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1.
Gene ; 806: 145921, 2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-34454033

RESUMEN

Maoto, a traditional Japanese medicine (Kampo), is widely used to treat upper respiratory tract infections, including influenza virus infection. Although maoto is known to inhibit pro-inflammatory responses in a rodent model of acute inflammation, its underlying mechanism remains to be determined. In this study, we investigated the involvement of immune responses and noradrenergic function in the inhibitory action of maoto. In a mouse model of polyI:C-induced acute inflammation, maoto was administered orally in conjunction with intraperitoneal injection of PolyI:C (6 mg/kg), and blood was collected after 2 h for measurement of plasma cytokines by ELISA. Maoto significantly decreased PolyI:C-induced TNF-α levels and increased IL-10 production. Neither pretreatment with IL-10 neutralizing antibodies nor T-cell deficiency using nude mice modified the inhibitory effect of maoto, indicating that the anti-inflammatory effects of maoto are independent of IL-10 and T cells. Furthermore, the inhibitory effects of maoto on PolyI:C-induced TNF-α production were not observed in ex vivo splenocytes, suggesting that maoto does not act directly on inflammatory cells. Lastly, pretreatment with a ß-adrenergic receptor antagonist partially cancelled the anti-inflammatory effects of maoto. Collectively, these results suggest that maoto mediates its anti-inflammatory effects via ß-adrenergic receptors in vivo.


Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Antiinflamatorios/farmacología , Inflamación/prevención & control , Interleucina-10/genética , Extractos Vegetales/farmacología , Receptores Adrenérgicos beta/genética , Administración Oral , Animales , Modelos Animales de Enfermedad , Efedrina/farmacología , Regulación de la Expresión Génica , Inyecciones Intraperitoneales , Interleucina-10/agonistas , Interleucina-10/inmunología , Japón , Masculino , Medicina Kampo/métodos , Ratones Endogámicos BALB C , Ratones Desnudos , Poli I-C/administración & dosificación , Poli I-C/antagonistas & inhibidores , Receptores Adrenérgicos beta/inmunología , Transducción de Señal , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
2.
World J Gastroenterol ; 27(36): 6079-6092, 2021 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-34629821

RESUMEN

BACKGROUND: Gastric cancer is a prevalent malignant cancer with a high incidence and significantly affects the health of modern people globally. Cisplatin (DDP) is one of the most common and effective chemotherapies for patients with gastric cancer, but DDP resistance remains a severe clinical challenge. AIM: To explore the function of M2 polarized macrophages-derived exosomal microRNA (miR)-588 in the modulation of DDP resistance of gastric cancer cells. METHODS: M2 polarized macrophages were isolated and identified by specific markers using flow cytometry analysis. The exosomes from M2 macrophages were identified by transmission electron microscopy and related markers. The uptake of the PKH67-labelled M2 macrophages-derived exosomes was detected in SGC7901 cells. The function and mechanism of exosomal miR-588 from M2 macrophages in the modulation of DDP resistance of gastric cancer cells was analyzed by CCK-8 assay, apoptosis analysis, colony formation assay, Western blot analysis, qPCR analysis, and luciferase reporter assay in SGC7901 and SGC7901/DDP cells, and by tumorigenicity analysis in nude mice. RESULTS: M2 polarized macrophages were isolated from mouse bone marrow stimulated with interleukin (IL)-13 and IL-4. Co-cultivation of gastric cancer cells with M2 polarized macrophages promoted DDP resistance. M2 polarized macrophages-derived exosomes could transfer in gastric cancer cells to enhance DDP resistance. Exosomal miR-588 from M2 macrophages contributed to DDP resistance of gastric cancer cells. miR-588 promoted DDP-resistant gastric cancer cell growth in vivo. miR-588 was able to target cylindromatosis (CYLD) in gastric cancer cells. The depletion of CYLD reversed miR-588 inhibition-regulated cell proliferation and apoptosis of gastric cancer cells exposed to DDP. CONCLUSION: In conclusion, we uncovered that exosomal miR-588 from M2 macrophages contributes to DDP resistance of gastric cancer cells by partly targeting CYLD. miR-588 may be applied as a potential therapeutic target for the treatment of gastric cancer.


