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1.
PLoS One ; 18(6): e0286454, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37352173

RESUMEN

The black garlic is produced from the raw garlic by Milliard reaction at high temperature (~60-90°C) and humidity (~70-90%). In this process, the pungent odor and gastrointestinal irritation effects of the raw garlic are reduced. At the same time, unstable compounds such as allicin are converted into stable organosulfur compounds with antioxidant activity. Previous studies have confirmed that black garlic extract has anti-tumor effects and could inhibit the proliferation of various tumor cells, including breast cancer cells MCF-7. However, the mechanisms of the anti-tumor effects remain unclear. In this study, we found that the black garlic extract could inhibit the proliferation, invasion, and metastasis of estrogen receptor-positive breast cancer cells, promote their apoptosis, and inhibit their epithelial-mesenchymal transition. Mechanistically, the black garlic extract reduced the expression of the anti-apoptotic protein MCL-1, which was achieved by modulating the ROS-JNK signaling pathway. In addition, the black garlic extract also decreased the expression of BCL-2 and increased the expression of BAX and BIM. We also found that the black garlic extract, in combination with venetoclax, a BCL-2 inhibitor, synergistically kills the estrogen receptor-positive breast cancer cells. These results suggested that black garlic extract has great therapeutic value and prospects for estrogen receptor-positive breast cancer treatment.


Asunto(s)
Neoplasias de la Mama , Ajo , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Antioxidantes/farmacología , Sistema de Señalización de MAP Quinasas , Especies Reactivas de Oxígeno/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Receptores de Estrógenos , Proteínas Proto-Oncogénicas c-bcl-2 , Apoptosis , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Línea Celular Tumoral
2.
Phytomedicine ; 117: 154918, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37329755

RESUMEN

BACKGROUND: BCR-ABL1-based resistance to imatinib, mainly resulting from BCR-ABL1 mutations, is largely solved after second- and third-generation tyrosine kinase inhibitors (TKIs) are discovered. Nonetheless, imatinib resistance without BCR-ABL1 mutations, including intrinsic resistance induced by stem cells within chronic myeloid leukemia (CML), remains the major clinical challenge for many patients. PURPOSE: To study the key active ingredients and corresponding target proteins in Huang-Lian-Jie-Du-Tang (HLJDT) against BCR-ABL1-independent CML resistance to therapeutics, and then explore its mechanism of against CML drug resistance. METHODS: Cytotoxicity of HLJDT and its active ingredients in BCR-ABL1-independent imatinib resistance cells was analyzed through MTT assay. The cloning ability was measured through soft agar assay. Monitoring therapeutic effect on Xenografted mice CML model by in vivo imaging technology and mice survival time. Predicting the potential target protein binding sites by the technology of photocrosslinking sensor chip, molecular space simulation docking, and use Surface Plasmon Resonance (SPR) technology . Flow cytometry to detect the ratio of stem progenitor cells (CD34+). Constructing bone marrow transplantation mice CML leukemia model, detect the effects on leukemia stem cells LSK (Lin-\ Sca-1+ \C-kit+) self-renewal. RESULTS: Treatment with HLJDT, berberine and baicalein inhibited cell viability and colony formation of BCR-ABL1-independent imatinib-resistant cells in vitro while prolonging survival in mouse with CML xenografts and transplatation CML-like mouse models in vivo. JAK2 and MCL1were identified as targets of berberine and baicalein. JAK2 and MCL1 are involved in multi-leukemia stem cell-related pathways. Moreover, the ratio of CD34+ cells in resistant CML cells is higher than in treatment-sensitive CML cells. Treatment with BBR or baicalein partially suppressed CML leukemic stem cells (LSCs) self-renewal in vitro and in vivo. CONCLUSION: From the above, we concluded that HLJDT and its key active ingredients (BBR and baicalein) allowed to overcome imatinib resistance with BCR-ABL1 independent by eradication of LSCs by targeting the JAK2 and MCL1 protein levels. Our results lay the foundation for applying HLJDT in patients with TKI-resistant CML.


