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1.
Artigo em Chinês | MEDLINE | ID: mdl-38965852

RESUMO

Objective: To explore the effects of hinokiol on the cell cyle and apoptosis of CNE1 nasopharyngeal carcinoma cells and the relevant molecular mechanism. Methods: The CNE1 cells were cultured in vitro and incubated with different concentrations of honokiol, and the cells were divided into blank control group, 10 µmol/L, 20 µmol/L and 40 µmol/L hinokiol treatment groups, and 10 µg/ml cisplatin group. Cell viability was determined by methylthiazolyldiphenyl- tetrazolium bromide (MTT) method, the cell cycle distribution was detected by flow cytometry, mitochondrial membrane potential was detected by mitochondrial membrane potential test kit, apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method, and the proteins expression of proliferating cell nuclear antigen (PCNA) and G1/S specific cyclin D1 (cyclin D1) were detected by immunoblotting. RNA-Seq was conducted in the hinokiol-treated cells. The mRNA expression of yes-associated protein delta (YAP) was detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The proteins expression of phosphor-YAP (p-YAP) and nuclear YAP were detected by immunoblotting, the nuclear distribution of YAP protein was detected by immunofluorescence in the cells with or without treated with the mammalian STE20-like kinase 1/2 (MST1/2) inhibitor (XMU-MP-1), hinokiol, and XMU-MP-1+hinokiol. Statistical analysis of the data was conducted using GraphPad Prism 8.0 software. Resluts Compared with the control group, the cell viablity of CNE1 cells, the levels of mitochondrial membrane potential, the proteins expression of PCNA and cyclin D1 in hinokiol treatment groups were markedly decreased (all P values<0.05), while the proportion of G0/G1 phase cells and the ratio of TUNEL-positive cells were significantly increased (both P values<0.05). Transcriptome analysis showed that differential genes were mainly enriched in Wnt signaling pathway, tumor necrosis factor pathway, and Hippo signaling pathway. The mRNA level of YAP and the protein expression of YAP in the nucleus were decreased and the level of p-YAP protein was increased in cells treated with hinokiol, which were significantly different from control group (all P values<0.05). Compared with the hinokiol group, XMU-MP-1+hinokiol groups showed the decrease of p-YAP protein expression (1.157±0.076 vs 0.479±0.038, t=37.120, P<0.05), the increase of YAP protein expression in the nucleus (0.143±0.012 vs 0.425±0.031, t=29.181, P<0.05), the reduced proportion of cells in G0/G1 phase [(72.494±3.309)% vs (58.747±2.865)%, t=17.265, P<0.05], and the decrease of apoptosis ratio [(53.158±3.376)% vs (29.621±2.713)%, t=28.584, P<0.05]. Conclusion: Hinokiol can arrest the cell cycle and induce the cell apoptosis of CNE1 cells via Hippo/YAP signaling pathway.


Assuntos
Apoptose , Compostos de Bifenilo , Ciclo Celular , Via de Sinalização Hippo , Lignanas , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Transdução de Sinais , Humanos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Carcinoma Nasofaríngeo/metabolismo , Ciclo Celular/efeitos dos fármacos , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Lignanas/farmacologia , Compostos de Bifenilo/farmacologia , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP , Proteínas Serina-Treonina Quinases/metabolismo , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo
2.
Sci Adv ; 10(27): eadm9211, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38968359

RESUMO

Decades ago, mitogen-promoted signaling duration and strength were observed to be sensed by the cell and to be critical for its decisions: to proliferate or differentiate. Landmark publications established the importance of mitogen signaling not only in the G1 cell cycle phase but also through the S and the G2/M transition. Despite these early milestones, how mitogen signal duration and strength, short and strong or weaker and sustained, control cell fate has been largely unheeded. Here, we center on cardinal signaling-related questions, including (i) how fluctuating mitogenic signals are converted into cell proliferation-differentiation decisions and (ii) why extended duration of weak signaling is associated with differentiation, while bursts of strong and short induce proliferation but, if too strong and long, induce irreversible senescence. Our innovative broad outlook harnesses cell biology and protein conformational ensembles, helping us to define signaling strength, clarify cell cycle decisions, and thus cell fate.


