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1.
Bioorg Chem ; 99: 103803, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32251945

RESUMO

Many peroxisome proliferator-activated receptors (PPARs) agonists have been developed for the treatment of metabolic disorders, while several PPARs agonists were discontinued in clinical trials because of PPARγ related side effects. In order to increase the selectivity against PPARγ, we performed a structure-activity relationship study based on PPARα/γ/δ agonist MHY2013. These efforts eventually led to the identification of compound 4, a dual PPARα/δ agonist with considerable potencies on PPARα/δ and high selectivity against PPARγ. In the Western Diet and CCl4-induced non-alcoholic steatohepatitis model, compound 4 alleviates the hepatic steatosis, inflammation, and fibrosis. These results indicated that dual PPARα/δ agonist 4 might be a promising lead compound for further investigations.

2.
Acta Biomater ; 108: 87-96, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32268237

RESUMO

Because of poor self-repair capacity, the repair of cartilage defect is always a great challenge in clinical treatment. In vitro cartilage regeneration provides a potential strategy for functional reconstruction of cartilage defect. Hydrogel has been known as an ideal cartilage regeneration scaffold. However, to date, in vitro cartilage regeneration based on hydrogel has not achieved satisfactory results. The current study explored the feasibility of in vitro 3D cartilage regeneration based on a moldable thermosensitive hydroxypropyl chitin (HPCH) hydrogel and its in vivo fate. The thermosensitive HPCH hydrogel was prepared and characterized. Goat auricular chondrocytes were encapsulated into the HPCH hydrogel to form a chondrocyte-hydrogel construct. The constructs were injected subcutaneously into nude mice or molded into different shapes for in vitro chondrogenic culture followed by in vivo implantation. The results demonstrated that the HPCH hydrogel possessed satisfactory gelation properties (gelation time < 18 s at 37 °C), biocompatibility (cell amount almost doubled within one week), and the ability to be applied as an injectable hydrogel for cartilage regeneration. All the constructs of in vitro culture basically maintained their original shapes (in vitro to initial: 110.8%) and displayed typical cartilaginous features with abundant lacunae and cartilage specific matrix deposition. These in vitro samples became more mature with prolonged in vivo implantation and largely maintained the original shape (in vivo to in vitro: 103.5%). These results suggested that the moldable thermosensitive HPCH hydrogel can serve as a promising scaffold for cartilage regeneration with defined shapes in vitro and in vivo. STATEMENT OF SIGNIFICANCE: Because of avascular and non-nervous characteristic of cartilage, in vitro regeneration plays an important role in reconstructing cartilage function. Hydrogel has been known as an ideal cartilage regeneration scaffold. However, to date, in vitro cartilage regeneration based on hydrogel has not achieved satisfactory results. The current study demonstrated that the chondrocyte-hydrogel construct generated by high density of chondrocytes encapsulated into a thermosensitive HPCH hydrogel could successfully regenerate in vitro typical cartilage-like tissue with defined shapes and further mature to form homogeneous cartilage with their original shapes after in vivo implantation. The current study indicated that the moldable thermosensitive HPCH hydrogel could serve as a promising scaffold for in vitro and in vivo cartilage regeneration with different shapes.

3.
J Mol Endocrinol ; 64(4): 249-258, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32197234

RESUMO

Decidualization is a critical process for embryo implantation and pregnancy maintenance in humans. The homeobox gene HOXA10 has been widely studied in endometrial receptivity establishment and decidualization. MEIS1, a three-amino-acid loop extension (TALE) family homeobox gene, has been proven to be a co-factor for HOXA10 in mouse uterus. However, the interaction between MEIS1 and HOXA10 in the human decidual cells remains to be elucidated. siRNA and CRISPR-Cas9 were employed to knockdown and knockout MEIS1 in the cultured human endometrial stromal cells, and it was found that MEIS1 deficiency leads to impaired decidualization. The physical interaction between the MEIS1 and HOXA10 in human endometrial stromal cell was confirmed by immunoprecipitation. Moreover, KAT2B and ETA were proved to be downregulated in the absence of MEIS1, and luciferase reporter and ChIP assays demonstrated that MEIS1-HOXA10 complex binds to the promoters of KAT2B and ETA and regulates their activity. Overexpression of KAT2B and ETA can partially rescue the decidualization defects in MEIS1-knockout HESCs. Taken together, these data suggest that MEIS1 plays an indispensable role in decidualization in human endometrial stromal cells, and MEIS1 interacts with HOXA10 to regulate the downstream genes, such as KAT2B and ETA. These findings will contribute to our understanding about the regulatory network in the process of decidualization in humans.

