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1.
Cancer Sci ; 110(8): 2442-2455, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148345

RESUMO

The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease-free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer-driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal-epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer-driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Metástase Neoplásica/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
2.
Mol Carcinog ; 58(8): 1450-1464, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31026381

RESUMO

Gastric cancer is the second leading cause of cancer-related mortality and the fourth most common cancer globally. High intratumor heterogeneity of advanced gastric cancer poses great challenges to targeted therapy due to simultaneous activation of many redundant cancer-driving pathways. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 inhibition exerts anticancer activity by blocking multiple cancer-driving pathways in some cancers, but its role in gastric cancer is not fully understood. Here we detected Pin1 protein expression in 1065 gastric cancer patients and paired normal tissues using immunohistochemistry and Western blot, and then examined the effects of Pin1 overexpression, and genetic and chemical Pin1 inhibition using Pin1 short hairpin RNA or small molecule inhibitor all-trans retinoic acid (ATRA) on tumorigenesis of human gastric cancer in vitro and in vivo, followed by biochemical analyses to elucidate Pin1 regulated oncogenic pathways. We found that Pin1 was significantly overexpressed in primary and metastasized tumors, with Pin1 overexpression being correlated with advanced stage and poor prognosis. Furthermore, whereas Pin1 overexpression promoted the transformed phenotype in immortalized and nontransformed human gastric cells, either genetic or chemical Pin1 inhibition in multiple human gastric cancer cells potently suppressed cell growth, G1/S transition and colony formation in vitro, as well as tumor growth in xenograft tumor models in vivo, which were further supported by downregulation of multiple key oncoproteins in PI3K/AKT and Wnt/ß-catenin signaling pathways. These results not only provide the first evidence for a critical role of Pin1 in the tumorigenesis of gastric cancer but also suggest that targeting Pin1 using ATRA or other inhibitors offers an effective new therapeutic approach for treating advanced gastric cancer.

3.
Cancer Lett ; 444: 82-93, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30583078

RESUMO

Hepatocellular carcinoma (HCC) is the second leading cancer death because of its high metastasis and drug resistance. Regorafenib was newly approved by FDA for HCC treatment, but its resistance is not understood. The unique isomerase Pin1 is critical for HCC development, but its role in metastasis and drug resistance is unknown. Here we generated Regorafenib-resistant HCC cells and found that they exhibited enhanced tumor invasion and metastasis in vitro and in vivo, and elevated Pin1 levels. Furthermore, Pin1 was highly overexpressed and closely related to the EMT in human HCC tissues. Depletion or overexpression of Pin1 correspondingly inhibited or promoted HCC cell migration and invasion, with altered expression of EMT-related molecules, E-cadherin and Snail. Significantly, Pin1 interacted with Gli1, a regulator of the EMT, and silencing Gli1 partly blocked Pin1-induced EMT in HCC cells. Moreover, genetic or chemical Pin1 inhibition reversed Regorafenib resistance of HCC with reducing EMT, migration, invasion and metastasis in vitro and in vivo. These results reveal a novel molecular mechanism underlying Regorafenib resistance in HCC, and also provide first evidence that Pin1 inhibitors offer an attractive strategy for treating Regorafenib-resistant HCC.

5.
Med Sci Monit ; 24: 4295-4304, 2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29933360

RESUMO

BACKGROUND Lead (Pb) is a widely used metal in modern industry and is regarded as a health hazard. Although lead-induced genotoxicity has been confirmed, the direct evidence that lead induces genotoxicity in human cells and its related mechanisms has not been fully elucidated. In this study, for the first time, we evaluated the genotoxicity induced by lead in human lymphoblastoid TK6 cells. MATERIAL AND METHODS The TK6 cells were incubated with various concentrations of Pb(Ac)2 for 6 h, 12 h, or 24 h. Cell viability was detected by CCK8 assay. Various biochemical markers were assessed by specific kits. Immunofluorescence assay was used to detect g-H2AX foci formation. The promoter methylation was assessed by methylation-specific PCR. The protein levels were determined by Western blot assay. RESULTS The results showed that after exposure to lead, cell viability was obviously decreased and γ-H2AX foci formation was significantly enhanced in TK6 cells. Moreover, the levels of 8-OHdG, ROS, MDA, and GSSG were increased, while the GSH level and SOD activity were decreased in lead-treated TK6 cells. The activation of the Nrf2-ARE signaling pathway was involved in lead-induced oxidative stress in TK6 cells. Finally, the expressions of DNA repair genes XRCC1, hOGG-1, BRCA1, and XPD were inhibited via enhancing their promoter methylation in TK6 cells after exposure to lead. CONCLUSIONS Taken together, our study provides the first published evidence that lead exposure results in DNA damage via promoting oxidative stress and the promoter methylation of DNA repair genes in human lymphoblastoid TK6 cells.