Assuntos
Ciclo Celular , Diferenciação Celular , Transdução de Sinais , Humanos , Animais , Mitógenos/metabolismo , Proliferação de Células
3.
Zhonghua Xue Ye Xue Za Zhi ; 45(4): 391-395, 2024 Apr 14.
Artigo em Chinês | MEDLINE | ID: mdl-38951069

RESUMO

The aim of this study was to investigate the effects of polyphyllin Ⅶ (PP Ⅶ) on proliferation, apoptosis, and cell cycle of diffuse large B-cell lymphoma (PLBCL) cell lines U2932 and SUDHL-4. The DLBCL cell lines were divided into a control group and a PPⅦ group, and experiments were conducted using MTT assay, flow cytometry, and Western blotting.Results showed that compared with the control group, PPⅦ significantly inhibited the proliferation of U2932 and SUDHL-4 cells (P<0.05). Apoptosis assays demonstrated that treatment with 0.50 and 1.00 µmol/L PP Ⅶ significantly increased the apoptosis rates of both cell lines (P<0.05), upregulated apoptosis-related proteins, and downregulated Bcl-2 protein level (P<0.05). Cell cycle analysis revealed that PPⅦ treatment led to an increase in G0/G1-phase cells (P<0.05) and a decrease in G2/M-phase cells (P<0.05), significantly downregulated cyclin D1, CDK4, CDK6, and survivin protein expression (P<0.05). In conclusion, PPⅦ exerted anti-lymphoma effects by inhibiting proliferation, promoting apoptosis, and inducing G0/G1 phase arrest in DLBCL cells.


Assuntos
Apoptose , Ciclo Celular , Proliferação de Células , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo Celular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Diosgenina/farmacologia , Diosgenina/análogos & derivados , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo
5.
Oncol Res ; 32(7): 1231-1237, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948023

RESUMO

Background: Despite the availability of chemotherapy drugs such as 5-fluorouracil (5-FU), the treatment of some cancers such as gastric cancer remains challenging due to drug resistance and side effects. This study aimed to investigate the effect of celastrol in combination with the chemotherapy drug 5-FU on proliferation and induction of apoptosis in human gastric cancer cell lines (AGS and EPG85-257). Materials and Methods: In this in vitro study, AGS and EPG85-257 cells were treated with different concentrations of celastrol, 5-FU, and their combination. Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The synergistic effect of 5-FU and celastrol was studied using Compusyn software. The DNA content at different phases of the cell cycle and apoptosis rate was measured using flow cytometry. Results: Co-treatment with low concentrations (10% inhibitory concentration (IC10)) of celastrol and 5-FU significantly reduced IC50 (p < 0.05) so that 48 h after treatment, IC50 was calculated at 3.77 and 6.9 µM for celastrol, 20.7 and 11.6 µM for 5-FU, and 5.03 and 4.57 µM for their combination for AGS and EPG85-257 cells, respectively. The mean percentage of apoptosis for AGS cells treated with celastrol, 5-FU, and their combination was obtained 23.9, 41.2, and 61.9, and for EPG85-257 cells 5.65, 46.9, and 55.7, respectively. In addition, the 5-FU and celastrol-5-FU combination induced cell cycle arrest in the synthesis phase. Conclusions: Although celastrol could decrease the concentration of 5-fluorouracil that sufficed to suppress gastric cancer cells, additional studies are required to arrive at conclusive evidence on the anticancer effects of celastrol.