4.
Cancer Biol Ther ; 21(4): 309-314, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-31959056

RESUMO

Acute promyelocytic leukemia (APL) is characterized by the presence of promyelocytic leukemia-retinoic acid receptor α (PML-RARα) fusion gene, which is formed following the specific chromosomal translocation t(15;17)(q22;q21). However, cases with PML-RARα generated by occult t(15;17) which are negative by both cytogenetics and fluorescence in situ hybridization (FISH), are difficult to diagnose, leading to impaired treatment effectiveness. In the present study, we reported a case of a 66-year-old male patient, and bone marrow morphology, flow cytometry and cytogenetics did not support the diagnosis of APL. Molecular techniques, such as reverse-transcription polymerase chain reaction (RT-PCR), showed the existence of a cryptic PML-RARα fusion gene, and sequence analysis revealed a new variable isoform. Hotspot gene mutation analysis showed a biallelic CEBPA mutation. He received IA chemotherapy and all-trans retinoic acid (ATRA) treatment, and finally achieved complete remission. This case report provided valuable insights into the relevance of the correct identification of atypical PML-RARα fusion gene and biallelic CEBPA mutation. Moreover, combination of IA chemotherapy and ATRA treatment suggested a good clinical effect in this atypical PML-RARα.

5.
Nano Lett ; 19(11): 8010-8020, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31639306

RESUMO

The diffusion of nanomedicines used to treat tumors is severely hindered by the microenvironment, which is a challenge that has emerged as a bottleneck for the effective outcome of nanotherapies. Classical strategies for enhancing tumor penetration rely on passive movement in the extracellular matrix (ECM). Here, we demonstrate that nanomedicine also penetrates tumor lesions via an active trans-cell transportation process. This process was discovered by directly observing the movement of nanoparticles between cells, evaluating the intracellular trafficking pathway of nanoparticles via Rab protein labeling, comparing endocytosis-exocytosis between nanoparticles administered with inhibitors, and correlating the transcytosis process with the micro-CT distribution of nanomedicines. We also demonstrated that enhanced tumor penetration promotes the therapeutic efficacy of a photodynamic therapeutic nanomedicine. Our research thus suggests that transcytosis could be an important positive factor for designing cancer nanomedicines.

6.
Bioorg Chem ; 92: 103254, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518760

RESUMO

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) were considered as potential anti-diabetic targets, and the dual FFA1/PPARδ agonists might provide synergistic effect in insulin secretion and sensibility. Herein, we further develop dual agonists by screening 7 series of heterocycles, resulting in the discovery of compound 19 with considerable oral pharmacokinetic profile. Compound 19 exhibited a balanced potency between FFA1 and PPARδ, and high selectivity over PPARα and PPARγ. Moreover, compound 19 exerted improved glucose-lowering effects and insulin sensitivity in a dose-dependent manner, which might be attributed to its dual effects to simultaneously regulate insulin secretion and resistance. Our results extended the existing chemical space, and provided a potent tool compound 19.