Assuntos
Dano ao DNA , Metilação de DNA/genética , Reparo do DNA/genética , Chumbo/toxicidade , Linfócitos/metabolismo , Linfócitos/patologia , Estresse Oxidativo/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Elementos de Resposta Antioxidante/genética , Reparo do DNA/efeitos dos fármacos , Humanos , Linfócitos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
J Hematol Oncol ; 11(1): 73, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29848341

RESUMO

BACKGROUND: The increasing genomic complexity of acute myeloid leukemia (AML), the most common form of acute leukemia, poses a major challenge to its therapy. To identify potent therapeutic targets with the ability to block multiple cancer-driving pathways is thus imperative. The unique peptidyl-prolyl cis-trans isomerase Pin1 has been reported to promote tumorigenesis through upregulation of numerous cancer-driving pathways. Although Pin1 is a key drug target for treating acute promyelocytic leukemia (APL) caused by a fusion oncogene, much less is known about the role of Pin1 in other heterogeneous leukemia. METHODS: The mRNA and protein levels of Pin1 were detected in samples from de novo leukemia patients and healthy controls using real-time quantitative RT-PCR (qRT-PCR) and western blot. The establishment of the lentiviral stable-expressed short hairpin RNA (shRNA) system and the tetracycline-inducible shRNA system for targeting Pin1 were used to analyze the biological function of Pin1 in AML cells. The expression of cancer-related Pin1 downstream oncoproteins in shPin1 (Pin1 knockdown) and Pin1 inhibitor all-trans retinoic acid (ATRA) treated leukemia cells were examined by western blot, followed by evaluating the effects of genetic and chemical inhibition of Pin1 in leukemia cells on transformed phenotype, including cell proliferation and colony formation ability, using trypan blue, cell counting assay, and colony formation assay in vitro, as well as the tumorigenesis ability using in vivo xenograft mouse models. RESULTS: First, we found that the expression of Pin1 mRNA and protein was significantly increased in both de novo leukemia clinical samples and multiple leukemia cell lines, compared with healthy controls. Furthermore, genetic or chemical inhibition of Pin1 in human multiple leukemia cell lines potently inhibited multiple Pin1 substrate oncoproteins and effectively suppressed leukemia cell proliferation and colony formation ability in cell culture models in vitro. Moreover, tetracycline-inducible Pin1 knockdown and slow-releasing ATRA potently inhibited tumorigenicity of U937 and HL-60 leukemia cells in xenograft mouse models. CONCLUSIONS: We demonstrate that Pin1 is highly overexpressed in human AML and is a promising therapeutic target to block multiple cancer-driving pathways in AML.

7.
Mol Med Rep ; 17(3): 4187-4194, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29344673

RESUMO

Various studies have previously demonstrated that Golgi protein-73 (GOLPH2) is overexpressed in tumorigenesis, which has been observed in hepatocellular carcinoma and prostate cancer. However, the expression levels and specific functions of GOLPH2 in the progression of pancreatic cancer remain to be elucidated. The present study aimed to investigate the expression of GOLPH2 in pancreatic ductal adenocarcinoma (PDAC) tissues and examined the effects of GOLPH2 on the growth and migration of pancreatic cancer cells. In the present study, the mRNA levels of GOLPH2 in PDAC cancer tissues were examined using RT­qPCR. The effects of GOLPH2 on the growth and migration of cancer cells were examined using crystal violet and Boyden chamber assays. The study demonstrated that the expression of GOLPH2 mRNA and protein was elevated in PDAC clinical tissues. The growth and motility of the PDAC cells was enhanced following overexpression of GOLPH2, whereas downregulating the expression of GOLPH2 impaired the growth, motility and tumorigenesis. Furthermore, GOLPH2 was observed to interact with protein kinase B (Akt), which subsequently increased the activity of Akt. In addition, GOLPH2 was revealed as a downstream gene of Ras signaling and promoted the transformation of normal pancreatic cells. The results of the present study revealed the important functions of GOLPH2 in PDAC, and suggest that GOLPH2 may act as a promising therapeutic target for the treatment of PDAC in the future.


