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1.
Braz. j. biol ; 84: e251336, 2024. graf
Artigo em Inglês | MEDLINE, LILACS, VETINDEX | ID: biblio-1355879

RESUMO

Abstract Bulbine natalensis and Chorophytum comosum are potential medicinal source for the treatment of cancers. Chronic myeloid leukaemia is a hematopoietic stem cells disorder treated by tyrosine kinase inhibitors but often cause recurrence of the leukaemia after cessation of therapy, hence require alternative treatment. This study determines the anti-cancer effect of leaf, root and bulb methanolic and aqueous extracts of B. natalensis and C. comosum in chronic human myelogenous leukaemia (K562) cell line by MTT, Hoechst bis-benzimide nuclear and annexin V stain assays. The root methanolic extract of B. natalensis and C. comosum showed a high cytotoxicity of 8.6% and 16.7% respectively on the K562 cell line at 1,000 μg/ml concentration. Morphological loss of cell membrane integrity causing degradation of the cell and fragmentation were observed in the root methanolic extract of both plants. A high apoptosis (p < 0.0001) was induced in the K562 cells by both leaf and root extracts of the C. comosum compared to the B. natalensis. This study shows both plants possess apoptotic effect against in vitro myelogenous leukaemia which contributes to the overall anti-cancer properties of B. natalensis and C. comosum to justify future therapeutic applications against chronic myelogenous leukaemia blood cancer.


Resumo Bulbine natalensis Baker e Chorophytum comosum (Thunb.) Jacques são potenciais fontes medicinais para o tratamento de cânceres. A Leucemia Mieloide Crônica (LMC) é um distúrbio das células-tronco hematopoiéticas que é tratado com inibidores da tirosina quinase, mas frequentemente, causa recorrência da leucemia após a interrupção da terapia, portanto, requer um tratamento alternativo. Este estudo determinou o efeito anticancerígeno de extratos metanólicos e aquosos de folha, raiz e bulbo de B. natalensis e C. comosum na linhagem celular de leucemia mieloide humana crônica (K562) por ensaios de MTT, Hoechst bis-benzimida nuclear e anexina V. O extrato metanólico da raiz de B. natalensis e C. comosum apresentou alta citotoxidade de 8,6% e 16,7% respectivamente, na linhagem celular K562 com a concentração de 1,000 μg / ml. Perda morfológica da integridade da membrana celular causando degradação dos núcleos, citoplasma e encolhimento celular foi observada no extrato metanólico da raiz de ambas as plantas. Uma alta apoptose (p <0,0001) foi induzida nas células K562 por extratos de folhas e raízes de C. comosum em comparação com B. natalensis. Este estudo mostrou que ambas as plantas possuem efeito apoptótico contra leucemia mieloide in vitro que contribui para as propriedades anticâncer gerais de B. natalensis e C. comosum para justificar futuras aplicações terapêuticas contra câncer de sangue de LMC.


Assuntos
Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Xanthorrhoeaceae , Apoptose , Células K562
2.
Mol Cancer ; 21(1): 32, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35090469

RESUMO

N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in recent years. M6A plays multifunctional roles in normal and abnormal biological processes, and its role may vary greatly depending on the position of the m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis and ferroptosis, most of which involve the breakdown of the plasma membrane. Based on the implications of m6A methylation on PCD, the regulators and functional roles of m6A methylation were comprehensively studied and reported. In this review, we focus on the high-complexity links between m6A and different types of PCD pathways, which are then closely associated with the initiation, progression and resistance of cancer. Herein, clarifying the relationship between m6A and PCD is of great significance to provide novel strategies for cancer treatment, and has a great potential prospect of clinical application.