7.
Cancer Biomark ; 26(2): 193-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31403941

RESUMO

OBJECTIVES: In men, human prostate cancer (PCa) has become the second most common cancer. miRNAs are short non-coding RNAs that can inhibit target gene mRNAs. Studies have showed that the alternation of miRNAs expression in cancer is relevant to pathogenesis of tumor. In present study, we aimed to investigate functions of miR-214-5p in PCa. MATERIALS AND METHODS: 10 paired human prostate tumor tissues and homologous para-tumor tissues were recruited, and the levels of miR-214-5p and CRMP5 were respectively determined by qRT-PCR assay. Luciferase activity analysis was performed to explore the regulation of CRMP5 mRNA 3'UTR by miR-214-5p. Then, cell experiments, including cell proliferation, apoptosis, cell cycle, migration and colony formation ability, were performed after proper plasmids or RNAs transfection. RESULTS: In PCa tissues and cell lines, expression of miR-214-5p was decreased compared with para-tumor tissues or normal prostate epithelial cell lines. Luciferase activity assay showed a direct combination of miR-214-5p and CRMP5 mRNA 3'UTR, and indicated that the absence of miR-214-5p in PCa cells may contributes to a high level of CRMP5. Cell experiments showed that miR-214-5p can induce inhibition of tumor cell growth, migration and colony forming efficiency, promotion of apoptosis and G1-phase arrest, on the other hand, co-expression of CRMP5 somewhat counteracted these phenotype induced by miR-214-5p. CONCLUSION: Taken together, miR-214-5p shows tumor suppression effects in PCa cells. Loss expression of miR-214-5p in PCa increase levels of CRMP5 through regulating CRMP5 3'UTR, which could be a potential therapy target for PCa.

8.
Nano Lett ; 19(8): 5515-5523, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31362507

RESUMO

Designing simple-structured nanomedicine without lacking key functionalities, thereby avoiding incomplete damage or relapse of tumor with the administration of a safe dose, is pivotal for successful cancer nanotherapy. We herein presented a nanomedicine of photodynamic therapy (PDT) that simply assembled amphiphilic macromolecules of poly-l-lysine conjugating with photosensitizers onto hydrophobic upconverting nanoparticles. We demonstrated that the nanoformulation, despite its simple structure and synthesis, simultaneously possesses multiple features, including substantial payload of photosensitizers, avid cellular internalization both in vitro and in vivo, efficient diffusion and broad distribution in tumor lesion, and potent fatality for cancer stem cells that are refractory to other therapy modalities. Because of the combination of these functionalities, the tumors in mice were eradicated and no relapse was observed after at least 40 days, just with an extremely low intraperitoneal injection dose of 5.6 mg/kg. Our results suggested a strategy for designing multifunctional nanomedicines with simple construct and efficacious therapeutic response and presented the promising potential of PDT for a radical cure of cancer.

9.
Virol J ; 16(1): 5, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621727

RESUMO

BACKGROUND: Understanding the prevalence and evolution of HIV-1 drug resistance (DR) and associated mutation patterns is critical to implementing free antiretroviral therapy in Yunnan, the first antiretroviral treatment location in China. Here We provide a basis for understanding the occurrence and development of HIV-1 resistance in Yunnan and a theoretical foundational for strategy to delay HIV-1 drug resistance and achieve successful individualized treatment. METHODS: Plasma samples from different cities/prefectures were collected at Yunnan Provincial Hospital of Infectious Disease from January 2010 to September 2016, and those from drug-resistant individuals were genotyped using in-house assays, 88 patients were selected for the study who had been on treatment for ≥6 months (and for whom drug resistance was then measured), and each patient had at least 3 genotype resistance tests and who were enrolled to analyze mutation and evolution of HIV resistance. RESULTS: 264 Pol sequences of 88 patients were obtained. Drug resistance levels to eight drugs increased to varying degrees with prolonged treatment. Resistance to efavirenz (EFV) and etravirine (ETR) showed the highest change, comparisons of resistant changes to second and first and to third and second agents showed altered level of drug resistance were 25 and 20 cases, 28 and 18 cases, respectively. The smallest change was Lopinavir/Ritonavir (LPV/r) present 2 and 3 cases; Resistance to lamivudine (3TC) and lopinavir/ritonavir (LPV/r) was high among patients detected thrice, whereas other drugs were distributed in all resistance levels. M184 V/I (26.14%), T69S (11.36%), and T215Y/I (10.23%) mutations were the most common in nucleoside reverse transcriptase inhibitors (NRTIs), and K103 N/R/S (21.59%), V179D/E (20.45%) in Non-NRTIs (NNRTIs). Furthermore, L10 V/F/I (6.82%), A71V (4.55%), and I54V (4.55%) mutations were common in protease inhibitors (PIs). CONCLUSIONS: We found dynamic genotypic changes in HIV-1 drug-resistance in Yunnan, with prolonged treatment, and drug resistance was inevitable. However, resistance to different drugs occurred at varying times, and mutation site emergence was the main cause. These findings enhance our understanding of evolution and regulation, and are valuable for developing HIV-1 DR prevention strategies in Yunnan.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Evolução Molecular , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Falha de Tratamento , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade , Criança , China/epidemiologia , Feminino , Genótipo , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Adulto Jovem
10.
Eur J Med Chem ; 164: 352-365, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30605833