Assuntos
Carcinoma Ductal Pancreático/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Neoplasias Pancreáticas/genética , RNA Mensageiro/genética , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Ensaios de Migração Celular , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Progressão da Doença , Feminino , Células HEK293 , Humanos , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Células NIH 3T3 , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteínas ras/genética , Proteínas ras/metabolismo
8.
J Control Release ; 269: 405-422, 2018 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-29170140

RESUMO

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide largely due to lack of effective targeted drugs to simultaneously block multiple cancer-driving pathways. The identification of all-trans retinoic acid (ATRA) as a potent Pin1 inhibitor provides a promising candidate for HCC targeted therapy because Pin1 is overexpressed in most HCC and activates numerous cancer-driving pathways. However, the efficacy of ATRA against solid tumors is limited due to its short half-life of 45min in humans. A slow-releasing ATRA formulation inhibits solid tumors such as HCC, but can be used only in animals. Here, we developed a one-step, cost-effective route to produce a novel biocompatible, biodegradable, and non-toxic controlled release formulation of ATRA for effective HCC therapy. We used supercritical carbon dioxide process to encapsulate ATRA in largely uniform poly L-lactic acid (PLLA) microparticles, with the efficiency of 91.4% and yield of 68.3%, and ~4-fold higher Cmax and AUC over the slow-releasing ATRA formulation. ATRA-PLLA microparticles had good biocompatibility, and significantly enhanced the inhibitory potency of ATRA on HCC cell growth, improving IC50 by over 3-fold. ATRA-PLLA microparticles exerted its efficacy likely through degrading Pin1 and inhibiting multiple Pin1-regulated cancer pathways and cell cycle progression. Indeed, Pin1 knock-down abolished ATRA inhibitory effects on HCC cells and ATRA-PLLA did not inhibit normal liver cells, as expected because ATRA selectively inhibits active Pin1 in cancer cells. Moreover ATRA-PLLA microparticles significantly enhanced the efficacy of ATRA against HCC tumor growth in mice through reducing Pin1, with a better potency than the slow-releasing ATRA formulation, consistent with its improved pharmacokinetic profiles. This study illustrates an effective platform to produce controlled release formulation of anti-cancer drugs, and ATRA-PLLA microparticles might be a promising targeted drug for HCC therapy as PLLA is biocompatible, biodegradable and nontoxic to humans.

9.
Sci Rep ; 7: 45915, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28383568

RESUMO

Hepatocellular carcinoma (HCC) is the second leading cause of cancer related-death. As a major common regulator of numerous cancer-driving pathways and a unique therapeutic target, the prolyl isomerase Pin1 is overexpressed in a majority of HCCs, whereas the mechanism underlying Pin1 overexpression remains elusive. Here we find that miR-140-5p inhibits HCC by directly targeting Pin1 to block multiple cancer-driving pathways. Bioinformatics analysis, miRNA binding and functional assays identify that miR-140-5p directly interacts with the 3'UTR of Pin1 and inhibits Pin1 translation. Furthermore, like stable Pin1 knockdown, moderate overexpression of miR-140-5p not only eliminates Pin1, but also inhibits cells growth and metastasis. Importantly, these effects of miR-140-5p are largely rescued by reconstitution of Pin1. Moreover, miR-140-5p inhibits multiple Pin1-dependent cancer pathways and suppresses tumor growth in mice. The clinical significance of these findings has been substantiated by the demonstrations that miR-140-5p is frequently down-regulated and inversely correlated with Pin1 overexpression in HCC tissues and cell lines. Given prevalent miR-140-5p downregulation in other cancers and major impact of Pin1 overexpression on activating numerous cancer-driving pathways including global miRNA downregulation, the miR-140-5p/Pin1 axis may play a major role in tumorigenesis and offer promising therapeutic targets for HCC and other cancers.