Assuntos
Adenosina , Neoplasias , Adenosina/análogos & derivados , Adenosina/metabolismo , Apoptose/genética , Humanos , Metilação , Neoplasias/genética , Neoplasias/metabolismo
3.
Inflamm Bowel Dis ; 28(4): 639-648, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-34871402

RESUMO

Ulcerative colitis (UC), an etiologically complicated and relapsing gastrointestinal disease, is characterized by the damage of mucosal epithelium and destruction of the intestinal homeostasis, which has caused a huge social and economic burden on the health system all over the world. Its pathogenesis is multifactorial, including environmental factors, genetic susceptibility, epithelial barrier defect, symbiotic flora imbalance, and dysregulated immune response. Thus far, although immune cells have become the focus of most research, it is increasingly clear that intestinal epithelial cells play an important role in the pathogenesis and progression of UC. Notably, apoptosis is a vital catabolic process in cells, which is crucial to maintain the stability of intestinal environment and regulate intestinal ecology. In this review, the mechanism of apoptosis induced by reactive oxygen species and endoplasmic reticulum stress, as well as excessive apoptosis in intestinal epithelial dysfunction and gut microbiology imbalance are systematically and comprehensively summarized. Further understanding the role of apoptosis in the pathogenesis of UC may provide a novel strategy for its therapy in clinical practices and the development of new drugs.


Recently, the prevalence of ulcerative colitis (UC) has increased, but the pathogenesis of UC remains poorly understood. A better understanding of the role of apoptosis in the pathogenesis of UC may provide a promising prospect for UC treatment.


Assuntos
Colite Ulcerativa , Apoptose , Colite Ulcerativa/tratamento farmacológico , Estresse do Retículo Endoplasmático , Homeostase , Humanos , Mucosa Intestinal/patologia , Espécies Reativas de Oxigênio/metabolismo
4.
Mol Cell Endocrinol ; 544: 111541, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34973370

RESUMO

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1ß, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation.


Assuntos
Glucocorticoides , MicroRNAs , Apoptose , Citocinas/metabolismo , Cabeça do Fêmur/metabolismo , Cabeça do Fêmur/patologia , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais
5.
Drug Dev Res ; 83(1): 208-216, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34347904

RESUMO

Breast cancer (BC), which is widely considered as the most common cancer in women around the world, evokes ~1.7 million new BC cases and 522,000 BC-related deaths each year. Triple negative breast cancer (TNBC) is clinically confirmed as one of the most aggressive subtypes of BC. ORY-1001, a clinically used lysine specific demethylase 1 (LSD1/KDM1A) inhibitor, was investigated herein to confirm its role in the progression of TNBC and reveal the potential mechanism. After treatment with ORY-1001 in MDA-MB-231 and BT549 cells, the cell proliferation and apoptosis were respectively measured by CCK-8 and TUNEL assays. The expression of proliferation- and apoptosis-associated proteins was tested by means of western blot analysis. Then, R1881, an androgen receptor (AR) agonist, was used to evaluate whether the effects of ORY-1001 on proliferation and apoptosis of TNBC cells was mediated by regulating AR. Results indicated that ORY-1001 treatment restrained the proliferation while enhanced the apoptosis of BC cells, accompanied by the change of proliferation- and apoptosis-related proteins expression. Furthermore, ORY-1001 reduced the level of AR in BC cells. After the activation of AR by R1881, the decreased proliferation and enhanced apoptosis of BC cells triggered by ORY-1001 intervention were partially abolished. In conclusion, this paper has presented the first evidence to suggest that ORY-1001 inhibits proliferation and promotes apoptosis of TNBC cells by suppressing AR expression, which may constitute the theoretical basis for the clinical use of ORY-1001 in the treatment of this disease.


Assuntos
Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Histona Desmetilases/farmacologia , Humanos , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
6.
Acta Histochem ; 124(2): 151856, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35077998

