RESUMEN
Purpose: : Polyvinyl alcohol-capped silver nanostructures (cAgNSs) were investigated in order to enhance the cytotoxicity, pro-apoptotic, and oxidant patterns of in human laryngeal carcinoma Hep-2 cells by employing a 50 mT electromagnetic field (LEMF) for 30 min. Methods: Wet chemical reduction was used to synthesize the cAgNSs, and after they had been capped with polyvinyl alcohol, they were specifically examined for particle size analysis and structural morphology. To visualize how the silver may attach to the protein targets, a molecular docking study was conducted. Estimation of cytotoxicity, cell cycle progression supported by mRNA expression of three apoptotic-promoting genes and one apoptotic-resisting. Results: Particle size analysis results were a mean particle size of 157.3±0.5 nm, zeta potential value of -29.6 mV±1.5 mV, and polydispersity index of 0.31±0.05. Significantly reduction of IC50 against Hep-2 cells by around 6-fold was concluded. Also, we obtained suppression of the proliferation of Hep-2 cells, especially in the G0/G1 and S phases. Significant enhanced mRNA expression revealed enhanced induced CASP3, p53, and Beclin-1 mediated pro-apoptosis and induced NF-κB mediated autophagy in Hep-2 cells. Augmented levels of GR, ROS and MDA as oxidative stress biomarkers were also obtained. HE staining of Hep-2 cells exposed to cAgNSs and LEMF confirmed the enhanced apoptotic potential comparatively. Conclusion: By conclusion, the developed nano-sized structures with the aid of extremely-low frequency electromagnetic field were successful to fortify the anti-cancer profile of cAgNSs in Hep-2 cells.
Asunto(s)
Apoptosis , Neoplasias Laríngeas , Nanopartículas del Metal , Alcohol Polivinílico , Plata , Humanos , Neoplasias Laríngeas/patología , Apoptosis/efectos de los fármacos , Plata/química , Plata/farmacología , Línea Celular Tumoral , Nanopartículas del Metal/química , Alcohol Polivinílico/química , Alcohol Polivinílico/farmacología , Tamaño de la Partícula , Campos Electromagnéticos , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Simulación del Acoplamiento Molecular , Nanoestructuras/química , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacosRESUMEN
Traditional chemotherapy drugs for cervical cancer often cause significant toxic side effects and drug resistance problems, highlighting the urgent need for more innovative and effective treatment strategies. Magnesium alloy is known to be degradable and biocompatible. The release of degradation products Mg2+, OH-, and H2 from magnesium alloy can alter the tumor microenvironment, providing potential anti-tumor properties. We explored the innovative use of magnesium alloy biomaterials in the treatment of cervical cancer, investigating how various concentrations of Mg2+ on the proliferation and cell death of cervical cancer cells. The results revealed that varying concentrations of Mg2+ significantly inhibited cervical cancer by arresting the cell cycle in the G0/G1 phase and inducing apoptosis in SiHa cells, effectively reducing tumor cell proliferation. In vivo experiments demonstrated that 20 mM Mg2+ group had the smallest tumor volume, exhibiting a potent inhibitory effect on the biological characteristics of cervical cancer. This enhances the therapeutic potential of this biomaterial as a local anti-tumor therapy and lays a theoretical foundation for the potential application of magnesium in the treatment of cervical cancer.