Assuntos
Apoptose , Proliferação de Células , Sinergismo Farmacológico , Fluoruracila , Triterpenos Pentacíclicos , Neoplasias Gástricas , Triterpenos , Humanos , Triterpenos Pentacíclicos/farmacologia , Fluoruracila/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Triterpenos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclo Celular/efeitos dos fármacos
6.
NPJ Syst Biol Appl ; 10(1): 71, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969664

RESUMO

This article reviews the current knowledge and recent advancements in computational modeling of the cell cycle. It offers a comparative analysis of various modeling paradigms, highlighting their unique strengths, limitations, and applications. Specifically, the article compares deterministic and stochastic models, single-cell versus population models, and mechanistic versus abstract models. This detailed analysis helps determine the most suitable modeling framework for various research needs. Additionally, the discussion extends to the utilization of these computational models to illuminate cell cycle dynamics, with a particular focus on cell cycle viability, crosstalk with signaling pathways, tumor microenvironment, DNA replication, and repair mechanisms, underscoring their critical roles in tumor progression and the optimization of cancer therapies. By applying these models to crucial aspects of cancer therapy planning for better outcomes, including drug efficacy quantification, drug discovery, drug resistance analysis, and dose optimization, the review highlights the significant potential of computational insights in enhancing the precision and effectiveness of cancer treatments. This emphasis on the intricate relationship between computational modeling and therapeutic strategy development underscores the pivotal role of advanced modeling techniques in navigating the complexities of cell cycle dynamics and their implications for cancer therapy.


Assuntos
Ciclo Celular , Simulação por Computador , Modelos Biológicos , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/patologia , Ciclo Celular/fisiologia , Transdução de Sinais , Microambiente Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biologia Computacional/métodos
7.
Sci Rep ; 14(1): 15479, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969743

RESUMO

Most organisms possess three biological oscillators, circadian clock, cell cycle, and redox rhythm, which are autonomous but interact each other. However, whether their interactions and autonomy are beneficial for organisms remains unclear. Here, we modeled a coupled oscillator system where each oscillator affected the phase of the other oscillators. We found that multiple types of coupling prevent a high H2O2 level in cells at M phase. Consequently, we hypothesized a high H2O2 sensitivity at the M phase and found that moderate coupling reduced cell damage due to oxidative stress by generating appropriate phase relationships between three rhythms, whereas strong coupling resulted in an elevated cell damage by increasing the average H2O2 level and disrupted the cell cycle. Furthermore, the multicellularity model revealed that phase variations among cells confer flexibility in synchronization with environments at the expense of adaptability to the optimal environment. Thus, both autonomy and synchrony among the oscillators are important for coordinating their phase relationships to minimize oxidative stress, and couplings balance them depending on environments.


Assuntos
Ciclo Celular , Ritmo Circadiano , Peróxido de Hidrogênio , Modelos Biológicos , Oxirredução , Estresse Oxidativo , Peróxido de Hidrogênio/metabolismo , Ritmo Circadiano/fisiologia , Relógios Circadianos/fisiologia , Animais
8.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 49(3): 392-399, 2024 Mar 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38970513

RESUMO

OBJECTIVES: Hypoxia is an important cause of chemotherapy resistance in gastric cancer. However, little is known about the growth of gastric cancer under purely hypoxia conditions. This study aims to study the effect of hypoxia on the growth patterns of gastric cancer cells and explore the response of gastric cancer cells to the chemotherapeutic drug 5-fluorouracil (5-FU) in a hypoxic environment. METHODS: Gastric cancer cells MKN45 were cultured under 1% oxygen hypoxia and conventional air conditions. An intervention group with the addition of the chemotherapeutic drug 5-FU was also established. The proliferation and apoptosis of gastric cancer cells under different oxygen conditions and intervention groups were detected using the cell counting kit-8 (CCK-8) method, JC-1 mitochondrial membrane potential assay, and Annexin-V/PI double staining method. Cell cycle changes were detected by flow cytometry, and mitochondrial changes were detected using electron microscopy. RESULTS: In the absence of 5-FU intervention, compared with the normoxia group, the hypoxia group showed higher rates of early and late apoptosis and higher cell death rates as indicated by the JC-1 mitochondrial membrane potential assay, Annexin-V/PI double staining, and CCK-8 results. Flow cytometry results showed that the cell cycle was arrested in the G0/G1 phase without progression. Electron microscopy revealed more severe mitochondrial destruction. However, with 5-FU intervention, the hypoxia group showed lower apoptosis rates, more cell cycle progression, and less mitochondrial destruction compared with the normoxia group. CONCLUSIONS: Hypoxic environments promote apoptosis and even death in gastric cancer cells, but hypoxia counteracts the efficacy of the chemotherapeutic drug 5-FU, which may contribute to 5-FU chemotherapy resistance.