10.
Oncotarget ; 8(18): 29771-29784, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28404959

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most common cancer, but is the second leading cause of cancer deaths, partially due to its heterogeneity and drug resistance. Sorafenib is the only medical treatment with a proven efficacy against advanced HCC, but its overall clinical efficacy is still modest. Therefore, a major challenge is how to improve its therapeutic efficacy. The unique prolyl isomerase Pin1 regulates numerous cancer-driving pathways. Notably, Pin1 is overexpressed in about 70% HBV-positive HCC patients and contributes to HCC tumorigenesis. However, the role of Pin1 in the efficacy of sorafenib against HCC is unknown. Here we found that sorafenib down-regulated Pin1 mRNA and protein expression, likely through inhibition of Pin1 transcription by the Rb/E2F pathway. Importantly, Pin1 knockdown potently enhanced the ability of sorafenib to induce cell death in HCC, which was further supported by the findings that Pin1 knockdown led to stabilization of Fbxw7 and destabilization of Mcl-1. Furthermore, all-trans retinoic acid (ATRA), a known anticancer drug that inhibits and ultimately induces degradation of active Pin1 in cancer cells, also potently sensitized HCC cells to sorafenib-induced cell death at least in part through a caspase-dependent manner. Moreover, ATRA also synergistically enhanced the ability of sorafenib to reduce Pin1 and inhibit tumor growth of HCC in mouse xenograft models. Collectively, these results not only demonstrate that Pin1 down-regulation is a key event underlying the anti-tumor effects of sorafenib, but also uncover that Pin1 inhibitors offer a novel approach to enhance the therapeutic efficacy of sorafenib against HCC.


Assuntos
Antineoplásicos/farmacologia , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Peptidilprolil Isomerase de Interação com NIMA/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Niacinamida/farmacologia , Sorafenibe , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Sci Rep ; 7: 43639, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28262728

RESUMO

Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant cancers with high inter- and intra-tumor heterogeneity. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 is prevalently overexpressed in human cancers including ~70% of HCC, and promotes tumorigenesis by activating multiple cancer-driving pathways. However, it was challenging to evaluate the significance of targeting Pin1 in cancer treatment until the recent identification of all-trans retinoic acid (ATRA) as a Pin1 inhibitor. Here we systematically investigate functions of Pin1 and its inhibitor ATRA in the development and treatment of HCC. Pin1 knockdown potently inhibited HCC cell proliferation and tumor growth in mice. ATRA-induced Pin1 degradation inhibited the growth of HCC cells, although at a higher IC50 as compared with breast cancer cells, likely due to more active ATRA metabolism in liver cells. Indeed, inhibition of ATRA metabolism enhanced the sensitivity of HCC cells to ATRA. Moreover, slow-releasing ATRA potently and dose-dependently inhibited HCC growth in mice. Finally, chemical or genetic Pin1 ablation blocked multiple cancer-driving pathways simultaneously in HCC cells. Thus, targeting Pin1 offers a promising therapeutic approach to simultaneously stop multiple cancer-driving pathways in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
JAMA Neurol ; 73(11): 1356-1362, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27654282

RESUMO

Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) share a common neuropathologic signature-neurofibrillary tangles made of phosphorylated tau-but do not have the same pathogenesis or symptoms. Although whether traumatic brain injury (TBI) could cause AD has not been established, CTE is shown to be associated with TBI. Until recently, whether and how TBI leads to tau-mediated neurodegeneration was unknown. The unique prolyl isomerase Pin1 protects against the development of tau-mediated neurodegeneration in AD by converting the phosphorylated Thr231-Pro motif in tau (ptau) from the pathogenic cis conformation to the physiologic trans conformation, thereby restoring ptau function. The recent development of antibodies able to distinguish and eliminate both conformations specifically has led to the discovery of cis-ptau as a precursor of tau-induced pathologic change and an early driver of neurodegeneration that directly links TBI to CTE and possibly to AD. Within hours of TBI in mice or neuronal stress in vitro, neurons prominently produce cis-ptau, which causes and spreads cis-ptau pathologic changes, termed cistauosis. Cistauosis eventually leads to widespread tau-mediated neurodegeneration and brain atrophy. Cistauosis is effectively blocked by the cis-ptau antibody, which targets intracellular cis-ptau for proteasome-mediated degradation and prevents extracellular cis-ptau from spreading to other neurons. Treating TBI mice with cis-ptau antibody not only blocks early cistauosis but also prevents development and spreading of tau-mediated neurodegeneration and brain atrophy and restores brain histopathologic features and functional outcomes. Thus, cistauosis is a common early disease mechanism for AD, TBI, and CTE, and cis-ptau and its antibody may be useful for early diagnosis, treatment, and prevention of these devastating diseases.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Encefalopatia Traumática Crônica/metabolismo , Encefalopatia Traumática Crônica/terapia , Proteínas tau/metabolismo , Doença de Alzheimer/prevenção & controle , Animais , Encefalopatia Traumática Crônica/prevenção & controle , Humanos
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 24(4): 1116-20, 2016 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-27531785

