...

An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed ... more An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed important for the induction and maintenance of transplantation tolerance. However, interactions between these cells remain unclear. We induced donor-specific tolerance in a fully MHC-mismatched murine model of cardiac transplantation by simultaneously targeting T cell and DC function using anti-CD45RB mAb and LF 15-0195, a novel analog of the antirejection drug 15-deoxyspergualin, respectively. Increases in splenic Treg and Tol-DC were observed in tolerant recipients as assessed by an increase in CD4 ؉ CD25 ؉ T cells and DC with immature phenotype. Both these cell types exerted suppressive effects in MLR. Tol-DC purified from tolerant recipients incubated with naive T cells induced the generation/expansion of CD4 ؉ CD25 ؉ Treg. Furthermore, incubation of Treg isolated from tolerant recipients with DC progenitors resulted in the generation of DC with Tol-DC phenotype. Treg and Tol-DC generated in vitro were functional based on their suppressive activity in vitro. These results are consistent with the notion that tolerance induction is associated with a self-maintaining regulatory loop in which Tol-DC induce the generation of Treg from naive T cells and Treg programs the generation of Tol-DC from DC progenitors.

Cellular Immunology, 2010

Since the days of Medawar, the goal of therapeutic tolerogenesis has been a "Holy Grail" for immu... more Since the days of Medawar, the goal of therapeutic tolerogenesis has been a "Holy Grail" for immunologists. While knowledge of cellular and molecular mechanisms of this process has been increasing at an exponential rate, clinical progress has been minimal. To provide a mechanistic background of tolerogenesis, we overview common processes in the naturally occurring examples of: pregnancy, cancer, oral tolerance and anterior chamber associated immune deviation. The case is made that an easily accessible byproduct of plastic surgery, the adipose stromal vascular fraction, contains elements directly capable of promoting tolerogenesis such as T regulatory cells and inhibitory macrophages. The high content of mesenchymal and hematopoietic stem cells from this source provides the possibility of trophic/regenerative potential, which would augment tolerogenic processes by decreasing ongoing inflammation. We discuss the application of this autologous cell source in the context of rheumatoid arthritis, concluding with some practical examples of its applications.

International Journal of Molecular Sciences, 2021

We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed ... more We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial–mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knock...

Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches ... more Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches to treat cancer. Dysfunction of miRNAs is a major cause of aberrant expression of IRs and contributes to the immune escape of cancer cells. How miRNAs regulate immune checkpoint proteins in breast cancer remains largely unknown. In this study, downregulation of miRNAs was observed in PD-1-overexpressing CD8+ T cells using miRNA array analysis of mouse breast cancer homografts. The data reveal that miR-149-3p was predicted to bind the 3'UTRs of mRNAs encoding T-cell inhibitor receptors PD-1, TIM-3, BTLA and Foxp1. Treatment of CD8+ T cells with an miR-149-3p mimic reduced apoptosis, attenuated changes in mRNA markers of T-cell exhaustion and downregulated mRNAs encoding PD-1, TIM-3, BTLA and Foxp1. On the other hand, T-cell proliferation and secretion of effector cytokines indicative of increased T-cell activation (IL-2, TNF-α, IFN-γ) were upregulated after miR-149-3p mimic treatment....

Nanoscale Research Letters, 2020

Liver cancer is one of the most common malignancies worldwide. The RAF kinase inhibitors are effe... more Liver cancer is one of the most common malignancies worldwide. The RAF kinase inhibitors are effective in the treatment of hepatocellular carcinoma (HCC); therefore, inhibition of the BRAF/MEK/ERK pathway has become a new therapeutic strategy for novel HCC therapy. However, targeted specific delivery systems for tumors are still significant obstacle to clinical applications. Galactose (GAL) can target the asialoglycoprotein receptor (ASGPR) that is highly expressed on liver cancer cells. In this study, we designed a novel multifunctional nanomaterial GAL-GNR-siBRAF which consists of three parts, GAL as the liver cancer-targeting moiety, golden nanorods (GNR) offering photothermal capability under near infrared light, and siRNA specifically silencing BRAF (siBRAF). The nanocarrier GAL-GNR-siBRAF showed high siRNA loading capacity and inhibited the degradation of siRNA in serum. Compared with naked gold nanorods, GAL-GNR-siBRAF possessed lower biotoxicity and higher efficacy of gene s...