Assuntos
Apoptose , Hipóxia Celular , Proliferação de Células , Fluoruracila , Potencial da Membrana Mitocondrial , Neoplasias Gástricas , Fluoruracila/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Humanos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Ciclo Celular/efeitos dos fármacos , Antimetabólitos Antineoplásicos/farmacologia
9.
Redox Rep ; 29(1): 2371173, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38972297

RESUMO

Objectives: To advance our knowledge of disease mechanisms and therapeutic options, understanding cell cycle regulation is critical. Recent research has highlighted the importance of reactive oxygen species (ROS) in cell cycle regulation. Although excessive ROS levels can lead to age-related pathologies, ROS also play an essential role in normal cellular functions. Many cell cycle regulatory proteins are affected by their redox status, but the precise mechanisms and conditions under which ROS promote or inhibit cell proliferation are not fully understood.Methods: This review presents data from the scientific literature and publicly available databases on changes in redox state during the cell cycle and their effects on key regulatory proteins.Results: We identified redox-sensitive targets within the cell cycle machinery and analysed different effects of ROS (type, concentration, duration of exposure) on cell cycle phases. For example, moderate levels of ROS can promote cell proliferation by activating signalling pathways involved in cell cycle progression, whereas excessive ROS levels can induce DNA damage and trigger cell cycle arrest or cell death.Discussion: Our findings encourage future research focused on identifying redox-sensitive targets in the cell cycle machinery, potentially leading to new treatments for diseases with dysregulated cell proliferation.


Assuntos
Ciclo Celular , Oxirredução , Espécies Reativas de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Humanos , Proliferação de Células , Transdução de Sinais , Dano ao DNA , Animais
11.
J Cancer Res Clin Oncol ; 150(7): 338, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38976072

RESUMO

OBJECTIVE: Glioma is a leading cause of mortality worldwide, its recurrence poses a major challenge in achieving effective treatment outcomes. Cancer stem cells (CSCs) have emerged as key contributors to tumor relapse and chemotherapy resistance, making them attractive targets for glioma cancer therapy. This study investigated the potential of FERMT1 as a prognostic biomarker and its role in regulating stemness through cell cycle in glioma. METHODS: Using data from TCGA-GBM, GSE4290, GSE50161 and GSE147352 for analysis of FERMT1 expression in glioma tissues. Then, the effects of FERMT1 knockdown on cell cycle, proliferation, sphere formation ability, invasion and migration were investigated. The influences of FERMT1 on expression of glycolysis-related proteins and levels of ATP, glucose, lactate and G6PDH were also explored. Furthermore, the effects of FERMT1 knockdown on cellular metabolism were evidenced. RESULTS: Significant upregulation of FERMT1 in glioma tissues was observed. Silencing FERMT1 not only affected the cell cycle but also led to a notable reduction in proliferation, invasion and migration. The expression of glycolysis-associated proteins including GLUT1, GLUT3, GLUT4, and SCO2 were reduced by FERMT1 knockdown, resulted in increased ATP and glucose as well as decreased lactic acid and G6PDH levels. FERMT1 knockdown also inhibited cellular metabolism. Moreover, FERMT1 knockdown significantly reduced sphere diameter, along with inhibiting the expression of transcription factors associated with stemness in glioma cells. CONCLUSION: These findings demonstrated that FERMT1 could be an ideal target for the advancement of innovative strategies against glioma treatment via modulating cellular process involved in stemness regulation and metabolism.