RESUMO

Neuroblastoma is a metastatic brain tumor particularly common in children. The cure rate is below 50% for patients of high-risk condition. Novel therapeutic agents and approaches are needed to improve the cure rate. Tumor necrosis factor-related and apoptosis-inducing ligand (TRAIL) is a promising proapoptotic factor that rapidly induces apoptosis preferentially in transformed and cancerous cells. Unfortunately, the common TRAIL resistance in cancers has hampered the clinical application of the ligand. Previously we prepared a novel TRAIL-armed ER derived nanosomal agent (ERN-T) that overcomes TRAIL resistance in some cancer lines when combined with a synthetic antagonist of inhibitors of apoptosis proteins (IAPs), AZD5582. However, how AZD5582 sensitizes cancer cells to ERN-T remains not well understood. In this study we continued to test the therapeutic efficacy of the combinatory therapy of ERN-T and AZD5582 on neuroblastoma, aiming to reveal the molecular mechanism underlying the synergism between AZD5582 and ERN-T. The obtained data revealed that ERN-Ts overcame TRAIL resistance and showed significant cytotoxicity on the resistant neuroblastoma line SH-SH5Y when combined with AZD5582 whilst sparing normal cells. The combination of low doses of ERN-Ts and AZD5582 induced intensive apoptosis in SH-SY5Y but not in normal skin fibroblasts (NSFs). Importantly we discovered that TRAIL sensitization in SH-SY5Y was associated with the concomitant downregulation of antiapoptotic factors cFLIP, MCL-1 and IAPs and upregulation of proapoptotic protein BAX and the death receptor 5 (DR5) by the cotreatment of ERN-T and AZD5582. In vivo study demonstrated that the combination of ERN-T and AZD5582 constituted a highly effective and safe therapy for subcutaneous SH-SY5Y xenograft neuroblastoma in nude mice. In conclusion, we identified that the concomitant regulation of both antiapoptotic and proapoptotic factors and DR5 is an essential molecular mechanism for overcoming TRAIL resistance in SH-SY5Y and the combination of ERN-T and AZD5582 potentially constitutes a novel therapeutic strategy, which is highly effective and safe for neuroblastoma.


Assuntos
Neuroblastoma , Ligante Indutor de Apoptose Relacionado a TNF , Alcinos , Animais , Apoptose , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Oligopeptídeos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico
7.
Mol Cancer ; 21(1): 37, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35130920

RESUMO

PURPOSE: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. RESULTS: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). CONCLUSIONS: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.


Assuntos
Antineoplásicos , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma de Células de Transição/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
8.
Clin. transl. oncol. (Print) ; 24(7): 1219-1230, julio 2022.
Artigo em Inglês | IBECS | ID: ibc-203823

RESUMO

Cancer is one of the leading causes of death, with a heavy socio-economical burden for countries. Despite the great advances that have been made in the treatment of cancer, chemotherapy is still the most common method of treatment. However, many side effects, including hepatotoxicity, renal toxicity, and cardiotoxicity, limit the efficacy of conventional chemotherapy. Over recent years, natural products have attracted attention as therapeutic agents against various diseases, such as cancer. Resveratrol (RES), a natural polyphenol occurring in grapes, nuts, wine, and berries, exhibited potential for preventing and treating various cancer types. RES also ameliorates chemotherapy-induced detrimental effects. Furthermore, RES could modulate apoptosis and autophagy as the main forms of cancer cell deaths by targeting various signaling pathways and up/downregulation of apoptotic and autophagic genes. This review will summarize the anti-cancer effects of RES and focus on the fundamental mechanisms and targets for modulating apoptosis and autophagy by RES.


Assuntos
Apoptose , Autofagia , Neoplasias/tratamento farmacológico , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Transdução de Sinais , Estilbenos/farmacologia
9.
Clin. transl. oncol. (Print) ; 24(7): 1238-1249, julio 2022.
Artigo em Inglês | IBECS | ID: ibc-203825

RESUMO

Histone lysine methylation plays a key role in gene activation and repression. The trimethylation of histone H3 on lysine-27 (H3K27me3) is a critical epigenetic event that is controlled by Jumonji domain-containing protein-3 (JMJD3). JMJD3 is a histone demethylase that specifically removes methyl groups. Previous studies have suggested that JMJD3 has a dual role in cancer cells. JMJD3 stimulates the expression of proliferative-related genes and increases tumor cell growth, propagation, and migration in various cancers, including neural, prostate, ovary, skin, esophagus, leukemia, hepatic, head and neck, renal, lymphoma, and lung. In contrast, JMJD3 can suppress the propagation of tumor cells, and enhance their apoptosis in colorectal, breast, and pancreatic cancers. In this review, we summarized the recent advances of JMJD3 function in cancer cells.