Diabetes Therapy, 2020

Introduction: Diabetic cardiomyopathy is a cardiac dysfunction in patients with diabetes which ma... more Introduction: Diabetic cardiomyopathy is a cardiac dysfunction in patients with diabetes which may lead to overt heart failure and death. Toll-like receptor (TLR) signaling triggers diabetic cardiomyopathy through various mechanisms, one of which is the upregulation of TLR4 expression. The aim of this study was to delineate the role of TLR4 in diabetic cardiomyopathy. Methods: C57BL/6 mice were injected with streptozotocin to induce diabetes. The experimental and control groups were treated with 5 lg of TLR4 small interfering RNA (siRNA) or scrambled siRNA. Cardiac histopathology was Digital Features To view digital features for this article go to

The Journal of Nutrition, 2001

The chemopreventive effects of five water-soluble organosulfur compounds, S-methylcysteine (SMC) ... more The chemopreventive effects of five water-soluble organosulfur compounds, S-methylcysteine (SMC) and four analogs, were examined on the promotion stage of diethylnitrosamine hepatocarcinogenesis in male F344 rats, using the medium-term bioassay (Ito test), which is based on the two-step model of hepatocarcinogenesis. In addition, we investigated the modifying effects of SMC and cysteine on the initiation stage of rat hepatocarcinogenesis. Carcinogenic potential was scored by comparing the numbers and areas of a putative neoplastic lesion, glutathione S-transferase placental form (GST-P)-positive hepatocellular foci. SMC and cysteine significantly decreased the number and area of GST-P-positive foci when given in the promotion stage of the Ito test. When given during the initiation stage, these two organosulfur compounds also significantly inhibited focus formation. Liver ornithine decarboxylase activity after two thirds partial hepatectomy and the proportion of hepatocytes positive for proliferating cell nuclear antigen significantly decreased the number of aberrant crypt foci in the colon in a multiorgan carcinogenesis bioassay of rats. These results support SMC and cysteine as chemopreventive agents for hepatocarcinogenesis and colon carcinogenesis. Their intake may be of importance for cancer.

Otolaryngology–Head and Neck Surgery, 2007

Objective 1) To estimate the effectiveness of intranasal administration of CpG DNA alone on aller... more Objective 1) To estimate the effectiveness of intranasal administration of CpG DNA alone on allergic rhinitis compared with intradermal administration; and 2) to find out how CpG DNA therapy is useful in treatment of allergic rhinitis. Study Design Mice were intraperitoneally sensitized and intranasally challenged with Japanese cedar. Therapy with CpG DNA alone was also performed during challenge, either intranasally or intradermally. Immunologic variables and nasal symptom were studied. Results Intranasal administration of CpG DNA alone significantly reduced the levels of IgE, IL-5 productions from nasal lymphocytes and splenocytes, nasal eosinophilia, and nasal symptoms, although intradermal administration of CpG DNA alone showed no significant reduction. Conclusion This study demonstrated that CpG DNA has effects not only on splenocytes but also on nasal lymphocytes to attenuate allergic rhinitis, and that intranasal administration, but not intradermal administration, of CpG DNA ...

Journal of Translational Medicine, 2009

Background It has been suggested that the initial differentiation of endothelial and hematopoieti... more Background It has been suggested that the initial differentiation of endothelial and hematopoietic cells during embryogenesis occurs from a common progenitor, called hemangioblast (hB). We hypothesized that these cells with dual hematopoietic/endothelial potential could be used in future regenerative medicine. Methods We used the two-step differentiation technology to generate bipotential blast cells from human embryonic stem cells (hES). This involved short differentiation in our in vitro EB system followed by differentiation in semisolid culture medium supplemented with mixture of cytokines. Results The occurrence of blast-colony-forming cells (BL-CFC) during EB differentiation (day 0–6) was transient and peaked on day 3. The emergence of this event was associated with expression of mesoderm gene T, and inversely correlated with expression of endoderm gene FoxA2. Similarly, the highest BL-CFC number was associated with increase in expression of early hematopoietic/endothelial gene...