RESUMO

The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/química , PPAR delta/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Tiazóis/farmacologia , Animais , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Camundongos , Tiazóis/química , Tiazóis/farmacocinética
11.
J Exp Bot ; 69(20): 4723-4737, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30295905

RESUMO

Grain length is one of the determinants of yield in rice and auxin plays an important role in regulating it by mediating cell growth. Although several genes in the auxin pathway are involved in regulating grain length, the underlying molecular mechanisms remain unclear. In this study we identify a RING-finger and wd40-associated ubiquitin-like (RAWUL) domain-containing protein, Gnp4/LAX2, with a hitherto unknown role in regulation of grain length by its influence on cell expansion. Gnp4/LAX2 is broadly expressed in the plant and subcellular localization analysis shows that it encodes a nuclear protein. Overexpression of Gnp4/LAX2 can significantly increase grain length and thousand-kernel weight. Moreover, Gnp4/LAX2 physically interacts with OsIAA3 and consequently interferes with the OsIAA3-OsARF25 interaction in vitro and in vivo. OsIAA3 RNAi plants consistently exhibit longer grains, while the mutant osarf25 has small grains. In addition, OsARF25 binds to the promoter of OsERF142/SMOS1, a regulator of organ size, and positively regulates its expression. Taken together, the results reveal that Gnp4/LAX2 functions as a regulator of grain length through participation in the OsIAA3-OsARF25-OsERF142 pathway and that it has potential value for molecular breeding in rice.


Assuntos
Grão Comestível/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/genética , Proteínas de Plantas/genética , Transdução de Sinais/genética , Sequência de Aminoácidos , Grão Comestível/genética , Proteínas Nucleares/metabolismo , Oryza , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/química , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Alinhamento de Sequência
12.
Small ; 14(19): e1800293, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29665272

RESUMO

Locating nanotherapeutics at the active sites, especially in the subcellular scale, is of great importance for nanoparticle-based photodynamic therapy (PDT) and other nanotherapies. However, subcellular targeting agents are generally nonspecific, despite the fact that the accumulation of a nanoformulation at active organelles leads to better therapeutic efficacy. A PDT nanoformulation is herein designed by using graphene oxide quantum dots (GOQDs) with rich functional groups as both the supporter for dual targeting modification and the photosensitizer for generating reactive oxygen species, and upconversion nanoparticles (UCNs) as the transducer of excitation light. A tumor-targeting agent, folic acid, and a mitochondrion-targeting moiety, carboxybutyl triphenylphosphonium, are simultaneously attached onto the UCNs-GOQDs hybrid nanoparticles by surface modification, and a synergistic targeting effect is obtained for these nanoparticles according to both in vitro and in vivo experiments. More significant cell death and a higher extent of mitochondrion damage are observed compared to the results of UCNs-GOQDs nanoparticles with no or just one targeting moiety. Furthermore, the PDT efficacy on tumor-bearing mice is also effectively improved. Overall, the current work presents a synergistic strategy to enhance subcellular targeting and the PDT efficacy for cancer therapy, which may also shed light on other kinds of nanotherapies.