Assuntos
Humanos , Apoptose , Histonas/genética , Histonas/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Lisina/metabolismo , Neoplasias/genética
10.
Clin. transl. oncol. (Print) ; 24(7): 1274-1289, julio 2022.
Artigo em Inglês | IBECS | ID: ibc-203828

RESUMO

Ephrin receptor A7 (EphA7) is a member of the Eph receptor family. It is widely involved in signal transduction between cells, regulates cell proliferation and differentiation, and participates in developing neural tubes and brain. In addition, EphA7 also has a dual role of tumor promoter and tumor suppressor. It can participate in cell proliferation, migration and apoptosis through various mechanisms, and affect tumor differentiation, staging and prognosis. EphA7 may be a potential diagnostic marker and tumor treatment target. This article reviews the effects of EphA7 on a variety of tumor biological processes and pathological characteristics, as well as specific effects and regulatory mechanisms.


Assuntos
Humanos , Apoptose , Proliferação de Células , Receptor EphA7/genética , Receptor EphA7/metabolismo , Neoplasias/genética , Transdução de Sinais
11.
Clin. transl. oncol. (Print) ; 24(7): 1311-1321, julio 2022. graf
Artigo em Inglês | IBECS | ID: ibc-203830

RESUMO

PurposeOral squamous cell carcinoma (OSCC) is the most frequent type of oral cancer and is associated with high mortality. Membrane-associated ring-CH type finger 1 (MARCH1) is an E3 ubiquitin ligase with roles in immune regulation and cancer development. Whether MARCH1 has a specific role in OSCC, and if so through what mechanism, has not been explored.MethodsImmunohistochemistry was performed to examine MARCH1 expression in OSCC clinical samples and adjacent paracancerous tissues. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot were conducted to determine mRNA expression and protein levels, respectively. Knockdown and overexpression experiments were carried out to evaluate the effects of MARCH1 on proliferation and apoptosis. To test protein–protein interaction, co-immunoprecipitation assay was performed. Finally, tumor cell grafting was utilized to test the function of MARCH in vivo.ResultsHigh MARCH1 expression in OSCC clinical samples correlated with poor patient prognosis. Functionally, MARCH1 knockdown in OSCC cells suppressed proliferation and promoted apoptosis, while MARCH1 overexpression displayed the opposite effects. We identified PH Domain And Leucine Rich Repeat Protein Phosphatase (PHLPP) 2 as an important target of MARCH1. Mechanistically, MARCH1 interacted with PHLPP2 and promoted PHLPP2 ubiquitination. Lastly, MARCH1 knockdown suppressed OSCC tumorigenicity in vivo and increased PHLPP2 protein level.


Assuntos
Humanos , Apoptose , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Neoplasias de Cabeça e Pescoço , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/patologia
12.
BMC Ophthalmol ; 22(1): 241, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641967