Journal of Translational Medicine, 2012

Background Proliferation and migration of vascular smooth muscle cells (VSMCs) play a key role in... more Background Proliferation and migration of vascular smooth muscle cells (VSMCs) play a key role in neointimal formation which leads to restenosis of vein graft in venous bypass. STAT-3 is a transcription factor associated with cell proliferation. We hypothesized that silencing of STAT-3 by siRNA will inhibit proliferation of VSMCs and attenuate intimal thickening. Methods Rat VSMCs were isolated and cultured in vitro by applying tissue piece inoculation methods. VSMCs were transfected with STAT 3 siRNA using lipofectamine 2000. In vitro proliferation of VSMC was quantified by the MTT assay, while in vivo assessment was performed in a venous transplantation model. In vivo delivery of STAT-3 siRNA plasmid or scramble plasmid was performed by admixing with liposomes 2000 and transfected into the vein graft by bioprotein gel applied onto the adventitia. Rat jugular vein-carotid artery bypass was performed. On day 3 and7 after grafting, the vein grafts were extracted, and analyzed morphol...

Cancer Letters, 1999

We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, w... more We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, with and without metastasis. However, the role of p53 dysfunctions during carcinogenesis remains unclear. In the present study, heterozygous and nullizygous p53-de®cient mice and their littermates were treated with the urinary bladder carcinogen, N-butyl-N-(4hydroxybutyl)-nitrosamine (BBN), at a concentration of 0.01% in the drinking water throughout the experiment. This markedly accelerated urinary bladder carcinogenesis but not development of other tumors in the nullizygous p53-de®cient mice. Thus the appearance of neoplastic urothelial lesions in nullizygotes (at day 60 of the experiment) was earlier than in wild-type mice and heterozygotes (at day 125). Moreover, malignant vascular tumors (hemangiosarcomas (HS)) were found in all four nullizygotes killed later than day 108. Mutational inactivation of the wild-type allele was not apparent in either the single transitional cell carcinoma observed in a wild-type mouse and a hemangiosarcoma in a heterozygote. Overall, it can be concluded that the number of normal p53 alleles is a signi®cant determining factor in the susceptibility of urothelial cells to carcinogens. The role of the p53 defect in mouse urinary bladder carcinogenesis may thus be to diminish the threshold for occurrence of additional genetic alterations.

Molecular Medicine Reports, 2019

Previous studies suggest that radiotherapy (rT) can induce immune activation, which not only redu... more Previous studies suggest that radiotherapy (rT) can induce immune activation, which not only reduces the progression of tumors, but also causes the release of tumor antigens. The combination of rT and immune checkpoint blockade, such as the inhibition of programmed cell death 1 (Pd-1) and programmed cell death ligand 1 (Pd-l1), has been demonstrated to yield impressive response rates. However, a substantial proportion of patients develop resistance such therapies. Previous studies have shown that indoleamine 2,3-dioxygenase (ido) causes T cell exhaustion and increased formation of regulatory T cells (Tregs), upregulating the expression of inhibitory receptors and ligands. Therefore, the application of ido inhibitors combined with rT may have a synergistic effect by relieving immunosuppression. lewis lung cancer cell-bearing mice were treated with the ido inhibitor 1-methyl-tryptophan (1MT) and/or 10 Gy rT. Tumor size was measured every day, flow cytometry was performed to measure the expression of dendritic cell (dc) maturation markers, inhibitory receptors, ligands, cytotoxic T cells and Treg phenotypic markers. reverse transcription-quantitative Pcr was used to evaluate the mrna expression levels of ido, Pd-l1, Pd-1, T cell immunoglobulin domain and mucin domain 3 (TiM-3), Band T-lymphocyte attenuator (BTla) and galectin-9. compared with the control group, treatment with 1MT or rT reduced tumor growth, however, the combination therapy was more effective than either treatment alone. Flow cytometry showed the upregulation of cd80, cd86 and the major histocompatibility complex ii in spleen dcs and the concurrent downregulation of cd4, cd25 and forkhead box protein P3 in lymphocytes in the treatment groups. compared with the control group, inhibitory receptors and ligands that affect dcs and T cells were observed, expression levels of Pd-l1, Pd-1, TiM-3, BTla and galectin-9 are decreased in treatment group compared with control. ido inhibition synergized with rT to downregulate Tregs, inhibitory receptors and ligands to prevent T cell exhaustion. By activating dcs and T cells, this combination therapy may strongly enhance antitumor immunity and inhibit tumor progression.