RESUMO

OBJECTIVE: To investigate the hematologic characteristics and gene diagnosis of patients with Thailand deleted α-thalassemia 1, so as to provide the information for clinical genetic counseling. METHODS: The clinical data of 32 patients with Thailand delated α-thalassemia 1 were analyzed retrospectively; the hematologic characteristics and gene diagnosis of Thailand deleted type were investigated by using routine hematologic examination, genetic detection of common thalassemia and Thailand deleted α-thalassemia 1. RESULTS: Among 32 cases, the Thailand deleted α-thalassemia 1 heterozygote was found in 29 cases, the Thailand deleted α-thalassemia 1 and α(3.7) gene deletion double heterozygote were found in 1 case, the Thailand deleted α-thalassemia 1 with ß-thalassemia (1 case with codons 41-42 mutation heterozygous, 1 case with CD17 mutation heterozygous) was found in 2 cases by detection. The MCV and MCH levels were decreased in all cases of Thailand deleted thalassemia 1, there were significant differences in RBC, MCV, MCH (P<0.05) between normal control and Thailand deletion α-thalassemia 1 group; there were also significant differences in MCHC (P<0.05) between Southeast asia thalassemia and Thailand deleted α-thalassemia 1 group. CONCLUSION: There are no significant differences in hematological parameters except MCHC between Southeast asia thalassemia and Thailand deleted α-thalassemia 1 group. moreover the Thailand deleted α-thalassemia 1 in a certain proportion exists in area with high incidence of thalassemia, therefor the clinicians should pay more attention to the screen and diagnosis of Thailand delated α-thalassemia and can exactly diagnose the Thailand delected α-thalassemia 1 on the basis of comprehensive analysis of conventional and Thailand delected α-thalassemia 1 detection results, clinical presentation, hematologic parameters and ultrasonic examination, so as to avoid the birth of child with severe and intermidiate type α-thalassemia caused by Thailand deleted α-thalassemia 1.


Assuntos
Talassemia alfa , Deleção de Genes , Heterozigoto , Humanos , Mutação , Fenótipo , Tailândia , Talassemia beta
14.
Int J Biol Sci ; 11(5): 587-94, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25892965

RESUMO

Both viral infection and DNA transfection expose single-stranded or double-stranded DNA to the cytoplasm of mammalian cells. Recognition of cytosolic DNA activates a series of cellular responses, including induction of pro-inflammatory genes such as type I interferon through the well-known cGAS-STING pathway. Here we show for the first time that intracellular administration of either single or double stranded interferon stimulating DNA (ISD), but not poly(dA) suppresses cell growth in many different cell types. Suppression of cell growth by cytosolic DNA is cGAS/STING independent and associated with inhibition of glucose metabolism, ATP depletion and subsequent cellular energy stress responses including activation of AMPK and inactivation of mTORC1. Our results suggest that in concert with but independent of innate immune response, recognition of cytosolic DNA induced cellular energy stress potentially functions as a metabolic barrier to viral replication.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Citosol/metabolismo , DNA/metabolismo , Metabolismo Energético/fisiologia , Glucose/metabolismo , Estresse Fisiológico/fisiologia , Regulação da Expressão Gênica/fisiologia , Células HEK293 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Poli A , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
15.
Cent Eur J Immunol ; 39(1): 77-82, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-26155104