Asunto(s)
Berberina , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide Aguda , Humanos , Ratones , Animales , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Berberina/farmacología , Resistencia a Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Células Madre
3.
J Ethnopharmacol ; 301: 115763, 2023 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-36183949

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is one of the fatal complications of respiratory virus infections such as influenza virus and coronavirus, which has high clinical morbidity and mortality. Jinhua Qinggan granules (JHQG) has been approved by China Food and Drug Administration in the treatment of H1N1 influenza and mild or moderate novel coronavirus disease 2019 (COVID-19), which is an herbal formula developed based on Maxingshigan decoction and Yinqiao powder that have been used to respiratory diseases in China for thousands of years. However, the underlying mechanism of JHQG in treating infectious diseases remains unclear. AIM OF THE STUDY: This study investigated the effects of JHQG on neutrophil apoptosis and key signaling pathways in lipopolysaccharide (LPS) -induced ALI mice in order to explore its mechanism of anti-inflammation. MATERIALS AND METHODS: The effect of JHQG on survival rate was observed in septic mouse model by intraperitoneal injection of LPS (20 mg/kg). To better pharmacological evaluation, the mice received an intratracheal injection of 5 mg/kg LPS. Lung histopathological changes, wet-to-dry ratio of the lungs, and MPO activity in the lungs and total protein concentration, total cells number, TNF-α, IL-1ß, IL-6, and MIP-2 levels in BALF were assessed. Neutrophil apoptosis rate was detected by Ly6G-APC/Annexin V-FITC staining. Key proteins associated with apoptosis including caspase 3/7 activity, Bcl-xL and Mcl-1 were measured by flow cytometry and confocal microscope, respectively. TLR4 receptor and its downstream signaling were analyzed by Western blot assay and immunofluorescence, respectively. RESULTS: JHQG treatment at either 6 or 12 g/kg/day resulted in 20% increase of survival in 20 mg/kg LPS-induced mice. In the model of 5 mg/kg LPS-induced mice, JHQG obviously decreased the total protein concentration in BALF, wet-to-dry ratio of the lungs, and lung histological damage. It also attenuated the MPO activity and the proportion of Ly6G staining positive neutrophils in the lungs, as well as the MIP-2 levels in BALF were reduced. JHQG inhibited the expression of Mcl-1 and Bcl-xL and enhanced caspase-3/7 activity, indicating that JHQG partially acted in promoting neutrophil apoptosis via intrinsic mitochondrial apoptotic pathway. The levels of TNF-α, IL-1ß, and IL-6 were significantly declined in LPS-induced mice treated with JHQG. Furthermore, JHQG reduced the protein expression of TLR4, MyD88, p-p65 and the proportion of nuclei p65, suggesting that JHQG treatment inhibited TLR4/MyD88/NF-κB pathway. CONCLUSION: JHQG reduced pulmonary inflammation and protected mice from LPS-induced ALI by promoting neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway, suggesting that JHQG may be a promising drug for treatment of ALI.


Asunto(s)
Lesión Pulmonar Aguda , COVID-19 , Subtipo H1N1 del Virus de la Influenza A , Ratones , Animales , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Lipopolisacáridos/toxicidad , Factor 88 de Diferenciación Mieloide/metabolismo , Neutrófilos , Factor de Necrosis Tumoral alfa/metabolismo , Subtipo H1N1 del Virus de la Influenza A/metabolismo , Interleucina-6/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/uso terapéutico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Apoptosis
4.
Cancer Lett ; 554: 216028, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36462556

RESUMEN

Ewing sarcoma is a pediatric bone and soft tissue cancer with an urgent need for new therapies to improve disease outcome. To identify effective drugs, phenotypic drug screening has proven to be a powerful method, but achievable throughput in mouse xenografts, the preclinical Ewing sarcoma standard model, is limited. Here, we explored the use of xenografts in zebrafish for high-throughput drug screening to discover new combination therapies for Ewing sarcoma. We subjected xenografts in zebrafish larvae to high-content imaging and subsequent automated tumor size analysis to screen single agents and compound combinations. We identified three drug combinations effective against Ewing sarcoma cells: Irinotecan combined with either an MCL-1 or an BCL-XL inhibitor and in particular dual inhibition of the anti-apoptotic proteins MCL-1 and BCL-XL, which efficiently eradicated tumor cells in zebrafish xenografts. We confirmed enhanced efficacy of dual MCL-1/BCL-XL inhibition compared to single agents in a mouse PDX model. In conclusion, high-content screening of small compounds on Ewing sarcoma zebrafish xenografts identified dual MCL-1/BCL-XL targeting as a specific vulnerability and promising therapeutic strategy for Ewing sarcoma, which warrants further investigation towards clinical application.