Journal of Translational Medicine, 2010

Background The current paradigm for cord blood transplantation is that HLA matching and immune su... more Background The current paradigm for cord blood transplantation is that HLA matching and immune suppression are strictly required to prevent graft versus host disease (GVHD). Immunological arguments and historical examples have been made that the use of cord blood for non-hematopoietic activities such as growth factor production, stimulation of angiogenesis, and immune modulation may not require matching or immune suppression. Methods 114 patients suffering from non-hematopoietic degenerative conditions were treated with non-matched, allogeneic cord blood. Doses of 1-3 × 107 cord blood mononuclear cells per treatment, with 4-5 treatments both intrathecal and intravenously were performed. Adverse events and hematological, immunological, and biochemical parameters were analyzed for safety evaluation. Results No serious adverse effects were reported. Hematological, immunological, and biochemical parameters did not deviate from normal ranges as a result of therapy. Conclusion The current...

Lipoxins (LXs), metabolites of arachidonic acid, are one of the most important endogenous lipid m... more Lipoxins (LXs), metabolites of arachidonic acid, are one of the most important endogenous lipid mediators which initiate inhibition inflammatory reaction as well as promote extinction of inflammation resolution. Nowadays, many advancements have been achieved in the research of their biosynthetic pathways, biological functions and effects in hepatic diseases. This article will review the progress in the related research.

The Journal of Heart and Lung Transplantation

Journal of translational medicine, Jan 15, 2010

Apoptosis is an early event involved in cardiomyopathy associated with diabetes mellitus. Toll-li... more Apoptosis is an early event involved in cardiomyopathy associated with diabetes mellitus. Toll-like receptor (TLR) signaling triggers cell apoptosis through multiple mechanisms. Up-regulation of TLR4 expression has been shown in diabetic mice. This study aimed to delineate the role of TLR4 in myocardial apoptosis, and to block this process through gene silencing of TLR4 in the myocardia of diabetic mice. Diabetes was induced in C57/BL6 mice by the injection of streptozotocin. Diabetic mice were treated with 50 μg of TLR4 siRNA or scrambled siRNA as control. Myocardial apoptosis was determined by TUNEL assay. After 7 days of hyperglycemia, the level of TLR4 mRNA in myocardial tissue was significantly elevated. Treatment of TLR4 siRNA knocked down gene expression as well as diminished its elevation in diabetic mice. Apoptosis was evident in cardiac tissues of diabetic mice as detected by a TUNEL assay. In contrast, treatment with TLR4 siRNA minimized apoptosis in myocardial tissues. M...

Transplantation Journal, 2004

Aims: To determine the effect of Campath 1-H induction therapy compared to basiliximab on outcome... more Aims: To determine the effect of Campath 1-H induction therapy compared to basiliximab on outcomes of kidney transplant recipients followed for 2 years. Methods: This is a single-center, retrospective study. The Campath 1-H [nϭ123 (cads 31, LD 92)] and basiliximab [nϭ155 (cads 58, LD 97)] cohorts were sequentially treated groups. The demographics of the groups were similar. The meanϮSD follow-up time for the Campath group was 21.8Ϯ4.7 mo. (tx dates: 10/01-9/02) and the basiliximab group was 45.8Ϯ10.0 mo. (tx dates: 9/98-9/01). The induction dose of Campath was 30 mg as a single dose intra-operatively, and Basiliximab 20 mg days 0 and 2. All kidney transplant recipients received a prednisone-free maintenance immunosuppression protocol of tacrolimus and MMF. Patient and graft survival and rejection rates were determined by Kaplan-Meier life table analysis. Rejections were biopsy-proven. Results: The table below shows the pertinent results. There were no statistically significant differences between groups in 2-year patient and graft survival rates. The 1-year rejection rates were similar, however, the mean time to rejection in the first year was significantly earlier in the basiliximab group (33.4 d.) vs Campath (116 d). Throughout the 2-year follow-up interval the Campath recipients consistently required less MMF immunosuppression. Important viral and fungal infectious disease occurred in 10% of Campath recipients and 15% of basiliximab recipients. One PTLD occurred in each group. Statistical analysis: a pϭ0.10; b pϭ0.15; c pϭ0.52; d pϽ0.001. Conclusions: This series is the largest long-term experience with Campath in kidney transplantation. The 2-year patient and graft survival results using Campath in a prednisone-free maintenance protocol compared favourably with basiliximab. The advantages of Campath were: it prevented very early rejection, a lower dose of maintenance MMF was required, a slight decrease in important infectious complications was observed, and it was less costly than basiliximab. Campath is a safe and effective induction agent for kidney transplant recipients.

