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1.
Pharmacol Res ; 202: 107126, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38432446

RESUMEN

PD-1 blockade therapy has made great breakthroughs in treatment of multiple solid tumors. However, patients with microsatellite-stable (MSS) colorectal cancer (CRC) respond poorly to anti-PD-1 immunotherapy. Although CRC patients with microstatellite instability (MSI) or microsatellite instability-high (MSI-H) can benefit from PD-1 blockade therapy, there are still some problems such as tumor recurrence. Tumor-associated macrophages (TAMs), most abundant immune components in tumor microenvironment (TME), largely limit the therapeutic efficacy of anti-PD-1 against CRC. The CSF1/CSF1R pathway plays a key role in regulating macrophage polarization, and blocking CSF1R signaling transduction may be a potential strategy to effectively reprogram macrophages and remodel TME. Here, we found that increasing expression of CSF1R in macrophages predicted poor prognosis in CRC cohort. Furthermore, we discovered a novel potent CSF1R inhibitor, PXB17, which significantly reprogramed M2 macrophages to M1 phenotype. Mechanically, PXB17 significantly blocked activation of PI3K/AKT/mTORC1 signaling, resulting in inhibition of cholesterol biosynthesis. Results from 3D co-culture system suggested that PXB17-repolarized macrophages could induce infiltration of CD8+ T lymphocytes in tumors and improve the immunosuppressive microenvironment. In vivo, PXB17 significantly halted CRC growth, with a stronger effect than PLX3397. In particular, PXB17 potently enhanced therapeutic activity of PD-1 mAb in CT-26 (MSS) model and prevented tumor recurrence in MC-38 (MSI-H) model by promoting formation of long-term memory immunity. Our study opens a new avenue for CSF1R in tumor innate and adaptive anti-tumor immunomodulatory activity and suggests that PXB17 is a promising immunotherapy molecule for enhancing the efficacy of PD-1 mAb or reducing tumor recurrence of CRC.


Asunto(s)
Neoplasias Colorrectales , Macrófagos Asociados a Tumores , Humanos , Receptor de Muerte Celular Programada 1 , Fosfatidilinositol 3-Quinasas , Recurrencia Local de Neoplasia , Neoplasias Colorrectales/genética , Microambiente Tumoral
2.
Zhongguo Yi Liao Qi Xie Za Zhi ; 48(4): 367-372, 2024 Jul 30.
Artículo en Zh | MEDLINE | ID: mdl-39155247

RESUMEN

With the continuous advancement of artificial intelligence in the field of prostate cancer research, numerous studies have shown that AI performance can rival that of physicians. This review examines the recent applications and developments of AI in the early, accurate, and non-invasive diagnosis of prostate cancer, subsequently elucidating its importance, benefits, and limitations. The review emphasizes the exploration of the potential integration of AI with multi-omics and other cutting-edge technologies. Considering the current status of AI in prostate cancer diagnosis, the review summarizes the challenges faced in the clinical adoption of AI technologies and looks forward to improved and enhanced AI-based prostate cancer diagnostic techniques. The goal is to offer a reference for the integration of artificial intelligence into clinical practice.


Asunto(s)
Inteligencia Artificial , Neoplasias de la Próstata , Neoplasias de la Próstata/diagnóstico , Masculino , Humanos , Diagnóstico por Computador
3.
ACS Omega ; 9(7): 7782-7792, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38405482