Asunto(s)
Sarcoma de Ewing , Humanos , Animales , Ratones , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Pez Cebra/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Evaluación Preclínica de Medicamentos , Xenoinjertos , Apoptosis , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Línea Celular Tumoral
5.
Planta Med ; 89(3): 286-294, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35896509

RESUMEN

Herein, we describe the antiproliferative effects of two natural dibenzo [b,f]oxepines, pacharin and bauhiniastatin-1, isolated from Bauhinia acuruana on a breast cancer cell line and the mode of action underlying the cytotoxicity. Both compounds were cytotoxic in a panel of six tumor lines analyzed by the MTT assay, and IC50 values ranged from 7.8 to 45.1 µM, including human breast adenocarcinoma (MCF-7) cells. In contrast, none of the compounds were cytotoxic on normal human peripheral blood mononuclear cells (IC50 > 100 µM). Human breast adenocarcinoma (MCF-7) cells treated with pacharin or bauhiniastatin-1 20 µM for 24 h presented a reduction in cell volume and intensification of chromatin condensation, DNA fragmentation, and apoptotic cells. These findings became more evident after 48 h of exposure. Antiapoptotic B-cell lymphoma-2 family members, such as myeloid cell leukemia-1 and B-cell lymphoma-extra large, are important targets in cancer cells since their overexpression confers resistance to cancer treatments. A significant reduction of the myeloid cell leukemia-1 protein levels in human breast adenocarcinoma (MCF-7) cells after 24 h of treatment with pacharin or bauhiniastatin-1 at 20 µM was observed, while the B-cell lymphoma-extra large protein content was reduced in bauhiniastatin-1-treated cells at 40 µM only. The cytotoxic effects of pacharin and bauhiniastatin-1 are likely linked to myeloid cell leukemia-1 inhibition, which leads to the apoptosis of breast adenocarcinoma cells.


Asunto(s)
Adenocarcinoma , Antineoplásicos , Bauhinia , Neoplasias de la Mama , Leucemia , Humanos , Femenino , Neoplasias de la Mama/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Células MCF-7 , Línea Celular Tumoral , Adenocarcinoma/tratamiento farmacológico
6.
J Biomol Struct Dyn ; 41(13): 6104-6120, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-35899385

RESUMEN

Clinacanthus nutans is a medicinal plant recognised for its anticancer properties. We previously discovered that the C. nutans extract had the most potent inhibitory effect on MCF7 breast cancer cell and significantly induced apoptosis. However, there is a scarcity of studies demonstrating the molecular interactions of C. nutans-derived chemical compounds associated with apoptosis-related proteins. Therefore, the objective of this study was to determine the potential chemical compounds found in the C. nutans extract and examine their interactions with the targeted apoptotic proteins using molecular docking and molecular dynamic simulations. To address this objective, the compounds found in the SF2 extract of C. nutans were analysed using Gas Chromatography-Mass Spectrometry (GC-MS). The molecular interaction of the compounds with the targeted apoptotic proteins were determined using molecular docking and molecular dynamic simulations. GC-MS analysis revealed a total of 32 compounds in the SF2 extract. Molecular docking analysis showed that compound ß-amyrenol had the highest binding affinity for MDM2-P53 (-7.26 kcal/mol), BCL2 (-11.14 kcal/mol), MCL1-BAX (-6.42 kcal/mol), MCL1-BID (-6.91 kcal/mol), and caspase-9 (-12.54 kcal/mol), whereas campesterol had the highest binding affinity for caspase-8 (-10.11 kcal/mol) and caspase-3 (-10.14 kcal/mol). These selected compounds were subjected to molecular dynamic simulation at 310 K for 100 ns. The results showed that the selected protein-ligand conformation complexes were stable, compact, and did not alter much when compared to the protein references. The findings indicate that ß-amyrenol and campesterol are potentially significant compounds that might provide insight into the molecular interactions of the compounds with the apoptosis-related proteins.Communicated by Ramaswamy H. Sarma.


Asunto(s)
Simulación de Dinámica Molecular , Extractos Vegetales , Cromatografía de Gases y Espectrometría de Masas , Extractos Vegetales/farmacología , Extractos Vegetales/química , Simulación del Acoplamiento Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Reguladoras de la Apoptosis , Apoptosis
7.
Int J Nanomedicine ; 17: 6257-6273, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36531117