Journal of Translational Medicine, 2009

Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like stem cells having pluri... more Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like stem cells having pluripotent differentiation activity and ability to induce neoangiogenesis. In vitro and animal studies suggest ERC are immune privileged and in certain situations actively suppress ongoing immune responses. In this paper we describe the production of clinical grade ERC and initial safety experiences in 4 patients with multiple sclerosis treated intravenously and intrathecally. The case with the longest follow up, of more than one year, revealed no immunological reactions or treatment associated adverse effects. These preliminary data suggest feasibility of clinical ERC administration and support further studies with this novel stem cell type.

The Journal of Immunology, 2008

Small interfering RNA (siRNA) is a potent means of inducing gene-specific silencing. Gene silenci... more Small interfering RNA (siRNA) is a potent means of inducing gene-specific silencing. Gene silencing strategies using siRNA have demonstrated therapeutic benefits in animal models of various diseases, and are currently in clinical trials. However, the utility of gene silencing as a treatment for allergic diseases has not yet been reported. In this study, we report a novel therapy for allergy through gene silencing of CD40, a critical costimulatory molecule and a key factor in allergic immune responses. Silencing CD40 resulted in generation of immunoregulatory dendritic cells (DCs). Administration of CD40 siRNA remarkably reduced nasal allergic symptoms and local eosinophil accumulation in the OVA-induced allergic mice. The OVA-specific T cell response was inhibited after the CD40 siRNA treatment. Additionally, anti-OVA specific IgE and production of IL-4 and IL-5 of T cells stimulated by OVA were significantly decreased in CD40 siRNA-treated mice. Furthermore, we demonstrated that th...

An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed ... more An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed important for the induction and maintenance of transplantation tolerance. However, interactions between these cells remain unclear. We induced donor-specific tolerance in a fully MHC-mismatched murine model of cardiac transplantation by simultaneously targeting T cell and DC function using anti-CD45RB mAb and LF 15-0195, a novel analog of the antirejection drug 15-deoxyspergualin, respectively. Increases in splenic Treg and Tol-DC were observed in tolerant recipients as assessed by an increase in CD4 ؉ CD25 ؉ T cells and DC with immature phenotype. Both these cell types exerted suppressive effects in MLR. Tol-DC purified from tolerant recipients incubated with naive T cells induced the generation/expansion of CD4 ؉ CD25 ؉ Treg. Furthermore, incubation of Treg isolated from tolerant recipients with DC progenitors resulted in the generation of DC with Tol-DC phenotype. Treg and Tol-DC generated in vitro were functional based on their suppressive activity in vitro. These results are consistent with the notion that tolerance induction is associated with a self-maintaining regulatory loop in which Tol-DC induce the generation of Treg from naive T cells and Treg programs the generation of Tol-DC from DC progenitors.

Cellular Immunology, 2010

Since the days of Medawar, the goal of therapeutic tolerogenesis has been a "Holy Grail" for immu... more Since the days of Medawar, the goal of therapeutic tolerogenesis has been a "Holy Grail" for immunologists. While knowledge of cellular and molecular mechanisms of this process has been increasing at an exponential rate, clinical progress has been minimal. To provide a mechanistic background of tolerogenesis, we overview common processes in the naturally occurring examples of: pregnancy, cancer, oral tolerance and anterior chamber associated immune deviation. The case is made that an easily accessible byproduct of plastic surgery, the adipose stromal vascular fraction, contains elements directly capable of promoting tolerogenesis such as T regulatory cells and inhibitory macrophages. The high content of mesenchymal and hematopoietic stem cells from this source provides the possibility of trophic/regenerative potential, which would augment tolerogenic processes by decreasing ongoing inflammation. We discuss the application of this autologous cell source in the context of rheumatoid arthritis, concluding with some practical examples of its applications.