Assuntos
Neoplasias Encefálicas , Proliferação de Células , Glioma , Proteínas de Membrana , Proteínas de Neoplasias , Células-Tronco Neoplásicas , Humanos , Glioma/patologia , Glioma/genética , Glioma/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular , Glicólise , Prognóstico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Ciclo Celular
12.
Sci Rep ; 14(1): 15195, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956443

RESUMO

The intestinal epithelium dynamically controls cell cycle, yet no experimental platform exists for directly analyzing cell cycle phases in non-immortalized human intestinal epithelial cells (IECs). Here, we present two reporters and a complete platform for analyzing cell cycle phases in live primary human IECs. We interrogate the transcriptional identity of IECs grown on soft collagen, develop two fluorescent cell cycle reporter IEC lines, design and 3D print a collagen press to make chamber slides for optimal imaging while supporting primary human IEC growth, live image cell cycle dynamics, then assemble a computational pipeline building upon free-to-use programs for semi-automated analysis of cell cycle phases. The PIP-FUCCI construct allows for assigning cell cycle phase from a single image of living cells, and our PIP-H2A construct allows for semi-automated direct quantification of cell cycle phase lengths using our publicly available computational pipeline. Treating PIP-FUCCI IECs with oligomycin demonstrates that inhibiting mitochondrial respiration lengthens G1 phase, and PIP-H2A cells allow us to measure that oligomycin differentially lengthens S and G2/M phases across heterogeneous IECs. These platforms provide opportunities for future studies on pharmaceutical effects on the intestinal epithelium, cell cycle regulation, and more.


Assuntos
Ciclo Celular , Células Epiteliais , Mucosa Intestinal , Humanos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Oligomicinas/farmacologia , Células Cultivadas
13.
Sci Rep ; 14(1): 16133, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38997414

RESUMO

Nickel(Ni)-containing materials have been widely used in a wide range of medical applications, including orthopaedics. Despite their excellent properties, there is still a problem with the release of nickel ions into the patient's body, which can cause changes in the behaviour of surrounding cells and tissues. This study aims to evaluate the effects of Ni on bone cells with an emphasis on the determination of Ni localization in cellular compartments in time. For these purposes, one of the most suitable models for studying the effects induced by metal implants was used-the patient's osteoarthritic cells. Thanks to this it was possible to simulate the pathophysiological conditions in the patient's body, as well as to evaluate the response of the cells which come into direct contact with the material after the implantation of the joint replacement. The largest differences in cell viability, proliferation and cell cycle changes occurred between Ni 0.5 mM and 1 mM concentrations. Time-dependent localization of Ni in cells showed that there is a continuous transport of Ni ions between the nucleus and the cytoplasm, as well as between the cell and the environment. Moreover, osteoarthritic osteoblasts showed faster changes in concentration and ability to accumulate more Ni, especially in the nucleus, than physiological osteoblasts. The differences in Ni accumulation process explains the higher sensitivity of patient osteoblasts to Ni and may be crucial in further studies of implant-derived cytotoxic effects.


Assuntos
Proliferação de Células , Sobrevivência Celular , Níquel , Osteoartrite , Osteoblastos , Níquel/metabolismo , Osteoblastos/metabolismo , Osteoblastos/efeitos dos fármacos , Humanos , Osteoartrite/metabolismo , Osteoartrite/patologia , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Íons/metabolismo , Ciclo Celular/efeitos dos fármacos , Células Cultivadas
14.
Nutrients ; 16(13)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38999849

RESUMO

Obesity is associated with one-fifth of cancer deaths, and breast cancer is one of the obesity-related cancers. Triple-negative breast cancer (TNBC) lacks estrogen and progesterone receptors and human epidermal growth factor receptor 2, leading to the absence of these therapeutic targets, followed by poor overall survival. We investigated if obesity could hasten TNBC progression and intermittent fasting (IF) could attenuate the progression of obesity-related TNBC. Our meta-analysis of the TNBC outcomes literature showed that obesity led to poorer overall survival in TNBC patients. Fasting-mimicking media reduced cell proliferation disrupted the cell cycle, and decreased cell migration and invasion. IF decreased body weight in obese mice but no change in normal mice. Obese mice exhibited elevated plasma glucose and cholesterol levels, increased tumor volume and weight, and enhanced macrophage accumulation in tumors. The obesity-exacerbated TNBC progression was attenuated after IF, which decreased cyclin B1 and vimentin levels and reduced the proinflammatory signature in the obesity-associated tumor microenvironment. IF attenuated obesity-induced TNBC progression through reduced obesity and tumor burdens in cell and animal experiments, supporting the potential of a cost-effective adjuvant IF therapy for TNBC through lifestyle change. Further evidence is needed of these IF benefits in TNBC, including from human clinical trials.