RESUMEN

The mechanism underlying the development of renal cell carcinoma (RCC) remains unclear, and effective prevention and therapeutic measures are lacking. BIRC6, a protein inhibitor of apoptosis, has attracted great interest. Our data indicated that overexpression of BIRC6 elevated cell growth, colony formation, migration, and invasion of cultured RCC cells, while siRNA knockdown of BIRC6 suppressed these processes. Additionally, BIRC6 was highly expressed in RCC clinical samples along with a downregulated level of Axin. Immunoprecipitation assays found that BIRC6 interacted with Axin and the two proteins colocalized within the cytoplasm of RCC cells. Overexpression of BIRC6 promoted the ubiquitination modification of Axin, while genetic knockdown of BIRC6 suppressed it. Furthermore, overexpression of BIRC6 significantly promoted the turnover of Axin, suggesting BIRC6's inhibitory effect on Axin protein stability. BIRC6 was also upregulated in cancer stem-like cells of RCC and increased the drug resistance of RCC cells against sunitinib. Western blotting assays showed that the overexpression of BIRC6 upregulated CXCR4 protein expression and activated the ß-catenin pathway. Two cell lines were then constructed with BIRC6 overexpressed by lentiviruses. Pharmacological administration of a Wnt/ß-catenin inhibitor, XAV-939, or genetic knockdown of ß-catenin inhibited cell growth, tumor sphere formation, colony formation, migration, and invasion of BIRC6-overexpressed cells. In vivo administration of XAV-939 markedly suppressed the tumorigenesis of BIRC6-overexpressed RCC cells in nude mice. In conclusion, we propose that BIRC6 activates the ß-catenin signaling pathway via mediating the ubiquitination and degradation of Axin, promoting the growth, stemness, and drug resistance of RCC cells. This project aims to elucidate the role of BIRC6 as a potential therapeutic target and provide new insights into the clinical treatment of RCC.

4.
Genes (Basel) ; 13(7)2022 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-35885896

RESUMEN

Adrenoceptors are suggested to mediate the functions of norepinephrine (NE) and epinephrine (EPI) in the central nervous system (CNS) and peripheral tissues in vertebrates. Compared to mammals, the functionality and expression of adrenoceptors have not been well characterized in birds. Here, we reported the structure, expression, and functionality of chicken functional α2A-adrenoceptor, named ADRA2A. The cloned chicken ADRA2A cDNA is 1335 bp in length, encoding the receptor with 444 amino acids (a.a.), which shows high amino acid sequence identity (63.4%) with its corresponding ortholog in humans. Using cell-based luciferase reporter assays and Western blot, we demonstrated that the ADRA2A could be activated by both NE and EPI through multiple signaling pathways, including MAPK/ERK signaling cascade. In addition, the mRNA expression of ADRA2A is found to be expressed abundantly in adult chicken tissues including thyroid, lung, ovary and adipose from the reported RNA-Seq data sets. Moreover, the mRNA expression of ADRA2A is also found to be highly expressed in the granulosa cells of 6-8 mm and F5 chicken ovarian follicles, which thus supports that ADRA2A signaling may play a role in ovarian follicular growth and differentiation. Taken together, our data provide the first proof that the α2A-adrenoceptor is functional in birds involving avian ovarian follicular development.


Asunto(s)
Pollos , Folículo Ovárico , Animales , Pollos/genética , Pollos/metabolismo , Clonación Molecular , ADN Complementario/genética , Femenino , Humanos , Mamíferos/genética , Folículo Ovárico/metabolismo , ARN Mensajero/metabolismo
5.
Front Genet ; 12: 687236, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34539732

RESUMEN

Prostate cancer (PCa) is a serious disease that affects men's health. To date, no effective and long-lasting treatment option for this condition is available in clinical practice. ANT2 is highly expressed in a variety of hormone-related cancers, but its relationship and regulatory mechanism with PCa are unclear. In this study, we found that ANT2 expression was significantly upregulated in PCa tissues relative to control samples. Genetic knockdown of ANT2 effectively inhibited, while overexpression promoted, proliferation, migration, and invasion of PCa cells. In addition, miR-137 expression was reduced in prostate cancer tissues relative to control tissues. We identified a regulatory site for miR-137 in the 3'-UTR of ANT2 mRNA; luciferase reporter assays indicated that ANT2 is a direct target gene for miR-137. Transfecting cells with miR-137 mimics and/or an ANT2-encoding plasmid revealed that ANT2 promotes proliferation, migration, and invasion of PCa, whereas co-expression of miR-137 mimics inhibited these behaviors. These observations suggest that miR-137 mimics inhibit development of PCa by antagonizing expression of ANT2. Furthermore, tumorigenic assays in nude mice showed that miR-137 inhibitors abolished the inhibitory effect of ANT2 knockdown on PCa tumor growth. Collectively, our findings suggest that ANT2, a target gene of miR-137, is intimately involved in development of PCa, providing new evidence for the mechanism underlying pathogenesis of PCa as well as new options for targeted therapy.