Asunto(s)
Apoptosis , Materiales Biocompatibles , Proliferación Celular , Magnesio , Neoplasias del Cuello Uterino , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/metabolismo , Femenino , Magnesio/farmacología , Magnesio/química , Humanos , Proliferación Celular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/química , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Aleaciones/farmacología , Aleaciones/química , Ensayos Antitumor por Modelo de Xenoinjerto , Ciclo Celular/efectos de los fármacosRESUMEN
Humans have been using plants in the treatment of various diseases for millennia. Currently, even with allopathic medicines available, numerous populations globally still use plants for therapeutic purposes. Although plants constitute a safer alternative compared to synthetic agents, it is well established that medicinal plants might also exert adverse effects. Thus, the present investigation aimed to assess the phytotoxic, cytotoxic, and genotoxic potential of two plants from the Brazilian Cerrado used in popular medicine, Davilla nitida (Vahl) Kubitzki, and Davilla elliptica (A. St.-Hil.). To this end, germination, growth, and cell cycle analyses were conducted using the plant model Lactuca sativa. Seeds and roots were treated with 0.0625 to 1 g/L for 48 hr under controlled conditions. The germination test demonstrated significant phytotoxic effects for both species at the highest concentrations tested, while none of the extracts produced significant effects in the lettuce growth test. In the microscopic analyses, the aneugenic and cytotoxic action of D. elliptica was evident. In the case of D. nitida greater clastogenic action and induction of micronuclei, (MN) were noted suggesting that the damage initiated by exposure to these extracts was not repaired or led to apoptosis. These findings indicated that the observed plant damage was transmitted to the next generation of cells by way of MN. These differences in the action of the two species may not be attributed to qualitative variations in the composition of the extracts as both are similar, but to quantitative differences associated with synergistic and antagonistic interactions between the compounds present in these extracts.
Asunto(s)
Dilleniaceae , Lactuca , Extractos Vegetales , Plantas Medicinales , Plantas Medicinales/toxicidad , Plantas Medicinales/química , Extractos Vegetales/toxicidad , Lactuca/efectos de los fármacos , Lactuca/crecimiento & desarrollo , Dilleniaceae/química , Germinación/efectos de los fármacos , Semillas/efectos de los fármacos , Brasil , Ciclo Celular/efectos de los fármacos , Raíces de Plantas/efectos de los fármacosRESUMEN
Amyloid-beta peptide (Aß) is a neurotoxic constituent of senile plaques in the brains of Alzheimer's disease (AD) patients. The detailed mechanisms by which protein kinase C-delta (PKCδ) contributes to Aß toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, we found that inhibition of Aß25-35-induced PKCδ increased cell viability with restoration of neuronal morphology. Using cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) as the respective markers for the G1-, S-, and G2/M-phases, PKCδ inhibition mitigated cell cycle reentry (CCR) and subsequent caspase-3 cleavage induced by both Aß25-35 and Aß1-42 in the post-mitotic cortical neurons. Upstream of PKCδ, signal transducers and activators of transcription (STAT)-3 mediated PKCδ induction, CCR, and caspase-3 cleavage upon Aß exposure. Downstream of PKCδ, aberrant neuronal CCR was triggered by overactivating cyclin-dependent kinase-5 (CDK5) via calpain2-dependent p35 cleavage into p25. Finally, PKCδ and CDK5 also contributed to Aß25-35 induction of p53-upregulated modulator of apoptosis (PUMA) in cortical neurons. Together, we demonstrated that, in the post-mitotic neurons exposed to Aßs, STAT3-dependent PKCδ expression triggers calpain2-mediated p35 cleavage into p25 to overactivate CDK5, thus leading to aberrant CCR, PUMA induction, caspase-3 cleavage, and ultimately apoptosis.
Asunto(s)
Péptidos beta-Amiloides , Apoptosis , Ciclo Celular , Corteza Cerebral , Neuronas , Proteína Quinasa C-delta , Péptidos beta-Amiloides/metabolismo , Animales , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratas , Proteína Quinasa C-delta/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/citología , Ciclo Celular/efectos de los fármacos , Quinasa 5 Dependiente de la Ciclina/metabolismo , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/metabolismo , Caspasa 3/metabolismo , Ratas Sprague-Dawley , Células Cultivadas , Transducción de Señal/efectos de los fármacosRESUMEN