RESUMEN

Purpose: Effective therapy for rheumatoid arthritis (RA) keeps a challenge due to the complex pathogenesis of RA. It is not enough to completely inhibit the process of RA with any single therapy method. The purpose of the research is to compensate for the insufficiency of monotherapy using multiple treatment regimens with different mechanisms. Material and Methods: In this study, we developed a new method to synthesize mesoporous silica nanoparticles hybridized with photosensitizer PCPDTBT (HNs). Branched polyethyleneimine-folic acid (PEI-FA) could be coated on the surface of HNs through electrostatic interactions. It simultaneously blocked the hypoxia-activated prodrug tirapazamine loaded into the mesopores and binded with Mcl-1 siRNA (siMcl-1) that interfered with the expression of the anti-apoptotic protein Mcl-1. Released from the co-delivery nanoparticles (PFHNs/TM) Tirapazamine and siMcl-1 upon exposure to acidic conditions of endosomes/lysosomes in activated macrophages. Under NIR irradiation, photothermal therapy and photodynamic therapy derived from PCPDTBT, hypoxia-activated chemotherapy derived from tirapazamine, and RNAi derived from siMcl-1 were used for the combined treatment for RA by killing activated macrophages. PEI-FA-coated PFHNs/TM exhibited activated macrophage-targeting characteristics, thereby enhancing the in vitro and in vivo NIR-induced combined treatment of RA. Results: The prepared PFHNs/TM have high blood compatibility (far below 5% of hemolysis) and ideal in vitro phototherapy effect while controlling the TPZ release and binding siMcl-1. We prove that PEI-FA-coated PFHNs/TM not only protect the bound siRNA but also are selectively uptaked by activated macrophages through FA receptor-ligand-mediated endocytosis, and effectively silence the target anti-apoptotic protein by siMcl-1 transfection. In vivo, PFHNs/TM have also been revealed to be selectively enriched at the inflammatory site of RA, exhibiting NIR-induced anti-RA efficacy. Conclusion: Overall, these FA-functionalized, pH-responsive PFHNs/TM represent a promising platform for the co-delivery of chemical drugs and nucleic acids for the treatment of RA cooperating with NIR-induced phototherapy.


Asunto(s)
Artritis Reumatoide , Nanopartículas , Humanos , Tirapazamina/farmacología , Interferencia de ARN , Sistema de Administración de Fármacos con Nanopartículas , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Fototerapia/métodos , Artritis Reumatoide/tratamiento farmacológico , ARN Interferente Pequeño , Ácido Fólico , Hipoxia
8.
An Acad Bras Cienc ; 94(4): e20210190, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36228216

RESUMEN

Duchenne muscular dystrophy (DMD) is a severe disease with no cure caused by a genetic abnormality, promoting progressive muscle degeneration. Corticosteroids are used drugs in treatment associated with adverse effects. The extract of Miconia ferruginata (Melastomataceae) (MF) has demonstrated potent antioxidant and anti-inflammatory potential in vitro. This study used a DMD model (mdx) to determine the toxic dose of this plant and found a possible non-toxic dose with therapeutic effects. The mdx groups received an intraperitoneal injection of 0 (control group), 50, 100, 200, 300, and 2000 mg kg-1 of the aqueous leaf extract following a single-dose acute toxicity protocol and were observed for 14 days. The range of toxicity of the extract and LD50 were determined. Histopathological analysis, the quantification of fibrosis, and immunohistochemical analysis of the tissues were performed. The results demonstrated that 2000 mg kg-1 was highly toxic, inducing histopathological changes in the tissues evaluated, with 100% mortality in 48 hours. The other doses caused no behavioral changes or signs of toxicity. The MF extract led reduction in histopathological changes, fibrosis, and inflammation, a reduction in HSP70 and an increase in MCL-1 proteins. Doses of 50-200 mg kg-1 demonstrated regenerative tissue and anti-inflammatory potential.


Asunto(s)
Melastomataceae , Distrofia Muscular de Duchenne , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/uso terapéutico , Extractos Vegetales/metabolismo , Extractos Vegetales/uso terapéutico , Extractos Vegetales/toxicidad
9.
Cell Physiol Biochem ; 56: 484-499, 2022 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-36126285

RESUMEN

BACKGROUND/AIMS: In kidney, extracellular [Ca2+] can modulate intracellular [Ca2+] to control key cellular processes. Hence, extracellular [Ca2+] is normally maintained within narrow range. We tested effect of extracellular ATP on viability of human proximal (HK-2) cells at high calcium. Modulation of intracellular calcium was assessed by imaging cytosolic [Ca2+], and expression of calcium-binding proteins (CaBPs). We present an artificial intelligence enabled deep learning model for prediction of injury and protection against extracellular [Ca2+] in HK-2 cells. METHODS: HK-2 cells were cultured in calcium-free DMEM supplemented with CaCl2. Morphological changes were detected using light microscopy. Cell viability was determined using MTT Assay. Intracellular [Ca2+] was detected using fluorescence microscopy. For easy detection of HK-2 cells injury, we performed light microscopy image classification based on Convolutional Neural Network. Expression of CaBPs, p21, and Mcl-1 was measured using real-time PCR. RESULTS: We show decreased viability of HK-2 cells cultured in elevated calcium levels, which was prevented by adenosine triphosphate (ATP). Exposure of cells to elevated extracellular [Ca2+] correlated with increasing fluorescence of intracellular calcium indicator, which was attenuated in presence of ATP. Since features cannot be detected easily by human eyes, we propose a customized deep learning-based CNN model for classification of HK-2 cells injury by extracellular calcium with high accuracy of 98%. Our data demonstrated significant increase in mRNA levels of calmodulin, S100A8, S100A14 and CaBP28k, with elevated extracellular [Ca2+]. Expression of these genes was enhanced with ATP. CONCLUSION: The results suggest that ATP protects human proximal (HK-2) cells against elevated extracellular calcium levels. We present a CNN model as user friendly tool to study calcium dependent injury in (HK-2) cells. Finally, we show that ATP-mediated protection is correlated with enhanced expression of calcium-binding proteins.