International Journal of Molecular Sciences, 2021

We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed ... more We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial–mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knock...

Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches ... more Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches to treat cancer. Dysfunction of miRNAs is a major cause of aberrant expression of IRs and contributes to the immune escape of cancer cells. How miRNAs regulate immune checkpoint proteins in breast cancer remains largely unknown. In this study, downregulation of miRNAs was observed in PD-1-overexpressing CD8+ T cells using miRNA array analysis of mouse breast cancer homografts. The data reveal that miR-149-3p was predicted to bind the 3'UTRs of mRNAs encoding T-cell inhibitor receptors PD-1, TIM-3, BTLA and Foxp1. Treatment of CD8+ T cells with an miR-149-3p mimic reduced apoptosis, attenuated changes in mRNA markers of T-cell exhaustion and downregulated mRNAs encoding PD-1, TIM-3, BTLA and Foxp1. On the other hand, T-cell proliferation and secretion of effector cytokines indicative of increased T-cell activation (IL-2, TNF-α, IFN-γ) were upregulated after miR-149-3p mimic treatment....

Nanoscale Research Letters, 2020

Liver cancer is one of the most common malignancies worldwide. The RAF kinase inhibitors are effe... more Liver cancer is one of the most common malignancies worldwide. The RAF kinase inhibitors are effective in the treatment of hepatocellular carcinoma (HCC); therefore, inhibition of the BRAF/MEK/ERK pathway has become a new therapeutic strategy for novel HCC therapy. However, targeted specific delivery systems for tumors are still significant obstacle to clinical applications. Galactose (GAL) can target the asialoglycoprotein receptor (ASGPR) that is highly expressed on liver cancer cells. In this study, we designed a novel multifunctional nanomaterial GAL-GNR-siBRAF which consists of three parts, GAL as the liver cancer-targeting moiety, golden nanorods (GNR) offering photothermal capability under near infrared light, and siRNA specifically silencing BRAF (siBRAF). The nanocarrier GAL-GNR-siBRAF showed high siRNA loading capacity and inhibited the degradation of siRNA in serum. Compared with naked gold nanorods, GAL-GNR-siBRAF possessed lower biotoxicity and higher efficacy of gene s...

Diabetes Therapy, 2020

Introduction: Diabetic cardiomyopathy is a cardiac dysfunction in patients with diabetes which ma... more Introduction: Diabetic cardiomyopathy is a cardiac dysfunction in patients with diabetes which may lead to overt heart failure and death. Toll-like receptor (TLR) signaling triggers diabetic cardiomyopathy through various mechanisms, one of which is the upregulation of TLR4 expression. The aim of this study was to delineate the role of TLR4 in diabetic cardiomyopathy. Methods: C57BL/6 mice were injected with streptozotocin to induce diabetes. The experimental and control groups were treated with 5 lg of TLR4 small interfering RNA (siRNA) or scrambled siRNA. Cardiac histopathology was Digital Features To view digital features for this article go to

The Journal of Nutrition, 2001

The chemopreventive effects of five water-soluble organosulfur compounds, S-methylcysteine (SMC) ... more The chemopreventive effects of five water-soluble organosulfur compounds, S-methylcysteine (SMC) and four analogs, were examined on the promotion stage of diethylnitrosamine hepatocarcinogenesis in male F344 rats, using the medium-term bioassay (Ito test), which is based on the two-step model of hepatocarcinogenesis. In addition, we investigated the modifying effects of SMC and cysteine on the initiation stage of rat hepatocarcinogenesis. Carcinogenic potential was scored by comparing the numbers and areas of a putative neoplastic lesion, glutathione S-transferase placental form (GST-P)-positive hepatocellular foci. SMC and cysteine significantly decreased the number and area of GST-P-positive foci when given in the promotion stage of the Ito test. When given during the initiation stage, these two organosulfur compounds also significantly inhibited focus formation. Liver ornithine decarboxylase activity after two thirds partial hepatectomy and the proportion of hepatocytes positive for proliferating cell nuclear antigen significantly decreased the number of aberrant crypt foci in the colon in a multiorgan carcinogenesis bioassay of rats. These results support SMC and cysteine as chemopreventive agents for hepatocarcinogenesis and colon carcinogenesis. Their intake may be of importance for cancer.