Activation of the Hedgehog (Hh) signaling pathway is often associated with the progression of various types of cancer. The purpose of study was to search for inhibitors of the Hh signaling pathway among eight compounds belonging to the group of isoxazolyl steroids. The evaluation of the effectiveness of the compounds was based on the analysis of their cytotoxicity, effect on the cell cycle, on the expression of key Hh-signaling-pathway genes (Ptch1, Smo, and Gli1) and putative target genes MMP-2 and MMP-9. Four compounds with the most pronounced cytotoxic effect were identified: compounds 1, 2 (HeLa cells) and 3, 4 (A549 cells). Compounds 1 and 2 significantly reduced the expression of the Ptch1, Smo, Gli1 genes, but had the opposite effect on MMP-2 gene expression: Compound 1 increased it, and compound 2 decreased it. Compounds 3 and 4 did not have a noticeable inhibitory effect on the expression of the Shh pathway receptors, but significantly inhibited MMP-2 and MMP-9 expression. Thus, it was shown that inhibition of the Shh signaling pathway by isoxazolyl steroids can have the opposite effect on MMPs gene expression, which is what should be taken into account in further studies of these compounds as therapeutic agents.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog , Transducción de Señal , Esteroides , Humanos , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Transducción de Señal/efectos de los fármacos , Esteroides/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células A549 , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Línea Celular Tumoral , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Antineoplásicos/farmacología , Proteína con Dedos de Zinc GLI1/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Receptor Smoothened/metabolismo , Receptor Smoothened/genética , Receptor Smoothened/antagonistas & inhibidores , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Ciclo Celular/efectos de los fármacosRESUMEN
Couroupita guianensis, a medicinal plant autochthonal to South America and South India, is widely used in the ethnomedicine of the indigenous peoples of these regions thanks to its alleged antimicrobial, anti-inflammatory, antioxidant and wound-healing properties. The majority of studies have mainly analyzed organic extracts of the Indian plant's flowers and leaves, with limited research on its bark decoction, traditionally used in Amazonian shamanic medicine. In this study, we investigated the anticancer effects of the bark decoction and its main fractions obtained through chromatographic separation, as well as the underlying molecular mechanisms in AGS gastric cancer cells. Viability, cell proliferation, cell cycle, apoptosis and protein expression related to these processes were evaluated. Both the bark decoction and fraction III significantly inhibited cell viability, and the cytotoxic effect was linked to cell cycle blockade and the induction of apoptosis also through an engulfment of the autophagic flux. Increased expression or activation of the key proteins (p53, p21, cdk2, Bak, caspases, pAMPK, pAkt, beclin, p62 and LC3BII) involved in these processes was observed. The results obtained confirmed an important anticancer effect of C. guianensis bark decoction, providing scientific validation for its use in traditional medicine and highlighting its potential as a therapeutic agent against gastric cancer.
Asunto(s)
Apoptosis , Proliferación Celular , Corteza de la Planta , Extractos Vegetales , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Extractos Vegetales/farmacología , Extractos Vegetales/química , Línea Celular Tumoral , Corteza de la Planta/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Antineoplásicos Fitogénicos/farmacología , Supervivencia Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Autofagia/efectos de los fármacosRESUMEN
Pyridaben is a broad-spectrum, contact-killing acaricide that can be used to control a variety of harmful food and plant mites. Pyridaben displays cardiotoxicity and liver toxicity toward fish, but the effects on fish embryonic development have not been characterized. We exposed early zebrafish embryos to 20, 30, and 40⯵g/L concentrations of pyridaben. The exposure caused developmental abnormalities, including delayed embryonic shield formation, yolk sac resorption, decreases in body length, reduced pigmentation, and delays in hatching. Pyridaben caused a significant increase in the transcription level of the endoderm marker foxa2, but the transcription levels of the ectoderm development marker foxb1a and the mesoderm development marker snaila were not significantly altered. The transcription levels of the genes SOX17 in early embryos were significantly reduced. After exposure to pyridaben, catalase (CAT) activity and glutathione (GSH) content were increased, and cyclin D1, that is involved in early embryonic development, was abnormally expressed. This study shows that pyridaben causes anomalous development in zebrafish embryos by interfering with the cell cycle order of early embryonic development and inducing excessive oxidative stress. Colivelin, an agonist of the STAT3 signaling pathway, acted as a salvage drug to restore the cell cycle order during embryonic development following exposure to pyridaben. Thus, the toxic effects may be caused by pyridaben's regulation of the STAT3 signaling pathway.
