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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.


Assuntos
Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Peptidilprolil Isomerase de Interação com NIMA/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Tretinoína/farmacologia , Via de Sinalização Wnt
3.
Cancer Lett ; 444: 82-93, 2019 03 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.

4.
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.

5.
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
6.
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
7.
Biomed Rep ; 4(3): 379-383, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26998280

RESUMO

A migraine is a disabling neurovascular disorder characterized by a unilateral throbbing headache that lasts from 4 to 72 h. The headache is often accompanied by nausea, vomiting, phonophobia and photophobia, and may be worsened by physical exercise. The trigeminovascular system (TVS) is speculated to have an important role in migraines, although the pathophysiology of this disorder remains to be elucidated. Trigeminal ganglion (TG) and spinal trigeminal nucleus caudalis (TNC) are important components of the TVS. Several clinical cases have provided evidence for the involvement of the brainstem in migraine initiation. Electrical stimulation of the trigeminal ganglion (ESTG) in rats can activate TVS during a migraine attack. Calcitonin gene-related peptide (CGRP) is an important vasoactive compound produced following TVS activation. Numerous studies have revealed that adenosine and its receptors have an important role in pain transmission and regulation process. However, only a few studies have examined whether adenosine A2a receptor (A2aR) and adenosine A1 receptor (A1R) are involved in migraine and nociceptive pathways. In the present study, CGRP, A2aR and A1R expression levels were detected in the TG and TNC of ESTG models through reverse transcription-quantitative polymerase chain reaction and western blot analysis. Tianshu capsule (TSC), a type of Chinese medicine, was also used in the ESTG rat models to examine its influence on the three proteins. Results demonstrated that CGRP, A2aR and A1R mediated pain transmission and the regulation process during migraine and the expression of the three proteins was regulated by TSC.

8.
Gene ; 577(1): 89-95, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26611525

RESUMO

The purpose of this study was to establish a rat model of a brain injury with tracheotomy and compared the wetting effects of different airway humidification liquids, afterward, the best airway humidification liquid was selected for the clinical trial, thus providing a theoretical basis for selecting a proper airway humidification liquid in a clinical setting. Rats were divided into a sham group, group A (0.9% NaCl), group B (0.45% NaCl), group C (0.9% NaCl+ambroxol) and group D (0.9% NaCl+Pulmicort). An established rat model of traumatic brain injury with tracheotomy was used. Brain tissue samples were taken to determine water content, while lung tissue samples were taken to determine wet/dry weight ratio (W/D), histological changes and expression levels of SP-A mRNA and SP-A protein. 30 patients with brain injury and tracheotomy were selected and divided into two groups based on the airway humidification liquid instilled in the trachea tube, 0.45% NaCl and 0.9% NaCl+ambroxol. Blood was then extracted from the patients to measure the levels of SP-A, interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-α (TNF-α). The difference between group C and other groups in lung W/D and expression levels of SP-A mRNA and SP-A protein was significant (P<0.05). In comparison, the histological changes showed that the lung tissue damage was smallest in group C compared to the three other groups. Aspect of patients, 0.45% NaCl group and 0.9% NaCl+ambroxol group were significantly different in the levels of SP-A, IL-6, IL-8 and TNF-α (P<0.01). In the present study, 0.9% NaCl+ambroxol promote the synthesis and secretion of pulmonary surfactant, and has anti-inflammatory and antioxidant effects, which inhibit the release of inflammatory factors and cytokines, making it an ideal airway humidification liquid.


Assuntos
Ambroxol/farmacologia , Lesões Encefálicas/tratamento farmacológico , Budesonida/farmacologia , Proteína A Associada a Surfactante Pulmonar/metabolismo , Surfactantes Pulmonares/metabolismo , Adulto , Animais , Encéfalo/patologia , Química Encefálica , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Humanos , Umidade , Pulmão/química , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio , Traqueotomia
9.
Exp Ther Med ; 10(3): 1109-1114, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26622448