Otolaryngology–Head and Neck Surgery, 2007

Objective 1) To estimate the effectiveness of intranasal administration of CpG DNA alone on aller... more Objective 1) To estimate the effectiveness of intranasal administration of CpG DNA alone on allergic rhinitis compared with intradermal administration; and 2) to find out how CpG DNA therapy is useful in treatment of allergic rhinitis. Study Design Mice were intraperitoneally sensitized and intranasally challenged with Japanese cedar. Therapy with CpG DNA alone was also performed during challenge, either intranasally or intradermally. Immunologic variables and nasal symptom were studied. Results Intranasal administration of CpG DNA alone significantly reduced the levels of IgE, IL-5 productions from nasal lymphocytes and splenocytes, nasal eosinophilia, and nasal symptoms, although intradermal administration of CpG DNA alone showed no significant reduction. Conclusion This study demonstrated that CpG DNA has effects not only on splenocytes but also on nasal lymphocytes to attenuate allergic rhinitis, and that intranasal administration, but not intradermal administration, of CpG DNA ...

Journal of Translational Medicine, 2009

Background It has been suggested that the initial differentiation of endothelial and hematopoieti... more Background It has been suggested that the initial differentiation of endothelial and hematopoietic cells during embryogenesis occurs from a common progenitor, called hemangioblast (hB). We hypothesized that these cells with dual hematopoietic/endothelial potential could be used in future regenerative medicine. Methods We used the two-step differentiation technology to generate bipotential blast cells from human embryonic stem cells (hES). This involved short differentiation in our in vitro EB system followed by differentiation in semisolid culture medium supplemented with mixture of cytokines. Results The occurrence of blast-colony-forming cells (BL-CFC) during EB differentiation (day 0–6) was transient and peaked on day 3. The emergence of this event was associated with expression of mesoderm gene T, and inversely correlated with expression of endoderm gene FoxA2. Similarly, the highest BL-CFC number was associated with increase in expression of early hematopoietic/endothelial gene...

Journal of Translational Medicine, 2012

Background Proliferation and migration of vascular smooth muscle cells (VSMCs) play a key role in... more Background Proliferation and migration of vascular smooth muscle cells (VSMCs) play a key role in neointimal formation which leads to restenosis of vein graft in venous bypass. STAT-3 is a transcription factor associated with cell proliferation. We hypothesized that silencing of STAT-3 by siRNA will inhibit proliferation of VSMCs and attenuate intimal thickening. Methods Rat VSMCs were isolated and cultured in vitro by applying tissue piece inoculation methods. VSMCs were transfected with STAT 3 siRNA using lipofectamine 2000. In vitro proliferation of VSMC was quantified by the MTT assay, while in vivo assessment was performed in a venous transplantation model. In vivo delivery of STAT-3 siRNA plasmid or scramble plasmid was performed by admixing with liposomes 2000 and transfected into the vein graft by bioprotein gel applied onto the adventitia. Rat jugular vein-carotid artery bypass was performed. On day 3 and7 after grafting, the vein grafts were extracted, and analyzed morphol...

Cancer Letters, 1999

We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, w... more We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, with and without metastasis. However, the role of p53 dysfunctions during carcinogenesis remains unclear. In the present study, heterozygous and nullizygous p53-de®cient mice and their littermates were treated with the urinary bladder carcinogen, N-butyl-N-(4hydroxybutyl)-nitrosamine (BBN), at a concentration of 0.01% in the drinking water throughout the experiment. This markedly accelerated urinary bladder carcinogenesis but not development of other tumors in the nullizygous p53-de®cient mice. Thus the appearance of neoplastic urothelial lesions in nullizygotes (at day 60 of the experiment) was earlier than in wild-type mice and heterozygotes (at day 125). Moreover, malignant vascular tumors (hemangiosarcomas (HS)) were found in all four nullizygotes killed later than day 108. Mutational inactivation of the wild-type allele was not apparent in either the single transitional cell carcinoma observed in a wild-type mouse and a hemangiosarcoma in a heterozygote. Overall, it can be concluded that the number of normal p53 alleles is a signi®cant determining factor in the susceptibility of urothelial cells to carcinogens. The role of the p53 defect in mouse urinary bladder carcinogenesis may thus be to diminish the threshold for occurrence of additional genetic alterations.