Asunto(s)
Ciclo Celular , Embrión no Mamífero , Desarrollo Embrionario , Pez Cebra , Animales , Pez Cebra/embriología , Desarrollo Embrionario/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Piridazinas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genéticaRESUMEN
The adult mammalian heart has extremely limited cardiac regenerative capacity. Most cardiomyocytes live in a state of permanent cell-cycle arrest and are unable to re-enter the cycle. Cardiomyocytes switch from cell proliferation to a maturation state during neonatal development. Although several signaling pathways are involved in this transition, the molecular mechanisms by which these inputs coordinately regulate cardiomyocyte maturation are not fully understood. Retinoic acid (RA) plays a pivotal role in development, morphogenesis, and regeneration. Despite the importance of RA signaling in embryo heart development, little is known about its function in the early postnatal period. We found that mRNA expression of aldehyde dehydrogenase 1 family member A2 (Aldh1a2), which encodes the key enzyme for synthesizing all-trans retinoic acid (ATRA) and is an important regulator for RA signaling, was transiently upregulated in neonatal mouse ventricles. Single-cell transcriptome analysis and immunohistochemistry revealed that Aldh1a2 expression was enriched in cardiac fibroblasts during the early postnatal period. Administration of ATRA inhibited cardiomyocyte proliferation in cultured neonatal rat cardiomyocytes and human cardiomyocytes. RNA-seq analysis indicated that cell proliferation-related genes were downregulated in prenatal rat ventricular cardiomyocytes treated with ATRA, while cardiomyocyte maturation-related genes were upregulated. These findings suggest that RA signaling derived from cardiac fibroblasts is one of the key regulators of cardiomyocyte proliferation and maturation during neonatal heart development.
Asunto(s)
Familia de Aldehído Deshidrogenasa 1 , Proliferación Celular , Miocitos Cardíacos , Retinal-Deshidrogenasa , Transducción de Señal , Tretinoina , Animales , Tretinoina/farmacología , Tretinoina/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Ratones , Familia de Aldehído Deshidrogenasa 1/metabolismo , Familia de Aldehído Deshidrogenasa 1/genética , Retinal-Deshidrogenasa/metabolismo , Retinal-Deshidrogenasa/genética , Proliferación Celular/efectos de los fármacos , Ratas , Humanos , Regulación hacia Arriba , Animales Recién Nacidos , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/crecimiento & desarrollo , Células CultivadasRESUMEN
Recently, surface engineering of the cell membrane with biomaterials has attracted great attention for various biomedical applications. In this study, we investigated the possibility of modulating cell cycle progression using alginate and gelatin-based hydrogel sheaths with a thickness of â¼1 µm. The hydrogel sheath was formed on cell surfaces through cross-linking catalyzed by horseradish peroxidase immobilized on the cell surface. The hydrogel sheath did not decrease the viability (>95% during 2 days of culture) of the human cervical carcinoma cell line (HeLa) expressing the fluorescent ubiquitination-based cell cycle indicator 2 (HeLa/Fucci2). Coating the HeLa/Fucci2 cells with the hydrogel sheath resulted in a cell cycle arrest in the G2/M phase, which can be caused by the reduced F-actin formation. As a result of this cell cycle arrest, an inhibition of cell growth was observed in the HeLa/Fucci2 cells. Taken together, our results demonstrate that the hydrogel sheath coating on the cell surface is a feasible approach to modulating cell cycle progression.
Asunto(s)
Hidrogeles , Humanos , Células HeLa , Hidrogeles/química , Hidrogeles/farmacología , Alginatos/química , Peroxidasa de Rábano Silvestre/química , Peroxidasa de Rábano Silvestre/metabolismo , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Gelatina/química , Proliferación Celular/efectos de los fármacosRESUMEN
Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10-5 M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial-mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells.