RESUMO

BACKGROUND: To investigate the effect of N-retinyl-N-retinylidene ethanolamine (A2E) on lysosome membrane permeability (LMP) during blue light-induced human retinal pigment epithelium cells (RPEs) apoptosis. METHODS: By building an A2E and blue light irradiation inducing RPEs damage model, the CCK-8 assay was used to detect RPEs viability loaded with different concentrations of A2E after different culturing time to determine the optimum A2E loading concentration. And the RPEs fluorescence intensity changes were observed by fluorescence microscopy loaded with different concentration of A2E. The RPEs were divided into four groups randomly: control group, A2E-loaded group, blue light irradiation group, and A2E-loaded + blue light irradiation group. Annexin V-FITC/PI and TUNEL/DAPI methods were used to detect RPEs apoptotic rate. Laser scanning confocal microscopy (LSCM) was used to observe RPEs LMP changes stained by acridine orange (AO) method. RESULTS: The CCK-8 result showed a downward trend in cells viability of RPEs loaded with increasing concentration of A2E and extending culturing time. The optimum A2E loading concentration was determined at 25 µmol/L. With increasing A2E loading concentrations, the intensity of fluorescence in RPEs decreased gradually. The RPEs apoptotic rate in blue light irradiation + A2E-loaded group was significantly higher than those in other three groups detected by Annexin V-FITC/PI method, which was similar to TUNEL/DAPI's result. After AO staining, cytoplasmic and nucleolar RNAs emits green fluorescence; lysosomes emit red fluorescence. Through the interference of A2E and blue light on RPEs, red fluorescent leakage from the lysosomes (means LMP increasing) can be observed. The mean red fluorescence intensity was chosen as the statistics indicator to estimate LMP change in RPEs cultured in vitro. Compared with the control group, the red fluorescence intensity decreased in A2E-loaded group, blue light irradiation group, and blue light irradiation + A2E-loaded group. Meanwhile, the mean red fluorescence intensity in blue light irradiation + A2E-loaded group was the lowest. CONCLUSIONS: Both A2E-loaded and blue light irradiation could induce human RPEs apoptosis, and the two factors had a synergistic effect. In addition, both A2E and blue light can lead to LMP increasing, which indicated LMP change might be the upstream part in inducing mitochondrion-dependent apoptotic pathway. These data provided evidence that A2E as the most important auto-fluorescence substance in lipofuscin is an initiator of blue light-mediated damage of RPEs and participate in pathogenesis of retinal degenerative diseases in humans.


Assuntos
Epitélio Pigmentado da Retina , Sincalida , Apoptose , Humanos , Lisossomos/metabolismo , Permeabilidade , Retinoides/farmacologia , Sincalida/metabolismo
13.
Med Sci Monit Basic Res ; 28: e935139, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35642437

RESUMO

BACKGROUND Melanoma is one of the most aggressive types of cancer and it has shown a remarkable surge in incidence during the last 50 years. Melanoma has been projected to be continuously rising in the future. Therapy for advanced-type melanoma is still a challenge due to the low response rate and poor 10-year survival. Interestingly, several epidemiological and preclinical studies had reported that vitamin D deficiency was associated with disease progression in several cancer types. In vivo and in vitro studies revealed anti-proliferative, anti-angiogenic, apoptosis, and differentiation induction effects of calcitriol in various cancers. However, information on the effects of calcitriol (1,25(OH)2D3) on melanoma is still limited, and its mechanism remains unclear. MATERIAL AND METHODS In the present study, by utilizing B16-F10 cells, which is a melanoma cell line, we explored the anti-proliferative effect of calcitriol using cell viability assay, near-infrared imaging, expression of apoptosis-related genes using real-time polymerase chain reactions (PCR), and the expression of apoptosis proteins levels using western blot. In addition, we also assessed calcitriol uptake by B16-F10 cells using high-performance liquid chromatography (HPLC). RESULTS We found that calcitriol inhibits melanoma cell proliferation with an IC50 of 93.88 ppm (0.24 µM), as shown by cell viability assay. Additionally, we showed that B16-F10 cells are capable of calcitriol uptake, with a peak uptake time at 60 min after administration. Calcitriol was also able to induce apoptosis-related proteins such as caspase-3, caspase 8, and caspase-9. These effects of calcitriol reflect its potential utility as a potent adjuvant therapy for melanoma. CONCLUSIONS Calcitriol inhibits cell proliferation and induces apoptosis in B16-F10 cells.


Assuntos
Calcitriol , Melanoma Experimental , Animais , Apoptose , Calcitriol/farmacologia , Calcitriol/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo
14.
Mol Med Rep ; 26(1)2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35642658