Asunto(s)
Calcio , Aprendizaje Profundo , Adenosina Trifosfato/metabolismo , Inteligencia Artificial , Calcio/metabolismo , Cloruro de Calcio/metabolismo , Calmodulina/metabolismo , Humanos , Riñón/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , ARN Mensajero
10.
J Food Biochem ; 46(10): e14368, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35945689

RESUMEN

Liver cancer or hepatocellular carcinoma (HCC) has become a leading cause for cancer burden across the globe, and incidences have tripled since the last two decades. Poor diagnosis of primary liver cancer and limited treatment strategies aggravate the challenges. Researchers globally have shown a steep inclination toward the exploration of plant-based compounds for their nutraceutical and anticancer potential to fit into the role of novel chemotherapeutics. Coleus aromaticus is a well-known culinary herb that earlier has been reported for several medicinal attributes. The current investigation deals with exploring the anticancer potential of ethanolic leaf extract of C. aromaticus (CoL-EtOH) against hepatocellular carcinoma HepG2 cell line. The observations made it evident that CoL-EtOH extract impeded the viability of HepG2 at 400 µg/ml (p < .01). Additionally, the extract also succeeded in escalating ROS production (p < .01) which aided dissipation of mitochondrial membrane potential and disruption of nuclear morphology. CoL-EtOH further activated caspase-8, -9, and -3 which was reaffirmed by increase in apoptosis at 400 µg/ml (p < .01). Moreover, post treatment with CaLEt-OH extract significantly reduced the expression of JAK-1 & STAT-3 genes (p < .01) along with regulated expression of Mcl1, Bcl-2, cyclinD1, p21, and p27 within HepG2 cells. This evidence portrays the promising anticancer potential of CoL-EtOH projecting it as a novel chemotherapeutic agent against HCC. PRACTICAL APPLICATIONS: The herb Coleus aromaticus belonging to Lamiaceae family and Coleus genus is known by various names in different regions of the world and several language-specific vernacular names. The herb has been used in therapeutic and medicinal applications as well as in culinary preparations. Various attributes of the nutritional strength and functional characteristics of the leaves in terms of carotenoids, minerals, phenols, dietary fiber, and antioxidant activity have been reported by several researchers. Carvacrol and thymol are majorly found in the plant, while chlorogenic acid and rosmarinic acid etc. as the phenolic components. The herb has been used in therapeutic and medicinal implications as well as in culinary preparations.


Asunto(s)
Carcinoma Hepatocelular , Coleus , Neoplasias Hepáticas , Antioxidantes , Apoptosis , Carcinoma Hepatocelular/tratamiento farmacológico , Carotenoides , Caspasa 8 , Proliferación Celular , Ácido Clorogénico , Fibras de la Dieta , Etanol , Células Hep G2 , Humanos , Quinasas Janus/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Fenoles , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno , Factores de Transcripción STAT/metabolismo , Timol
11.
Am J Chin Med ; 50(6): 1529-1551, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35931662

RESUMEN

Our study aimed to explore the function and mechanism of Dexmedetomidine (Dex) in regulating myocardial ischemia/reperfusion (I/R)-induced mitochondrial apoptosis through lncRNA HCP5. We demonstrated Dex suppressed I/R-induced myocardial infarction and mitochondrial apoptosis in vivo. Dex induced the expression of lncRNA HCP5 and MCL1, inhibited miR-29a expression and activated the JAK2/STAT3 signaling. Dex attenuated hypoxia/reoxygenation (H/R)-induced mitochondrial apoptosis by upregulating lncRNA HCP5 in cardiomyocytes. Overexpression of lncRNA HCP5 sponged miR-29a to suppress H/R-induced mitochondrial apoptosis. Knockdown of miR-29a also alleviated cardiomyocyte apoptosis by upregulating MCL1. Overexpression of lncRNA HCP5 activated the JAK2/STAT3 signaling through sponging miR-29a and enhancing MCL1 expression in cardiomyocytes. Dex mitigated myocardial I/R-induced mitochondrial apoptosis through the lncRNA HCP5/miR-29a/MCL1 axis and activation of the JAK2/STAT3 signaling.