Asunto(s)
Dioxoles , Transición Epitelial-Mesenquimal , Células Madre Neoplásicas , Poliploidía , Pirroles , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Pirroles/farmacología , Femenino , Línea Celular Tumoral , Dioxoles/farmacología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fungicidas Industriales/farmacología , Fungicidas Industriales/toxicidad , Movimiento Celular/efectos de los fármacos , Metástasis de la Neoplasia , Células Gigantes/efectos de los fármacos , Células Gigantes/metabolismo , Células Gigantes/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the effects of selinexor, a inhibitor of nuclear export protein 1 (XPO1) on the proliferation inhibition and apoptosis of Kasumi-1 cells in acute myeloid leukemia (AML). METHODS: MTS method was used to detect the inhibitory effect of different concentrations of selinexor on the proliferation of Kasumi-1 cells at different time points. The apoptosis rate and cell cycle changes after treatment with different concentration of selinexor were detected by flow cytometry. RESULTS: Selinexor inhibited the growth of Kasumi-1 cells at different time points in a concentration-dependent manner (r 24 h=0.7592, r 48 h=0.9456, and r 72 h=0.9425). Selinexor inhibited Kasumi-1 cells growth in a time-dependent manner (r =0.9057 in 2.5 µmol/L group, r =0.9897 in 5 µmol/L group and r =0.9994 in 10 µmol/L group). Selinexor could induce apoptosis of Kasumi-1 cells in a dose-dependent manner (r =0.9732), and the apoptosis of Kasumi-1 cells was more obvious with the increase of drug concentration. The proportion of G0/G1 phase was significantly increased and the proportion of S phase was significantly decreased after the treatment of Kasumi-1 cells by selinexor. With the increase of drug concentration, the proportion of Kasumi-1 cells cycle arrest in G0/G1 phase was increased and the cell synthesis was decreased. CONCLUSION: Selinexor can promote the death of tumor cells by inhibiting Kasumi-1 cells proliferation, inducing apoptosis and blocking cell cycle.
Asunto(s)
Apoptosis , Proliferación Celular , Hidrazinas , Leucemia Mieloide Aguda , Triazoles , Hidrazinas/farmacología , Triazoles/farmacología , Apoptosis/efectos de los fármacos , Humanos , Proliferación Celular/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Línea Celular Tumoral , Ciclo Celular/efectos de los fármacos , Proteína Exportina 1 , CarioferinasRESUMEN
Marine algae, encompassing both macroalgae and microalgae, have emerged as a promising and prolific source of bioactive compounds with potent anticancer properties. Despite their significant therapeutic potential, the clinical application of these peptides is hindered by challenges such as poor bioavailability and susceptibility to enzymatic degradation. To overcome these limitations, innovative delivery systems, particularly nanocarriers, have been explored. Nanocarriers, including liposomes, nanoparticles, and micelles, have demonstrated remarkable efficacy in enhancing the stability, solubility, and bioavailability of marine algal peptides, ensuring controlled release and prolonged therapeutic effects. Marine algal peptides encapsulated in nanocarriers significantly enhance bioavailability, ensuring more efficient absorption and utilization in the body. Preclinical studies have shown promising results, indicating that nanocarrier-based delivery systems can significantly improve the pharmacokinetic profiles and therapeutic outcomes of marine algal peptides. This review delves into the diverse anticancer mechanisms of marine algal peptides, which include inducing apoptosis, disrupting cell cycle progression, and inhibiting angiogenesis. Further research focused on optimizing nanocarrier formulations, conducting comprehensive clinical trials, and continued exploration of marine algal peptides holds great promise for developing innovative, effective, and sustainable cancer therapies.
Asunto(s)
Antineoplásicos , Apoptosis , Reparación del ADN , Neoplasias , Péptidos , Humanos , Apoptosis/efectos de los fármacos , Péptidos/farmacología , Péptidos/química , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/química , Animales , Reparación del ADN/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Algas Marinas/química , Microalgas/química , Nanopartículas/química , Organismos AcuáticosRESUMEN
The placenta is crucial for fetal development, yet the impact of environmental stressors such as arsenic exposure remains poorly understood. We apply single-cell RNA sequencing to analyze the response of the mouse placenta to arsenic, revealing cell-type-specific gene expression, function, and pathological changes. Notably, the Prap1 gene, which encodes proline-rich acidic protein 1 (PRAP1), is significantly upregulated in 26 placental cell types including various trophoblast cells. Our study shows a female-biased increase in PRAP1 in response to arsenic and localizes it in the placenta. In vitro and ex vivo experiments confirm PRAP1 upregulation following arsenic treatment and demonstrate that recombinant PRAP1 protein reduces arsenic-induced cytotoxicity and downregulates cell cycle pathways in human trophoblast cells. Moreover, PRAP1 knockdown differentially affects cell cycle processes, proliferation, and cell death depending on the presence of arsenic. Our findings provide insights into the placental response to environmental stress, offering potential preventative and therapeutic approaches for environment-related adverse outcomes in mothers and children.