Assuntos
Ciclo Celular , Progressão da Doença , Transição Epitelial-Mesenquimal , Jejum , Obesidade , Neoplasias de Mama Triplo Negativas , Animais , Obesidade/complicações , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Inflamação , Proliferação de Células , Microambiente Tumoral , Camundongos Obesos , Movimento Celular , Jejum Intermitente
15.
Int J Mol Sci ; 25(13)2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-39000427

RESUMO

The amyloid-beta peptide (Aß) is the neurotoxic component in senile plaques of Alzheimer's disease (AD) brains. Previously we have reported that Aß toxicity is mediated by the induction of sonic hedgehog (SHH) to trigger cell cycle re-entry (CCR) and apoptosis in post-mitotic neurons. Basella alba is a vegetable whose polysaccharides carry immunomodulatory and anti-cancer actions, but their protective effects against neurodegeneration have never been reported. Herein, we tested whether polysaccharides derived from Basella alba (PPV-6) may inhibit Aß toxicity and explored its underlying mechanisms. In differentiated rat cortical neurons, Aß25-35 reduced cell viability, damaged neuronal structure, and compromised mitochondrial bioenergetic functions, all of which were recovered by PPV-6. Immunocytochemistry and western blotting revealed that Aß25-35-mediated induction of cell cycle markers including cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) in differentiated neurons was all suppressed by PPV-6, along with mitigation of caspase-3 cleavage. Further studies revealed that PPV-6 inhibited Aß25-35 induction of SHH; indeed, PPV-6 was capable of suppressing neuronal CCR and apoptosis triggered by the exogenous N-terminal fragment of sonic hedgehog (SHH-N). Our findings demonstrated that, in the fully differentiated neurons, PPV-6 exerts protective actions against Aß neurotoxicity via the downregulation of SHH to suppress neuronal CCR and apoptosis.


Assuntos
Peptídeos beta-Amiloides , Apoptose , Ciclo Celular , Proteínas Hedgehog , Neurônios , Polissacarídeos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Proteínas Hedgehog/metabolismo , Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Apoptose/efeitos dos fármacos , Ratos , Polissacarídeos/farmacologia , Polissacarídeos/química , Ciclo Celular/efeitos dos fármacos , Fragmentos de Peptídeos , Sobrevivência Celular/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia
16.
Development ; 151(20)2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-38980277

RESUMO

Many animals share a lifelong capacity to adapt their growth rates and body sizes to changing environmental food supplies. However, the cellular and molecular basis underlying this plasticity remains only poorly understood. We therefore studied how the sea anemones Nematostella vectensis and Aiptasia (Exaiptasia pallida) respond to feeding and starvation. Combining quantifications of body size and cell numbers with mathematical modelling, we observed that growth and shrinkage rates in Nematostella are exponential, stereotypic and accompanied by dramatic changes in cell numbers. Notably, shrinkage rates, but not growth rates, are independent of body size. In the facultatively symbiotic Aiptasia, we show that growth and cell proliferation rates are dependent on the symbiotic state. On a cellular level, we found that >7% of all cells in Nematostella juveniles reversibly shift between S/G2/M and G1/G0 cell cycle phases when fed or starved, respectively. Furthermore, we demonstrate that polyp growth and cell proliferation are dependent on TOR signalling during feeding. Altogether, we provide a benchmark and resource for further investigating the nutritional regulation of body plasticity on multiple scales using the genetic toolkit available for Nematostella.