6.
Biomed Res Int ; 2019: 7201562, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31355278

RESUMEN

Increasing evidence indicates that immunoglobulins are important for the regulation of various cancers including prostate cancer (PCa). However, the underlying mechanisms of IgG regulated PCa development remain to be further explored. Here, we demonstrated that IgG1 heavy chain (IGHG1) was increased in tissues from PCa patients. Inhibition of IGHG1 by antibody blocking or genetic knockdown suppressed cell growth and induced cell cycle arrest and ultimate apoptosis. Expression levels of c-Myc were positively correlated with the levels of IGHG1. Furthermore, MEK/ERK/c-Myc pathway lied downstream of IGHG1 in cultured prostate cancer cells. Inhibition of IGHG1 restrained the tumor growth in nude mice and inactivated MEK/ERK/c-Myc pathway both in vitro and in vivo. These findings suggest that IGHG1 play a crucial role during the development of prostate cancer and inhibition of IGHG1 may be a potential therapy in the treatment of PCa.


Asunto(s)
Proteínas Portadoras/genética , Proliferación Celular/genética , Neoplasias de la Próstata/genética , Animales , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-myc/genética
7.
Bing Du Xue Bao ; 32(2): 141-4, 2016 Mar.
Artículo en Zh | MEDLINE | ID: mdl-27396155

RESUMEN

Preparation of maternal strain A/PR/8/34 HA antiserum for influenza virus classical reassortment. A/PR/8/34 virus was digested by bromelain after inactivation and purification. 5%-20% sucrose continuous density gradient centrifugation method was used to purify HA protein. SIRD method was used to select the target protein. SDS-PAGE method was used to identified HA protein. High Immunogenic A/PR/8/34 HA protein was successfully prepared and HI titer reached 10240. High purity HA antiserum was identified by SIRD method. The key reagent in the classical reassortment of influenza virus was prepared, and the complete set of technical methods were explored, which laid the foundation for the independent research and development of seasonal influenza vaccine strains of China.


Asunto(s)
Glicoproteínas Hemaglutininas del Virus de la Influenza/análisis , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/virología , Virus Reordenados/inmunología , Animales , Anticuerpos Antivirales/inmunología , Electroforesis en Gel de Poliacrilamida , Femenino , Pruebas de Inhibición de Hemaglutinación , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Gripe Humana/inmunología , Conejos , Virus Reordenados/genética
8.
Chem Biol Drug Des ; 86(4): 487-95, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25581878

RESUMEN

The emergence and dissemination of antibiotic-resistant bacterial pathogens have spurred the urgent need to develop novel antimicrobial agents with different mode of action. In this respect, we turned several fusogenic peptides (FPs) derived from the hemagglutinin glycoproteins (HAs) of IAV into potent antibacterials by replacing the negatively or neutrally charged residues of FPs with positively charged lysines. Their antibacterial activities were evaluated by testing the MICs against a panel of bacterial strains including S. aureus, S. mutans, P. aeruginosa, and E. coli. The results showed that peptides HA-FP-1, HA-FP-2-1, and HA-FP-3-1 were effective against both Gram-positive and Gram-negative bacteria with MICs ranging from 1.9 to 16.0 µm, while the toxicities toward mammalian cells were low. In addition, the mode of action and the secondary structure of these peptides were also discussed. These data not only provide several potent peptides displaying promising potential in development as broad antimicrobial agents, but also present a useful strategy in designing new antimicrobial agents.