Asunto(s)
Arsénico , Placenta , Análisis de la Célula Individual , Trofoblastos , Femenino , Embarazo , Placenta/metabolismo , Placenta/efectos de los fármacos , Animales , Humanos , Ratones , Trofoblastos/metabolismo , Trofoblastos/efectos de los fármacos , Trofoblastos/citología , Arsénico/toxicidad , Análisis de Secuencia de ARN , Estrés Fisiológico/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Proliferación Celular/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Kuwanon C is a unique flavonoid found in the mulberry family, characterized by two isopentenyl groups. While previous research has focused on various properties of kuwanon C, such as antioxidant, hypoglycemic, antimicrobial, food preservation, skin whitening, and nematode lifespan extension, little attention has been given to its potential role in oncological diseases. In this study, we investigate the antitumor effect of kuwanon C in cervical cancer cells and elucidate its specific mechanism of action. We assessed the antitumor effects of kuwanon C using various experimental techniques, including cell proliferation assay, wound healing assays, EdU 488 proliferation assay, mitochondrial membrane potential assay, ROS level assay, cell cycle, apoptosis analysis, and studies on kuwanon C target sites and molecular docking. The results revealed that kuwanon C significantly impacted the cell cycle progression of HeLa cells, disrupted their mitochondrial membrane potential, and induced a substantial increase in intracellular ROS levels. Moreover, kuwanon C exhibited notable anti-proliferative and pro-apoptotic effects on HeLa cells, surpassing the performance of commonly used antitumor drugs such as paclitaxel and cisplatin. Notably, kuwanon C demonstrated superior efficacy while also being more easily accessible compared to paclitaxel. Our study demonstrates that kuwanon C exerts potent antitumor effects by its interaction with the mitochondrial and endoplasmic reticulum membranes, induces a significant production of ROS, disrupts their normal structure, inhibits cell cycle progression, and stimulates apoptotic signaling pathways, ultimately resulting in the death of HeLa tumor cells. As an isopentenyl compound derived from Morus alba, kuwanon C holds great promise as a potential candidate for the development of effective antitumor drugs.
Asunto(s)
Apoptosis , Proliferación Celular , Retículo Endoplásmico , Potencial de la Membrana Mitocondrial , Mitocondrias , Especies Reactivas de Oxígeno , Humanos , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Células HeLa , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Simulación del Acoplamiento Molecular , Femenino , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacosRESUMEN
Gastric cancer (GC)-diabetes co-morbidity is nowadays growing into a rising concern. However, no separate treatment procedures have been outlined for such patients. Phytochemicals and their derivatives can therefore be used as therapeutics as they have greater effectiveness, reduced toxicity, and a reduced likelihood of developing multi-drug resistance in cancer treatments. The present study intended to assess the therapeutic efficacy of Shatavarin-IV - a major steroidal saponin from the roots of Asparagus racemosus, in human gastric adenocarcinoma cell line under hyperglycemic conditions and explore its mechanism of action in controlling GC progression. For the present study, AGS cells were incubated in high glucose-containing media and the effects of Shatavarin-IV therein have been evaluated. Cell proliferation, confocal microscopic imaging, flow-cytometric analysis for cell cycle and apoptosis, immunoblotting, zymography, reverse zymography, wound-healing, colony formation, and invasion assays were performed. Shatavarin-IV has a prominent effect on AGS cell proliferation; with IC50 of 2.463 µ M under hyperglycemic conditions. Shatavarin-IV induces cell cycle arrest at the G0/G1 phase, thereby preventing hyperglycemia-induced excessive cell proliferation that later on leads to apoptotic cell death at 36 h of incubation. Shatavarin-IV further inhibits the migratory and invasive potential of AGS cells by altering the expression patterns of different EMT markers. It also inhibits MMP-9 while promoting TIMP-1 activity and expression; thereby regulating ECM turnover. This is the first report demonstrating the therapeutic efficacy of Shatavarin-IV against AGS cells grown in hyperglycemic conditions, implicating new insights into the treatment paradigm of patients with GC-diabetes co-morbidity.