RESUMO

At present, the growing spread of tumor cases worldwide renders the research of new promising and selective anticancer drugs urgent. The biological action of extracts of medicinal plants or their essential oils (EOs) is an emerging field of interest, since they could comprise a rich source of phytochemicals that can prove promising. In the present study, the biological activity and mechanism of action of the EO of Foeniculum vulgare subsp. piperitum fruits (FVPEO) were investigated using MTT assays, morphological analyses and western blotting in MDA­MB231 cells, a triple­negative breast cancer cell line. The findings revealed that FVPEO could exert strong anticancer effects, causing a dose­dependent inhibition of breast cancer MDA­MB231 cell growth, accompanied with DNA condensation and fragmentation. The cytotoxic effect of FVPEO was counteracted by the addition of the antioxidant N­acetylcysteine and was associated with a marked increase in reactive oxygen species and stress­related proteins; such as manganese superoxide dismutase, c­Jun, phospho­c­Jun N­terminal kinase and nuclear factor E2­related factor 2, and the latter's transcriptional targets, Heme oxygenase­1 and NAD(P)H quinone oxidoreductase 1 (NQO1). As evidenced by the activation of caspase­3 and fragmentation of poly(ADP­ribose) polymerase­1, which are typical apoptosis markers, FVPEO promoted apoptotic cell death accompanied with an increase in phosphorylated H2A histone family member X and the activation of the NQO1/p53 axis. In combination, the present experiments provided evidence that FVPEO could represent a reservoir of biologically active compounds suitable for both cancer prevention and treatment.


Assuntos
Antineoplásicos , Foeniculum , Óleos Voláteis , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Apoptose , Foeniculum/química , Frutas , Humanos , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
15.
Pak J Pharm Sci ; 35(2): 553-559, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35642412

RESUMO

The herb Oroxylum indicum has been used for treating several diseases and also has anticancer activity. This research examined the anticancer effects of ethanolic extract of O. indicum seeds on HeLa cervical cancer cells and investigates underlying mechanisms. The data indicated that the extract inhibited HeLa cells growth with low IC50 values and arrested the cell cycle at G0/G1 phase at a dose of 50 µg/mL. Moreover, this extract produced a marked increase in the apoptosis of cancer cells which was demonstrated by acridine orange/ethidium bromide (AO/EB) staining and was significant at a dose of 250 µg/mL for 24 h. Correlating with apoptotic data by flow cytometric analysis, the results indicated that viable cells were significantly reduced and late apoptotic cells were induced starting at the dose of 50 µg/mL of the extract. These extracts significantly induced cancer cell apoptosis which was mediating through reduction of mitochondrial function by stimulating intracellular reactive oxygen species (ROS) formation. Furthermore, the extract caused inactivation of cervical cancer cell migration and was detected with the wound healing method. The data in this study strongly indicated that O. indicum seed extract has powerful activity against cervical cancer.


Assuntos
Extratos Vegetais/farmacologia , Neoplasias do Colo do Útero , Apoptose , Proliferação de Células , Feminino , Células HeLa , Humanos , Extratos Vegetais/uso terapêutico , Sementes/química , Neoplasias do Colo do Útero/tratamento farmacológico
16.
Biomed Res Int ; 2022: 9912776, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35647179

RESUMO

Objective: To study the mechanism of curcumol affecting the proliferation and apoptosis of liver cancer cells through the DJ-1/PTEN/PI3K/AKT pathway. Method: HepG2 cells were cultured in vitro, treated with curcumol at concentrations of 10, 30, and 100 µg/mL, and DMSO was used as a control. The levels of cell proliferation and apoptosis were measured by CCK-8 and flow cytometry, respectively. RT-PCR and western blot were used to detect PTEN, p-AKT, DJ-1, and PI3K gene and protein expression changes. Result: (1) Compared with the DMSO blank control group, the proliferation level of liver cancer cells in the 10 µg/mL curcumol group decreased, and the proportion of apoptosis increased (p <0.05). (2) Compared with the blank control group and the 10 and 30 µg/mL concentration groups, the proliferation level of liver cancer cells in the 100 µg/mL curcumol group was significantly reduced, and the proportion of cell apoptosis was significantly increased (p < 0.05). (3) Curcumol can significantly increase the expression of PTEN gene and protein in liver cancer cells and reduce the expression of DJ-1 and PI3K genes and protein in liver cancer cells (p < 0.05). Conclusion: Curcumol can regulate DJ-1, PTEN, PI3K, and AKT signal transduction pathways, inhibit cell proliferation, and cause a significant increase in the proportion of cell apoptosis, and the pharmacodynamic effect of curcumol is dependent on the time and dose of action.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Dimetil Sulfóxido/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos
17.
Mol Med ; 28(1): 65, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705919