Asunto(s)
MicroARNs , Neoplasias Gástricas , Animales , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Humanos , Macrófagos , Ratones , Ratones Desnudos , MicroARNs/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética
3.
Anticancer Res ; 41(10): 4907-4916, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34593438

RESUMEN

BACKGROUND: Interleukin-6 receptor antibody (IL6R) inhibits colony formation and invasion by colorectal carcinoma (CRC) in vitro. We examined the effect of IL6R antibody on tumor growth of CRC xenografts in vivo. MATERIALS AND METHODS: SW480 cells inoculated subcutaneously into NU/NU mice were treated with anti-IL6R and tumor histology and growth-related signaling were subsequently estimated by hematoxylin and eosin and immunohistochemical staining. RESULTS: Tumor growth was inhibited by anti-IL6R treatment at dosages of both 0.1 and 1.0 mg/kg. Tumor cells had invaded into surrounding tissues in untreated mice, while there was no invasion of tumors in the IL6R antibody-treated mice. The expression of Ki-67, signal transducer and activator of transcription protein 3 (STAT3) and phosphor-extracellular signal-regulated kinase 1 and 2 (ERK1/2) were suppressed in anti-IL6R-treated tumors. CONCLUSION: IL6R antibody inhibited tumor growth and invasiveness in vivo by suppressing the expression of Ki-67, STAT3 and phosphor-ERK1/2. The results imply that the anti-IL6R may be a promising targeted drug for CRC.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Neoplasias Colorrectales/prevención & control , Neovascularización Patológica/prevención & control , Receptores de Interleucina-6/antagonistas & inhibidores , Animales , Apoptosis , Proliferación Celular , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Humanos , Masculino , Ratones , Ratones Desnudos , Neovascularización Patológica/inmunología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Receptores de Interleucina-6/inmunología , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1387-1393, 2021 Oct.
Artículo en Chino | MEDLINE | ID: mdl-34627415

RESUMEN

OBJECTIVE: To investigate the inhibitory effects of novel phosphodiesterase 4 inhibitor ZL-n-91 to the proliferation of leukemia cells L1210 and K562. METHODS: CCK-8 method was used to detect the effect of ZL-n-91 to the proliferation of L1210 and K562 cells, and the proliferation rate, IC50 were calculated. The effects of ZL-n-91 to the cycle of L1210 and K562 cells was detected by PE single staining, and the effects of ZL-n-91 to the apoptosis of L1210 and K562 cells was detected by PE/7AA-D double staining. Western blot was used to detect the effect of ZL-n-91 to the expression levels of apoptosis related proteins. Subcutaneous tumor transplantation model of acute lymphoblastic leukemia L1210 was established in the nude mice, and the inhibitory effect of oral administration of ZL-n-91 to the xenograft was observed. RESULTS: ZL-n-91 showed a significant inhibitory effect to the proliferation of leukemia cells L1210 and K562 in a dose-dependent manner (P<0.001). After treated by ZL-n-91, the leukemia cells L1210 and K562 in the S-phase in cell cycle decreased significantly compared with those in control group (P<0.01). The apoptosis of leukemia cells L1210 and K562 could be induced by ZL-n-91 (P<0.001), and the expression level of apoptosis related protein BAX significantly increased. In the animal experiment, the result showed that ZL-n-91 could significantly inhibit the growth of subcutaneously transplantation tumor (P<0.05). CONCLUSION: The novel phosphodiesterase 4 inhibitor ZL-n-91 can effectively inhibit the proliferation of leukemia cells L1210 and K562, which has the potential of anti-leukemia drug development.


Asunto(s)
Leucemia , Inhibidores de Fosfodiesterasa 4 , Animales , Proliferación Celular , Humanos , Células K562 , Ratones , Ratones Desnudos , Inhibidores de Fosfodiesterasa 4/farmacología
5.
Gen Physiol Biophys ; 40(5): 397-407, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34602453

RESUMEN

The present study was conducted to explore the anti-acute myeloid leukaemia (AML) effects of leonurine. HL-60 and U-937 cells were used to assess the antileukaemia effect of leonurine in vitro, and HL-60 and U-937 xenograft nude mice were used to evaluate its antitumour effect in vivo. Leonurine inhibited the proliferation of HL-60 and U-937 cells in a time- and dose-dependent manner. Moreover, leonurine therapy prevented the growth of tumours in both xenograft animal models. Leonurine could induce apoptosis in HL-60 and U-937 cells. The cytotoxic effects of leonurine on HL-60 and U-937 cells were associated with an increased ratio of Bax/Bcl-2, activation of caspase-3, caspase-8 and caspase-9, and increased expression of cytochrome c in the cytoplasm. Leonurine inhibited activation of the PI3K/Akt pathway in HL-60 and U-937 cells by lowering the phosphorylation levels of PI3K and Akt. Our results indicate that leonurine is a potential anti-AML agent, and this activity may be associated with its repression of the phosphorylation of PI3K and Akt.