RESUMO

BACKGROUND: It is now clear that there are two histological types (type 1 and type 2) of autoimmune pancreatitis (AI P). The histological substance of type 1 AI P is known as lymphoplasmacytic sclerosing pancreatitis (LPSP) or traditional AIP, and type 2 AIP is characterized by distinct histology called idiopathic duct centric pancreatitis (IDCP). Serum IgG4 increase is considered as a marker for type 1 AI P. Far less is known about type 2 and it lacks predicting markers, so it easily leads to missed diagnosis and misdiagnosis. THE AIM OF THIS STUDY: The aim of this study was to describe multi-gene mutations in patients with type 2 AI P and its clinical features. MATERIAL AND METHODS: Three unrelated patients with type 2 AI P, 10 cases with type 1 AIP, 15 cases with other chronic pancreatitis and 120 healthy individuals were studied. The mutations and polymorphisms of 6 genes involved in chronic pancreatitis or pancreatic cancer - PRSS1, SPINK1, CFTR, MEN1, PKHD1, and mitochondrial DNA - were sequenced. Information of clinical data was collected by personal interview using a structured questionnaire. RESULTS: Novel mutations were found in the genes encoding for MEN1 (p.546 Ala > The) and PKHD1 (c. 233586 A > G and c. 316713 C > T) from patients with type 2 AIP. What is more, the serum TCR (T cell receptor) level is relatively higher in patients with type 2 AIP than in patients with type 1 AIP and other chronic pancreatitis or normal controls. Weight loss was the major manifestation and no patients had extrapancreatic involvement in type 2 AIP. CONCLUSIONS: Type 2 AIP may occur with multi-gene mutations. For screening purposes, it is more reasonable to evaluate TCR levels in serum.

16.
Hemoglobin ; 34(6): 599-603, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21077770

RESUMO

In this study we present the first report of the detection of a new ß-thalassemia (ß-thal) mutation at codon 36 (-C) in the Chinese population. This frameshift mutation generates a TGA stop codon at position 60, resulting in a thalassemia phenotype. This is the first example of a premature stop codon at position 60 because of codon 36. The characterization of uncommon mutations is useful for the screening of ß-thal carriers, genetic counseling and prenatal diagnosis.


Assuntos
Deleção de Sequência , Globinas beta/genética , Talassemia beta/genética , Adulto , Sequência de Bases , China , Códon/genética , Análise Mutacional de DNA , Feminino , Humanos , Dados de Sequência Molecular
17.
Mol Cell Biochem ; 330(1-2): 31-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19381781

RESUMO

Genetic variations of the human RETN gene are associated with metabolic phenotypes, including obesity, insulin sensitivity, diabetes, and coronary heart disease (CHD). There are few studies of two gene variants, -394C>G and -420C>G, in Chinese population. This study investigated the distribution of RETN gene, single nucleotide polymorphisms (SNPs), in Chinese Han population and the association of the polymorphisms with type 2 diabetes mellitus (T2DM) and CHD. In a population-based, case-control genetic association study, a total of 961 subjects were recruited from the community, including 318 T2DM patients, 273 CHD patients, and 370 unrelated healthy control individuals. Serum lipid levels were detected. Two SNPs of RETN gene, -394C>G and -420C>G, were genotyped by PCR-RFLP. Unknown Polymorphisms were screened with the technique of denaturing high performance liquid chromatography (DHPLC). The frequencies of RETN -394G allele in T2DM group, CHD group, and control group were 0.3066, 0.3555, and 0.3481, respectively, which are met with the Hardy-Weinberg equilibrium. There is a significant difference of the comparison of sex in T2DM group of RETN gene SNP-394C>G (P < 0.05). Compared with controls, there was no significant difference in the distribution of genotypes and allele frequencies of -394C>G polymorphic site in T2DM patients and CHD patients, respectively. No direct association was found between the -394C>G polymorphism and T2DM or CHD. The frequencies of RETN -420G allele in T2DM group, CHD group, and control group were 0.4009, 0.3725, and 0.3859, respectively, which are met with the Hardy-Weinberg equilibrium. The frequencies of RETN -420G allele in T2DM groups and control groups of Chinese population are significantly different from those in European population (0.40 vs. 0.27, 0.39 vs. 0.26) (P < 0.01). Compared with controls, there was no significant difference in distribution of genotypes and allele frequencies of -420C>G polymorphic site in T2DM patients and CHD patients, respectively. No direct association was found between the -420C>G polymorphism and T2DM or CHD. In addition, we found new potential SNP +593G>C in exon 3 of RETN gene using DHPLC. The RETN gene exhibits sex and ethnic differences. +593G>C of RETN gene might be a new potential SNP in exon 3 of RETN gene. Association between SNP -394C>G and -420C>G of RETN gene with T2DM and CHD in Chinese needs more exploration.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Resistina/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
18.
Diabetes Res Clin Pract ; 84(3): 205-10, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19359061