Assuntos
Tamanho Corporal , Proliferação de Células , Anêmonas-do-Mar , Animais , Anêmonas-do-Mar/citologia , Anêmonas-do-Mar/fisiologia , Ciclo Celular/fisiologia , Comportamento Alimentar/fisiologia , Transdução de Sinais , Simbiose , Serina-Treonina Quinases TOR/metabolismo
17.
Theranostics ; 14(10): 3927-3944, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994017

RESUMO

Rationale: Myocardial infarction (MI) is a severe global clinical condition with widespread prevalence. The adult mammalian heart's limited capacity to generate new cardiomyocytes (CMs) in response to injury remains a primary obstacle in developing effective therapies. Current approaches focus on inducing the proliferation of existing CMs through cell-cycle reentry. However, this method primarily elevates cyclin dependent kinase 6 (CDK6) and DNA content, lacking proper cytokinesis and resulting in the formation of dysfunctional binucleated CMs. Cytokinesis is dependent on ribosome biogenesis (Ribo-bio), a crucial process modulated by nucleolin (Ncl). Our objective was to identify a novel approach that promotes both DNA synthesis and cytokinesis. Methods: Various techniques, including RNA/protein-sequencing analysis, Ribo-Halo, Ribo-disome, flow cytometry, and cardiac-specific tumor-suppressor retinoblastoma-1 (Rb1) knockout mice, were employed to assess the series signaling of proliferation/cell-cycle reentry and Ribo-bio/cytokinesis. Echocardiography, confocal imaging, and histology were utilized to evaluate cardiac function. Results: Analysis revealed significantly elevated levels of Rb1, bur decreased levels of circASXL1 in the hearts of MI mice compared to control mice. Deletion of Rb1 induces solely cell-cycle reentry, while augmenting the Ribo-bio modulator Ncl leads to cytokinesis. Mechanically, bioinformatics and the loss/gain studies uncovered that circASXL1/CDK6/Rb1 regulates cell-cycle reentry. Moreover, Ribo-Halo, Ribo-disome and circRNA pull-down assays demonstrated that circASXL1 promotes cytokinesis through Ncl/Ribo-bio. Importantly, exosomes derived from umbilical cord mesenchymal stem cells (UMSC-Exo) had the ability to enhance cardiac function by facilitating the coordinated signaling of cell-cycle reentry and Ribo-bio/cytokinesis. These effects were attenuated by silencing circASXL1 in UMSC-Exo. Conclusion: The series signaling of circASXL1/CDK6/Rb1/cell-cycle reentry and circASXL1/Ncl/Ribo-bio/cytokinesis plays a crucial role in cardiac repair. UMSC-Exo effectively repairs infarcted myocardium by stimulating CM cell-cycle reentry and cytokinesis in a circASXL1-dependent manner. This study provides innovative therapeutic strategies targeting the circASXL1 signaling network for MI and offering potential avenues for enhanced cardiac repair.


Assuntos
Ciclo Celular , Citocinese , Camundongos Knockout , Infarto do Miocárdio , Miócitos Cardíacos , Ribossomos , Animais , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ribossomos/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Nucleolina , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteína do Retinoblastoma/metabolismo , Proteína do Retinoblastoma/genética , Proliferação de Células , Masculino , Humanos
18.
J Math Biol ; 89(2): 27, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38970664

RESUMO

Cancer, a disease intimately linked to cellular mutations, is commonly believed to exhibit a positive association with the cell count and lifespan of a species. Despite this assumption, the observed uniformity in cancer rates across species, referred to as the Peto's paradox, presents a conundrum. Recognizing that tumour progression is not solely dependent on cancer cells but involves intricate interactions among various cell types, this study employed a Lotka-Volterra (LV) ordinary differential equation model to analyze the evolution of cancerous cells and the cancer incidence in an immune environment. As a result, this study uncovered the sufficient conditions underlying the absence of correlation in Peto's paradox and provide insights into the reasons for the equitable distribution of cancer incidence across diverse species by applying nondimensionalization and drawing an analogy between the characteristic time interval for the variation of cell populations in the ODE model and that of cell cycles of a species.