Asunto(s)
Leucemia , Fosfatidilinositol 3-Quinasas , Animales , Ácido Gálico/análogos & derivados , Células HL-60 , Humanos , Ratones , Ratones Desnudos
6.
Anticancer Res ; 41(10): 4715-4718, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34593419

RESUMEN

BACKGROUND/AIM: Primary osteosarcoma of the breast is an exceedingly-rare malignant tumor that shares histological characteristics with osteosarcoma of the bone. Since effective therapies have not yet been established, standard therapy for osteosarcoma of the bone was examined in the present study for efficacy against primary osteosarcoma of the breast in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. MATERIALS AND METHODS: The PDOX mouse models were established by surgical implantation of the primary osteosarcoma of the breast specimen into the mammary gland of nude mice. Mice with tumors were randomized into four groups, each n=4: control group; cisplatinum (CDDP)-treatment group; doxorubicin (DOX)-treatment group; and CDDP/DOX-combination-treatment group. Mice were treated for twenty-one days, three weeks after implantation. Tumor size and body weight were measured during three weeks of treatment. RESULTS: Significant tumor growth inhibition was observed, compared to the control, in the CDDP-treatment group, the DOX-treatment group, and the combination-treatment-group. Only the combination treatment regressed the tumor. CONCLUSION: CDDP and DOX which are standard first-line therapies for osteosarcoma, may be clinically effective against primary osteosarcoma of the breast, and in particular, their combination.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/uso terapéutico , Doxorrubicina/uso terapéutico , Osteosarcoma/tratamiento farmacológico , Animales , Neoplasias de la Mama/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Desnudos , Osteosarcoma/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
7.
BMC Cancer ; 21(1): 1085, 2021 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-34620126

RESUMEN

BACKGROUND: Circular RNAs (circRNAs) are implicated in the development of oral squamous cell carcinoma (OSCC). The aim of current research is to elucidate the role and mechanism of circ_0011946 in the functional behaviors of OSCC cells. METHODS: Circ_0011946, microRNA (miR)-216a-5p, B cell lymphoma-2-like 2 protein (BCL2L2) abundances were exposed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or western blot. Cell proliferation, migration, invasion and apoptosis were detected by MTT, colony formation assay, transwell, wound-healing and flow cytometry assays, respectively. Target correlation was tested by dual-luciferase reporter and RNA pull-down assays. An in vivo xenograft experiment was employed to investigate the function of circ_0011946 on tumor growth in vivo. RESULTS: Circ_0011946 and BCL2L2 levels were increased, while miR-216a-5p level was decreased in OSCC tissues and cells. Circ_0011946 knockdown impeded proliferation, migration, and invasion, but promoted apoptosis in OSCC cells. Circ_0011946 functioned as a sponge for miR-216a-5p, and BCL2L2 was targeted by miR-216a-5p. Besides, miR-216a-5p or BCL2L2 knockdown partly attenuated the inhibitory influences of circ_0011946 silence or miR-216a-5p overexpression on OSCC cell progression. Furthermore, circ_0011946 post-transcriptionally regulated BCL2L2 through sponging miR-216a-5p. Moreover, circ_0011946 knockdown constrained OSCC tumor growth in vivo. CONCLUSION: Circ_0011946 silence repressed OSCC cell proliferation, migration, and invasion, but promoted apoptosis through the regulation of the miR-216a-5p/BCL2L2 axis.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Carcinoma de Células Escamosas/metabolismo , MicroARNs/metabolismo , Neoplasias de la Boca/metabolismo , ARN Circular/metabolismo , Animales , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Silenciador del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , Neoplasias de la Boca/patología , Invasividad Neoplásica/genética , Trasplante de Neoplasias , Interferencia de ARN
8.
Mater Sci Eng C Mater Biol Appl ; 128: 112311, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34474862