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that results from widespread immune complex deposition and secondary tissue injury. Hydroxychloroquine (HCQ) has been used clinically to treat SLE, while its exact mechanism has still remained elusive. Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of SLE. In this study, we aimed to explore the effects of HCQ on the apoptosis of MDSCs in lupus mice and its possible molecular regulatory mechanism. METHODS: We constructed the imiquimod (IMQ)-induced lupus model in mice. The proportion and apoptosis of MDSCs were measured by flow cytometry. CD81-overexpressed adeno-associated virus was intraperitoneally injected into the lupus mice. We also transfected the CD81 siRNA into bone marrow-derived MDSCs, and employed qRT-PCR and Western blotting to quantify the level of CD81. RESULTS: The results showed that HCQ ameliorated IMQ-induced lupus symptoms, and simultaneously inhibited the expansion of MDSCs. In particular, HCQ induced the apoptosis of MDSCs, and also up-regulated the expression level of CD81 in MDSCs, which might indicate the relationship between the expression level of CD81 and the apoptosis of MDSCs. CD81 was further confirmed to participate in the apoptosis of MDSCs and lupus disease progression by overexpressing CD81 in vivo. Molecular docking experiment further proved the targeting effect of HCQ on CD81. And then we interfered CD81 in bone marrow derived MDSCs in vitro, and it was revealed that HCQ rescued the decreased expression level of CD81 and relieved the immune imbalance of Th17/Treg cells. CONCLUSION: In summary, HCQ promoted the apoptosis of MDSCs by up-regulating the expression level of CD81 in MDSCs, and ultimately alleviated lupus symptoms. Our results may assist scholars to develop further effective therapies for SLE.


Assuntos
Antirreumáticos , Lúpus Eritematoso Sistêmico , Células Supressoras Mieloides , Animais , Antirreumáticos/uso terapêutico , Apoptose , Hidroxicloroquina/metabolismo , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Camundongos , Simulação de Acoplamento Molecular , Células Supressoras Mieloides/metabolismo , Regulação para Cima
18.
Cardiovasc Diabetol ; 21(1): 106, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705980

RESUMO

BACKGROUND: Empagliflozin has been reported to protect endothelial cell function, regardless of diabetes status. However, the role of empagliflozin in microvascular protection during myocardial ischemia reperfusion injury (I/R) has not been fully understood. METHODS: Electron microscopy, western blots, immunofluorescence, qPCR, mutant plasmid transfection, co-immunoprecipitation were employed to explore whether empagliflozin could alleviate microvascular damage and endothelial injury during cardiac I/R injury. RESULTS: In mice, empagliflozin attenuated I/R injury-induced microvascular occlusion and microthrombus formation. In human coronary artery endothelial cells, I/R injury led to adhesive factor upregulation, endothelial nitric oxide synthase inactivation, focal adhesion kinase downregulation, barrier dysfunction, cytoskeletal degradation and cellular apoptosis; however, empagliflozin treatment diminished these effects. Empagliflozin improved mitochondrial oxidative stress, mitochondrial respiration and adenosine triphosphate metabolism in I/R-treated human coronary artery endothelial cells by preventing the phosphorylation of dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1), thus repressing mitochondrial fission. The protective effects of empagliflozin on mitochondrial homeostasis and endothelial function were abrogated by the re-introduction of phosphorylated Fis1, but not phosphorylated Drp1, suggesting that Fis1 dephosphorylation is the predominant mechanism whereby empagliflozin inhibits mitochondrial fission during I/R injury. Besides, I/R injury induced Fis1 phosphorylation primarily by activating the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) pathway, while empagliflozin inactivated this pathway by exerting anti-oxidative effects. CONCLUSIONS: These results demonstrated that empagliflozin can protect the microvasculature by inhibiting the DNA-PKcs/Fis1/mitochondrial fission pathway during myocardial I/R injury.