Assuntos
Conceitos Matemáticos , Modelos Biológicos , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/epidemiologia , Mutação , Progressão da Doença , Microambiente Tumoral/imunologia , Ciclo Celular , Animais , Contagem de Células/estatística & dados numéricos , Incidência , Simulação por Computador
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(6): 1117-1125, 2024 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-38977341

RESUMO

OBJECTIVE: To investigate the mechanism by which CDHR2 overexpression inhibits breast cancer cell growth and cell cycle pragression via the PI3K/Akt signaling pathway. METHODS: Bioinformatic analysis was performed to investigate CDHR2 expression in breast cancer and its correlation with survival outcomes of the patients. Immunohistochemistry was used to examine CDHR2 expressions in surgical specimens of tumor and adjacent tissues from 10 patients with breast cancer. CDHR2 expression levels were also detected in 5 breast cancer cell lines and a normal human mammary epithelial cell line using qRT-PCR and Western blotting. Breast cancer cell lines MDA-MB-231 and MCF7 with low CDHR2 expression were transfected with a CDHR2-overexpressing plasmid, and the changes in cell proliferation and cell cycle were evaluated using CCK-8 assay, EdU assay, and cell cycle assay; the changes in expressions of PI3K/Akt signaling pathway and cell cycle pathway proteins were detected with Western blotting. RESULTS: Bioinformatic analysis showed low CDHR2 expression level in both breast cancer and adjacent tissues without significant difference between them (P > 0.05), but breast cancer patients with a high expression of CDHR2 had a more favorable prognosis. Immunohistochemistry, qRT-PCR and Western blotting showed that the expression of CDHR2 was significantly down-regulated in breast cancer tissues and breast cancer cells (P < 0.01), and its overexpression strongly inhibited cell proliferation, caused cell cycle arrest, and significantly inhibited PI3K and Akt phosphorylation and the expression of cyclin D1. CONCLUSION: Overexpression of CDHR2 inhibits proliferation and causes cell cycle arrest in breast cancer cells possibly by inhibiting the PI3K/Akt signaling pathway.


Assuntos
Neoplasias da Mama , Proliferação de Células , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Feminino , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Ciclo Celular , Células MCF-7
20.
Nat Commun ; 15(1): 5775, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38982125

RESUMO

The epitranscriptome includes a diversity of RNA modifications that influence gene expression. N3-methylcytidine (m3C) mainly occurs in the anticodon loop (position C32) of certain tRNAs yet its role is poorly understood. Here, using HAC-Seq, we report comprehensive METTL2A/2B-, METTL6-, and METTL2A/2B/6-dependent m3C profiles in human cells. METTL2A/2B modifies tRNA-arginine and tRNA-threonine members, whereas METTL6 modifies the tRNA-serine family. However, decreased m3C32 on tRNA-Ser-GCT isodecoders is only observed with combined METTL2A/2B/6 deletion. Ribo-Seq reveals altered translation of genes related to cell cycle and DNA repair pathways in METTL2A/2B/6-deficient cells, and these mRNAs are enriched in AGU codons that require tRNA-Ser-GCT for translation. These results, supported by reporter assays, help explain the observed altered cell cycle, slowed proliferation, and increased cisplatin sensitivity phenotypes of METTL2A/2B/6-deficient cells. Thus, we define METTL2A/2B/6-dependent methylomes and uncover a particular requirement of m3C32 tRNA modification for serine codon-biased mRNA translation of cell cycle, and DNA repair genes.


Assuntos
Ciclo Celular , Códon , Dano ao DNA , Biossíntese de Proteínas , RNA Mensageiro , RNA de Transferência , Serina , Humanos , Ciclo Celular/genética , Códon/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , RNA de Transferência/genética , RNA de Transferência/metabolismo , Serina/metabolismo , Metiltransferases/metabolismo , Metiltransferases/genética , Citidina/análogos & derivados , Citidina/metabolismo , Citidina/genética , Reparo do DNA , Células HEK293 , Anticódon/genética
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