RESUMO

The antidepressive effects of the antidiabetic medicine, pioglitazone, were recently reported in several studies. These effects may ameliorate the depressive symptoms of patients with post-stroke depression (PSD). The present study aimed to evaluate the antidepressive effect of pioglitazone in patients with PSD combined with type 2 diabetes. A total of 118 consecutive patients with stroke who had depression were studied for an average of 3 months. The Diagnostic and Statistical Manual of Mental Disorders (fourth edition) was used to assess whether a patient was depressed or not. The severity of depression was evaluated by the Hamilton depression rating scale (HAMD). In accordance with their HAMD scores, the 118 patients were divided into a severe depression group (n=40) and a mild and moderate (MM) depression group (n=78). These subjects were then divided into pioglitazone [30 mg once daily (qd)] and metformin (0.5 g twice daily) subgroups. All patients were given fluoxetine (20 mg qd). Follow-up evaluations, which included HAMD scores, activities of daily living (ADL) scores, fasting blood glucose (FBG) levels and fasting insulin (FINS) levels, were conducted on the first and third month following the beginning of the treatment. In the MM depression group, the HAMD score in the pioglitazone subgroup was lower than that in the metformin subgroup following treatment for 1 or 3 months. In the severe depression group, the HAMD score in the pioglitazone subgroup was lower than that in the metformin subgroup following 3 months of treatment. The FINS levels of the pioglitazone subgroup gradually decreased in the 3 months of treatment. No noticeable improvement was observed in the ADL scores and FBG values. In conclusion, the results of the current study demonstrate that pioglitazone effectively decreased HAMD scores and FINS values in patients with PSD, suggesting that pioglitazone may be useful for the treatment of patients with PSD combined with type 2 diabetes.

10.
Environ Technol ; 35(21-24): 2813-20, 2014 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25176485

RESUMO

Nitrogen (N) and phosphorus (P) are the two main factors causing water eutrophication. Immobilized micro-organisms have been widely studied in N and P removal. However, the effects of various immobilizing conditions on the removal efficiency of N and P using immobilized micro-organism beads (IMOBs) remain unclear. Polyvinyl alcohol (PVA) and alginate, as the two frequently immobilizing-used matrixes, were used for co-immobilizing Pseudomonas stutzeri YHA-13 and Alcaligenes sp. ZGED-12. PVA, alginate and CaCl2contents, immobilization time and different wet biomass ratios of P. stutzeri to Alcaligenes sp. were conducted to elucidate their roles in and influences on the removal efficiency of N and P from synthetic wastewater. The application potential of IMOBs was estimated as well. Results showed that IMOBs prepared by cross-link of 4% PVA and 2-3% alginate with 5% CaCl2and saturated boric acid solution for 10-15 min are the best ones in removal of N and P. Though IMOBs containing P. stutzeri and/or Alcaligenes sp. were capable of removal of the two nutrients, the highest removal efficiency was observed when the wet biomass ratio of P. stutzeri to Alcaligenes sp. was adjusted to 2:2. In addition, the IMOBs were of good ability to remove chemical oxygen demand (COD), NO(3)(-), NO(2)(-), NH(4)(+)- N, total nitrogen (TN) and total phosphorus (TP) from artificial wastewater. Of which, micro-organisms immobilized in matrixes were mainly responsible for NO(3)(-) and TP removal. Therefore, P. stutzeri YHA-13 and Alcaligenes sp. ZGED-12 are reliable bioresources to remove N and P from wastewater.


Assuntos
Alcaligenes/metabolismo , Alginatos , Álcool de Polivinil , Pseudomonas stutzeri/metabolismo , Eliminação de Resíduos Líquidos/métodos , Cloreto de Cálcio , Ácido Glucurônico , Ácidos Hexurônicos , Nitrogênio/metabolismo , Fósforo/metabolismo , Poluentes Químicos da Água/metabolismo
11.
Zhongguo Dang Dai Er Ke Za Zhi ; 14(8): 593-7, 2012 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-22898280

RESUMO

OBJECTIVE: To study the main factors influencing prognosis of hemophagocytic lymphohistiocytosis (HLH) in children by summarizing the clinical features of HLH and investigating the relationship between relevant factors and prognosis. METHODS: The medical data of 63 children with HLH were retrospectively reviewed. Kaplan-Meier method was employed to draw survival curves. Factors influencing prognosis were assessed with Cox univariate analysis, and Cox multivariate analysis was done on statistically significant factors. RESULTS: The 3-year and 5-year survival rates were both 62.9%. The survival rate decreased from 98.4% at 1 day after definite diagnosis to 73.2% at 4 months. Univariate analysis demonstrated only one factor, which was that the condition of platelet recovery after treatment of 2 to 3 weeks was significantly related to prognosis (P=0.002). In children receiving etoposide therapy, temperature recovery after one day of treatment was significantly related to prognosis (P=0.016). CONCLUSIONS: Children with HLH have a satisfactory prognosis, but the survival rate reduces rapidly in the first 4 months after definite diagnosis. Platelet recovery after treatment of 2 to 3 weeks and temperature recovery after one day of treatment are factors influencing prognosis of HLH in children.


Assuntos
Linfo-Histiocitose Hemofagocítica/mortalidade , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida
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