Assuntos
Traumatismo por Reperfusão Miocárdica , Traumatismo por Reperfusão , Animais , Apoptose , Compostos Benzidrílicos , DNA , Dinaminas/metabolismo , Células Endoteliais/metabolismo , Glucosídeos , Homeostase , Isquemia , Camundongos , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle
19.
Bioengineered ; 13(5): 13739-13751, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35707846

RESUMO

Glucose fluctuation is more harmful than sustained hyperglycemia, but the effect on cardiomyocyte apoptosis have not yet been clarified. In this study, we aim to identify the effect of glucose fluctuation on cardiomyocyte apoptosis and explore the underlying mechanism. Sprague-Dawley rats were intraperitoneally injected with streptozotocin (STZ) and divided into three groups: controlled diabetic group (C-STZ); uncontrolled diabetic group (U-STZ) and glucose fluctuated diabetic group (GF-STZ). After twelve weeks, echocardiography, Hematoxylin-eosin (HE) staining, and Masson staining were adopted to assess the cardiac function and pathological changes. TUNEL staining was used to detect apoptotic cells. Expressions of apoptosis-related proteins and key molecules in the endoplasmic reticulum (ER) stress pathway were determined via western blots. Further, primary cardiomyocytes incubated in different glucose conditions were treated with the inhibitor of ER stress to explore the causative role of ER stress in glucose fluctuation-induced cardiomyocyte apoptosis. In vivo, we demonstrated that glucose fluctuation promoted cardiomyocyte apoptosis, and were more harmful to cardiomyocytes than sustained hyperglycemia. Moreover, glucose fluctuation significantly triggered ER stress signaling pathway. In vitro, primary cardiomyocyte apoptosis induced by glucose fluctuation and the activation of ER stress were significantly attenuated by 4-PBA, which is an ER stress inhibitor. Above all, glucose fluctuation can promote cardiomyocyte apoptosis through triggering the ER stress signaling pathway in diabetic rats and in primary cardiomyocytes.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Hiperglicemia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Retículo Endoplasmático/metabolismo , Glucose/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
20.
Mol Immunol ; 148: 54-67, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35671559

RESUMO

Mastitis, an inflammation of the mammary gland, is a complex disease that affects the health of dairy cows worldwide. Sodium butyrate (SB) is a short-chain fatty acid that has recently been shown to have antioxidant, anti-inflammatory and anti-apoptotic potential in various cells types, although its role in bovine mammary epithelial cells (bMECs) has not been comprehensively reported. Therefore, the aim of this study was to assess the protective effect of sodium butyrate on Lipopolysaccharide (LPS)-induced mastitis model in vitro and to elucidate the possible underlying molecular mechanisms. The in vitro mastitis model was designed to investigate the regulatory effect of SB on LPS-induced inflammatory conditions in bMECs, with particular emphasis on oxidative stress, inflammatory response, apoptosis, and mitochondrial dysfunction. The results showed that SB co-treatment markedly prevented LPS-induced death of bMECs in a concentration-dependent manner. In addition, SB attenuated LPS-induced oxidative stress (OS) (Increased Intracellular ROS, MDA, and decreased SOD, GSH-Px and CAT activity), thereby reduced inflammation (increased expression of IL-6, IL-Iß, and TNF-α), and apoptosis (Increased the expression of caspases and Bax and decreased Bcl-2) via inhibiting NF-kB and caspase/bax signaling pathways. Furthermore, the protective effect of SB was also associated with the activation of endogenous antioxidant system (Nrf2, Keap1, NQO-1 and HO-1). Nrf2 silencing significantly abolished the protective effect of SB on bMECs. In conclusion, our findings suggest that SB has a significant protective effect on LPS-induced OS, inflammatory responses and apoptosis by activating Nrf2 and inhibiting NF-kB and ROS-mediated mitochondrial dysfunction. These results propose that SB may be an important regulator of OS and its subsequent inflammatory responses, and thus could be used as a therapeutic agent for bovine mastitis.


Assuntos
Lipopolissacarídeos , Mastite , Animais , Apoptose , Ácido Butírico/metabolismo , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Caspases/metabolismo , Bovinos , Células Epiteliais/metabolismo , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/farmacologia , Mastite/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/metabolismo
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