13.
Am J Transl Res ; 10(3): 975-988, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29636887

RESUMO

Effects of maternal aging on the offspring cognitive function remain controversial in population-based investigations, and information available in animal studies is very limited. We investigated the impact of a delayed first natural pregnancy on pregnancy outcomes in the mouse model. Spatial learning capacity in young adult mouse offspring was observed by step-down passive avoidance task and Morris water maze (MWM). Maternal serum α-klotho was measured by ELISA. Morphological characteristics of fetoplacental unit and offspring brain were identified by H&E and immunohistochemistry. Klotho, VDR and other related genes expression were quantified by real-time-RT-PCR and western blot. We found delayed pregnancy reduced fertility in female mice by three-fold (Young vs. Old: 5.0% vs. 20.7%), and increased adverse pregnant outcomes by eight-fold (Young vs. Old: 3.0% vs. 27.5%). Mice born to old mothers exhibited shorter retention trial latency in passive avoidance task and longer latency to find the platform in MWM, suggesting worse performance on the tests that measure learning and memory. Serum α-klotho level was lower in old female mice before pregnancy, whereas became comparable after pregnancy. Vitamin D receptor (VDR) expression, both in mRNA and protein, markedly decreased during the early stage of fetoplacental unit in old mice, especially in trophoblast giant cells when compared with that of young mice. Importantly, consistent with fetoplacental unit, VDR expression also declined in hippocampus from offspring born to old mice. These results suggest that young adult offspring from aged mothers exhibited worse cognitive function and the reduced VDR expression during fetoplacental development might play an important role.

14.
World J Urol ; 36(7): 1117-1126, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29459994

RESUMO

PURPOSE: Bipolar endoscopic enucleation of the prostate (BEEP) was recommended by the 2016 EAU guidelines as the first choice of surgical treatment in men with a substantially enlarged prostate and moderate-to-severe lower urinary tract symptoms. The main aim of this study was to compare a modified diode laser enucleation of the prostate (DiLEP) to BEEP. METHODS: A total of 114 patients with prostate (20-160 mL) were randomized 1:1 into either DiLEP or BEEP in a dual-centre, non-inferiority-design randomized-controlled trial. The primary outcomes included Qmax and IPSS at 12 months. Non-inferiority was evaluated by comparing the two-sided 95% CI for the mean differences of Qmax and IPSS. Secondary endpoints included other perioperative parameters, postoperative micturition variables, and complication rate. RESULTS: A total of 111 patients (97%) had completed the intent-to-treat analysis, The results showed that DiLEP was comparable to BEEP regarding Qmax (28.0 ± 7.0 vs. 28.1 ± 7.2 mL/s) and IPSS (3.0 ± 2.2 vs. 2.9 ± 2.6) at 12 months, the non-inferiority was met for both Qmax and IPSS. There were also no significant difference between two groups regarding tissue removal rate (71.8 vs. 73.8%), hemoglobin decrease (0.33 ± 0.66 vs. 0.36 ± 0.75 g/dL), sodium decrease (1.0 ± 2.7 vs. 0.3 ± 2.9 mmol/L), and Clavien III complications (5.3 vs. 1.8%) at 12 months. CONCLUSIONS: This DiLEP is an anatomical endoscopic enucleation technique for the treatment of benign prostatic hyperplasia, it is non-inferior to BEEP regarding Qmax and IPSS at 12 months postoperatively.


Assuntos
Terapia a Laser/métodos , Sintomas do Trato Urinário Inferior/cirurgia , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata/métodos , Idoso , Seguimentos , Humanos , Análise de Intenção de Tratamento , Lasers Semicondutores , Tempo de Internação , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Hiperplasia Prostática/complicações , Qualidade de Vida , Fatores de Tempo , Resultado do Tratamento
15.
Asian J Urol ; 5(1): 48-54, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29379737