Asunto(s)
Dexmedetomidina , MicroARNs , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , ARN Largo no Codificante , Apoptosis , Dexmedetomidina/farmacología , Humanos , MicroARNs/genética , Mitocondrias/efectos de los fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Isquemia Miocárdica/genética , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , ARN Largo no Codificante/genética
12.
PLoS One ; 17(5): e0267961, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35536789

RESUMEN

Natural compounds are proper tools for inhibiting cancer cell proliferation. Hence, the search for these ligands of overexpressed receptors in breast cancer has been a competitive challenge recently and opens new avenues for drug discovery. In this research, we have investigated molecular interactions between natural products and overexpressed receptors in breast cancer using molecular docking and dynamic simulation approaches followed by extraction of the best ligand from Citrus limetta and developing for nanoscale encapsulation composed of soy lecithin using a sonicator machine. The encapsulation process was confirmed by DLS and TEM analyses. Anticancer activity was also examined using MTT method. Among the investigated natural compounds, hesperidin was found to bind to specific targets with stronger binding energy. The molecular dynamics results indicated that the hesperidin-MCL-1 complex is very stable at 310.15 K for 200 ns. The RP-HPLC analysis revealed that the purity of extracted hesperidin was 98.8% with a yield of 1.72%. The results of DLS and TEM showed a strong interaction between hesperidin and lecithin with an entrapped efficiency of 92.02 ± 1.08%. Finally, the cytotoxicity effect of hesperidin was increased against the MDA-MB-231 cell line with an IC50 value of 62.93 µg/mL after encapsulation, whereas no significant effect against the MCF10A cell line. We showed for the first time that hesperidin is a flexible and strong ligand for the MCL-1 receptor. Also, it has the in vitro ability to kill the MDA-MB-231 cell lines without having a significant effect on the MCF10A cell lines. Therefore, hesperidin could be used as a food ingredient to generate functional foods.


Asunto(s)
Productos Biológicos , Neoplasias de la Mama , Hesperidina , Productos Biológicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Hesperidina/química , Hesperidina/farmacología , Humanos , Lecitinas , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo
13.
Eur J Pharmacol ; 922: 174918, 2022 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-35341784

RESUMEN

Intermittent fasting as an adjuvant therapy in clinical practice is an emerging treatment modality to target tumor growth by reducing glucose utilization. Berberine, an alkaloid extracted from the traditional Chinese medicine Coptidis Rhizoma, has been shown to be a safe and effective antitumor agent in several cancers. Hence, the purpose of the present study was to investigate the effects of the combination of berberine and low glucose on gastric cancer. Our results showed that the combination of berberine and low glucose effectively inhibited cell viability, promoted apoptosis, and reduced the migration ability of MGC803 cells. In addition, the combination was shown to activate the PP2A/GSK3ß signaling axis, leading to the downregulation of the downstream pro-survival protein MCL-1, which leads to the death of gastric cancer cells. In addition, the inhibitor of GSK3ß partially reversed the effect of this combination on MGC803 cells. In vivo experiments demonstrated that berberine effectively impaired the growth of xenograft tumors, when administered during intermittent fasting (hypoglycemic conditions), and was well tolerated by nude mice without the occurrence of any adverse effects. Based on these results, we conclude that the berberine/low-glucose combination can inhibit the growth of gastric cancer through the PP2A/GSK3ß/MCL-1 signaling pathway. Accordingly, this combination of drugs and lifestyle may become a new type of safe and effective anti-cancer therapy.


Asunto(s)
Antineoplásicos , Berberina , Neoplasias Gástricas , Animales , Antineoplásicos/farmacología , Apoptosis , Berberina/farmacología , Berberina/uso terapéutico , Glucosa/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Ratones , Ratones Desnudos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/uso terapéutico , Transducción de Señal , Neoplasias Gástricas/patología
14.
Nutr Cancer ; 74(7): 2644-2656, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34907814

RESUMEN

Targeting Bcr-Abl is the key to the treatment of chronic myeloid leukemia. Despite great progress in the treatment of patients with chronic CML, advanced CML patients are still unable to obtain effective and safe drugs. Momordica cochinchinensis seed is the dried ripe seed of Momordica cochinchinensis, which is a kind of fruit and consumed for dietary as well as medicinal uses. This study aimed to investigate the anticancer activity of Momordica cochinchinensis seed extract (MCSE) in CML cells. CML cells (KBM5 and KBM5-T315I) were treated with MCSE and analyzed for growth, apoptosis, and signal transduction. Nude mouse xenograft model was used to evaluate the antitumor activity of MCSE In Vivo. MCSE significantly reduced the cell viability of CML cells, triggered G0/G1 phase arrest in KBM5 cells and S phase arrest in KBM5-T315I cells. Concurrently, MCSE caused the activation of caspase-3, -8, -9, PARP and the degradation of Mcl-1, ultimately triggering endogenous and exogenous cell apoptosis. Meanwhile, MCSE downregulated Bcr-Abl levels and its downstream signaling pathways. Additionally, MCSE inhibited the growth of CML cells in nude mouse xenografts. Taken together, this study demonstrated the anticancer mechanism of MCSE, namely blocking Bcr-Abl and downregulating Mcl-1, and finally induced apoptosis of CML cells.


Asunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Momordica , Animales , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Momordica/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Pak J Pharm Sci ; 34(3): 883-889, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-34602410

RESUMEN

The in silico molecular dynamics and structure-based site-specific drug design of indigenous plant biomolecules and selected proteins have remarkable potential for cancer therapy. A set of five proteins included for this research were epidermal growth factor protein (PDB ID; 1M17), crystal structure of mutated EGFR kinase (PDB ID; 2EB3), crystal structure of Bcl-xl (PDB ID; 2YXJ), apoptosis regulator protein MCL-1 BH3 (PDB ID; 3MK8) and apoptosis proteins (PDB ID; 5C3H). The present study on in silico investigation of fifteen indigenous medicinal plants were selected there one hundred thirty four ligands available literature were docked against five proteins involved in carcinogenesis. The highest scoring in silico plant, Fagonia indica was subjected to in vitro cytotoxic effects on HCT116, HepG-2 and HeLa human carcinoma cell lines. Molecular dynamics showed best ligand-protein inhibition interaction between Coumarin-2xyj and Kaempferol-2eb3 with promising binding affinities. Whereas, on HeLa human cervical cancer cell line IC50 was 28.3±0.102/ml. Fagonia indica could be potential source from natural products that have cytotoxic properties against cervical cancer cells by blocking mutant epidermal growth factor tyrosine or peroxisome proliferators activated receptor proteins.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Supervivencia Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Zygophyllaceae/química , Antineoplásicos Fitogénicos/química , Simulación por Computador , Cumarinas/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Técnicas In Vitro , Concentración 50 Inhibidora , Quempferoles/metabolismo , Simulación del Acoplamiento Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Fitoquímicos/química , Fitoquímicos/metabolismo , Fitoquímicos/farmacología , Extractos Vegetales/química , Proteína bcl-X/metabolismo
16.
Cell Death Dis ; 12(8): 736, 2021 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-34312366

RESUMEN

Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Sorafenib/uso terapéutico , Apoptosis/efectos de los fármacos , Proteína 11 Similar a Bcl2/metabolismo , Compuestos de Bifenilo/farmacología , Carcinoma Hepatocelular/patología , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Nitrofenoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sorafenib/farmacología , Sulfonamidas/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología
17.
Neurochem Int ; 147: 105051, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33979572

RESUMEN

Glioblastoma (GBM) is a highly aggressive brain tumor. During screening work, we found a new compound named phragmunis A (PGA), which is derived from the fruitbody of Trogia venenata, exhibits a potential cytotoxic effect on patient-derived recurrent GBM cells and temozolomide (TMZ)-resistant cell lines. The present study was designed to investigate the potential molecular mechanism of the anti-glioma effects of PGA in vitro and in vivo. Studies investigating the mechanism revealed that PGA diminished the binding efficiency of ETS family of transcription factor (ELK1) and Serum response factor (SRF), and suppressed ELK1-SRF complex-dependent transcription, which decreased the transcriptional levels of downstream genes Early growth response protein 1 (EGR1)-Polycomb ring finger (BMI1), thus inducing the imbalanced regulation between Myeloid cell leukaemia-1 (MCL1) and F-Box and WD repeat domain containing 7 (FBXW7). Finally, orthotopic xenograft models were established to confirm the anti-glioma effect of PGA on tumour growth. We showed, for the first time, that the cytotoxic effects of PGA occurred by inducing MCL1 inhibition and FBXW7 activation by blocking ELK1-SRF complex-dependent transcription. The blockage of ELK1-mediated transcription resulted in the suppression of EGR1-BMI1, which led to the upregulation of FBXW7 expression and downregulation of MCL1. These findings suggested that PGA could be a therapeutic drug candidate for the treatment of recurrent GBM by targeting the ELK1-SRF complex.