RESUMEN

Herein, we design a rGO-based magnetic nanocomposite by decorating rGO with citrate-coated magnetic nanoparticles (CMNP). The magnetic rGO (mrGO) was modified by phospholipid-polyethylene glycol to prepare PEGylated mrGO, for conjugating with gastrin-releasing peptide receptor (GRPR)-binding peptide (mrGOG). The anticancer drug doxorubicin (DOX) was bound to mrGO (mrGOG) by π-π stacking for drug delivery triggered by the low pH value in the endosome. The mrGOG showed enhanced photothermal effect under NIR irradiation, endorsing its role for dual targeted DOX delivery. With efficient DOX release in the endosomal environment and heat generation from light absorption in the NIR range, mrGOG/DOX could be used for combination chemo-photothermal therapy after intracellular uptake by cancer cells. We characterized the physico-chemical as well as biological properties of the synthesized nanocomposites. The mrGOG is stable in biological buffer solution, showing high biocompatibility and minimum hemolytic properties. Using U87 glioblastoma cells, we confirmed the magnetic drug targeting effect in vitro for selective cancer cell killing. The peptide ligand-mediated targeted delivery increases the efficiency of intracellular uptake of both nanocomposite and DOX up to ~3 times due to the over-expressed GRPR on U87 surface, leading to higher cytotoxicity. The increased cytotoxicity using mrGOG over mrGO was shown from a decreased IC50 value (0.70 to 0.48 µg/mL) and an increased cell apoptosis rate (19.8% to 47.1%). The IC50 and apoptosis rate changed further to 0.19 µg/mL and 76.8% in combination with NIR laser irradiation, with the photothermal effect supported from upregulation of heat shock protein HSP70 expression. Using U87 tumor xenograft model created in nude mice, we demonstrated that magnetic guidance after intravenous delivery of mrGOG/DOX could significantly reduce tumor size and prolong animal survival over free DOX and non-magnetic guided groups. Augmented with NIR laser treatment for 5 min, the anti-cancer efficacy significantly improves with elevated cell apoptosis and reduced cell proliferation. Together with safety profiles from hematological as well as major organ histological analysis of treated animals, the mrGOG nanocomposite is an effective nanomaterial for combination chemo-photothermal cancer therapy.


Asunto(s)
Hipertermia Inducida , Nanocompuestos , Neoplasias , Animales , Línea Celular Tumoral , Doxorrubicina/farmacología , Liberación de Fármacos , Grafito , Fenómenos Magnéticos , Ratones , Ratones Desnudos , Fototerapia , Receptores de Bombesina
9.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4167-4174, 2021 Aug.
Artículo en Chino | MEDLINE | ID: mdl-34467729

RESUMEN

This study aimed to explore the effects of galangin on energy metabolism and autophagy in gastric cancer MGC803 cells and the underlying mechanism. Cell counting kit-8(CCK-8) was used to detect the effects of galangin at different concentrations on via-bility of MGC803 cells after 48 h intervention. Western blot was carried out to measure the effects of galangin on expression of proteins related to autophagy, nuclear factor-κB(NF-κB) pathway and energy metabolism, followed by the determination of its effects on mRNA expression of energy metabolism-related proteins by Real-time quantitative PCR(qPCR). The impact of galangin on autophagy was explored using AutophagyGreen dye reagent, with autophagosomes and lysosomes observed under the transmission electron microscope(TEM). Nude mice transplanted with gastric cancer MGC803 cells via subcutaneous injection were randomly divided into the following three groups: control(0.5% sodium carboxymethyl cellulose, once a day), 5-fluorouracil(5-FU, 50 mg·kg~(-1), twice a week), and galangin(120 mg·kg~(-1), once a day) groups. The body weight and tumor volume were measured once every three days with a vernier caliper at the same time point by the same person. After 21-d treatment, the tumor tissue was isolated and weighed for the calculation of the tumor-suppressing rate. The comparison with the control group revealed that galangin inhibited the viability of MGC803 cells, up-regulated the protein expression of microtuble-associated protein 1 light chain 3 B(LC3 B) Ⅱ, inhibited the phosphorylation of NF-κB pathway-related proteins, and promoted the formation of autophagosomes in MGC803 cells. However, it did not obviously affect the expression of energy metabolism-related proteins. Furthermore, galangin at 120 mg·kg~(-1) significantly reduced the tumor weight and volume in mice, enhanced LC3 BⅡ protein expression, and inhibited the phosphorylation of NF-κB pathway-related proteins. All these have suggested that galangin inhibited the growth of gastric cancer MGC803 cells both in vivo and in vitro, possibly by inhibiting the NF-κB pathway and enhancing autophagy.