RESUMO

In order to explore the different genetic backgrounds of non-obese and obese type 2 diabetes, we tried to genotype six SNPs (-11391G/A, -11377C/G, -10068G/A, G54V, Y111H and 4545G/C) in the adipose most abundant gene transcript-1 (APM1) gene in 338 type 2 diabetes (T2D) patients and 460 non-diabetic subjects by PCR-RFLP. Among these mutations, the 4545G/C mutation (rs1063539) contributed to the genetic risk of T2D in the non-obese group (OR=2.34, 95%CI: 1.31-4.21, P=0.004), and 57% of the risk is related to this polymorphism. On the contrary, -11377C/G (rs266729) was associated with type 2 diabetes in the obese group only (OR=2.45, 95%CI: 1.13-5.31, P=0.02), and 59% risk of diabesity could be attributed to that. All the associations above were adjusted for age and gender in unconditional logistic regression. Besides, the -11377G/4545C haplotype was merely related to obese diabetes (OR=2.12, 95%CI: 1.08-4.14, P=0.03). In addition, the obese diabetic group had significantly higher levels of triglyceride and insulin, better beta-cell function but lower glucose levels than the non-obese group (all P values <0.01). This study suggests that the genetic susceptibility is different between type 2 diabetes with and without obesity in Chinese Han population.


Assuntos
Diabetes Mellitus Tipo 2/genética , Variação Genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adiponectina/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Glicemia/metabolismo , China , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Éxons , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Razão de Chances , Polimorfismo Genético
19.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 16(4): 742-5, 2008 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-18718051

RESUMO

This study was aimed to investigate the gene expression profile of TGF-beta signal transduction pathway in B-cell type acute lymphocytic leukemia (B-ALL). The gene expression profiles in B-ALL primary cells and cell lines (NALM6 cells, Raji cells), B-lymphocyte of control were detected by cDNA microarray including 113 different genes in human TGF-beta/BMP signal transduction pathway, and TGF-beta(1) mRNA expression was detected by real time RT-PCR. The B lymphocytes in peripheral blood of heacthy persons sorted by flow cytometry were used as control. The difference between them was compared. The results showed that as compared with B lymphocytes in peripheral blood of heacthy persons, the TGF-beta(1) expression in B-ALL cells, NALM6 cells and Raji cells were down-regulationed, myc and smad1 gene expressions were up-regulated, IL-6, smad 7 gene expressions were down-regulated. It is concluded that TGF-beta signal transduction is abnormal in B-cell type acute lymphocytic leukemia.


Assuntos
Perfilação da Expressão Gênica , Leucemia de Células B/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/metabolismo , Doença Aguda , Humanos , Leucemia de Células B/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/genética
20.
J Genet Genomics ; 34(10): 877-84, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17945166

RESUMO

The authors investigated the possible association of -4522C/T variation of adiponectin gene with coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM). Genotyping of SNP -4522C/T in 304 patients with CHD, 389 patients with T2DM, and 405 age and sex-matched healthy control subjects was carried out by means of PCR-RFLP approach. No significant difference in the genotype or allele frequencies was found, either between patients with CHD and control subjects, or between patients with T2DM and control subjects. However, in the subgroup analysis, an association of the T/T genotype and T allele with type 2 diabetes combined with obesity (BMI > or = 25 kg/m(2)) was found (P = 0.014 and P = 0.034, respectively). Also the homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM patients with T/T genotype was significantly higher than that in T2DM patients carrying C allele (P = 0.0069). The authors' findings for the first time demonstrated that SNP -4522 in the adiponectin gene was associated with T2DM that combined with obesity and higher insulin resistance index in patients with T2DM. This indicated that the variation might associate with an increased susceptibility to type 2 diabetic obesity and insulin resistance. But -4522C/T polymorphism did not contribute to the susceptibility of CHD.


Assuntos
Adiponectina/genética , Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Doença das Coronárias/sangue , Doença das Coronárias/complicações , Doença das Coronárias/genética , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/complicações , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sítios de Splice de RNA
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