Asunto(s)
Asparagus , Proliferación Celular , Transición Epitelial-Mesenquimal , Hiperglucemia , Saponinas , Humanos , Saponinas/farmacología , Saponinas/química , Saponinas/aislamiento & purificación , Asparagus/química , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hiperglucemia/tratamiento farmacológico , Línea Celular Tumoral , Ciclo Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Neoplasias Gástricas/patología , Neoplasias Gástricas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacosRESUMEN
Epothilones are one of the common prescribed anticancer drugs for solid tumors, for their exceptional binding affinity with ß-tubulin microtubule, stabilizing their disassembly, causing an ultimate arrest to the cellular growth. Epothilones were initially isolated from Sornagium cellulosum, however, their extremely slow growth rate and low yield of epothilone is the challenge. So, screening for a novel fungal endophyte dwelling medicinal plants, with higher epothilone productivity and feasibility of growth manipulation was the objective. Aspergillus niger EFBL-SR OR342867, an endophyte of Latania loddegesii, has been recognized as the heady epothilone producer (140.2 µg/L). The chemical structural identity of the TLC-purified putative sample of A. niger was resolved from the HPLC, FTIR and LC-ESI-MS/MS analyses, with an identical molecular structure of the authentic epothilone B. The purified A. niger epothilone B showed a resilient activity against MCF-7 (0.022 µM), HepG-2 (0.037 µM), and HCT-116 (0.12 µM), with selectivity indices 21.8, 12.9 and 4, respectively. The purified epothilone B exhibited a potential anti-wound healing activity to HepG-2 and MCF-7 cells by ~ 54.07 and 60.0%, respectively, after 24 h, compared to the untreated cells. The purified epothilone has a significant antiproliferative effect by arresting the cellular growth of MCF-7 at G2/M phase by ~ 2.1 folds, inducing the total apoptosis by ~ 12.2 folds, normalized to the control cells. The epothilone B productivity by A. niger was optimized by the response surface methodology, with ~ 1.4 fold increments (266.9 µg/L), over the control. The epothilone productivity by A. niger was reduced by ~ 2.4 folds by 6 months storage as a slope culture at 4 °C, however, the epothilone productivity was slightly restored with ethylacetate extracts of L. loddegesii, confirming the plant-derived chemical signals that partially triggers the biosynthetic genes of A. niger epothilones. So, this is the first report emphasizing the metabolic potency of A. niger, an endophyte of L. loddegesii, to produce epothilone B, that could be a new platform for industrial production of this drug.
Asunto(s)
Antineoplásicos , Aspergillus niger , Endófitos , Epotilonas , Cicatrización de Heridas , Epotilonas/farmacología , Epotilonas/biosíntesis , Epotilonas/química , Epotilonas/metabolismo , Humanos , Endófitos/metabolismo , Endófitos/química , Aspergillus niger/efectos de los fármacos , Aspergillus niger/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Cicatrización de Heridas/efectos de los fármacos , Células MCF-7 , Células Hep G2 , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacosRESUMEN
Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ N-oxide derivatives in two isomeric families, both exhibiting nanomolar GI50 against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI50 > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI50 concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI50 values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound 25 inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.
Asunto(s)
Antineoplásicos , Proliferación Celular , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Isoquinolinas/farmacología , Isoquinolinas/química , Isoquinolinas/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Fluoresceínas/síntesis química , Fluoresceínas/química , Fluoresceínas/farmacologíaRESUMEN
Previous studies have shown that modified citrus pectin (MCP) is an anti-tumor material of food grade. In this study, two enzymatically modified Ougan (Citrus Suavissima Hort. ex Tanaka) peel pectins (EMP1 and EMP2, the ones extracted by alkali and enzymatic methods) were used to investigate their differential effects on viability and physiology of Hela cells. The results showed that EMP1 and EMP2 had 88.00 % and 81.01 % galacturonic acid, 21.31 % and 20.25 % esterification degree, 10,417 g/mol and 6416 g/mol molecular weight (Mw), 82.86 % and 50.62 % RG-I, and 8.91 % and 15.70 % HG, respectively. EMP2 had higher intensities of absorption peaks than EMP1. They were irregularly shaped, with more holes on EMP1 but more wrinkles on EMP2. Both could inhibit the growth, proliferation, migration, and invasion of HeLa cells in a concentration-dependent manner, with better efficiency in EMP2. Meanwhile, EMP2 was more efficient than EMP1 in blocking the cell cycle in S phase, resulting in apoptosis. In conclusion, the variations caused by extraction resulted in differences in anti-tumor activity of MCP and EMP2 with lower Mw and higher HG exhibited better anti-tumor effects. This study would provide an experimental basis and reference for the research and development of anti-tumor supplements from citrus pectin.