Asunto(s)
FN-kappa B , Neoplasias Gástricas , Animales , Autofagia , Flavonoides , Ratones , Ratones Desnudos , FN-kappa B/genética , Transducción de Señal , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética
10.
J Transl Med ; 19(1): 383, 2021 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-34496870

RESUMEN

BACKGROUND: Antiangiogenic therapy has increasingly become an important strategy for the treatment of colorectal cancer. Recent studies have shown that the tumour microenvironment (TME) promotes tumour angiogenesis. Bufalin is an active antitumour compound whose efficacy has been indicated by previous studies. However, there are very few studies on the antiangiogenic effects of bufalin. METHODS: Herein, human umbilical vein endothelial cell (HUVEC) tube formation, migration and adhesion tests were used to assess angiogenesis in vitro. Western blotting and quantitative PCR were used to detect relevant protein levels and mRNA expression levels. A subcutaneous xenograft tumour model and a hepatic metastasis model were established in mice to investigate the influence of bufalin on angiogenesis mediated by the TME in vivo. RESULTS: We found that angiogenesis mediated by cells in the TME was significantly inhibited in the presence of bufalin. The results demonstrated that the proangiogenic genes in HUVECs, such as VEGF, PDGFA, E-selectin and P-selectin, were downregulated by bufalin and that this downregulation was mediated by inhibition of the STAT3 pathway. Overexpression of STAT3 reversed the inhibitory effects of bufalin on angiogenesis. Furthermore, there was little reduction in angiogenesis when bufalin directly acted on the cells in the tumour microenvironment. CONCLUSION: Our findings demonstrate that bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signalling pathway in vascular endothelial cells, revealing that bufalin may be used as a new antiangiogenic adjuvant therapy medicine to treat colorectal cancer.


Asunto(s)
Neoplasias Hepáticas , Microambiente Tumoral , Inhibidores de la Angiogénesis/farmacología , Animales , Bufanólidos , Movimiento Celular , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Factor de Transcripción STAT3/metabolismo
11.
Anticancer Res ; 41(9): 4215-4228, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34475041

RESUMEN

BACKGROUND/AIM: Tyrosine kinase inhibitors (TKIs) are used for the treatment of both wild type and mutant non-small cell lung cancer (NSCLC); however, acquired resistance is a major clinical challenge. Herein, we aimed to investigate the effects of telmisartan (Tel), CFM 4.16 and sorafenib combination in rociletinib resistant NSCLC tumors. MATERIALS AND METHODS: 3D spheroid cultures and western blotting were used for evaluating cytotoxic effects and protein expression. An in vivo rociletinib resistant H1975 xenograft model of NSCLC was developed by subcutaneous injection of rociletinib resistant H1975 cells into nude mice. RESULTS: Tel, CFM 4.16 and sorafenib combination displayed superior anti-cancer effects in 3D spheroid cultures and a rociletinib resistant H1975 xenograft model of NSCLC by decreasing the protein expression of oncogenic and cancer stem cell markers (Nanog, Sox2 and Oct4). CONCLUSION: Tel facilitates effective penetration of CFM 4.16 and sorafenib in rociletinib resistant H1975 models of NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Esferoides Celulares/citología , Compuestos de Espiro/administración & dosificación , Telmisartán/administración & dosificación , Tiadiazoles/administración & dosificación , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéutico , Esferoides Celulares/efectos de los fármacos , Compuestos de Espiro/farmacología , Telmisartán/farmacología , Tiadiazoles/farmacología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Nat Immunol ; 22(10): 1219-1230, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34556881

RESUMEN

Blind mole rats (BMRs) are small rodents, characterized by an exceptionally long lifespan (>21 years) and resistance to both spontaneous and induced tumorigenesis. Here we report that cancer resistance in the BMR is mediated by retrotransposable elements (RTEs). Cells and tissues of BMRs express very low levels of DNA methyltransferase 1. Following cell hyperplasia, the BMR genome DNA loses methylation, resulting in the activation of RTEs. Upregulated RTEs form cytoplasmic RNA-DNA hybrids, which activate the cGAS-STING pathway to induce cell death. Although this mechanism is enhanced in the BMR, we show that it functions in mice and humans. We propose that RTEs were co-opted to serve as tumor suppressors that monitor cell proliferation and are activated in premalignant cells to trigger cell death via activation of the innate immune response. Activation of RTEs is a double-edged sword, serving as a tumor suppressor but contributing to aging in late life via the induction of sterile inflammation.