RESUMO

Objective: According to the EAU Guidelines, transurethral resection of the prostate (TURP) has so far still been considered as the gold standard for surgical treatment for patients with obstructing clinical benign prostate hyperplasia (BPH). However, its relatively high rate of complications and postoperative recurrence necessitates further modification and innovation on the surgery technique. We reported the patient outcomes with our technique. Methods: We retrospectively analyzed 52 patients with obstructing clinical BPH who underwent bipolar transurethral enucleation and resection of the prostate (B-TUERP) between March 2015 and September 2015. Pre- and perioperative parameters were obtained from medical charts. Postoperative follow-ups were administrated at 1, 3, 6, 12 and 24 month(s) after surgery, respectively. Results: All the operations were performed successfully with a mean operative time of 43.1 min and an average tissue removal rate of 74.7%. Qmax was significantly improved immediately after surgery, followed by a continuous improvement throughout the follow-ups. Following a steep decrease in mean prostate specific antigen (PSA) and post void residual (PVR) observed within the first half year after surgery, the serum PSA was then maintained at a constant level of 0.61 ng/mL. Temporary urinary retention was found in four cases (7.7%). Stress urinary incontinence occurred in five patients (9.6%), with the condition resolved in 1-2 weeks without extra treatment. Urethral strictures and bladder neck contractures, as the most commonly observed long-term complications, developed in four patients (7.7%). No recurrence was found during 2 years of follow-ups. An improvement in International Index of Erectile Function (IIEF-5) scores was witnessed in 17 patients preoperatively with normal sexual function during the first 6 months after surgery, and sustained throughout the 24-month period. Conclusions: Enucleation reflects an improvement on surgical technique in many ways with a need for surgical equipment that can be broadly accessible in clinical practice. Currently, bipolar resection is a commonly employed procedure in clinical settings, and its similarity shared with bipolar enucleation technique warrants a quick learning of B-TUERP by urologists. Based on these findings, we believe that the substitution of TURP by TUERP as the gold standard for prostate endoscopic procedure can be expected in the future.

16.
Oncotarget ; 8(13): 21177-21186, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28416753

RESUMO

Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma de Células Renais/terapia , Inibidores do Crescimento/farmacologia , Fenantridinas/farmacologia , Extratos Vegetais/farmacologia , Alcaloides de Amaryllidaceae/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Terapia Combinada , Sinergismo Farmacológico , Feminino , Inibidores do Crescimento/uso terapêutico , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais , Fenantridinas/uso terapêutico , Extratos Vegetais/uso terapêutico , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento
17.
Small ; 13(13)2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28060457

RESUMO

Singlet oxygen (1 O2 ), as an important kind of reactive oxygen species (ROS) and main therapeutic agent in photodynamic therapy (PDT), only have a half-life of 40 ns and an effective radius of 20 nm, which cause significant obstacles for improving PDT efficacy. In this work, novel upconversion nanoparticle (UCN)-based nanoplatforms are developed with a minimized distance between UCNs and a photosensitizer, protoporphyrin IX (PpIX), and a controllable payload of PpIX, to enhance and control ROS production. The ability of the nanoplatform to target different subcellular organelles such as cell membrane and mitochondria is demonstrated via surface modification of the nanoplatform with different targeting ligands. The results show that the mitochondria-targeting nanoplatforms result in significantly increased capability of both tumor cell killing and inhibition of tumor growth. Subcellular targeting of nanoparticles leads to the death of cancer cells in different manners. However, the efficiency of ROS generation almost have no influence on the tumor cell viability during the period of evaluation. These findings suggest that specific subcellular targeting of the nanoplatforms enhances the PDT efficacy more effectively than the increase of ROS production, and may shed light on future novel designs of effective and controllable PDT nanoplatforms.


Assuntos
Nanopartículas/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/química , Espécies Reativas de Oxigênio , Oxigênio Singlete/farmacologia
18.
Biochem Biophys Res Commun ; 483(1): 197-202, 2017 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-28042037

RESUMO

Lycorine, an alkaloid extracted from Amaryllidaceae genera, exhibits antitumor activities against several human solid-tumor and leukemia cells with extensive influence on various cell signaling molecules. However, the effect of lycorine on bladder cancer has not yet been investigated. In this study, we demonstrated that lycorine induced apoptosis in human bladder cancer T24 cells, an effect that is mediated via inhibition of phospho-Akt expression and the consequent activation of caspase-3 and Bax in vitro. In an in vivo experiment, T24 cells were subcutaneously implanted in the right rear flank of nu/nu mice. Lycorine treatment for 14 days significantly inhibited tumor growth compared with that in controls. Collectively, our findings suggest that lycorine suppressed the Akt pathway and activated the intrinsic apoptotic cascade, leading to the apoptosis of bladder cancer cells. We suggest that lycorine can be a viable therapeutic option for bladder cancer patients.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Apoptose/efeitos dos fármacos , Fenantridinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacologia , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Bexiga Urinária/citologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 37(1): 130-134, 2017.
Artigo em Chinês | MEDLINE | ID: mdl-28109113