Molecular Medicine Reports, 2019

Previous studies suggest that radiotherapy (rT) can induce immune activation, which not only redu... more Previous studies suggest that radiotherapy (rT) can induce immune activation, which not only reduces the progression of tumors, but also causes the release of tumor antigens. The combination of rT and immune checkpoint blockade, such as the inhibition of programmed cell death 1 (Pd-1) and programmed cell death ligand 1 (Pd-l1), has been demonstrated to yield impressive response rates. However, a substantial proportion of patients develop resistance such therapies. Previous studies have shown that indoleamine 2,3-dioxygenase (ido) causes T cell exhaustion and increased formation of regulatory T cells (Tregs), upregulating the expression of inhibitory receptors and ligands. Therefore, the application of ido inhibitors combined with rT may have a synergistic effect by relieving immunosuppression. lewis lung cancer cell-bearing mice were treated with the ido inhibitor 1-methyl-tryptophan (1MT) and/or 10 Gy rT. Tumor size was measured every day, flow cytometry was performed to measure the expression of dendritic cell (dc) maturation markers, inhibitory receptors, ligands, cytotoxic T cells and Treg phenotypic markers. reverse transcription-quantitative Pcr was used to evaluate the mrna expression levels of ido, Pd-l1, Pd-1, T cell immunoglobulin domain and mucin domain 3 (TiM-3), Band T-lymphocyte attenuator (BTla) and galectin-9. compared with the control group, treatment with 1MT or rT reduced tumor growth, however, the combination therapy was more effective than either treatment alone. Flow cytometry showed the upregulation of cd80, cd86 and the major histocompatibility complex ii in spleen dcs and the concurrent downregulation of cd4, cd25 and forkhead box protein P3 in lymphocytes in the treatment groups. compared with the control group, inhibitory receptors and ligands that affect dcs and T cells were observed, expression levels of Pd-l1, Pd-1, TiM-3, BTla and galectin-9 are decreased in treatment group compared with control. ido inhibition synergized with rT to downregulate Tregs, inhibitory receptors and ligands to prevent T cell exhaustion. By activating dcs and T cells, this combination therapy may strongly enhance antitumor immunity and inhibit tumor progression.

Journal of Translational Medicine, 2010

Background The current paradigm for cord blood transplantation is that HLA matching and immune su... more Background The current paradigm for cord blood transplantation is that HLA matching and immune suppression are strictly required to prevent graft versus host disease (GVHD). Immunological arguments and historical examples have been made that the use of cord blood for non-hematopoietic activities such as growth factor production, stimulation of angiogenesis, and immune modulation may not require matching or immune suppression. Methods 114 patients suffering from non-hematopoietic degenerative conditions were treated with non-matched, allogeneic cord blood. Doses of 1-3 × 107 cord blood mononuclear cells per treatment, with 4-5 treatments both intrathecal and intravenously were performed. Adverse events and hematological, immunological, and biochemical parameters were analyzed for safety evaluation. Results No serious adverse effects were reported. Hematological, immunological, and biochemical parameters did not deviate from normal ranges as a result of therapy. Conclusion The current...

Lipoxins (LXs), metabolites of arachidonic acid, are one of the most important endogenous lipid m... more Lipoxins (LXs), metabolites of arachidonic acid, are one of the most important endogenous lipid mediators which initiate inhibition inflammatory reaction as well as promote extinction of inflammation resolution. Nowadays, many advancements have been achieved in the research of their biosynthetic pathways, biological functions and effects in hepatic diseases. This article will review the progress in the related research.

The Journal of Heart and Lung Transplantation