Asunto(s)
Elementos Transponibles de ADN/inmunología , Inmunidad Innata/inmunología , Ratas Topo/inmunología , Neoplasias/inmunología , Animales , Carcinogénesis/inmunología , Línea Celular Tumoral , Proliferación Celular/fisiología , Células Cultivadas , ADN/inmunología , Células HeLa , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Ratas , Transducción de Señal/inmunología
13.
Anal Chem ; 93(39): 13311-13318, 2021 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-34569224

RESUMEN

As a global health challenge, hepatocellular carcinoma (HCC) is strongly associated with chronic inflammation. Targeting inflammation, particularly inflammatory factors, is regarded as an important strategy for HCC diagnosis and treatment. Pyroglutamic aminopeptidase I (PGP-I), a common exopeptidase, was recently identified as a novel inflammatory cytokine in cells. However, whether PGP-I is involved in HCC development and can be regarded as a biomarker remains unclear. To address this issue, endogenous PGP-I was imaged in live cells and in vivo, and the related biochemical and pathological processes were analyzed accordingly with a newly developed fluorogenic PGP-I biosensor. Bioimaging with the specific biosensor demonstrated the aberrant expression of PGP-I in HCC cell lines and tumor-bearing nude mice. Moreover, overexpression of PGP-I in HCC cells promoted tumor progression, whereas knockdown of PGP-I significantly suppressed tumor cell growth and migration. The activity of PGP-I was further identified to be highly related to the phosphorylation of STAT3, which could be impeded by the natural product parthenolide. Collectively, these findings suggest that PGP-I, which can promote hepatocellular tumor progression through the classical inflammation-/tumor-related IL-6/STAT3 pathway, may serve as a potential HCC biomarker and therapeutic target.


Asunto(s)
Técnicas Biosensibles , Carcinoma Hepatocelular , Interleucina-6/metabolismo , Neoplasias Hepáticas , Piroglutamil-Peptidasa I , Factor de Transcripción STAT3/metabolismo , Animales , Ratones , Ratones Desnudos , Ácido Pirrolidona Carboxílico
14.
FASEB J ; 35(10): e21885, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34478585

RESUMEN

In a recently published phase III clinical trial, gemcitabine (GEM) plus cisplatin (DDP) induction chemotherapy significantly improved recurrence-free survival and overall survival and became the standard of care among patients with locoregionally advanced NPC. However, the molecular mechanisms of GEM synergized with DPP in NPC cells remain elucidated. These findings prompt us to explore the effect of the combination between GEM and DDP in NPC cell lines through proliferative phenotype, immunofluorescence, flow cytometry, and western blotting assays. In vitro studies reveal that GEM or DPP treated alone induces cell cycle arrest, promotes cell apoptosis, forces DNA damage response, and GEM synergism with DDP significantly increases the above effects in NPC cells. In vivo studies indicate that GEM or DPP treated alone significantly inhibits the tumor growth and prolongs the survival time of mice injected with SUNE1 cells compared to the control group. Moreover, the mice treated with GEM combined with DDP have smaller tumors and survive longer than those in GEM or DPP treated alone group. In addition, P-gp may be the key molecule that regulates the synergistic effect of gemcitabine and cisplatin. GEM synergizes with DPP to inhibit NPC cell proliferation and tumor growth by inducing cell cycle arrest, cell apoptosis, and DNA damage response, which reveals the mechanisms of combined GEM and DDP induction chemotherapy in improving locoregionally advanced NPC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proliferación Celular/efectos de los fármacos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Cisplatino/agonistas , Cisplatino/farmacología , Desoxicitidina/agonistas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Sinergismo Farmacológico , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
15.
FASEB J ; 35(10): e21906, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34490940

RESUMEN

Glioblastoma (GBM) is a refractory disease that has a highly infiltrative characteristic. Over the past decade, GBM perivascular niche (PVN) has been described as a route of dissemination. Here, we investigated that trailed membrane structures, namely retraction fibers (RFs), are formed by perivascular extracellular matrix (ECM) proteins. By using the anatomical GBM database, we validated that the ECM-related genes were highly expressed in the cells within the PVN where fibronectin (FN) induced RF formation. By disrupting candidates of FN-binding integrins, integrin α5ß1 was identified as the main regulator of RF formation. De novo RFs were produced at the trailing edge, and focal adhesions were actively localized in RFs, indicating that adhesive force makes RFs remain at the bottom surface. Furthermore, we observed that GBM cells more frequently migrated along the residual RFs formed by preceding cells in microfluidic channels in comparison to those in the channels without RFs, suggesting that the infiltrative characteristics GBM could be attributed to RFs formed by the preceding cells in concert with chemoattractant cues. Altogether, we demonstrated that shedding membrane structures of GBM cells are maintained by FN-integrin α5ß1 interaction and promoted their motility .