Asunto(s)
Antiinfecciosos , Bacterias/crecimiento & desarrollo , Virus de la Influenza A/química , Péptidos , Proteínas Virales de Fusión , Antiinfecciosos/química , Antiinfecciosos/farmacología , Péptidos/química , Péptidos/farmacología , Proteínas Virales de Fusión/química , Proteínas Virales de Fusión/farmacología
9.
World J Gastroenterol ; 9(4): 829-32, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12679942

RESUMEN

AIM: Bioartificial liver is a hope of supporting liver functions in acute liver failure patients. Using polysulfon fibers, a new bioartificial liver was developed. The aim of this study was to show whether this bioartificial liver could support liver functions or not. METHODS: Hepatocytes were procured from swine using Seglen's methods. The bioartificial liver was constructed by polysulfon bioreactor and more than 10(10) hepatocytes. It was applied 14 times in 12 patients, who were divided into 7 cases of simultaneous HBAL and 5 cases of non-simultaneous HBAL. Each BAL treatment lasted 6 hours. The general condition of the patients and the biochemical indexes were studied. RESULTS: After treatment with bioartificial liver, blood ammonia, prothrombin time and total bilirubin showed significant decrease. 2 days later, blood ammonia still showed improvment. within one month period, 1 case (1/7) in simultaneous group died while in non-simultaneous group 2 cases (2/5) died. The difference was significant. Mortality rate was 25 %. CONCLUSION: The constructed bioartificial liver can support liver functions in acute liver failure. The simultaneous HBAL is better than non-simultaneous HBAL.


Asunto(s)
Fallo Hepático Agudo/terapia , Pruebas de Función Hepática , Hígado Artificial , Adolescente , Adulto , Amoníaco/sangre , Animales , Bilirrubina/metabolismo , Modelos Animales de Enfermedad , Diseño de Equipo , Femenino , Hepatocitos/metabolismo , Humanos , Fallo Hepático Agudo/mortalidad , Masculino , Persona de Mediana Edad , Tiempo de Protrombina , Porcinos , Porcinos Enanos
10.
Ann Clin Lab Sci ; 34(1): 87-93, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15038673

RESUMEN

A bioartificial liver (BAL) based on viable porcine hepatocytes can serve as a bridge to liver transplantation in patients with acute liver failure (ALF). To support liver functions, an adequate mass of hepatocytes is needed, which depends upon the cell density in the BAL device. This study evaluated the optimal density of hepatocytes within BAL devices that were constructed by perfusing porcine hepatocyte suspensions mixed with cytodex-3 into polysulfon hollow-fibers. The BAL devices were prepared with 6 different cell densities. The mass of hepatocytes in each device was evaluated for (a) cell viability, (b) ability to degrade diazepam, (c) ability to synthesize urea, (d) incorporation of [3H]-leucine into protein, (e) glucose-6-phosphatase activity, (f) total RNA content, and (g) p53 gene expression. Hepatocyte viability was about 90% in each device. With increasing hepatocyte density, the diazepam concentration in the medium decreased from 9.26 +/- 0.96 mg/L at 1 x 10(5) cells/ml to a minimum of 5.25 +/- 1.02 mg/L at 5 x 10(6) cells/ml and thereafter remained at low levels. Urea production and [3H]-leucine incorporation into protein increased progressively until the cell density reached 5 x 10(6)/ml and thereafter remained at high levels. Glucose-6-phosphatase activity and total RNA content stayed at high levels until the cell density reached 5 x 10(6)/ml and then progressively decreased. p53 gene expression differed from the other parameters, since it increased only when the cell density reached 5 x 10(7)/ml. In conclusion, the density of 5 x 10(6) cells/ml is a critical inflection point for most of the functional parameters, although p53 gene expression is not elevated at this cell density. These findings suggest that 5 x 10(6) cells/ml is the optimal hepatocyte density in the hollow-fiber BAL device.