RESUMO

OBJECTIVE: To investigate the effect of sodium phenylbutyrate (SPB) in modulating docetaxel resistance in human prostate cancer cells in vitro. METHODS: A PC3/docetaxel-resistant human prostate cancer cell line PC3/DTX was induced and examined for proliferation, viability, and cell inhibition rate in the presence of SPB. The concentration of concentration of docetaxel required to kill 50% of PC3/DTX cells incubated with 0, 1, 2, and 4 mmol/L SPB was determined using MTT assay. Cell apoptosis rate was analyzed with flow cytometry and the cellular expressions of p21, cyclin D1 and survivin proteins were detected using Western blotting. RESULTS: Treatment of PC3/DTX cells with 0, 1, 2, and 4 mmol/L of SPB for 48 h resulted in cell viabilities of (99.85∓2.69)%, (84.68∓3.87)%, (68.65∓4.54)% and (43.54∓5.69)%, and cell inhibition rates of (10.69∓3.65)%, (25.78∓4.58)%, (54.68∓3.98)% and (69.84∓6.54)%, respectively (P<0.05). The concentration of docetaxel required to kill 50% of PC3/DTX cells cultured in the presence of with 0, 1, 2, and 4 mmol/L SPB was 135.98∓2.69, 109.65∓3.87, 87.65∓3.84 and 64.62∓2.98 nmol/L, respectively (P<0.05), and the cell apoptosis rates were (7.2∓0.8)%, (10.2∓0.9)%, (19.8∓2.1)% and (27.4∓2.5)%, respectively. SPB treatment promoted the protein expression of p21 and suppressed the expressions of cyclin D1 and survivin in PC3/DTX cells. CONCLUSION: SPB can affect the expressions of p21, cyclin D1, and survivin in PC3/DTX cells and increase the sensitivity to the drug-resistant cells to docetaxel.


Assuntos
Antineoplásicos/farmacologia , Fenilbutiratos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Taxoides/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/metabolismo , Docetaxel , Humanos , Proteínas Inibidoras de Apoptose , Masculino , Sódio
20.
World J Urol ; 35(3): 395-402, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27380209

RESUMO

OBJECTIVE: To illustrate a ligation-free technique and compare perioperative and postoperative outcomes of this technique versus the standard suture method. PATIENTS AND METHODS: This study is a retrospective review of 233 consecutive patients with localized prostate cancer who underwent ligation-free technique (n = 180, Group 1) or standard ligation (n = 53, Group 2) at an academic institution from February 2010 to January 2014. RESULTS AND LIMITATIONS: Operative time was significantly shorter in Group 1 than in Group 2 (148.47 vs. 164.25 min, p = 0.000). No difference in EBL was noted between the groups (191.11 vs. 185.06 mL, p = 0.055). Postoperative continence rates at 3, 6, and 12 months in Groups 1 and 2 were 40.0 versus 24.5, 54.4 versus 37.7, and 73.9 versus 71.7 %, respectively. These differences were statistically significant. No patient in either group had a positive apical surgical margin. During follow-up, tumor recurrence or metastasis was not observed in any patient. Limitations of the study include this retrospective study of a single-center experience and lack of potency appraisal. CONCLUSIONS: This present ligation-free technique showed a statistically significant shorter interval to recovery of continence and higher continence rates in short-term postoperative results by contrast to conventional suture ligation, but no significant difference was revealed in long-term urinary control. We offer this technique and the correlative data to provide more information for deeply understanding the precise construction of the dorsal vascular complex and the mechanism of urinary control.


Assuntos
Laparoscopia/métodos , Complicações Pós-Operatórias/epidemiologia , Próstata/irrigação sanguínea , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Incontinência Urinária/epidemiologia , Idoso , Perda Sanguínea Cirúrgica , China , Seguimentos , Humanos , Ligadura , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Duração da Cirurgia , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Técnicas de Sutura
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