Asunto(s)
Neoplasias Encefálicas/metabolismo , Movimiento Celular , Fibronectinas/metabolismo , Glioblastoma/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Vitronectina/metabolismo , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Glioblastoma/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
16.
Nat Commun ; 12(1): 5196, 2021 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-34465793

RESUMEN

Bone metastasis is an incurable complication of breast cancer. In advanced stages, patients with estrogen-positive tumors experience a significantly higher incidence of bone metastasis (>87%) compared to estrogen-negative patients (<56%). To understand the mechanism of this bone-tropism of ER+ tumor, and to identify liquid biopsy biomarkers for patients with high risk of bone metastasis, the secreted extracellular vesicles and cytokines from bone-tropic breast cancer cells are examined in this study. Both exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP) are found to be significantly upregulated and secreted from bone-tropic ER+ breast cancer cells, increasing their levels in the circulation of patients. IBSP is found to attract osteoclast cells and create an osteoclast-enriched environment in the bone, assisting the delivery of exosomal miR-19a to osteoclast to induce osteoclastogenesis. Our findings reveal a mechanism by which ER+ breast cancer cells create a microenvironment favorable for colonization in the bone. These two secreted factors can also serve as effective biomarkers for ER+ breast cancer to predict their risks of bone metastasis. Furthermore, our screening of a natural compound library identifies chlorogenic acid as a potent inhibitor for IBSP-receptor binding to suppress bone metastasis of ER+ tumor, suggesting its preventive use for bone recurrence in ER+ patients.


Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Exosomas/metabolismo , Sialoproteína de Unión a Integrina/metabolismo , MicroARNs/metabolismo , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Exosomas/genética , Femenino , Humanos , Sialoproteína de Unión a Integrina/genética , Ratones , Ratones Noqueados , Ratones Desnudos , MicroARNs/genética , Metástasis de la Neoplasia , Osteoclastos/metabolismo , Receptores de Estrógenos/metabolismo
17.
Nature ; 597(7876): 420-425, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34471290

RESUMEN

Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with 18O2 or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with 18O2 to identify the polar oxy-metabolome, defined as polar metabolites labelled with 18O under different physiological O2 tensions. The most highly 18O-labelled feature was 4-hydroxymandelate (4-HMA). We demonstrate that 4-HMA is produced by hydroxyphenylpyruvate dioxygenase-like (HPDL), a protein of previously unknown function in human cells. We identify 4-HMA as an intermediate involved in the biosynthesis of the coenzyme Q10 (CoQ10) headgroup in human cells. The connection of HPDL to CoQ10 biosynthesis provides crucial insights into the mechanisms underlying recently described neurological diseases related to HPDL deficiencies1-4 and cancers with HPDL overexpression5.


Asunto(s)
4-Hidroxifenilpiruvato Dioxigenasa/metabolismo , Ácidos Mandélicos/metabolismo , Metaboloma , Ubiquinona/análogos & derivados , Animales , Línea Celular , Femenino , Humanos , Ácidos Mandélicos/análisis , Ratones , Ratones Desnudos , Tirosina/metabolismo , Ubiquinona/biosíntesis
18.
Molecules ; 26(17)2021 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-34500557

RESUMEN

In this study, we aimed to evaluate the anticancer effect of benzimidazole derivatives on triple-negative breast cancer (TNBC) and investigate its underlying mechanism of action. Several types of cancer and normal breast cells including MDA-MB-231, radiotherapy-resistant (RT-R) MDA-MB-231, and allograft mice were treated with six benzimidazole derivatives including mebendazole (MBZ). Cells were analyzed for viability, colony formation, scratch wound healing, Matrigel invasion, cell cycle, tubulin polymerization, and protein expression by using Western blotting. In mice, liver and kidney toxicity, changes in body weight and tumor volume, and incidence of lung metastasis were analyzed. Our study showed that MBZ significantly induced DNA damage, cell cycle arrest, and downregulation of cancer stem cell markers CD44 and OCT3/4, and cancer progression-related ESM-1 protein expression in TNBC and RT-R-TNBC cells. In conclusion, MBZ has the potential to be an effective anticancer agent that can overcome treatment resistance in TNBC.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Mebendazol/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Biomarcadores de Tumor/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Neoplasias Pulmonares/metabolismo , Células MCF-7 , Ratones , Ratones Desnudos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo
19.
J Biomed Nanotechnol ; 17(8): 1574-1583, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-34544535