Asunto(s)
Proteína 7 que Contiene Repeticiones F-Box-WD/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Extractos Vegetales/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Regulación de la Expresión Génica/fisiología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/efectos de los fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Factor de Respuesta Sérica/efectos de los fármacos , Factor de Respuesta Sérica/metabolismo , Proteína Elk-1 con Dominio ets/efectos de los fármacos , Proteína Elk-1 con Dominio ets/metabolismo
18.
Neuroreport ; 32(3): 177-187, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33323840

RESUMEN

OBJECTIVE: The traditional Chinese medicine, Dendrobium nobile Lindl. polysaccharides (DNLP), reportedly has neuroprotective effects. However, its effects following ischemic stroke remain unclear. This study aimed to explore the role and mechanism of DNLP in experimental models of inflammation and apoptosis. METHODS: Inflammation and apoptosis were induced by in vivo ischemia/reperfusion and by in vitro oxygen glucose deprivation/reperfusion (OGD/R). In the in vivo model, immediately after the induction of cerebral ischemia, 50, 100, and 200 mg/kg DNLP were injected intraperitoneally. We subsequently detected indicators of neuronal damage. RESULTS: Treatment with Dendrobium nobile Lindl. polysaccharide significantly reduced cerebral ischemic injury. After in vivo and in vitro middle cerebral artery occlusion/reperfusion or OGD/R-induced hypoxia injury, miR-134 expression in neurons was significantly increased. Altering the expression of miR-134 induced changes in myeloid cell leukemia 1 (MCL-1), one of its target proteins. In addition, DNLP significantly downregulated the in vivo and in vitro expression of miR-134 after ischemic injury, and influenced inflammation and apoptotic proteins by altering the level of MCL-1 protein. DNLP also had a protective effect on neurons damaged by OGD/R, which could improve cell survival rates and inhibit lactate dehydrogenase release as well as apoptosis. CONCLUSIONS: DNLP may protect the brain and neurons from hypoxic damage in mice with ischemic stroke by activating MCL-1 and downregulating miR-134, providing a new therapeutic target for ischemic stroke.


Asunto(s)
Isquemia Encefálica/metabolismo , Encéfalo/efectos de los fármacos , Dendrobium , Medicamentos Herbarios Chinos/farmacología , MicroARNs/efectos de los fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/efectos de los fármacos , Polisacáridos/farmacología , Daño por Reperfusión/metabolismo , Animales , Apoptosis/efectos de los fármacos , Encéfalo/metabolismo , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Técnicas In Vitro , Infarto de la Arteria Cerebral Media/metabolismo , Inflamación/metabolismo , Ratones , MicroARNs/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo
19.
J Med Chem ; 63(24): 15564-15590, 2020 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-33306391

RESUMEN

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.


Asunto(s)
Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Animales , Apoptosis/efectos de los fármacos , Sitios de Unión , Línea Celular Tumoral , Quinasa 9 Dependiente de la Ciclina/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Semivida , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Humanos , Ratones , Simulación del Acoplamiento Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Ratas , Solubilidad , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
20.
J Mater Chem B ; 8(48): 11096-11106, 2020 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-33210699

RESUMEN

Mcl-1 amplification has been observed in breast cancer and demonstrated as a key determinant of breast cancer cell survival. However, the clinical use of available effective Mcl-1-specific inhibitors for breast cancer treatment remains a challenge. An RNA-guided CRISPR/Cas13a system targeting RNAs can be used to specifically knock down mRNA expression in mammalian cells. The goal of this work is to develop a self-degradable nanoplatform based on polylysine (PLL)-functionalized black phosphorus (PBP) for the delivery of Cas13a/crRNA complexes to specifically inhibit Mcl-1 at transcriptional level for breast cancer therapy. The constructed Cas13a/crRNA complex is delivered into the cytoplasm by PBP via endocytosis, followed by endosomal escape based on the biodegradation of PBP, and this efficiently knocks down the specific gene at transcriptional level up to an efficiency of 58.64%. Through designing CRISPR RNA crMcl-1, Mcl-1 can be specifically knocked down at transcriptional level in breast cancer cells, resulting in the down-regulation of the expression of Mcl-1 protein and inhibition of the cell activity. Notably, PBP/Cas13a/crMcl-1 shows an excellent tumor suppression efficacy up to 65.16% after intratumoral injection. Therefore, biodegradable PBP is an ideal nanoplatform for the delivery of CRISPR/Cas13a, which could provide a potential strategy for gene therapy.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas Asociadas a CRISPR/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Nanoestructuras , Fósforo/metabolismo , ARN Circular/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteínas Asociadas a CRISPR/administración & dosificación , Proteínas Asociadas a CRISPR/genética , Femenino , Humanos , Células MCF-7 , Nanoestructuras/administración & dosificación , Fósforo/administración & dosificación , ARN Circular/administración & dosificación , ARN Circular/genética
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