Asunto(s)
Hepatocitos/citología , Hígado Artificial , Animales , Supervivencia Celular , Diazepam/farmacología , Hepatocitos/fisiología , Hepatocitos/trasplante , Leucina/análisis , ARN/análisis , Porcinos , Porcinos Enanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Urea/metabolismo
11.
Ann Clin Lab Sci ; 33(3): 306-12, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12956446

RESUMEN

The goal of this study was to determine whether a new internal bioartificial liver utilizing porcine hepatocytes can perform detoxification and other metabolic functions. Such a system might aid in treating patients with moderate to severe liver failure and prolong patient survival until a matching organ is found for transplantation. Porcine hepatocytes were attached to a microcarrier and an internal artificial liver was constructed by perfusing the hepatocytes into a polysulfon hollow fiber. The 4 experimental groups were: (a) control group, (b) microcarrier group, (c) hollow fiber group, and (d) internal bioartificial liver group. Viability of hepatocytes, alanine aminotransferase (ALT) and lactate dehydrogenase (LD) activities in the medium, urea production, diazepam transformation, protein synthesis, and glucose-6-phosphatase activity of cells were monitored during a 7-day culture period. Viability of porcine hepatocytes in the internal bioartificial liver group was maintained at >80% during the culture period, and alanine aminotransferase and lactate dehydrogenase activities did not fluctuate significantly. These enzyme activities were significantly lower in the internal bioartificial liver group than in the control or microcarrier groups. Urea production, diazepam transformation, [3H]-leucine incorporation, and glucose-6-phosphatase activity were significantly higher in the internal bioartificial liver group than in the control and hollow fiber groups. These results show that the new internal bioartificial liver produces small amounts of ALT and LD and exhibits detoxification and protein synthetic functions.


Asunto(s)
Alanina Transaminasa/metabolismo , Hepatocitos/fisiología , L-Lactato Deshidrogenasa/metabolismo , Hígado Artificial , Animales , Supervivencia Celular , Células Cultivadas , Medio de Cultivo Libre de Suero/farmacología , Diazepam/farmacología , Hepatocitos/citología , Hepatocitos/trasplante , Técnicas In Vitro , Biosíntesis de Proteínas , Porcinos , Porcinos Enanos , Urea/metabolismo
12.
Hepatobiliary Pancreat Dis Int ; 3(2): 254-8, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15138121

RESUMEN

BACKGROUND: Appropriate animal models are important for studying acute liver failure. This study was to assess a new suitable rat model for acute liver failure. METHODS: After the right influent hepatic vessels were clamped for a period of time (45, 60 or 90 minutes respectively), the animal model was established by removal of the clamp for restoring blood flow of the right lobes while immediately removal of the median, left lateral and caudate lobes. Animal survival rate was observed in the following 14 days in each group. To study the pathophysiological changes of the model, some biochemical parameters in 5 consecutive days were evaluated in the 60-minute group. Internal bioartificial liver was transplanted in the peritoneal cavity to test the reversibility of the model. RESULTS: The survival rate of the models decreased, as the ischemia time of the right lobes prolonged to zero in the 90-minute group, to 50% in the 60-minute group and to 100% in the 45-minute group on the fifth day after operation. The levels of ammonia, alanine aminotransferase, alkaline phosphatase, total bilirubin and prothrombin were elevated dramatically 12 to 24 hours after operation in the 60-minute group. When internal bioartificial liver was transplanted, the survival rate increased significantly in addition to the levels of ammonia and total bilirubin. CONCLUSION: A period time of ischemic injury in the right lobe followed by 70% liver resection can produce a graded acute hepatic failure model in rats.


Asunto(s)
Fallo Hepático Agudo/fisiopatología , Fallo Hepático Agudo/terapia , Hígado Artificial , Animales , Hepatectomía/efectos adversos , Hígado/irrigación sanguínea , Fallo Hepático Agudo/etiología , Modelos Animales , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/complicaciones , Índice de Severidad de la Enfermedad , Análisis de Supervivencia
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