RESUMEN

Cytokine-induced killer cell immunotherapy is an ideal candidate for adoptive cell transfer therapy. However, therapeutic approaches to enhance the anti-tumor activity of cytokine-induced killer cells remain to be explored. Here, we described the successful development of a novel antibody-chemokine fusion protein containing the anti-human Endoglin antibody in the single-chain variable fragment format and human interferon-gamma-induced protein 10 (hENG scFv/hIP-10). Its anti-Endoglin immunoreactivity and chemotactic activity against the cytokine-induced killer cells were characterized in vitro. To evaluate the anti-tumor effect in vivo, cytokine-induced killer cells were intravenously injected into human hepatocellular carcinoma-bearing nude mice, together with intratumoral administration of the fusion protein hENG scFv/hIP-10 as an enhancer. The tumor volume and survival time of the mice were monitored, whilst the tumor-infiltrating cytokine-induced killer cells, serum levels of interferon-gamma, tumor cell proliferation, apoptosis, and angiogenesis were measured. The results demonstrated that hENG scFv/hIP-10 and cytokine-induced killer cells synergistically inhibited tumor growth and prolonged survival of tumor-bearing mice. Moreover, the number of tumor-infiltrating cytokine-induced killer cells, serum levels of interferon-gamma, and tumor cell apoptosis were increased, accompanied with decreased tumor proliferation and angiogenesis. Thus, our study suggests that hENG scFv/hIP-10 could enhance the anti-tumor activity of cytokine-induced killer cells against human hepatocellular carcinoma.


Asunto(s)
Células Asesinas Inducidas por Citocinas , Neoplasias Hepáticas , Anticuerpos de Cadena Única , Animales , Línea Celular Tumoral , Quimiocinas , Endoglina , Humanos , Ratones , Ratones Desnudos , Anticuerpos de Cadena Única/genética
20.
Mater Sci Eng C Mater Biol Appl ; 129: 112393, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34579912

RESUMEN

Peripheral nerve injury can cause various degrees of damage to the morphological structure and physiological function of the peripheral nerve. At present, compared with "gold standard" autologous nerve transplantation, tissue engineering has certain potential for regeneration and growth; however, achieving oriented guidance is still a challenge. In this study, we used 3D bioprinting to construct a nerve scaffold of RSC96 cells wrapped in sodium alginate/gelatin methacrylate (GelMA)/bacterial nanocellulose (BNC) hydrogel. The 5% sodium alginate+5% GelMA+0.3% BNC group had the thinnest lines among all groups after printing, indicating that the inherent shape of the scaffold could be maintained after adding BNC. Physical and chemical property testing (Fourier transform infrared, rheometer, conductivity, and compression modulus) showed that the 5% alginate+5% GelMA+0.3% BNC group had better mechanical and rheological properties. Live/dead cell staining showed that no mass cell death was observed on days 1, 3, 5, and 7 after printing. In the 5% alginate+5% GelMA group, the cells grew and formed linear connections in the scaffold. This phenomenon was more obvious in the 5% alginate+5% GelMA+0.3% BNC group. In the 5% alginate+5% GelMA+0.3% BNC group, S-100ß immunofluorescence staining and cytoskeleton staining showed oriented growth. Polymerase chain reaction (PCR) array results showed that mRNA levels of related neurofactors ASCL1, POU3F3, NEUROG1, DLL1, NOTCH1 and ERBB2 in the 5%GelMA+0.3%BNC group were higher than those of other groups. Four weeks after implantation in nude mice, RSC96 cells grew and proliferated well, blood vessels grew, and S-100ß immunofluorescence was positive. These results indicate that a 3D-bioprinted sodium alginate/GelMA/BNC composite scaffold can improve cell-oriented growth, adhesion and the expression of related factors. This 3D-bioprinted composite scaffold has good biocompatibility and is expected to become a new type of scaffold material in the field of neural tissue engineering.


Asunto(s)
Bioimpresión , Gelatina , Alginatos , Animales , Bacterias , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Hidrogeles/farmacología , Metacrilatos , Ratones , Ratones Desnudos , Proteínas del Tejido Nervioso , Impresión Tridimensional , Ingeniería de Tejidos , Andamios del Tejido
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