Asunto(s)
Proliferación Celular , Citrus , Pectinas , Humanos , Células HeLa , Pectinas/farmacología , Pectinas/química , Citrus/química , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacosRESUMEN
Natural non-psychoactive cannabinoids such as cannabigerol (CBG), cannabidiol (CBD), cannabichromene (CBC), cannabidivarin (CBDV), and cannabinol (CBN) are increasingly consumed as constituents of dietary products because of the health benefits claims. Cannabinoids may reduce certain types of pain, nausea, and anxiety. Anti-inflammatory and even anti-carcinogenic properties have been discussed. However, there are insufficient data available regarding their potential (geno-)toxic effects. Therefore, we tested CBG, CBD, CBC, CBDV, and CBN for their genotoxic potential and effects on mitosis and cell cycle in human lymphoblastoid TK6 cells. The selected cannabinoids (except CBDV) induced increased micronuclei formation, which was reduced with the addition of a metabolic activation system (S9 mix). CBDV induced micronuclei only after metabolic activation. Mitotic disturbances were observed with all tested cannabinoids, while G1 phase accumulation of cells was observed for CBG, CBD and CBDV. The genotoxic effects occurred at about 1000-fold higher concentrations than are reported as blood levels from human consumption. However, the results clearly indicate a need for further research into the genotoxic effects of cannabinoids. The mechanism of the mitotic disturbance, the shape of the dose-response curves and the possible effects of mixtures of cannabinoids are aspects which need clarification.
Asunto(s)
Cannabinoides , Linfocitos , Pruebas de Micronúcleos , Mitosis , Mutágenos , Humanos , Cannabinoides/toxicidad , Mitosis/efectos de los fármacos , Linfocitos/efectos de los fármacos , Línea Celular , Mutágenos/toxicidad , Ciclo Celular/efectos de los fármacos , Micronúcleos con Defecto Cromosómico/inducido químicamente , Relación Dosis-Respuesta a Droga , Daño del ADN/efectos de los fármacos , Pruebas de Mutagenicidad , Cannabidiol/toxicidadRESUMEN
The usage of peptides in the colorectal cancer (CRC) treatment promises to be a new anti-cancer therapy with improved treatment efficacy. Carnosine, a natural dipeptide molecule, has been demonstrated to be a potential anti-cancer drug. Nonetheless, it shows an exhibition of high-water solubility and is quickly degraded by carnosinase. Meanwhile, agar and magnetic iron oxide are the most used materials for drug delivery due to some of their advantages such as the low cost and the larger biocompatibility feature. The purpose of this study was to investigate the anti-cancer ability of agar-encapsulated carnosine nanoparticles (AgCa-NPs) and agar-encapsulated carnosine nanoparticles-coated magnetic iron oxide nanoparticles (AgCaN-MNPs) in human CRC cells, HCT-116. We evaluated the effects of AgCa-NPs and AgCaN-MNPs with a variety of concentrations (0, 5, 10, 15, 30, 40, or 50 mM) on HCT-116 cells after 72 h and 96 h by using MTT assay and observation cell morphology. We then analyzed the cell cycle progression and assessed the expression changes of genes related to apoptosis, autophagy, necroptosis, and angiogenesis after treatment for 96 h. The results showed that AgCa-NPs and AgCaN-MNPs in vitro study decreased HCT-116 cells viability. This effect was attributed to arrest of cell cycle, induction of programmed cell death, and suppression of angiogenesis by AgCa-NPs and AgCaN-MNPs. These findings revealed the antitumor efficacy of AgCa-NPs or AgCaN-MNPs for CRC treatment.